Atlas of Diseases of the Kidney

Diseases of Water Metabolism Sumit Kumar Tomas Berl

T

he maintenance of the tonicity of body fluids within a very narrow physiologic range is made possible by homeostatic mechanisms that control the intake and excretion of water. Critical to this process are the osmoreceptors in the hypothalamus that control the secretion of antidiuretic hormone (ADH) in response to changes in tonicity. In turn, ADH governs the excretion of water by its end-organ effect on the various segments of the renal collecting system. The unique anatomic and physiologic arrangement of the nephrons brings about either urinary concentration or dilution, depending on prevailing physiologic needs. In the first section of this chapter, the physiology of urine formation and water balance is described. The kidney plays a pivotal role in the maintenance of normal water homeostasis, as it conserves water in states of water deprivation, and excretes water in states of water excess. When water homeostasis is deranged, alterations in serum sodium ensue. Disorders of urine dilution cause hyponatremia. The pathogenesis, causes, and management strategies are described in the second part of this chapter. When any of the components of the urinary concentration mechanism is disrupted, hypernatremia may ensue, which is universally characterized by a hyperosmolar state. In the third section of this chapter, the pathogenesis, causes, and clinical settings for hypernatremia and management strategies are described.

CHAPTER

1

1.2

Disorders of Water, Electrolytes, and Acid-Base

Normal water intake (1.0–1.5 L/d)

Water of cellular metabolism (350–500 mL/d) Extracellular compartment (15 L)

Total body water 42L (60% body weight in a 70-kg man)

Variable water excretion

Fixed water excretion

Filtrate/d 180L Stool 0.1 L/d

Sweat 0.1 L/d

Total insensible losses ~0.5 L/d

Pulmonary 0.3 L/d

Total urine output 1.0–1.5 L/d

Water excretion

Intracellular compartment (27 L)

Water intake and distribution

Physiology of the Renal Diluting and Concentrating Mechanisms FIGURE 1-1 Principles of normal water balance. In most steady-state situations, human water intake matches water losses through all sources. Water intake is determined by thirst (see Fig. 1-12) and by cultural and social behaviors. Water intake is finely balanced by the need to maintain physiologic serum osmolality between 285 to 290 mOsm/kg. Both water that is drunk and that is generated through metabolism are distributed in the extracellular and intracellular compartments that are in constant equilibrium. Total body water equals approximately 60% of total body weight in young men, about 50% in young women, and less in older persons. Infants’ total body water is between 65% and 75%. In a 70-kg man, in temperate conditions, total body water equals 42 L, 65% of which (22 L) is in the intracellular compartment and 35% (19 L) in the extracellular compartment. Assuming normal glomerular filtration rate to be about 125 mL/min, the total volume of blood filtered by the kidney is about 180 L/24 hr. Only about 1 to 1.5 L is excreted as urine, however, on account of the complex interplay of the urine concentrating and diluting mechanism and the effect of antidiuretic hormone to different segments of the nephron, as depicted in the following figures.

Diseases of Water Metabolism

Generation of medullary hypertonicity Normal function of the thick ascending limb of loop of Henle Urea delivery Normal medullary blood flow

;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;; ;;; ;;; NaCl

H 2O

GFR

ADH

H 2O

ADH

NaCl

H 2O

NaCl

Determinants of delivery of NaCl to distal tubule: GFR Proximal tubular fluid and solute (NaCl) reabsorption

NaCl

NaCl

H 2O

ADH

NaCl

H 2O

NaCl

H 2O

H 2O

H 2O

;; ;;

Water delivery NaCl movement Solute concentration

Collecting system water permeability determined by Presence of arginine vasopressin Normal collecting system

FIGURE 1-2 Determinants of the renal concentrating mechanism. Human kidneys have two populations of nephrons, superficial and juxtamedullary. This anatomic arrangement has important bearing on the formation of urine by the countercurrent mechanism. The unique anatomy of the nephron [1] lays the groundwork for a complex yet logical physiologic arrangement that facilitates the urine concentration and dilution mechanism, leading to the formation of either concentrated or dilute urine, as appropriate to the person’s needs and dictated by the plasma osmolality. After two thirds of the filtered load (180 L/d) is isotonically reabsorbed in the proximal convoluted tubule, water is handled by three interrelated processes: 1) the delivery of fluid to the diluting segments; 2) the separation of solute and water (H2O) in the diluting segment; and 3) variable reabsorption of water in the collecting duct. These processes participate in the renal concentrating mechanism [2]. 1. Delivery of sodium chloride (NaCl) to the diluting segments of the nephron (thick ascending limb of the loop of Henle and the distal convoluted tubule) is determined by glomerular filtration rate (GFR) and proximal tubule function. 2. Generation of medullary interstitial hypertonicity, is determined by normal functioning of the thick ascending limb of the loop of Henle, urea delivery from the medullary collecting duct, and medullary blood flow. 3. Collecting duct permeability is determined by the presence of antidiuretic hormone (ADH) and normal anatomy of the collecting system, leading to the formation of a concentrated urine.

1.3

1.4

Disorders of Water, Electrolytes, and Acid-Base

Normal functioning of Thick ascending limb of loop of Henle Cortical diluting segment

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H 2O

GFR

H 2O

NaCl NaCl

Determinants of delivery of H2O to distal parts of the nephron GFR Proximal tubular H2O and NaCl reabsorption

Impermeable collecting duct

FIGURE 1-3 Determinants of the urinary dilution mechanism include 1) delivery of water to the thick ascending limb of the loop of Henle, distal convoluted tubule, and collecting system of the nephron; 2) generation of maximally hypotonic fluid in the diluting segments (ie, normal thick ascending limb of the loop of Henle and cortical diluting segment); 3) maintenance of water impermeability of the collecting system as determined by the absence of antidiuretic hormone (ADH) or its action and other antidiuretic substances. GFR—glomerular filtration rate; NaCl—sodium chloride; H2O—water.

H 2O

NaCl

H 2O

NaCl

H 2O

H 2O

Collecting duct impermeability depends on Absence of ADH Absence of other antidiuretic substances

Distal tubule Urea H 2O

Cortex Na+ K+ 2Cl2– NaCl

Outer medulla

Na+ K+ 2Cl2–

2 H 2O

Na+ 1 K+ 2Cl2– Urea

Outer medullary collecting duct

Na+ K+ 2Cl2– Urea

H 2O

H 2O

Inner medullary collecting duct

4 3 H 2O Urea NaCl

NaCl

Urea

5 NaCl Inner medulla

Loop of Henle

Collecting tubule

FIGURE 1-4 Mechanism of urine concentration: overview of the passive model. Several models of urine concentration have been put forth by investigators. The passive model of urine concentration described by Kokko and Rector [3] is based on permeability characteristics of different parts of the nephron to solute and water and on the fact that the active transport is limited to the thick ascending limb. 1) Through the Na+, K+, 2 Cl cotransporter, the thick ascending limb actively transports sodium chloride (NaCl), increasing the interstitial tonicity, resulting in tubular fluid dilution with no net movement of water and urea on account of their low permeability. 2) The hypotonic fluid under antidiuretic hormone action undergoes osmotic equilibration with the interstitium in the late distal tubule and cortical and outer medullary collecting duct, resulting in water removal. Urea concentration in the tubular fluid rises on account of low urea permeability. 3) At the inner medullary collecting duct, which is highly permeable to urea and water, especially in response to antidiuretic hormone, the urea enters the interstitium down its concentration gradient, preserving interstitial hypertonicity and generating high urea concentration in the interstitium. (Legend continued on next page)

Diseases of Water Metabolism FIGURE 1-4 (continued) 4) The hypertonic interstitium causes abstraction of water from the descending thin limb of loop of Henle, which is relatively impermeable to NaCl and urea, making the tubular fluid hypertonic with high NaCl concentration as it arrives at the bend of the loop of

Henle. 5) In the thin ascending limb of the loop of Henle, NaCl moves passively down its concentration gradient into the interstitium, making tubular fluid less concentrated with little or no movement of water. H2O—water. FIGURE 1-5 Pathways for urea recycling. Urea plays an important role in the generation of medullary interstitial hypertonicity. A recycling mechanism operates to minimize urea loss. The urea that is reabsorbed into the inner medullary stripe from the terminal inner medullary collecting duct (step 3 in Fig. 1-4) is carried out of this region by the ascending vasa recta, which deposits urea into the adjacent descending thin limbs of a short loop of Henle, thus recycling the urea to the inner medullary collecting tubule (pathway A). Some of the urea enters the descending limb of the loop of Henle and the thin ascending limb of the loop of Henle. It is then carried through to the thick ascending limb of the loop of Henle, the distal collecting tubule, and the collecting duct, before it reaches the inner medullary collecting duct (pathway B). This process is facilitated by the close anatomic relationship that the hairpin loop of Henle and the vasa recta share [4].

Cortex Urea

Urea

Urea

Urea Outer stripe

Outer medulla

Urea

Inner stripe

Urea

1.5

Collecting duct

Urea Urea Ascending vasa recta

Pathway B Pathway A

Inner medulla

Urea

1500 20 mL

0.3 mL

Osmolality, mOsm/kg H2O

1200

900

600

Maximal ADH

300 100 mL

2.0 mL

30 mL 20 mL

no ADH

16 mL

0 Proximal tubule

Loop of Henle

Distal tubule and cortical collecting tubule

Outer and inner medullary collecting ducts

FIGURE 1-6 Changes in the volume and osmolality of tubular fluid along the nephron in diuresis and antidiuresis. The osmolality of the tubular fluid undergoes several changes as it passes through different segments of the tubules. Tubular fluid undergoes marked reduction in its volume in the proximal tubule; however, this occurs iso-osmotically with the glomerular filtrate. In the loop of Henle, because of the aforementioned countercurrent mechanism, the osmolality of the tubular fluid rises sharply but falls again to as low as 100 mOsm/kg as it reaches the thick ascending limb and the distal convoluted tubule. Thereafter, in the late distal tubule and the collecting duct, the osmolality depends on the presence or absence of antidiuretic hormone (ADH). In the absence of ADH, very little water is reabsorbed and dilute urine results. On the other hand, in the presence of ADH, the collecting duct, and in some species, the distal convoluted tubule, become highly permeable to water, causing reabsorption of water into the interstitium, resulting in concentrated urine [5].

1.6

Disorders of Water, Electrolytes, and Acid-Base Paraventricular neurons

Osmoreceptors Pineal

Baroreceptors

Third ventricle VP,NP

Supraoptic neuron

Tanycyte SON Optic chiasm Superior hypophysial artery Portal capillaries in zona externa of median eminence

Mammilary body

VP,NP

FIGURE 1-7 Pathways of antidiuretic hormone release. Antidiuretic hormone is responsible for augmenting the water permeability of the cortical and medullary collecting tubules, thus promoting water reabsorption via osmotic equilibration with the isotonic and hypertonic interstitium, respecively. The hormone is formed in the supraoptic and paraventricular nuclei, under the stimulus of osmoreceptors and baroreceptors (see Fig. 1-11), transported along their axons and secreted at three sites: the posterior pituitary gland, the portal capillaries of the median eminence, and the cerebrospinal fluid of the third ventricle. It is from the posterior pituitary that the antidiuretic hormone is released into the systemic circulation [6]. SON—supraoptic nucleus; VP—vasopressin; NP—neurophysin.

Posterior pituitary Long portal vein Systemic venous system Anterior pituitary Short portal vein

VP,NP

Exon 1

Pre-pro-vasopressin (164 AA)

AVP

Gly

Exon 3

Exon 2

Lys

Arg

Neurophysin II

Arg

Glycopeptide

Neurophysin II

Arg

Glycopeptide

Neurophysin II

+

Glycopeptide

(Cleavage site) Signal peptide

Pro-vasopressin

AVP

Gly

Products of pro-vasopressin

AVP

NH2

Lys

Arg

+

FIGURE 1-8 Structure of the human arginine vasopressin (AVP/antidiuretic hormone) gene and the prohormone. Antidiuretic hormone (ADH) is a cyclic hexapeptide (mol. wt. 1099) with a tail of three amino acids. The biologically inactive macromolecule, pre-pro-vasopressin is cleaved into the smaller, biologically active protein. The protein of vasopressin is translated through a series of signal transduction pathways and intracellular cleaving. Vasopressin, along with its binding protein, neurophysin II, and the glycoprotein, are secreted in the form of neurosecretory granules down the axons and stored in nerve terminals of the posterior lobe of the pituitary [7]. ADH has a short half-life of about 15 to 20 minutes and is rapidly metabolized in the liver and kidneys. Gly—glycine; Lys—lysine; Arg—arginine.

Diseases of Water Metabolism

AQP-3 Recycling vesicle Endocytic retrieval AQP-2

cAMP ATP AQP-2 PKA

H 2O

Gαs

AQP-2

Gαs

Exocytic insertion Recycling vesicle

AVP

AQP-4 Basolateral

Luminal

1.7

FIGURE 1-9 Intracellular action of antidiuretic hormone. The multiple actions of vasopressin can be accounted for by its interaction with the V2 receptor found in the kidney. After stimulation, vasopressin binds to the V2 receptor on the basolateral membrane of the collecting duct cell. This interaction of vasopressin with the V2 receptor leads to increased adenylate cyclase activity via the stimulatory G protein (Gs), which catalyzes the formation of cyclic adenosine 3’, 5’monophosphate (cAMP) from adenosine triphosphate (ATP). In turn, cAMP activates a serine threonine kinase, protein kinase A (PKA). Cytoplasmic vesicles carrying the water channel proteins migrate through the cell in response to this phosphorylation process and fuse with the apical membrane in response to increasing vasopressin binding, thus increasing water permeability of the collecting duct cells. These water channels are recyled by endocytosis once the vasopressin is removed. The water channel responsible for the high water permeability of the luminal membrane in response to vasopressin has recently been cloned and designated as aquaporin-2 (AQP-2) [8]. The other members of the aquaporin family, AQP-3 and AQP-4 are located on the basolateral membranes and are probably involved in water exit from the cell. The molecular biology of these channels and of receptors responsible for vasopressin action have contributed to the understanding of the syndromes of genetically transmitted and acquired forms of vasopressin resistance. AVP—arginine vasopressin.

AQUAPORINS AND THEIR CHARACTERISTICS

Size (amino acids) Permeability to small solutes Regulation by antidiurectic hormone Site Cellular localization Mutant phenotype

AQP-1

AQP-2

AQP-3

AQP-4

269 No No Proximal tubules; descending thin limb Apical and basolateral membrane Normal

271 No Yes Collecting duct; principal cells

285 Urea glycerol No Medullary collecting duct; colon Basolateral membrane

301 No No Hypothalamic—supraoptic, paraventricular nuclei; ependymal, granular, and Purkinje cells Basolateral membrane of the prinicpal cells

Unknown

Unknown

Apical membrane and intracellular vesicles Nephrogenic diabetes insipidus

FIGURE 1-10 Aquaporins and their characteristics. An ever growing family of aquaporin (AQP) channels are being described. So far, about seven

different channels have been cloned and characterized; however, only four have been found to have any definite physiologic role.

1.8

Disorders of Water, Electrolytes, and Acid-Base

50

Isotonic volume depletion Isovolemic osmotic increase

45 Plasma AVP, pg/mL

40 35 30 25 20 15 10 5 0 0

5

10 15 Change, %

20

FIGURE 1-11 Osmotic and nonosmotic regulation of antidiuretic hormone (ADH) secretion. ADH is secreted in response to changes in osmolality and in circulating arterial volume. The “osmoreceptor” cells are located in the anterior hypothalamus close to the supraoptic nuclei. Aquaporin-4 (AQP-4), a candidate osmoreceptor, is a member of the water channel family that was recently cloned and characterized and is found in abundance in these neurons. The osmoreceptors are sensitive to changes in plasma osmolality of as little as 1%. In humans, the osmotic threshold for ADH release is 280 to 290 mOsm/kg. This system is so efficient that the plasma osmolality usually does not vary by more than 1% to 2% despite wide fluctuations in water intake [9]. There are several other nonosmotic stimuli for ADH secretion. In conditions of decreased arterial circulating volume (eg, heart failure, cirrhosis, vomiting), decrease in inhibitory parasympathetic afferents in the carotid sinus baroreceptors affects ADH secretion. Other nonosmotic stimuli include nausea, which can lead to a 500-fold rise in circulating ADH levels, postoperative pain, and pregnancy. Much higher ADH levels can be achieved with hypovolemia than with hyperosmolarity, although a large fall in blood volume is required before this response is initiated. In the maintenance of tonicity the interplay of these homeostatic mechanisms also involves the thirst mechanism, that under normal conditions, causes either intake or exclusion of water in an effort to restore serum osmolality to normal.

Control of Water Balance and Serum Sodium Concentration Increased plasma osmolality or decreased arterial circulating volume

Decreased plasma osmolality or increased arterial circulating blood volume

Increased thirst

Increased ADH release

Decreased thirst

Decreased ADH release

Increased water intake

Decreased water excretion

Decreased water intake

Decreased water excretion

A

Water retention

Water excretion

Decreased plasma osmolality or increased arterial circulating volume

Increased plasma osmolality and decreased arterial circulating volume

Decreased ADH release and thirst

FIGURE 1-12 Pathways of water balance (conservation, A, and excretion, B). In humans and other terrestrial animals, the thirst mechanism plays an important role in water (H2O) balance. Hypertonicity is the most potent stimulus for thirst: only 2% to 3 % changes in plasma osmolality produce a strong desire to drink water. This absolute level of osmolality at which the sensation of thirst arises in healthy persons, called the osmotic threshold for thirst, usually averages about 290 to 295 mOsm/kg H2O (approximately 10 mOsm/kg H2O above that of antidiuretic hormone [ADH] release). The socalled thirst center is located close to the osmoreceptors but is

B

Increased ADH release and thirst

anatomically distinct. Between the limits imposed by the osmotic thresholds for thirst and ADH release, plasma osmolality may be regulated still more precisely by small osmoregulated adjustments in urine flow and water intake. The exact level at which balance occurs depends on various factors such as insensible losses through skin and lungs, and the gains incurred from eating, normal drinking, and fat metabolism. In general, overall intake and output come into balance at a plasma osmolality of 288 mOsm/kg, roughly halfway between the thresholds for ADH release and thirst [10].

Diseases of Water Metabolism

Plasma osmolality 280 to 290 mOsm/kg H2O Decrease Supression of thirst

Supression of ADH release

Increase Stimulation of thirst

Stimulation of ADH release

Dilute urine

Concentrated urine

Disorder involving urine dilution with H2O intake

Disorder involving urine concentration with inadequate H2O intake

Hyponatremia

Hypernatremia

1.9

FIGURE 1-13 Pathogenesis of dysnatremias. The countercurrent mechanism of the kidneys in concert with the hypothalamic osmoreceptors via antidiuretic hormone (ADH) secretion maintain a very finely tuned balance of water (H2O). A defect in the urine-diluting capacity with continued H2O intake results in hyponatremia. Conversely, a defect in urine concentration with inadequate H2O intake culminates in hypernatremia. Hyponatremia reflects a disturbance in homeostatic mechanisms characterized by excess total body H2O relative to total body sodium, and hypernatremia reflects a deficiency of total body H2O relative to total body sodium [11]. (From Halterman and Berl [12]; with permission.)

Approach to the Hyponatremic Patient EFFECTS OF OSMOTICALLY ACTIVE SUBSTANCES ON SERUM SODIUM

Substances the increase osmolality without changing serum sodium Urea Ethanol Ethylene glycol Isopropyl alcohol Methanol

Substances that increase osmolality and decrease serum sodium (translocational hyponatremia) Glucose Mannitol Glycine Maltose

FIGURE 1-14 Evaluation of a hyponatremic patient: effects of osmotically active substances on serum sodium. In the evaluation of a hyponatremic patient, a determination should be made about whether hyponatremia is truly hypo-osmotic and not a consequence of translocational or

pseudohyponatremia, since, in most but not all situations, hyponatremia reflects hypo-osmolality. The nature of the solute plays an important role in determining whether or not there is an increase in measured osmolality or an actual increase in effective osmolality. Solutes that are permeable across cell membranes (eg, urea, methanol, ethanol, and ethylene glycol) do not cause water movement and cause hypertonicity without causing cell dehydration. Typical examples are an uremic patient with a high blood urea nitrogen value and an ethanolintoxicated person. On the other hand, in a patient with diabetic ketoacidosis who is insulinopenic the glucose is not permeant across cell membranes and, by its presence in the extracellular fluid, causes water to move from the cells to extracellular space, thus leading to cell dehydration and lowering serum sodium. This can be viewed as translocational at the cellular level, as the serum sodium level does not reflect changes in total body water but rather movement of water from intracellular to extracellular space. Glycine is used as an irrigant solution during transurethral resection of the prostate and in endometrial surgery. Pseudohyponatremia occurs when the solid phase of plasma (usually 6% to 8%) is much increased by large increments of either lipids or proteins (eg, in hypertriglyceridemia or paraproteinemias).

1.10

Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-15 Pathogenesis of hyponatremia. The normal components of the renal diluting mechanism are depicted in Figure 1-3. Hyponatremia results from disorders of this diluting capacity of the kidney in the following situations:

↓ Reabsorption of sodium chloride in distal convoluted tubule Thiazide diuretics

↓ Reabsorption of sodium chloride in thick ascending limb of loop of Henle Loop diuretics Osmotic diuretics Interstitial disease

GFR diminished Age Renal disease Congestive heart failure Cirrhosis Nephrotic syndrome Volume depletion

NaCl

↑ ADH release or action Drugs Syndrome of inappropriate antidiuretic hormone secretion, etc.

1. Intrarenal factors such as a diminished glomerular filtration rate (GFR), or an increase in proximal tubule fluid and sodium reabsorption, or both, which decrease distal delivery to the diluting segments of the nephron, as in volume depletion, congestive heart failure, cirrhosis, or nephrotic syndrome. 2. A defect in sodium chloride transport out of the water-impermeable segments of the nephrons (ie, in the thick ascending limb of the loop of Henle). This may occur in patients with interstitial renal disease and administration of thiazide or loop diuretics. 3. Continued secretion of antidiuretic hormone (ADH) despite the presence of serum hypo-osmolality mostly stimulated by nonosmotic mechanisms [12].

NaCl—sodium chloride.

Assessment of volume status

Hypovolemia •Total body water ↓ •Total body sodium ↓↓

Hypervolemia •Total body water ↑↑ •Total body sodium ↑

Euvolemia (no edema) •Total body water ↑ •Total body sodium ←→

UNa >20

UNa 20

UNa >20

UNa 100 mOsm/kg H2O) Clinical euvolemia Elevated urinary sodium concentration (U[Na]), with normal salt and H2O intake Absence of adrenal, thyroid, pituitary, or renal insufficiency or diuretic use Supplemental Abnormal H2O load test (inability to excrete at least 90% of a 20–mL/kg H2O load in 4 hrs or failure to dilute urinary osmolality to < 100 mOsm/kg) Plasma antidiuretic hormone level inappropriately elevated relative to plasma osmolality No significant correction of plasma sodium with volume expansion, but improvement after fluid restriction

1.11

CAUSES OF THE SYNDROME OF INAPPROPRIATE DIURETIC HORMONE SECRETION

Carcinomas Bronchogenic Duodenal Pancreatic Thymoma Gastric Lymphoma Ewing’s sarcoma Bladder Carcinoma of the ureter Prostatic Oropharyngeal

Pulmonary Disorders Viral pneumonia Bacterial pneumonia Pulmonary abscess Tuberculosis Aspergillosis Positive-pressure breathing Asthma Pneumothorax Mesothelioma Cystic fibrosis

Central Nervous System Disorders Encephalitis (viral or bacterial) Meningitis (viral, bacterial, tuberculous, fungal) Head trauma Brain abscess Brain tumor Guillain-Barré syndrome Acute intermittent porphyria Subarachnoid hemorrhage or subdural hematoma Cerebellar and cerebral atrophy Cavernous sinus thrombosis Neonatal hypoxia Hydrocephalus Shy-Drager syndrome Rocky Mountain spotted fever Delirium tremens Cerebrovascular accident (cerebral thrombosis or hemorrhage) Acute psychosis Multiple sclerosis

FIGURE 1-18 Causes of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Though SIADH is the commonest cause of hyponatremia in hospitalized patients, it is a diagnosis of exclusion. It is characterized by a defect in osmoregulation of ADH in which plasma ADH levels are not appropriately suppressed for the degree of hypotonicity, leading to urine concentration by a variety of mechanisms. Most of these fall into one of three categories (ie, malignancies, pulmonary diseases, central nervous system disorders) [14]. FIGURE 1-19 Diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Clinically, SIADH is characterized by a decrease in the effective extracellular fluid osmolality, with inappropriately concentrated urine. Patients with SIADH are clinically euvolemic and are consuming normal amounts of sodium and water (H2O). They have elevated urinary sodium excretion. In the evaluation of these patients, it is important to exclude adrenal, thyroid, pituitary, and renal disease and diuretic use. Patients with clinically suspected SIADH can be tested with a water load. Upon administration of 20 mL/kg of H2O, patients with SIADH are unable to excrete 90% of the H2O load and are unable to dilute their urine to an osmolality less than 100 mOsm/kg [15]. (Modified from Verbalis [15]; with permission.)

1.12

Disorders of Water, Electrolytes, and Acid-Base

SIGNS AND SYMPTOMS OF HYPONATREMIA Central Nervous System

Gastrointestinal System

Mild Apathy Headache Lethargy Moderate Agitation Ataxia Confusion Disorientation Psychosis Severe Stupor Coma Pseudobulbar palsy Tentorial herniation Cheyne-Stokes respiration Death

Anorexia Nausea Vomiting

Musculoskeletal System Cramps Diminished deep tendon reflexes

FIGURE 1-20 Signs and symptoms of hyponatremia. In evaluating hyponatremic patients, it is important to assess whether or not the patient is symptomatic, because symptoms are a better determinant of therapy than the absolute value itself. Most patients with serum sodium values above 125 mEq/L are asymptomatic. The rapidity with which hyponatremia develops is critical in the initial evaluation of such patients. In the range of 125 to 130 mEq/L, the predominant symptoms are gastrointestinal ones, including nausea and vomiting. Neuropsychiatric symptoms dominate the picture once the serum sodium level drops below 125 mEq/L, mostly because of cerebral edema secondary to hypotonicity. These include headache, lethargy, reversible ataxia, psychosis, seizures, and coma. Severe manifestations of cerebral edema include increased intracerebral pressure, tentorial herniation, respiratory depression and death. Hyponatremia-induced cerebral edema occurs principally with rapid development of hyponatremia, typically in patients managed with hypotonic fluids in the postoperative setting or those receiving diuretics, as discussed previously. The mortality rate can be as great as 50%. Fortunately, this rarely occurs. Nevertheless, neurologic symptoms in a hyponatremic patient call for prompt and immediate attention and treatment [16,17].

FIGURE 1-21 Cerebral adaptation to hyponatremia. 3 Na+/H2O ↓Na+/↑H2O ↓Na+/↑H2O A, Decreases in extracellular osmolality 2 cause movement of water (H2O) into the cells, increasing intracellular volume and K+, Na+ ↓K+, ↓Na+ K+, Na+ thus causing tissue edema. This cellular H 2O ↑H2O H 2O osmolytes osmolytes ↓osmolytes edema within the fixed confines of the cranium causes increased intracranial pressure, leading to neurologic symptoms. To prevent this from happening, mechanisms geared toward volume regulation come into operaNormonatremia Acute hyponatremia Chronic hyponatremia A tion, to prevent cerebral edema from developing in the vast majority of patients with hyponatremia. After induction of extracellular fluid hypo-osmolality, H2O moves into the brain in response to osmotic gradients, producing cerebral edema (middle panel, 1). However, within 1 to 3 hours, a decrease in cerebral extracellular volume occurs by movement of K+ fluid into the cerebrospinal fluid, which is then shunted back into the systemic circulation. Glutamate This happens very promptly and is evident by the loss of extracellular and intracellular solutes (sodium and chloride ions) as early as 30 minutes after the onset of hyponatremia. Na+ As H2O losses accompany the losses of brain solute (middle panel, 2), the expanded brain Urea volume decreases back toward normal (middle panel, 3) [15]. B, Relative decreases in individual osmolytes during adaptation to chronic hyponatremia. Thereafter, if hyponatremia persists, other organic osmolytes such as phosphocreatine, myoinositol, and amino acids Inositol like glutamine, and taurine are lost. The loss of these solutes markedly decreases cerebral Cl– swelling. Patients who have had a slower onset of hyponatremia (over 72 to 96 hours or Taurine longer), the risk for osmotic demyelination rises if hyponatremia is corrected too rapidly Other B [18,19]. Na+—sodium; K+—potassium; Cl-—chloride. 1

Diseases of Water Metabolism

HYPONATREMIC PATIENTS AT RISK FOR NEUROLOGIC COMPLICATIONS Complication

Persons at Risk

Acute cerebral edema

Postoperative menstruant females Elderly women taking thiazides Children Psychiatric polydipsic patients Hypoxemic patients

Osmotic demyelination syndrome

Alcoholics Malnourished patients Hypokalemic patients Burn victims Elderly women taking thiazide diuretics

FIGURE 1-22 Hyponatremic patients at risk for neurologic complications. Those at risk for cerebral edema include postoperative menstruant women, elderly women taking thiazide diuretics, children, psychiatric patients with polydipsia, and hypoxic patients. In women, and, in particular, menstruant ones, the risk for developing neurologic complications is 25 times greater than that for nonmenstruant women or men. The increased risk was independent of the rate of development, or the magnitude of the hyponatremia [21]. The osmotic demyelination syndrome or central pontine myelinolysis seems to occur when there is rapid correction of low osmolality (hyponatremia) in a brain already chronically adapted (more than 72 to 96 hours). It is rarely seen in patients with a serum sodium value greater than 120 mEq/L or in those who have hyponatremia of less than 48 hours’ duration [20,21]. (Adapted from Lauriat and Berl [21]; with permission.)

A

1.13

SYMPTOMS OF CENTRAL PONTINE MYELINOLYSIS Initial symptoms Mutism Dysarthria Lethargy and affective changes Classic symptoms Spastic quadriparesis Pseudobulbar palsy Lesions in the midbrain, medulla oblongata, and pontine tegmentum Pupillary and oculomotor abnormalities Altered sensorium Cranial neuropathies Extrapontine myelinolysis Ataxia Behavioral abnormalities Parkinsonism Dystonia

FIGURE 1-23 Symptoms of central pontine myelinolysis. This condition has been described all over the world, in all age groups, and can follow correction of hyponatremia of any cause. The risk for development of central pontine myelinolysis is related to the severity and chronicity of the hyponatremia. Initial symptoms include mutism and dysarthria. More than 90% of patients exhibit the classic symptoms of myelinolysis (ie, spastic quadriparesis and pseudobulbar palsy), reflecting damage to the corticospinal and corticobulbar tracts in the basis pontis. Other symptoms occur on account of extension of the lesion to other parts of the midbrain. This syndrome follows a biphasic course. Initially, a generalized encephalopathy, associated with a rapid rise in serum sodium, occurs. This is followed by the classic symptoms 2 to 3 days after correction of hyponatremia, however, this pattern does not always occur [22]. (Adapted from Laureno and Karp [22]; with permission.)

B

FIGURE 1-24 A, Imaging of central pontine myelinolysis. Brain imaging is the most useful diagnostic technique for central pontine myelinolysis. Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT). On CT, central pontine and extrapontine lesions appear as symmetric areas of hypodensity (not shown). On T2 images of MRI, the lesions appear as hyperintense and on T1

images, hypointense. These lesions do not enhance with gadolinium. They may not be apparent on imaging until 2 weeks into the illness. Other diagnostic tests are brainstem auditory evoked potentials, electroencephalography, and cerebrospinal fluid protein and myelin basic proteins [22]. B, Gross appearance of the pons in central pontine myelinolysis. (From Laureno and Karp [22]; with permission.)

1.14

Disorders of Water, Electrolytes, and Acid-Base

Severe hyponatremia (50 20–50 24 mg/24 hrs)

Mg deficiency present

Hypertension

FIGURE 4-16 Mechanism whereby magnesium (Mg) deficiency could lead to hypertension. Mg deficiency does the following: increases angiotensin II (AII) action, decreases levels of vasodilatory prostaglandins (PGs), increases levels of vasoconstrictive PGs and growth factors, increases vascular smooth muscle cytosolic calcium, impairs insulin release, produces insulin resistance, and alters lipid profile. All of these results of Mg deficiency favor the development of hypertension and atherosclerosis [10,11]. Na+—ionized sodium; 12-HETE—hydroxy-eicosatetraenoic [acid]; TXA2—thromboxane A2. (From Nadler and coworkers [17].)

Low (< 24 mg/24 hrs)

Check for nonrenal causes

Mg deficiency present Renal Mg wasting

Normal Mg retention

Mg retention

No Mg deficiency Normal

Mg deficiency present Check for nonrenal causes

FIGURE 4-17 Evaluation in suspected magnesium (Mg) deficiency. Serum Mg levels may not always indicate total body stores. More refined tools used to assess the status of Mg in erythrocytes, muscle, lymphocytes, bone, isotope studies, and indicators of intracellular Mg, are not routinely available. Screening for Mg deficiency relies on the fact that urinary Mg decreases rapidly in the face of Mg depletion in the presence of normal renal function [2,6,8–15,18]. (Adapted from Al-Ghamdi and coworkers [11].) FIGURE 4-18 The magnesium (Mg) tolerance test, in various forms [2,6,8–12,18], has been advocated to diagnose Mg depletion in patients with normal or near-normal serum Mg levels. All such tests are predicated on the fact that patients with normal Mg status rapidly excrete over 50% of an acute Mg load; whereas patients with depleted Mg retain Mg in an effort to replenish Mg stores. (From Ryzen and coworkers [18].)

4.11

Divalent Cation Metabolism: Magnesium

MAGNESIUM SALTS USED IN MAGNESIUM REPLACEMENT THERAPY Magnesium salt

Chemical formula

Mg content, mg/g

Examples*

Mg content

Diarrhea

27-mg tablet 54 mg/5 mL

±

Gluconate

Cl2H22MgO14

58

Magonate®

Chloride

MgCl2 . (H2O)6

120

Mag-L-100

100-mg capsule

+

Lactate

C6H10MgO6

120

MagTab SR*

84-mg caplet

+

Citrate

C12H10Mg3O14

Multiple

47–56 mg/5 mL

++

Hydroxide

Mg(OH)2

410

Maalox®, Mylanta®, Gelusil® Riopan®

83 mg/ 5 mL and 63-mg tablet 96 mg/5 mL

++

Oxide

MgO

600

Mag-Ox 400® Uro-Mag® Beelith®

241-mg tablet 84.5-mg tablet 362-mg tablet

++

Sulfate

MgSO4 . (H2O)7

100

IV IV Oral epsom salt

10%—9.9 mg/mL 50%—49.3 mg/mL 97 mg/g

++

Phillips’ Milk of Magnesia®

168 mg/ 5 mL

++

53

Milk of Magnesia

++

Data from McLean [9], Al-Ghamdi and coworkers [11], Oster and Epstein [19], and Physicians’ Desk Reference [20]. *Magonate®, Fleming & Co, Fenton, MD; MagTab Sr®, Niche Pharmaceuticals, Roanoke, TX; Maalox®, Rhone-Poulenc Rorer Pharmaceutical, Collegeville, PA; Mylanta®, J & J-Merck Consumer Pharm, Ft Washinton, PA; Riopan®, Whitehall Robbins Laboratories, Madison, NJ; Mag-Ox 400® and Uro-Mag®, Blaine, Erlanger, KY; Beelith®, Beach Pharmaceuticals, Conestee, SC; Phillips’ Milk of Magnesia, Bayer Corp, Parsippany, NJ.

FIGURE 4-19 Magnesium (Mg) salts that may be used in Mg replacement therapy.

GUIDELINES FOR MAGNESIUM (Mg) REPLACEMENT Life-threatening event, eg, seizures and cardiac arrhythmia I. 2–4 g MgSO4 IV or IM stat (2–4 vials [2 mL each] of 50% MgSO4) Provides 200–400 mg of Mg (8.3–16.7 mmol Mg) Closely monitor: Deep tendon reflexes Heart rate Blood pressure Respiratory rate Serum Mg ( 20 mEq/L)

↑NH4+entry in medulla and secretion in medullary collecting duct

• Vomiting, gastric suction • Postdiuretic phase of loop and distal agents • Posthypercapnic state • Villous adenoma of the colon • Congenital chloridorrhea • Post alkali loading

Urinary [K+] Low (< 20 mEq/L)

+

+

FIGURE 6-36 Maintenance of chloride-resistant metabolic alkalosis. Increased renal bicarbonate reabsorption is the sole basic mechanism that maintains chloride-resistant metabolic alkalosis. As its name implies, factors independent of chloride intake mediate the height-

Abundant (> 30 mEq/L)

↑Na+ reabsorption and consequent ↑H+ and K+ secretion

Cl

+

α-cell

–

Urinary [Cl–]

+

K Na

• Laxative abuse • Other causes of profound K+ depletion

• Diuretic phase of loop and distal agents • Bartter's and Gitelman's syndromes • Primary aldosteronism • Cushing's syndrome • Exogenous mineralocorticoid agents • Secondary aldosteronism malignant hypertension renovascular hypertension primary reninism • Liddle's syndrome

Cl–

HCO–3 Cl– H+ K+ ß-cell HCO

↑H+ secretion coupled to K+ reabsorption

↑H+ secretion

H+

– –Cl 3

NH3

NH+4

ened bicarbonate reabsorption and include mineralocorticoid excess and potassium depletion. The participation of these factors in the nephronal processes that maintain chloride-resistant metabolic alkalosis is depicted [22–24, 26]. FIGURE 6-37 Urinary composition in the diagnostic evaluation of metabolic alkalosis. Assessing the urinary composition can be an important aid in the diagnostic evaluation of metabolic alkalosis. Measurement of urinary chloride ion concentration ([Cl-]) can help distinguish between chloride-responsive and chloride-resistant metabolic alkalosis. The virtual absence of chloride (urine [Cl-] < 10 mEq/L) indicates significant chloride depletion. Note, however, that this test loses its diagnostic significance if performed within several hours of administration of chloruretic diuretics, because these agents promote urinary chloride excretion. Measurement of urinary potassium ion concentration ([K+]) provides further diagnostic differentiation. With the exception of the diuretic phase of chloruretic agents, abundance of both urinary chloride and potassium signifies a state of mineralocorticoid excess [22].

Disorders of Acid-Base Balance

6.25

SIGNS AND SYMPTOMS OF METABOLIC ALKALOSIS Central Nervous System Headache Lethargy Stupor Delirium Tetany Seizures Potentiation of hepatic encephalopathy

Cardiovascular System

Respiratory System

Neuromuscular System

Metabolic Effects

Supraventricular and ventricular arrhythmias Potentiation of digitalis toxicity Positive inotropic ventricular effect

Hypoventilation with attendant hypercapnia and hypoxemia

Chvostek’s sign Trousseau’s sign Weakness (severity depends on degree of potassium depletion)

Increased organic acid and ammonia production Hypokalemia Hypocalcemia Hypomagnesemia Hypophosphatemia

FIGURE 6-38 Signs and symptoms of metabolic alkalosis. Mild to moderate metabolic alkalosis usually is accompanied by few if any symptoms, unless potassium depletion is substantial. In contrast, severe metabolic alkalosis ([HCO3] > 40 mEq/L) is usually a symptomatic disorder. Alkalemia, hypokalemia, hypoxemia, hypercapnia, and decreased plasma ionized calcium concentration all contribute to

Ingestion of large amounts of calcium

Augmented body content of calcium

Urine alkalinization

Augmented body bicarbonate stores

Nephrocalcinosis

Hypercalcemia

Renal vasoconstriction

Renal insufficiency

Reduced renal bicarbonate excretion

Decreased urine calcium excretion

Polyuria Polydipsia Urinary concentration defect Cortical and medullary renal cysts

these clinical manifestations. The arrhythmogenic potential of alkalemia is more pronounced in patients with underlying heart disease and is heightened by the almost constant presence of hypokalemia, especially in those patients taking digitalis. Even mild alkalemia can frustrate efforts to wean patients from mechanical ventilation [23,24].

Ingestion of large amounts of absorbable alkali

Increased urine calcium excretion (early phase)

Renal (Associated Potassium Depletion)

Metabolic alkalosis

Increased renal reabsorption of calcium

Increased renal H+ secretion

FIGURE 6-39 Pathophysiology of the milk-alkali syndrome. The milk-alkali syndrome comprises the triad of hypercalcemia, renal insufficiency, and metabolic alkalosis and is caused by the ingestion of large amounts of calcium and absorbable alkali. Although large amounts of milk and absorbable alkali were the culprits in the classic form of the syndrome, its modern version is usually the result of large doses of calcium carbonate alone. Because of recent emphasis on prevention and treatment of osteoporosis with calcium carbonate and the availability of this preparation over the counter, milk-alkali syndrome is currently the third leading cause

of hypercalcemia after primary hyperparathyroidism and malignancy. Another common presentation of the syndrome originates from the current use of calcium carbonate in preference to aluminum as a phosphate binder in patients with chronic renal insufficiency. The critical element in the pathogenesis of the syndrome is the development of hypercalcemia that, in turn, results in renal dysfunction. Generation and maintenance of metabolic alkalosis reflect the combined effects of the large bicarbonate load, renal insufficiency, and hypercalcemia. Metabolic alkalosis contributes to the maintenance of hypercalcemia by increasing tubular calcium reabsorption. Superimposition of an element of volume contraction caused by vomiting, diuretics, or hypercalcemia-induced natriuresis can worsen each one of the three main components of the syndrome. Discontinuation of calcium carbonate coupled with a diet high in sodium chloride or the use of normal saline and furosemide therapy (depending on the severity of the syndrome) results in rapid resolution of hypercalcemia and metabolic alkalosis. Although renal function also improves, in a considerable fraction of patients with the chronic form of the syndrome serum creatinine fails to return to baseline as a result of irreversible structural changes in the kidneys [27].

6.26

Disorders of Water, Electrolytes, and Acid-Base

Clinical syndrome

Affected gene

Affected chromosome

Localization of tubular defect TAL

Bartter's syndrome Type 1

NKCC2

15q15-q21 TAL CCD

Type 2

ROMK

11q24

TSC

16q13

Gitelman's syndrome

Tubular lumen Na+ K+,NH+4 Cl– Loop diuretics H+

DCT

Peritubular space

Cell

3Na

+

2K+ ATPase

+

K 3HCO–3 Na+

Tubular lumen Na

+

Cl– Thiazides

Peritubular space

Cell 3Na+ +

2K+ ATPase

Tubular lumen

Peritubular space

Cell

Na+

Cl– 3Na

K Cl–

K+

+

ATPase + 2K

+

K Cl–

K+

3Na+ 2+

Ca

2+

Ca

Ca2+ Mg2+ Thick ascending limb (TAL)

Distal convoluted tuble (DCT)

Cortical collecting duct (CCD)

FIGURE 6-40 Clinical features and molecular basis of tubular defects of Bartter’s and Gitelman’s syndromes. These rare disorders are characterized by chloride-resistant metabolic alkalosis, renal potassium wasting and hypokalemia, hyperreninemia and hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and normotension. Regarding differentiating features, Bartter’s syndrome presents early in life, frequently in association with growth and mental retardation. In this syndrome, urinary concentrating ability is usually decreased, polyuria and polydipsia are present, the serum magnesium level is normal,

and hypercalciuria and nephrocalcinosis are present. In contrast, Gitelman’s syndrome is a milder disease presenting later in life. Patients often are asymptomatic, or they might have intermittent muscle spasms, cramps, or tetany. Urinary concentrating ability is maintained; hypocalciuria, renal magnesium wasting, and hypomagnesemia are almost constant features. On the basis of certain of these clinical features, it had been hypothesized that the primary tubular defects in Bartter’s and Gitelman’s syndromes reflect impairment in sodium reabsorption in the thick ascending limb (TAL) of the loop of Henle and the distal tubule, respectively. This hypothesis has been validated by recent genetic studies [28-31]. As illustrated here, Bartter’s syndrome now has been shown to be caused by loss-of-function mutations in the loop diuretic–sensitive sodium-potassium-2chloride cotransporter (NKCC2) of the TAL (type 1 Bartter’s syndrome) [28] or the apical potassium channel ROMK of the TAL (where it recycles reabsorbed potassium into the lumen for continued operation of the NKCC2 cotransporter) and the cortical collecting duct (where it mediates secretion of potassium by the principal cell) (type 2 Bartter’s syndrome) [29,30]. On the other hand, Gitelman’s syndrome is caused by mutations in the thiazide-sensitive Na-Cl cotransporter (TSC) of the distal tubule [31]. Note that the distal tubule is the major site of active calcium reabsorption. Stimulation of calcium reabsorption at this site is responsible for the hypocalciuric effect of thiazide diuretics.

Disorders of Acid-Base Balance

Management of metabolic alkalosis

For alkali gain

For H+ loss Eliminate source of excess alkali

For H+ shift

Discontinue administrationof bicarbonate or its precursors. via gastric route Administer antiemetics; discontinue gastric suction; administer H2 blockers or H+-K+ ATPase inhibitors. via renal route Discontinue or decrease loop and distal diuretics; substitute with amiloride, triamterene, or spironolactone; discontinue or limit drugs with mineralocorticoid activity. Potassium repletion

For decreased GFR

Interrupt perpetuating mechanisms

For Cl– responsive acidification defect

For Cl– resistant acidification defect

ECF volume repletion; renal replacement therapy

6.27

FIGURE 6-41 Metabolic alkalosis management. Effective management of metabolic alkalosis requires sound understanding of the underlying pathophysiology. Therapeutic efforts should focus on eliminating or moderating the processes that generate the alkali excess and on interrupting the mechanisms that perpetuate the hyperbicarbonatemia. Rarely, when the pace of correction of metabolic alkalosis must be accelerated, acetazolamide or an infusion of hydrochloric acid can be used. Treatment of severe metabolic alkalosis can be particularly challenging in patients with advanced cardiac or renal dysfunction. In such patients, hemodialysis or continuous hemofiltration might be required [1].

Administer NaCl and KCl

Adrenalectomy or other surgery, potassiuim repletion, administration of amiloride, triamterene, or spironolactone.

References 1. Adrogué HJ, Madias NE: Management of life-threatening acid-base disorders. N Engl J Med, 1998, 338:26–34, 107–111. 2. Madias NE, Adrogué HJ: Acid-base disturbances in pulmonary medicine. In Fluid, Electrolyte, and Acid-Base Disorders. Edited by Arieff Al, DeFronzo RA. New York: Churchill Livingstone; 1995:223–253. 3. Madias NE, Adrogué HJ, Horowitz GL, et al.: A redefinition of normal acid-base equilibrium in man: carbon dioxide tension as a key determinant of plasma bicarbonate concentration. Kidney Int 1979, 16:612–618. 4. Adrogué HJ, Madias NE: Mixed acid-base disorders. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995:953–962. 5. Krapf R: Mechanisms of adaptation to chronic respiratory acidosis in the rabbit proximal tubule. J Clin Invest 1989, 83:890–896. 6. Al-Awqati Q: The cellular renal response to respiratory acid-base disorders. Kidney Int 1985, 28:845–855. 7. Bastani B: Immunocytochemical localization of the vacuolar H+ATPase pump in the kidney. Histol Histopathol 1997, 12:769–779. 8. Teixeira da Silva JC Jr, Perrone RD, Johns CA, Madias NE: Rat kidney band 3 mRNA modulation in chronic respiratory acidosis. Am J Physiol 1991, 260:F204–F209. 9. Respiratory pump failure: primary hypercapnia (respiratory acidosis). In Respiratory Failure. Edited by Adrogué HJ, Tobin MJ. Cambridge, MA: Blackwell Science; 1997:125–134. 10. Krapf R, Beeler I, Hertner D, Hulter HN: Chronic respiratory alkalosis: the effect of sustained hyperventilation on renal regulation of acidbase equilibrium. N Engl J Med 1991, 324:1394–1401. 11. Hilden SA, Johns CA, Madias NE: Adaptation of rabbit renal cortical Na+-H+-exchange activity in chronic hypocapnia. Am J Physiol 1989, 257:F615–F622.

12. Adrogué HJ, Rashad MN, Gorin AB, et al.: Arteriovenous acid-base disparity in circulatory failure: studies on mechanism. Am J Physiol 1989, 257:F1087–F1093. 13. Adrogué HJ, Rashad MN, Gorin AB, et al.: Assessing acid-base status in circulatory failure: differences between arterial and central venous blood. N Engl J Med 1989, 320:1312–1316. 14. Madias NE: Lactic acidosis. Kidney Int 1986, 29:752–774. 15. Kraut JA, Madias NE: Lactic acidosis. In Textbook of Nephrology. Edited by Massry SG, Glassock RJ. Baltimore: Williams and Wilkins; 1995:449–457. 16. Hindman BJ: Sodium bicarbonate in the treatment of subtypes of acute lactic acidosis: physiologic considerations. Anesthesiology 1990, 72:1064–1076. 17. AdroguÈ HJ: Diabetic ketoacidosis and hyperosmolar nonketotic syndrome. In Therapy of Renal Diseases and Related Disorders. Edited by Suki WN, Massry SG. Boston: Kluwer Academic Publishers; 1997:233–251. 18. Adrogué HJ, Barrero J, Eknoyan G: Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis. JAMA 1989, 262:2108–2113. 19. Bastani B, Gluck SL: New insights into the pathogenesis of distal renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396–409. 20. DuBose TD Jr: Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic insights. Kidney Int 1997, 51:591–602. 21. Madias NE, Bossert WH, Adrogué HJ: Ventilatory response to chronic metabolic acidosis and alkalosis in the dog. J Appl Physiol 1984, 56:1640–1646. 22. Gennari FJ: Metabolic alkalosis. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St Louis: Mosby-Year Book; 1995:932–942.

6.28

Disorders of Water, Electrolytes, and Acid-Base

23. Sabatini S, Kurtzman NA: Metabolic alkalosis: biochemical mechanisms, pathophysiology, and treatment. In Therapy of Renal Diseases and Related Disorders Edited by Suki WN, Massry SG. Boston: Kluwer Academic Publishers; 1997:189–210. 24. Galla JH, Luke RG: Metabolic alkalosis. In Textbook of Nephrology. Edited by Massry SG, Glassock RJ. Baltimore: Williams & Wilkins; 1995:469–477. 25. Madias NE, Adrogué HJ, Cohen JJ: Maladaptive renal response to secondary hypercapnia in chronic metabolic alkalosis. Am J Physiol 1980, 238:F283–289. 26. Harrington JT, Hulter HN, Cohen JJ, Madias NE: Mineralocorticoidstimulated renal acidification in the dog: the critical role of dietary sodium. Kidney Int 1986, 30:43–48. 27. Beall DP, Scofield RH: Milk-alkali syndrome associated with calcium carbonate consumption. Medicine 1995, 74:89–96.

28. Simon DB, Karet FE, Hamdan JM, et al.: Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 1996, 13:183–188. 29. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 1996, 14:152–156. 30. International Collaborative Study Group for Bartter-like Syndromes. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. Hum Mol Genet 1997, 6:17–26. 31. Simon DB, Nelson-Williams C, et al.: Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996, 12:24–30.

Disorders of Phosphate Balance Moshe Levi Mordecai Popovtzer

T

he physiologic concentration of serum phosphorus (phosphate) in normal adults ranges from 2.5 to 4.5 mg/dL (0.80–1.44 mmol/L). A diurnal variation occurs in serum phosphorus of 0.6 to 1.0 mg/dL, the lowest concentration occurring between 8 AM and 11 AM. A seasonal variation also occurs; the highest serum phosphorus concentration is in the summer and the lowest in the winter. Serum phosphorus concentration is markedly higher in growing children and adolescents than in adults, and it is also increased during pregnancy [1,2]. Of the phosphorus in the body, 80% to 85% is found in the skeleton. The rest is widely distributed throughout the body in the form of organic phosphate compounds. In the extracellular fluid, including in serum, phosphorous is present mostly in the inorganic form. In serum, more than 85% of phosphorus is present as the free ion and less than 15% is protein-bound. Phosphorus plays an important role in several aspects of cellular metabolism, including adenosine triphosphate synthesis, which is the source of energy for many cellular reactions, and 2,3-diphosphoglycerate concentration, which regulates the dissociation of oxygen from hemoglobin. Phosphorus also is an important component of phospholipids in cell membranes. Changes in phosphorus content, concentration, or both, modulate the activity of a number of metabolic pathways. Major determinants of serum phosphorus concentration are dietary intake and gastrointestinal absorption of phosphorus, urinary excretion of phosphorus, and shifts between the intracellular and extracellular spaces. Abnormalities in any of these steps can result either in hypophosphatemia or hyperphosphatemia [3–7]. The kidney plays a major role in the regulation of phosphorus homeostasis. Most of the inorganic phosphorus in serum is ultrafilterable at the level of the glomerulus. At physiologic levels of serum phosphorus and during a normal dietary phosphorus intake, approximately 6 to 7 g/d of phosphorous is filtered by the kidney. Of that

CHAPTER

7

7.2

Disorders of Water, Electrolytes, and Acid-Base

amount, 80% to 90% is reabsorbed by the renal tubules and the rest is excreted in the urine. Most of the filtered phosphorus is reabsorbed in the proximal tubule by way of a sodium gradient-dependent process (Na-Pi cotransport) located on the apical brush border membrane [8–10]. Recently two distinct Na-Pi cotransport proteins have been cloned from the kidney

(type I and type II Na-Pi cotransport proteins). Most of the hormonal and metabolic factors that regulate renal tubular phosphate reabsorption, including alterations in dietary phosphate content and parathyroid hormone, have been shown to modulate the proximal tubular apical membrane expression of the type II Na-Pi cotransport protein [11–16]. FIGURE 7-1 Summary of phosphate metabolism for a normal adult in neutral phosphate balance. Approximately 1400 mg of phosphate is ingested daily, of which 490 mg is excreted in the stool and 910 mg in the urine. The kidney, gastrointestinal (GI) tract, and bone are the major organs involved in phosphorus homeostasis.

Bone

GI intake 1400 mg/d

Digestive juice phosphorus 210 mg/d

Formation 210 mg/d

Resorption 210 mg/d

Extracellular fluid Total absorbed intestinal phosphorus 1120 mg/d

Urine 910 mg/d Stool 490 mg/d

FIGURE 7-2 Major determinants of extracellular fluid or serum inorganic phosphate (Pi) concentration include dietary Pi intake, intestinal Pi absorption, urinary Pi excretion and shift into the cells.

Major determinants of ECF or serum inorganic phosphate (Pi) concentration Dietary intake Intestinal absorption

Serum Pi Urinary excretion

Cells

Disorders of Phosphate Balance

7.3

Renal Tubular Phosphate Reabsorption 100% PCT 55-75%

DCT 5-10%

PST 10-20%

FIGURE 7-3 Renal tubular reabsorption of phosphorus. Most of the inorganic phosphorus in serum is ultrafilterable at the level of the glomerulus. At physiologic levels of serum phosphorus and during a normal dietary phosphorus intake, most of the filtered phosphorous is reabsorbed in the proximal convoluted tubule (PCT) and proximal straight tubule (PST). A significant amount of filtered phosphorus is also reabsorbed in distal segments of the nephron [7,9,10]. CCT—cortical collecting tubule; IMCD—inner medullary collecting duct or tubule; PST—proximal straight tubule.

CCT 2-5%

IMCD 0.5 mg/dL/d Previous SCr normal

ARF

CRF

+

Urinary tract dilatation

Echography ↑ SCr < 0.5 mg/dL/d Normal Flare of previous disease

Acute-on-chronic renal failure

Repeat echograph after 24 h

Normal No Data indicating glomerular or systemic disease?

Prerenal factors?

Parenchymatous glomerular or systemic ARF

Yes

Vascular ARF

Yes

Great or small vessel disease?

No

Acute tubulointerstitial nephritis

Yes

Data indicating interstitial disease?

No

Yes

Crystals or tubular deposits?

No

Tumor lysis Sulfonamides Amyloidosis Other

FIGURE 8-8 The most frequent causes of acute renal failure (ARF) in patients with preexisting chronic renal failure are acute tubular necrosis (ATN) and prerenal failure. The distribution of causes of ARF in these patients is similar to that observed in patients without previous kidney diseases. (Data from Liaño et al. [1])

No

Yes

Obstructive ARF

Improvement with specific treatment? Yes Prerenal ARF

No

Acute tubular necrosis

Acute Renal Failure: Causes and Prognosis

BIOPSY RESULTS IN THE MADRID STUDY Disease

Patients, n

Primary GN Extracapillary Acute proliferative Endocapillary and extracapillary Focal sclerosing Secondary GN Antiglomerular basement membrane Acute postinfectious Diffuse proliferative (systemic lupus erythematosus) Vasculitis Necrotizing Wegener’s granulomatosis Not specified Acute tubular necrosis Acute tubulointerstitial nephritis Atheroembolic disease Kidney myeloma Cortical necrosis Malignant hypertension ImmunoglobulinA GN + ATN Hemolytic-uremic syndrome Not recorded

12 6 3 2 1 6 3 2 1* 10 5* 3 2 4* 4 2 2* 1 1 1 1 2

8.5

FIGURE 8-10 Biopsy results in the Madrid acute renal failure (ARF) study. Kidney biopsy has had fluctuating roles in the diagnostic work-up of ARF. After extrarenal causes of ARF are excluded, the most common cause is acute tubular necrosis (ATN). Patients with well-established clinical and laboratory features of ATN receive no benefit from renal biopsy. This histologic tool should be reserved for parenchymatous ARF cases when there is no improvement of renal function after 3 weeks’ evolution of ARF. By that time, most cases of ATN have resolved, so other causes could be influencing the poor evolution. Biopsy is mandatory when a potentially treatable cause is suspected, such as vasculitis, systemic disease, or glomerulonephritis (GN) in adults. Some types of parenchymatous non-ATN ARF might have histologic confirmation; however kidney biopsy is not strictly necessary in cases with an adequate clinical diagnosis such as myeloma, uric acid nephropathy, or some types of acute tubulointerstitial nephritis . Other parenchymatous forms of ARF can be accurately diagnosed without a kidney biopsy. This is true of acute post-streptococcal GN and of hemolytic-uremic syndrome in children. Kidney biopsy was performed in only one of every 16 ARF cases in the Madrid ARF Study [1]. All patients with primary GN, 90% with vasculitis and 50% with secondary GN were diagnosed by biopsy at the time of ARF. As many as 15 patients were diagnosed as having acute tubulointerstitial nephritis, but only four (27%) were biopsied. Only four of 337 patients with ATN (1.2%) underwent biopsy. (Data from Liaño et al. [1].)

* One patient with acute-on-chronic renal failure.

Predisposing Factors for Acute Renal Failure Renal insult Advanced age

Very elderly

Elderly

Young

11%

12%

17%

11%

7%

Proteinuria 20% Volume depletion

29%

Other Obstructive Prerenal Acute tubular necrosis

21%

30% Myeloma

Diuretic use

39% Diabetes mellitus

Previous cardiac or renal insufficiency

Higher probability for ARF

FIGURE 8-11 Factors that predispose to acute renal failure (ARF). Some of them act synergistically when they occur in the same patient. Advanced age and volume depletion are particularly important.

(n=103)

48%

(n=256)

56%

(n=389)

FIGURE 8-12 Causes of acute renal failure (ARF) relative to age. Although the cause of ARF is usually multifactorial, one can define the cause of each case as the most likely contributor to impairment of renal function. One interesting approach is to distribute the causes of ARF according to age. This

figure shows the main causes of ARF, dividing a population diagnosed with ARF into the very elderly (at least 80 years), elderly (65 to 79), and young (younger than 65). Essentially, acute tubular necrosis (ATN) is less frequent (P=0.004) and obstructive ARF more frequent (P1); THF + alloTHF/THE—ratio of the combined urinary tetrahydrocortisol and allotetrahydrocortisol to urinary tetrahydrocortisone (normal: 90%) inherit NDI as an X-linked recessive trait. In these patients, defects in the V2 receptor have been identified. In the remaining patients, the disease is transmitted as either an autosomal recessive or autosomal dominant trait involving mutations in the AQP2 gene [38,39]. ADH— antidiuretic hormone; ATP—adenosine triphosphate.

Renal Tubular Disorders

12.15

Urolithiases INHERITED CAUSES OF UROLITHIASES Disorder

Stone characteristics

Treatment

Cystinuria

Cystine

Dent’s disease X-linked recessive nephrolithiasis X-linked recessive hypophosphatemic rickets Hereditary renal hypouricemia

Calcium-containing Calcium-containing Calcium-containing

High fluid intake, urinary alkalization Sulfhydryl-containing drugs High fluid intake, urinary alkalization High fluid intake, urinary alkalization High fluid intake, urinary alkalization

Hypoxanthine-guanine phosphoribosyltransferase deficiency Xanthinuria Primary hyperoxaluria

Uric acid

Uric acid, calcium oxalate

Xanthine Calcium oxalate

High fluid intake, urinary alkalization Allopurinol High fluid intake, urinary alkalization Allopurinol High fluid intake, dietary purine restriction High fluid intake, dietary oxalate restriction Magnesium oxide, inorganic phosphates

FIGURE 12-23 Urolithiases are a common urinary tract abnormality, afflicting 12% of men and 5% of women in North America and Europe [40]. Renal stone formation is most commonly associated with hypercalciuria. Perhaps in as many as 45% of these patients, there seems to be a familial predisposition. In comparison, a group of relatively rare disorders exists, each of which is transmitted as a Mendelian trait and causes a variety of different crystal nephropathies. The most common of these disorders is cystinuria, which involves defective cystine and dibasic

amino acid transport in the proximal tubule. Cystinuria is the leading single gene cause of inheritable urolithiasis in both children and adults [41,42]. Three Mendelian disorders, Dent’s disease, X-linked recessive nephrolithiasis, and X-linked recessive hypophosphatemic rickets cause hypercalciuric urolithiasis. These disorders involve a functional loss of the renal chloride channel ClC-5 [43]. The common molecular basis for these three inherited kidney stone diseases has led to speculation that ClC-5 also may be involved in other renal tubular disorders associated with kidney stones. Hereditary renal hypouricemia is an inborn error of renal tubular transport that appears to involve urate reabsorption in the proximal tubule [16]. In addition to renal transport deficiencies, defects in metabolic enzymes also can cause urolithiases. Inherited defects in the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or in the catabolic enzyme xanthine dehydrogenase (XDH) all can lead to stone formation [44]. Finally, defective enzymes in the oxalate metabolic pathway result in hyperoxaluria, oxalate stone formation, and consequent loss of renal function [45].

Acknowledgment The author thanks Dr. David G. Warnock for critically reviewing this manuscript.

References 1. Wells R, Kanai Y, Pajor A, et al.: The cloning of a human cDNA with similarity to the sodium/glucose cotransporter. Am J Physiol 1992, 263:F459–F465. 2. Hediger M, Coady M, Ikeda T, Wright E: Expression cloning and cDNA sequencing of the Na/glucose co-transporter. Nature 1987, 330:379–381. 3. Woolf L, Goodwin B, Phelps C: Tm-limited renal tubular reabsorption and the genetics of renal glycosuria. J Theor Biol 1966, 11:10–21. 4. Meuckler M: Facilitative glucose transporters. Euro J Biochem 1994, 219:713–725. 5. Morris JR, Ives HE: Inherited disorders of the renal tubule. In The Kidney. Edited by Brenner B, Rector F. Philadelphia: WB Saunders, 1996:1764–1827. 6. Kanai Y, Hediger M: Primary structure and functional characterization of a high affinity glutamate transporter. Nature 1992, 360:467–471.

7. Oynagi K, Sogawa H, Minawi R,et al.: The mechanism of hyperammonemia in congenital lysinuria. J Pediatr 1979, 94:255. 8. Smith A, Strang L: An inborn error of metabolism with the urinary excretion of -hydroxybutric acid and phenyl-pyruvic acid. Arch Dis Child 1958, 33:109. 9. Rosenberg LE, Downing S, Durant JL, Segal S: Cystinuria: biochemical evidence for three genetically distinct diseases. J Clin Invest 1966, 45:365–371. 10. Pras E, Arber N, Aksentijevich I, et al.: Localization of a gene causing cystinuria to chromosome 2p. Nature Genet 1994, 6:415–419. 11. Calonge MJ, Gasparini P, Chillaron J, et al.: Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nature Genet 1994, 6:420–425. 12. Calonge M, Volpini V, Bisceglia L, et al.: Genetic heterogeneity in cystinuria: the SLC3A1 gene is linked to type I but not to type III cystinuria. Proc Am Acad Sci USA 1995, 92:9667–9671.

12.16

Tubulointerstitial Disease

13. Wartenfeld R, Golomb E, Katz G, Bale S, et al.: Molecular analysis of cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping a new locus on 19q. Am J Med Genet 1997, 60:617–624.

30. White P, Mune T, Rogerson F, et al.: 11--hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess. Pediatr Res 1997, 41:25–29.

14. Stephens AD: Cystinuria and its treatment: 25 years’ experience at St. Bartholomew’s Hospital. J Inherited Metab Dis 1989, 12:197–209.

31. Yiu V, Dluhy R, Lifton R, Guay-Woodford L: Low peripheral plasma renin activity as a critical marker in pediatric hypertension. Pediatr Nephrol 1997, 11:343–346.

15. Perazella M, Buller G: Successful treatment of cystinuria with captopril. Am J Kidney Dis 1993, 21:504–507. 16. Grieff M: New insights into X-linked hypophosphatemia. Curr Opin Nephrol Hypertens 1997, 6:15–19. 17. Robertson GL: Vasopressin in osmotic regulation in man. Annu Rev Med 1974, 25:315. 18. Econs M, Drezner M: Tumor-induced osteomalacia: unveiling a new hormone. N Engl J Med 1994, 330:1679–1681. 19. The HYP Consortium: A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nature Genet 1995, 11:130–136. 20. Bergeron M, Gougoux A, Vinay P: The renal Fanconi syndrome. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill, 1995:3691–3704. 21. Sly W, Hu P: The carbonic anhydrase II deficiency syndrome: osteopetrosis with renal tubular acidosis and cerebral calcification. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1965:3581–3602. 22. Bastani B, Gluck S: New insights into the pathogenesis of distal renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396–409.

32. Chang S, Grunder S, Hanukoglu A, et al.: Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalemic acidosis, pseudohypoaldosteronism type 1. Nature Genet 1996, 12:248–253. 33. Kuhle U: Pseudohypoaldosteronism: mutation found, problem solved? Mol Cell Endocrinol 1997, 133:77–80. 34. Gordon R: Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension 1986, 8:93–102. 35. Mansfield T, Simon D, Farfel Z, et al.: Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q2. Nature Genet 1997, 16:202–205. 36. Robertson GL, et al: Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest 1973, 52:2340–2352. 37. Bichet D, Osche A, Rosenthal W: Congenital nephrogenic diabetes insipidus. JASN 1997, 12:1951–1958. 38. van Lieburg A, Verdijk M, Knoers N, et al.: Patients with autosomal recessive nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water channel gene. Am J Hum Genet 1994, 55:648–652.

23. Bruce L, Cope D, Jones G, et al.: Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (band 3, AE1) gene. J Clin Invest 1997, 100:1693–1707. 24. Jarolim P, Shayakul C, Prabakaran D, et al.: Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl-/HCO-3 exchanger. J Biol Chem, 1998, 273:6380–6388. 25. Guay-Woodford L: Bartter syndrome: unraveling the pathophysiologic enigma. Am J Med, 1998, 105:151–161. 26. Spiegel A, Weinstein L: Pseudohypoparathyroidism. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:3073–3085.

39. Bichet D, Arthus M-F, Lonergan M, et al.: Autosomal dominant and autosomal recessive nephrogenic diabetes insipidus: novel mutations in the AQP2 gene. J Am Soc Nephrol 1995, 6:717A.

27. Van Dop C: Pseudohypoparathyroidism: clinical and molecular aspects. Semin Nephrol 1989, 9:168–178.

44. Cameron J, Moro F, Simmonds H: Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol 1993, 7:105–118.

28. Lifton RP, Dluhy RG, Powers M., et al.: A chimaeric 11--hydroxylase aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992, 355:262–265.

45. Danpure C, Purdue P: Primary Hyperoxaluria. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:2385–2424.

29. Shimkets RA, Warnock DG, Bositis CM, et al.: Liddle’s syndrome: heritable human hypertension caused by mutations in the  subunit of the epithelial sodium channel. Cell 1994, 79:407–414.

40. Coe F, Parks J, Asplin J: The pathogenesis and treatment of kidney stones. N Engl J Med 1992, 327:1141–1152. 41. Segal S, Thier S: Cystinuria. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. York: McGraw-Hill; 1995:3581–3602. 42. Polinsky MS, Kaiser BA, Baluarte HJ: Urolithiasis in childhood. Pediatr Clin North Am 1987, 34:683–710. 43. Lloyd S, Pearce S, Fisher S, et al.: A common molecular basis for three inherited kidney stone diseases. Nature 1996, 379:445–449.

The Kidney in Blood Pressure Regulation L. Gabriel Navar L. Lee Hamm

D

espite extensive animal and clinical experimentation, the mechanisms responsible for the normal regulation of arterial pressure and development of essential or primary hypertension remain unclear. One basic concept was championed by Guyton and other authors [1–4]: the long-term regulation of arterial pressure is intimately linked to the ability of the kidneys to excrete sufficient sodium chloride to maintain normal sodium balance, extracellular fluid volume, and blood volume at normotensive arterial pressures. Therefore, it is not surprising that renal disease is the most common cause of secondary hypertension. Furthermore, derangements in renal function from subtle to overt are probably involved in the pathogenesis of most if not all cases of essential hypertension [5]. Evidence of generalized microvascular disease may be causative of both hypertension and progressive renal insufficiency [5,6]. The interactions are complex because the kidneys are a major target for the detrimental consequences of uncontrolled hypertension. When hypertension is left untreated, positive feedback interactions may occur that lead progressively to greater hypertension and additional renal injury. These interactions culminate in malignant hypertension, stroke, other sequelae, and death [7]. In normal persons, an increased intake of sodium chloride leads to appropriate adjustments in the activity of various humoral, neural, and paracrine mechanisms. These mechanisms alter systemic and renal hemodynamics and increase sodium excretion without increasing arterial pressure [3,8]. Regardless of the initiating factor, decreases in sodium excretory capability in the face of normal or increased sodium intake lead to chronic increases in extracellular fluid volume and blood volume. These increases can result in hypertension. When the derangements also include increased levels of humoral or neural factors that directly cause vascular smooth muscle constriction, these effects increase peripheral vascular resistance or decrease vascular capacitance. Under these conditions the effects of subtle increases in blood volume are compounded because of increases in the blood volume relative to

CHAPTER

1

1.2

Hypertension and the Kidney

Aortic pressure, mm Hg

160

Isolated systolic hypertension (61 y)

120

Aortic blood flow, mL/s

80

A

400 0

Normotensive (56 y)

Arterial pressure, mm Hg

the capacitance, often referred to as the effective blood volume. Through the mechanism of pressure natriuresis, however, the increases in arterial pressure increase renal sodium excretion, allowing restoration of sodium balance but at the expense of persistent elevations in arterial pressure [9]. In support of this overall concept, various studies have demonstrated strong relationships between kidney disease and the incidence of hypertension. In addition, transplantation studies have shown that normotensive recipients from genetically hypertensive donors have a higher likelihood of developing hypertension after transplantation [10]. This unifying concept has helped delineate the cardinal role of the kidneys in the normal regulation of arterial pressure as well as in the pathophysiology of hypertension. Many different

B

200 180 160 140 120 100 80 60 40 20

extrinsic influences and intrarenal derangements can lead to reduced sodium excretory capability. Many factors also exist that alter cardiac output, total peripheral resistance, and cardiovascular capacitance. Accordingly, hypertension is a multifactorial dysfunctional process that can be caused by a myriad of different conditions. These conditions range from stimulatory influences that inappropriately enhance tubular sodium reabsorption to overt renal pathology, involving severe reductions in filtering capacity by the renal glomeruli and associated marked reductions in sodium excretory capability. An understanding of the normal mechanisms regulating sodium balance and how derangements lead to altered sodium homeostasis and hypertension provides the basis for a rational approach to the treatment of hypertension.

C

A

B

PP = 72 mm Hg PP = 40 mm Hg PP = 30 mm Hg

500

600 700 800 900 Arterial volume, mL

FIGURE 1-1 Aortic distensibility. The cyclical pumping nature of the heart places a heavy demand on the distensible characteristics of the aortic tree. A, During systole, the aortic tree is rapidly filled in a fraction of a second, distending it and increasing the hydraulic pressure. B, The distensibility characteristics of the arterial tree determine the pulse pressure (PP) in response to a specific stroke volume. The normal relationship is shown in curve A, and arrows designate the PP. A highly distensible arterial tree, as depicted in curve B, can accommodate the stroke volume with a smaller PP. Pathophysiologic processes and aging lead to decreases in aortic distensibility. These decreases lead to marked increases in PP and overall mean arterial pressure for any given arterial volume, as shown in curve C. Decreased distensibility is partly responsible for the isolated systolic hypertension often found in elderly persons. Recordings of actual aortic pressure and flow profiles in persons with normotension and systolic hypertension are shown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A from Nichols et al. [12].)

HEMODYNAMIC DETERMINANTS For any vascular bed: Arterial pressure gradient Blood flow = Vascular resistance For total circulation averaged over time: Blood flow = cardiac output Therefore, Arterial pressure - right atrial pressure Cardiac output = Total peripheral resistance and: Mean arterial pressure = Cardiac output  total peripheral resistance

FIGURE 1-2 Hemodynamic determinants of arterial pressure. During the diastolic phase of the cardiac cycle, the elastic recoil characteristics of the arterial tree provide the kinetic energy that allows a continuous delivery of blood flow to the tissues. Blood flow is dependent on the arterial pressure gradient and total peripheral resistance. Under normal conditions the right atrial pressure is near zero, and thus the arterial pressure is the pressure gradient. These relationships apply for any instant in time and to timeintegrated averages when the mean pressure is used. The time-integrated average blood flow is the cardiac output that is normally 5 to 6 L/min for an adult of average weight (70 to 75 kg).

1.3

The Kidney in Blood Pressure Regulation

Dietary Insensible losses Urinary intake (skin, respiration, fecal) excretion

+

–

–

Arterial baroreflexes Atrial reflexes Renin-angiotensin-aldosterone Adrenal catecholamines Vasopressin Natriuretic peptides Endothelial factors: nitric oxide, endothelin kallikrein-kinin system Prostaglandins and other eicosanoids

Net sodium and fluid balance

ECF volume Arterial pressure Blood volume

Mean circulatory pressure

(Autoregulation)

Neurohumoral systems

Total peripheral resistance

Interstitial fluid volume

Venous return

Heart rate and contractility

Cardiac output

FIGURE 1-3 Volume determinants of arterial pressure. The two major determinants of arterial pressure, cardiac output and total peripheral resistance, are regulated by a combination of short- and long-term mechanisms. Rapidly adjusting mechanisms regulate peripheral vascular resistance, cardiovascular capacitance, and cardiac performance. These mechanisms include the neural and humoral mechanisms listed. On a long-term basis, cardiac output is determined by venous return, which is regulated primarily by the mean circulatory pressure. The mean circulatory pressure depends on blood volume and overall cardiovascular capacitance. Blood volume is closely linked to extracellular fluid (ECF) volume and sodium balance, which are dependent on the integration of net intake and net losses [13]. (Adapted from Navar [3].)

Cardiovascular capacitance

If increased

Concentrated urine: Increased free water reabsorption

6

Thirst: Increased water intake

5

+

Na+ and Cl– Quantity of Extracellular concentrations ÷ = NaCl in ECF fluid volume in ECF volume

–

If decreased NaCl losses (urine insensible)

A

Blood volume, L

Antidiuretic hormone release

NaCl intake

Decreased water intake Increased salt intake

FIGURE 1-4 A, Relationship between net sodium balance and extracellular fluid (ECF) volume. Sodium balance is intimately linked to volume balance because of powerful mechanisms that tightly regulate plasma and ECF osmolality. Sodium and its accompanying anions constitute the major contributors to ECF osmolality. The integration of sodium intake and losses establishes the net amount of sodium in the body, which is compartmentalized primarily in the ECF volume. The quotient of these two parameters (sodium and volume) determines the sodium concentration and, thus, the osmolality. Osmolality is subject to very tight regulation by vasopressin and other mechanisms. In particular, vasopressin is a very powerful regulator of plasma osmolality; however, it achieves this regulation primarily by regulating the relative solute-free water retention or excretion by the kidney [13–15]. The important point is that the osmolality is rapidly regulated by adjusting the ECF volume to the total solute present. Corrections of excesses in extracellular fluid volume involve more complex interactions that regulate the sodium excretion rate.

4 3 2

Antidiuretic hormone inhibition Dilute urine: Increased solute-free water excretion

Edema

0 10

B

15 Extracellular fluid volume, L

20

B, Relationship between the ECF volume and blood volume. Under normal conditions a consistent relationship exists between the total ECF volume and blood volume. This relationship is consistent as long as the plasma protein concentration and, thus, the colloid osmotic pressure are regulated appropriately and the microvasculature maintains its integrity in limiting protein leak into the interstitial compartment. The shaded area represents the normal operating range [13]. A chronic increase in the total quantity of sodium chloride in the body leads to a chronic increase in ECF volume, part of which is proportionately distributed to the blood volume compartment. When accumulation is excessive, disproportionate distribution to the interstitium may lead to edema. Chronic increases in blood volume increase mean circulatory pressure (see Fig. 1-3) and lead to an increase in arterial pressure. Therefore, the mechanisms regulating sodium balance are primarily responsible for the chronic regulation of arterial pressure. (Panel B adapted from Guyton and Hall [13].)

1.4

Hypertension and the Kidney

Intrarenal Mechanisms Regulating Sodium Balance Sodium excretion, normal

6 High sodium intake Normal sodium intake Low sodium intake

5

B

A

4 3

2

Elevated sodium intake

4

2 1

C

5 1

Normal sodium intake Reduced

3

0 60

80

100 120 140 160 Renal arterial pressure, mm Hg

180

200

Filtered sodium load, µmol/min/g

FIGURE 1-5 Arterial pressure and sodium excretion. In principle, sodium balance can be regulated by altering sodium intake or excretion by the kidney. However, intake is dependent on dietary preferences and usually is excessive because of the abundant salt content of most foods. Therefore, regulation of sodium balance is achieved primarily by altering urinary sodium excretion. It is therefore of major significance that, for any given set of conditions and neurohumoral environment, acute elevations in arterial pressure produce natriuresis, whereas

150 100 50

Low Normal High

0

Fractional sodium reabsorption, %

100 98 96 94 92

Fractional sodium excretion, %

8 6 4 2 0 75 100 125 150 175 Renal arterial pressure, mm Hg

reductions in arterial pressure cause antinatriuresis [9]. This phenomenon of pressure natriuresis serves a critical role linking arterial pressure to sodium balance. Representative relationships between arterial pressure and sodium excretion under conditions of normal, high, and low sodium intake are shown. When renal function is normal and responsive to sodium regulatory mechanisms, steady state sodium excretion rates are adjusted to match the intakes. These adjustments occur with minimal alterations in arterial pressure, as exemplified by going from point 1 on curve A to point 2 on curve B. Similarly, reductions in sodium intake stimulate sodiumretaining mechanisms that prevent serious losses, as exemplified by point 3 on curve C. When the regulatory mechanisms are operating appropriately, the kidneys have a large capability to rapidly adjust the slope of the pressure natriuresis relationship. In doing so, the kidneys readily handle sodium challenges with minimal long-term changes in extracellular fluid (ECF) volume or arterial pressure. In contrast, when the kidney cannot readjust its pressure natriuresis curve or when it inadequately resets the relationship, the results are sodium retention, expansion of ECF volume, and increased arterial pressure. Failure to appropriately reset the pressure natriuresis is illustrated by point 4 on curve A and point 5 on curve C. When this occurs the increased arterial pressure directly influences sodium excretion, allowing balance between intake and excretion to be reestablished but at higher arterial pressures. (Adapted from Navar [3].)

FIGURE 1-6 Intrarenal responses to changes in arterial pressure at different levels of sodium intake. The renal autoregulation mechanism maintains the glomerular filtration rate (GFR) during changes in arterial pressure, GFR, and filtered sodium load. These values do not change significantly during changes in arterial pressure or sodium intake [3,16]. Therefore, the changes in sodium excretion in response to arterial pressure alterations are due primarily to changes in tubular fractional reabsorption. Normal fractional sodium reabsorption is very high, ranging from 98% to 99%; however, it is reduced by increased sodium chloride intake to effect the large increases in the sodium excretion rate. These responses demonstrate the importance of tubular reabsorptive mechanisms in modulating the slope of the pressure natriuresis relationship. (Adapted from Navar and Majid [9].)

The Kidney in Blood Pressure Regulation

RA

πB140/90 mm Hg) is common and almost universally observed in patients with acute glomerulonephritis (GN). Many of these patients have lower pressures as the course of acute renal injury subsides, although residual abnormalities in renal function and sediment may remain. Blood pressure returns to normal in some but not all of these patients. Overall, 39% of patients with acute renal failure develop new hypertension. IN—interstitial nephritis. (Adapted from RodriguezIturbe and coworkers [3]; with permission.)

20 10 0 Acute GN

Acute IN

FIGURE 2-6 (see Color Plate) Micrograph of an onion skin lesion from a patient with malignant hypertension.

2.4

Hypertension and the Kidney

Pathophysiology of Hypertension in Renal Disease

Increased vasoconstriction Increased adrenergic stimuli Inappropriate renin-endothelin release Increased endothelin-derived contracting factor Increased thromboxane

Decreased vasodilation Decreased prostacyclin Decreased nitric oxide

7

6

6

Intake and output of water and salt (x normal)

7

5 4

D

High intake

E s se n hyp tial erte nsio n

3 2 Normal intake

1

Low intake

0 0

50

A

B

4 3

High intake

F

ass lm na e r of ss D Lo C

E

2 Normal intake

1

Low intake

C

100 150 Arterial pressure, mm Hg

5

kid G o ld ne blat t ys

Systemic vascular resistance

Al do ste ron e-s tim ula ted

Increased contraction Increased adrenergic activation

Normal

Intake and output of water and salt (x normal)

Increased extracellular fluid volume Decreased glomerular filtration rate Impaired sodium excretion Increased renal nerve activity Ineffective natriuresis, eg, atrial natriuretic peptide resistance

A

x

Cardiac output

Normal

Blood pressure =

FIGURE 2-7 Pathophysiologic mechanisms related to hypertension in parenchymal renal disease: schematic view of candidate mechanisms. The balance between cardiac output and systemic vascular resistance determines blood pressure. Numerous studies suggest that cardiac output is normal or elevated, whereas overall extracellular fluid volume is expanded in most patients with chronic renal failure. Systemic vascular resistance is inappropriately elevated relative to cardiac output, reflecting a net shift in vascular control toward vasoconstricting mechanisms. Several mechanisms affecting vascular tone are disturbed in patients with chronic renal failure, including increased adrenergic tone and activation of the reninangiotensin system, endothelin, and vasoactive prostaglandins. An additional feature in some disorders appears to depend on reduced vasodilation, such as in impaired production of nitric oxide.

A

B H

G

0 200

FIGURE 2-8 A, The relationship between renal artery perfusion pressure and sodium excretion (which defines “pressure natriuresis”) has been the subject of extensive research. Essential hypertension is characterized by higher renal perfusion pressures required to achieve daily sodium balance. B, Distortion of this relationship routinely occurs in patients with parenchymal renal disease, illustrated here

0

B

50

100 150 Arterial pressure, mm Hg

200

as “loss of renal mass.” Similar effects are observed in conditions with disturbed hormonal effects on sodium excretion (aldosterone-stimulated kidneys) or reduced renal blood flow as a result of an arterial stenosis (“Goldblatt” kidneys). In all of these instances, higher arterial pressures are required to maintain sodium balance.

2.5

Renal Parenchymal Disease and Hypertension

35

30

122

118

Cumulative daily sodium intake

0 Cumulative urinary sodium loss

–400 Sodium, mEq

Percentage of body weight, kg

126

40

Total blood volume, mL/cm

200 Hemodialysis

130

–800

–1200 F

S

S

M

T

W TH Days

F

S

S

Sodium losses during hemodialysis or ultrafiltration Net sodium loss

M –1600

Total net loss of sodium=1741 mEq

A

Blood pressure, mm Hg

Plasma renin activity, mg/mL/h

10.0 Uremic control subjects

5.0

F

B

180 Captopril, 25 mg

140

100

FIGURE 2-9 Sodium expansion in chronic renal failure. The degree of sodium expansion in patients with chronic renal failure can be difficult to ascertain. A, Shown are data regarding body weight, plasma renin

Blood pressure, mm Hg

Angiotensin II inhibitor, µg/kg/min 5 10 50 100 10 10 Saline infusion L40

200

150

Plasma renin Cumulative sodium balance, mEq activity, ng/mL/hr

100 200

100 0 100 50 0 0

1

11 35 38 41 Hours

65 67

S

S

M T

W TH F Days

S

S M

T

activity, and blood pressure (before and after administration of an ACE inhibitor) over 11 days of vigorous fluid ultrafiltration. Sequential steps were undertaken to achieve net negative sodium and volume losses by means of restricting sodium intake (10 mEq/d) and initiating ultrafiltration to achieve several liters of negative balance with each treatment. A negative balance of nearly 1700 mEq was required before evidence of achieving dry weight was observed, specifically a reduction of blood pressure. Measured levels of plasma renin activity gradually increased during sodium removal, and blood pressure became dependent on the renin-angiotensin system, as defined by a reduction in blood pressure after administration of the angiotensin-converting enzyme inhibitor captopril. Achieving adequate reduction of both extracellular fluid volume and sodium is essential to satisfactory control of blood pressure in patients with renal failure. B, Daily and cumulative sodium balance.

FIGURE 2-10 Interaction between sodium balance and angiotensin-dependence in malignant hypertension. Studies in a patient with renal dysfunction and accelerated hypertension during blockade of the renin-angiotensin system using Sar-1-ala-8-angiotensin II demonstrate the interaction between angiotensin and sodium. Reduction of blood pressure induced by the angiotensin II antagonist was reversed during saline infusion with a positive sodium balance and reduction in circulating plasma renin activity. Administration of a loop diuretic (L40 [furosemide], 40 mg intravenously) induced net sodium losses, restimulated plasma renin activity, and restored sensitivity to the angiotensin II antagonist. Such observations further establish the reciprocal relationship between the sodium status and activation of the renin-angiotensin system [5]. (From Brunner and coworkers [5]; with permission.)

2.6

Hypertension and the Kidney

15 s

Normal person

Hemodialysis, bilateral nephrectomy

Hemodialysis, no nephrectomy

Neurogram

Electrocardiogram 3s

A

Systolic blood pressure, mm Hg

200

Sham Renal denervated

190 180 170 160 150 140 130 120 110

NS

0

B

NS

1 degree, after coronary artery bypass graft surgery Nitroprusside equally efficacious in catecholaminerelated crises

Delayed onset Nasal congestion, None—not CNS sedation, recommended for of action, unpredictable bradycardia, use in hypertenhypotensive effect exacerbates pepsive crises tic ulcer disease, depression

Contraindicated in hypertensive encephalopathy, CNS catastrophe, cumulative hypotensive response

Contraindicated in hypertensive encephalopathy, CNS catastrophe

aortic dissection, atherosclerotic coronary vascular disease

Tachycardia, arrhythmias, nausea, vomiting, diarrhea, exacerbation of peptic ulcer disease Headache, angina Contraindicated in Delayed onset IV bolus: 5–10 mg over Proven efficacy of action, 20–30 min or continuand safety in ous infusion 400 µg/mL hypertensive crises unpredictable hypotensive effect solution Loading dose: of pregnancy 200–300 µg/min for 30–60 min Maintenance infusion: 50–150 µg/min Delayed onset Sedation IV of 250–500 mg None—not over 6–8 h recommended for of action, unpredictable use in hypertenhypotensive effect sive crises

IV bolus: 1–5 mg over 5 min

Fails to control BP Headache, nausea, Theoretic advanin some patients vomiting, tages over nitropalpitations, prusside in setting abdominal pain of myocardial ischemia -blockage can Nausea, vomiting, IV minibolus: Initial, 20 Continuous worsen congestive paresthesias, mg over 2 min Then monitoring not heart failure, headache, 40–80 mg over 10 min. required bronchospasm, bradycardia Maximum, 300 mg heart block

1–5 min after infusion Continuous infusion: stopped Initially, 5 µg/min Increase by 5 µg/min over 3–5 min

insufficiency and glaucoma; potentiates succinylcholine Dilates intracoronary collaterals

Comments

Discontinue if 2–3 min after infusion Continuous infusion: Precise titration of Monitoring in ICU Nausea, vomiting, required apprehension. stopped Initial, 0.5 µg/kg/min BP. Consistently thiocyanate level Thiocyanate toxic- >10 mg/dL Average, 3 µg/kg/min effective when ity with prolonged Maximum, 10 µg/kg/min other drugs fail. infusion, renal Parenteral agent insufficiency of choice for hypertensive crises Sustained Nausea, vomiting, Contraindicated in 4–24 h IV minibolus: 50–100 mg Long duration of hypotension with hyperglycemia, IV given rapidly over action. Constant aortic dissection, CNS and myocarmyocardial 5–10 min. Total dose, monitoring not cerebrovascular ischemia, uterine 150–600 mg required after ini- dial ischemic can disease, myocardial occur. Reflex sym- atony tial titration ischemia pathetic cardiac stimulation Dry mouth, blurred Tilt-bed enhances 5–10 min after infuContinuous infusion: Blocks barorecep- Parasympathetic blockade vision, urinary sion stopped Initial, 0.5 mg/min tor-mediated effect; tachyphylaxis retention, paralyt- after 24–48 h; Maximum, 5.0 mg/min sympathetic ic ileus, respiratocardiac stimulation contraindicated ry arrest in respiratory

Method of Duration of action administration

BP—blood pressure; CNS—central nervous system; CO—cardiac output; ICU—intensive care unit; IV—intravenous; SVR—systemic vascular resistance.

Reserpine

10–30 min

2–3 min

Minutes

Minutes Ganglionic blockage with venodilation and arteriolar vasodilation

Trimethaphan camsylate

Labetalol

10–15 min

1–2 min

Direct arteriolar vasodilation

Diazoxide

Minutes

Immediate

Onset of action Peak effect Instantaneous

Mechanism of action

Sodium Direct arteriolar nitroprusside vasodilation and venodilation

Drug

VARIOUS ANTIHYPERTENSIVE DRUGS FOR PARENTERAL USE IN THE MANAGEMENT OF MALIGNANT HYPERTENSION AND OTHER HYPERTENSIVE CRISES

Hypertensive Crises

8.27

8.28

Hypertension and the Kidney

Mean arterial pressure, mm Hg

200

Uncontrolled hypertensives (n=13) Controlled hypertensives (n=9) Normotensives (n=10)

150

100 79 72 ± 74 10% ± 29% ± 12%

50

0 Baseline mean arterial pressure

Lower limit of autoregulation

45 ± 6%

46 45 ± ± 16% 12%

Lowest tolerated mean arterial pressure

FIGURE 8-35 Risks of rapid blood pressure reduction in hypertensive crises. It has been argued over the years that rapid reduction of blood pressure in the setting of hypertensive crises may have a detrimental effect on cerebral perfusion because the autoregulatory curve of cerebral blood flow is shifted upward in patients with chronic hypertension. Conversely, this upward shift protects the brain from hypertensive encephalopathy in the face of severe hypertension. However, this autoregulatory shift could be deleterious when the blood pressure is reduced acutely because the lower limit of autoregulation is shifted to a higher level of blood pressure. Theoretically, aggressive reduction of the blood pressure in chronically hypertensive patients could induce cerebral ischemia. Nonetheless, in clinical practice, moderately controlled reduction of blood pressure in patients with hypertensive crises rarely causes cerebral ischemia. This clinical observation may be explained by the fact that even though the cerebral autoregulatory curve is shifted in patients with chronic hypertension, a considerable difference still exists between the initial blood pressure at presentation and the lower limit of autoregulation. Illustrated are the differences in the lower autoregulatory threshold during blood pressure reduction with trimethaphan in patients with uncontrolled hypertension and treated hypertension, and those in the control group [53]. At least eight of the 13 patients with uncontrolled hypertension had hypertensive neuroretinopathy consistent with malignant hypertension. The control groups included nine patients with a history of severe hypertension in the past whose blood pressure was effectively controlled at the time of study and a group of 10 normotensive persons. Baseline mean arterial pressures (MAPs) in the three groups were 145 ±17 mm Hg, 116 ±18 mm Hg, and 96 ±17 mm Hg, respectively. The lower limit of blood pressure at which autoregulation failed was 113 ±17 mm Hg in persons with uncontrolled hypertension, 96 ±17mm Hg in persons with treated hypertension, and 73 ±9 mm Hg in normotensive persons. Although the absolute level at which autoregulation failed was substantially higher in patients with uncontrolled hypertension, the percentage reduction in blood pressure from the baseline level required to reach the autoregulatory threshold was similar in each group. The numbers on the bars indicate the percentage reduction from the baseline

blood pressure required to reach the autoregulatory limit. Thus, a reduction in MAP of approximately 20% to 25% was required in each group to reach the threshold. This result indicates that a considerable safety margin exists for blood pressure reduction before cerebral autoregulation of blood flow fails, even in patients with severe untreated hypertension. Moreover, symptoms of cerebral ischemia did not develop until the blood pressure was reduced substantially below the autoregulatory threshold because even in the face of reduced blood flow, cerebral metabolism can be maintained and ischemia prevented by an increase in oxygen extraction by the tissues. The lowest tolerated MAP, defined as the level at which mild symptoms of brain hypoperfusion developed (ie, yawning, nausea, and hyperventilation), was 65 ±10 mm Hg in patients with uncontrolled hypertension, 53 ±18 mm Hg in persons with treated hypertension, and 43 ±8 mm Hg in normotensive persons. The numbers on the bars illustrate that these MAP values were approximately 45% of the baseline blood pressure level in each group. Thus, symptoms of cerebral hypoperfusion did not occur until the MAP was reduced by an average of 55% from the presenting level. In the reported cases of neurologic sequelae sustained during rapid reduction of blood pressure in patients with hypertensive crises, the MAP was reduced by more than 55% of the presenting blood pressure. This frank hypotension was sustained for a period of hours to days, mostly as a result of treatment with bolus diazoxide, which has long duration of action [54]. The general guideline for acute blood pressure reduction in the treatment of hypertensive crises is reduction of systolic blood pressure to 160 to 170 mm Hg and diastolic pressure to 100 to 110 mm Hg, which equates to MAPs of 120 to 130 mm Hg. Alternatively, the initial goal of antihypertensive therapy can be a 20% reduction of the MAP from the patient’s initial level at presentation. This level should be above the predicted autoregulatory threshold. Once this goal is obtained the patient should be evaluated carefully for evidence of cerebral hypoperfusion. Further reduction of blood pressure can then be undertaken in a controlled fashion based on the overall clinical status of the patient. Of course, in previously normotensive persons in whom hypertensive crises develop, such as patients with acute glomerulonephritis complicated by hypertensive encephalopathy, the autoregulatory curve should not yet be shifted. Therefore, the initial goal of therapy should be normalization of blood pressure. In terms of avoiding sustained overshoot hypotension in the treatment of hypertensive crises, the use of potent parenteral agents with short duration of action, such as sodium nitroprusside or intravenous nitroglycerin, has obvious advantages. If neurologic sequelae develop during blood pressure reduction with these agents, these sequelae can be reversed quickly by tapering the infusion and allowing the blood pressure to stabilize at a higher level. Agents with a long duration of action have an inherent disadvantage in that excessive reduction of blood pressure cannot be reversed easily. Thus, bolus diazoxide, labetalol, minoxidil, hydralazine, converting enzyme inhibitors, calcium channel blockers, and central 2-agonists should be used with extreme caution in patients requiring rapid but controlled blood pressure reduction in the setting of hypertensive crises. (Adapted from Strandgaard [53]; with permission.)

Hypertensive Crises

Severe uncomplicated hypertension Severe hypertension (diastolic blood pressure > 115 mm Hg)

Hypertensive neuroretinopathy present (striate hemorrhages, cotton-wool spots with or without papilledema) Treat malignant hypertension (Fig. 8-20)

Hypertensive neuroretinopathy absent

No acute end-organ dysfunction

Acute end-organ dysfunction Treat as hypertensive crisis (see preceding figures)

Severe uncomplicated hypertension Step 1 Patient education regarding the chronic nature of hypertension and importance of long-term compliance and blood pressure control to prevent complications

Step 2

Step 3

Evaluate reason for inadequate blood pressure control and adjust maintenance antihypertensive drug regimen

Noncompliant

Arrange outpatient follow-up to document adequate blood pressure control over the ensuing days to weeks and change drug treatment regimen as required

Compliant with current blood pressure regimen

"Ran out" of medications

Drug side effects

Cannot afford drugs

Restart

Switch to drug of another class

Switch to generic thiazide diuretic

Add low-dose thiazide diuretic to existing monotherapy with CCB, CEI, β-blocker, α2-agonist

FIGURE 8-36 Severe uncomplicated hypertension. The benefits of acute reduction in blood pressure in the setting of true hypertensive crises are obvious. Fortunately, true hypertensive crises are relatively rare events that almost never affect hypertensive patients. Another type of presentation that is much more common than are true hypertensive crises is that of the patient who initially exhibits severe hypertension (diastolic blood pressure >115 mm Hg) in the absence of hypertensive neuroretinopathy or acute end-organ damage that would signify a true crisis. This entity, known as severe uncomplicated hypertension, is very commonly seen in the emergency department or other acute-care settings. Of patients with severe uncomplicated hypertension, 60% are entirely asymptomatic and present for prescription refills or routine blood pressure checks, or are found to have elevated pressure during routine physical examinations. The other 40% of patients initially exhibit nonspecific findings such as headache, dizziness, or weakness in the absence of evidence of acute end-organ dysfunction. In the past, this entity was referred to as urgent hypertension, reflecting the erroneous notion that acute reduction of blood pressure, over a few hours before discharge from the acute-care facility, was essential to minimize the risk of short-term complications from severe hypertension. Commonly employed treatment regimens included oral clonidine loading or sublingual nifedipine. However, in recent years the practice of acute blood pressure reduction in severe uncomplicated hypertension has been questioned [55,56]. In the Veterans Administration Cooperative Study of patients with severe hypertension, there were 70 placebo-treated patients who had an average diastolic blood pressure of 121 mm Hg at entry. Among these untreated patients, 27 experienced morbid events at a mean of 11 ± 8 months of follow-up. However, the earliest morbid event occurred only after 2 months [57]. These data suggest that in patients with severe uncomplicated hypertension in which severe hypertension is not accompanied by evidence of malignant hypertension or acute end-organ dysfunction, eventual complications from stroke, myocardial infarction, or congestive

8.29

heart failure tend to occur over months to years, rather than hours to days. Although long-term control of blood pressure clearly can prevent these eventual complications, a hypertensive crisis cannot be diagnosed because no evidence exists that acute reduction of blood pressure results in an improvement in short- or long-term prognosis. Acute reduction of blood pressure in patients with severe uncomplicated hypertension with sublingual nifedipine or oral clonidine loading was once the de facto standard of care. This practice, however, often was an emotional response on the part of the treating physician to the dramatic elevation of blood pressure or motivated by the fear of medico-legal repercussions in the unlikely event of a hypertensive complication occurring within hours to days [55]. Although observing and documenting the dramatic decrease in blood pressure is a satisfying therapeutic maneuver, there is no scientific basis for this approach. At present, no literature exists to support the notion that some goal level of blood pressure reduction must be achieved before the patient with severe uncomplicated hypertension leaves the acute-care setting [58]. In fact, acute reduction of blood pressure often is counterproductive because it can produce untoward side effects that render the patient less likely to comply with long-term drug therapy. Instead, the therapeutic intervention should focus on tailoring an effective welltolerated maintenance antihypertensive regimen with patient education regarding the chronic nature of the disease process and the importance of long-term compliance and medical follow-up. If the patient has simply run out of medicines, reinstitution of the previously effective drug regimen should suffice. If the patient is thought to be compliant with an existing drug regimen, a sensible change in the regimen is appropriate, such as an increase in a suboptimal dosage of an existing drug or the addition of a drug of another class. In this regard, addition of a low dose of a thiazide diuretic as a second-step agent to existing monotherapy with converting enzyme inhibitor (CEI), angiotensin II receptor blocker, calcium channel blocker (CCB), -blocker, or central 2-agonist often is remarkably effective. Another essential goal of the acute intervention should be to arrange suitable outpatient follow-up within a few days. Gradual reduction of blood pressure to normotensive levels over the next few days to a week should be accomplished in conjunction with frequent outpatient visits to modify the drug regimen and reinforce the importance of lifelong compliance with therapy. Although less dramatic than acute reduction of blood pressure in the acute-care setting, this type of approach to the treatment of chronic hypertension is more likely to prevent long-term hypertensive complications and recurrent episodes of severe uncomplicated hypertension.

8.30

Hypertension and the Kidney

References 1. Nolan CR, Linas SL: Malignant hypertension and other hypertensive crises. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:1475–1554. 2. Derow HA, et al.: The nature of malignant hypertension. Ann Intern Med 1941, 14:1768. 3. Perez-Fontan M, et al.: Idiopathic IgA nephropathy presenting as malignant hypertension. Am J Nephrol 1986, 6:482. 4. Holland NH, et al.: Hypertension in children with chronic pyelonephritis. Kidney Int 1975, 8(suppl):S234. 5. Nanra RS, et al.: Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia. Kidney Int 1978, 13:79. 6. Davis BA, et al.: Prevalence of renovascular hypertension in patients with grade III or grade IV hypertensive neuroretinopathy. N Engl J Med 1979, 301:1273. 7. Lim K, et al.: Malignant hypertension in women of childbearing age and its relation to the contraceptive pill. Br Med J 1987, 294:1057. 8. Traub YM, et al.: Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Medicine 1983, 62:335. 9. Cacoub P, et al.: Malignant hypertension with antiphospholipid syndrome without overt lupus nephritis. Clin Exp Rheumatol 1993, 11:479–485. 10. McAllister RG, et al.: Malignant hypertension: effect of therapy on renin and aldosterone. Circ Res 1971, 28(suppl II):II–160. 11. Keith NM, Wagener HP, Barker NW: Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1939, 197:332. 12. Kirkendall WM: Retinal changes of hypertension. In The Eye in Systemic Disease. Edited by Mausolf FA. St Louis: Mosby; 1975:212–222. 13. Dollery CT: Hypertensive retinopathy. In Hypertension: Pathophysiology and Treatment. Edited by Genest O, Kuchel O, Hamet P. New York: McGraw-Hill; 1983:723–732. 14. McGregor E, Isles CG, Jay JL, et al.: Retinal changes in malignant hypertension. Br Med J 1986, 292:233–234. 15. Sinclair RA, Antonovych TT, Mostofi FL: Renal proliferative arteriopathies and associated glomerular changes: a light and electron microscopy study. Hum Pathol 1976, 7:565. 16. Pitcock JA, et al.: Malignant hypertension in blacks: malignant intrarenal arterial disease as observed by light and electron microscopy. Hum Pathol 1976, 7:33. 17. Jones DB: Arterial and glomerular lesions associated with severe hypertension. Lab Invest 1974, 31:303. 18. Mattern WD, Sommers SC, Kassiere JP: Oliguric acute renal failure in malignant hypertension. Am J Med 1972, 52:187. 19. Isles CG, McLay A, Boulton-Jones JM: Recovery in malignant hypertension presenting as acute renal failure. Q J Med 1984, 53:439. 20. Bacon BR, Ricanatie ES: Severe and prolonged renal insufficiency. Reversal in a patient wit malignant hypertension. JAMA 1978, 239:1159. 21. Shirley D, et al.: Clinical documentation of end-stage renal disease due to hypertension . Am J Kidney Dis 1994, 23:655. 22. Freedman BI, Iskander SS, Appel RG: The link between hypertension and nephrosclerosis. Am J Kidney Dis 1995, 25:207. 23. Rerneger TV, et al.: Diagnosis of hypertensive end-stage renal disease: effect of patient’s race. Am J Epidemiol 1995, 141:10. 24. Möhring J, et al.: Effects of saline drinking on the malignant course of renal hypertension in rats. Am J Physiol 1976, 230:849. 25. Gifford RW Jr, et al.: Hypertensive encephalopathy: mechanisms, clinical features, and treatment. Progr Cardiovasc Dis 1974, 17:115. 26. Dinsdale HB: Hypertensive encephalopathy. Neurol Clin 1983, 1:83. 27. Ziegler DK, et al.: Hypertensive encephalopathy. Arch Neurol 1965, 12:472. 28. Cohn JN, Rodriguera E, Guiha NH: Left ventricular function in hypertensive heart disease. In Hypertension Mechanisms and Management. Edited by Onesti O, Kim KE, Moyer JH. New York: Grune & Stratton; 1973:191–197. 29. Wheat MW Jr: Acute dissecting aneurysms of the aorta: diagnosis and treatment, 1979. Am Heart J 1980, 99:373. 30. DeSanctis RW, et al.: Aortic dissection. N Engl J Med 1987, 317:1060.

31. Goldman L, Caldera DL: Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesiology 1979, 50:285. 32. Breslin DR, et al.: Elective surgery in hypertensive patients: preoperative considerations. Surg Clin North Am 1970, 50:585. 33. Prys-Roberts C: Hypertension and anesthesia: fifty years on. Anesthesiology 1979, 50:281. 34. Reichgott MJ: Hypertension in the perioperative patient. In Medical Care of the Surgical Patient: A Problem-Oriented Approach to Management. Edited by Goldman DR, Brown FH, Levy KW et al. Philadelphia: Lippincott; 1982:78–86. 35. Estafanous RG, Tarazi RC: Systemic arterial hypertension associated with cardiac surgery. Am J Cardiol 1980, 46:685. 36. Fouad FM, et al.: Hemodynamics of postmyocardial revascularization hypertension. Am J Cardiol 1978, 41:564. 37. Cohn JN: Paroxysmal hypertension and hypovolemia. N Engl J Med 1966, 275:643. 38. Skydell JL, et al.: Incidence and mechanism of post-carotid endarterectomy hypertension. Arch Surg 1987, 122:1153. 39. Towne JB, Bernhard VM: The relationship of postoperative hypertension to complications after carotid endarterectomy. Surgery 1980, 88:575. 40. Wallace JD, et al.: Blood pressure after stroke. JAMA 1981, 246:2177. 41. Britton M, et al.: Hazards of therapy for excessive hypertension in acute stroke. Acta Med Scand 1980, 207:253. 42. Lavin P: Management of hypertension in patients with acute stroke. Arch Intern Med 1986, 146:66. 43. Meyer JS, et al.: Impaired neurogenic cerebrovascular control and dysautoregulation after stroke. Stroke 1973, 4:169. 44. Cuneo RA, et al.: The neurologic complications of hypertension. Med Clin North Am 1977, 61:565. 45. Kaneko T, et al.: Lower limit of blood pressure in treatment of acute hypertensive intracranial hemorrhage. J Cerebral Blood Flow Metab 1983, 3(suppl 1):S51. 46. Shapiro B, Rig LM: Management of pheochromocytoma. Endocrinol Metab Clin North Am 1989, 18:443. 47. Pinaud M, et al.: Preoperative acute volume loading in patients with pheochromocytoma. Care Med 1985, 13:460. 48. Glazener RS, et al.: Pargyline, cheese, and acute hypertension. JAMA 1964, 188:754. 49. Blackwell B, et al.: Hypertensive interactions between monoamine oxidase inhibitors and foodstuffs. Br J Psychiatry 1967, 113:349. 50. Palmer RF, Lasseter KC: Sodium nitroprusside. N Engl J Med 1975, 292:294. 51. Gruetter CA, et al.: Relationship between cyclic guanosine 3’:5’ monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide. J Pharmacol Exp Ther 1981, 219:181. 52. Ignarro IJ, et al.: Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside, and nitric oxide. J Pharmacol Exp Ther 1981, 218:739. 53. Strandgaard S: Autoregulation of cerebral blood flow in hypertensive patients. Circulation 1976, 53:720. 54. Franklin SS: Hypertensive emergencies: the case for more rapid lowering of blood pressure. In Controversies in Nephrology and Hypertension. Edited by Narins RG. New York: Grune & Stratton; 1973:191–197. 55. Fagan TC: Acute reduction of blood pressure in asymptomatic patients with severe hypertension. An idea whose time has come–and gone. Arch Intern Med 1989, 149:2169. 56. Ferguson RK, Vlasses PH: Hypertensive emergencies and urgencies. JAMA 1986, 255:1607. 57. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. Result in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967, 202:1028. 58. Zeller KR, et al.: Rapid reduction of severe asymptomatic hypertension. Arch Intern Med 1989, 149:2186.

Diabetic Nephropathy: Impact of Comorbidity Eli A. Friedman

T

hroughout the industrialized world, diabetes mellitus is the leading cause of end-stage renal disease (ESRD), surpassing glomerulonephritis and hypertension. Both the incidence and the prevalence of ESRD caused by diabetes have risen each year over the past decade, according to reports from European, Japanese, and North American registries of patients with renal failure. Illustrating the dominance of diabetes in ESRD is the 1997 report of the United States Renal Data System (USRDS), which noted that of 257,266 patients receiving either dialytic therapy or a kidney transplant in 1995 in the United States, 80,667 had diabetes [1], a prevalence rate of 31.4%. Also, during 1995 (the most recent year for which summative data are available), of 71,875 new (incident) cases of ESRD, 28,740 (40%) patients were listed as having diabetes. In America, Europe, and Japan, the form of diabetes is predominantly type II; fewer than 8% of diabetic Americans are insulinopenic, C-peptide-negative persons with type I disease. It follows that ESRD in diabetic persons reflects the demographics of diabetes per se [2]: 1) The incidence is higher in women [3], blacks [4], Hispanics [5], and native Americans [6]. 2) The peak incidence of ESRD occurs from the fifth to the seventh decade. Consistent with these attack rates is the fact that blacks older than the age of 65 face a seven times greater risk of diabetes-related renal failure than do whites. Within our Brooklyn and New York state hospital ambulatory hemodialysis units in October 1997, 97% of patients had type II diabetes. Despite widespread thinking to the contrary, vasculopathic complications of diabetes, including hypertension, are at least as severe in type II as in type I diabetes [7,8]. When carefully followed over a decade or longer, cohorts of type I and type II diabetic individuals have equivalent rates of proteinuria, azotemia, and ultimately ESRD. Both types of diabetes show strong similarities in their rate of renal functional deterioration [9] and onset of comorbid complications. Initial nephromegaly as well as both glomerular hyperfiltration and microalbuminuria (previously thought to be limited to type I) is now recognized as equally in type II [10].

CHAPTER

1

1.2

Systemic Diseases and the Kidney

Overview and Prevalence DIABETIC NEPHROPATHY Epidemiology IDDM vs. NIDDM Natural history Intervention measures ESRD options Promising strategies

FIGURE 1-1 Diabetic neuropathy topics. People with diabetes and progressive kidney disease are more difficult to manage than age- and gender-matched nondiabetic persons because of extensive, often life-threatening extrarenal (comorbid) disease. Diabetic patients manifesting end-stage renal disease (ESRD) suffer a higher death rate than do nondiabetic patients with ESRD owing to greater incidence rates for cardiac decompensation, stroke, sepsis, and pulmonary disease. Concurrent extrarenal disease—especially blindness, limb amputations, and cardiac disease—limits and may preempt their rehabilitation. For most diabetic patients with ESRD, the difference between rehabilitation and heartbreaking invalidism hinges on attaining a renal transplant as well as comprehensive attention to comorbid conditions. Gradually, over a quarter century, understanding of the impact of diabetes on the kidney has followed elucidation of the epidemiology, clinical course, and options in therapy available for diabetic individuals who progress to ESRD. For each of the discussion points listed, improvement in patient outcome has been contingent on a simple counting (point prevalence) of the number of individuals under consideration. For example, previously the large number of diabetic patients with ESRD were excluded from therapy owing to the belief that no benefit would result. A reexamination of exactly why dialytic therapy or kidney transplantation failed in diabetes, however, was stimulated. IDDM—insulin dependent diabetes mellitus; NIDDM—non–insulin-dependent diabetes mellitus. FIGURE 1-2 Maintenance hemodialysis. In the United States, the large majority (more than 80%) of diabetic persons who develop end-stage renal disease (ESRD) will be treated with maintenance hemodialysis. Approximately 12% of diabetic persons with ESRD will be treated with peritoneal dialysis, while the remaining 8% will receive a kidney transplant. A typical hemodialysis regimen requires three weekly treatments lasting 4 to 5 hours each, during which extracorporeal blood flow must be maintained at 300 to 500 mL/min. Motivated patients trained to perform self-hemodialysis at home gain the longest survival and best rehabilitation afforded by any dialytic therapy for diabetic ESRD. When given hemodialysis at a facility, however, diabetic patients fare less well, receiving significantly less dialysis than nondiabetic patients, owing in part to hypotension and reduced blood flow [11]. Maintenance hemodialysis does not restore vigor to diabetic patients, as documented by Lowder and colleagues [12]. In 1986, they reported that of 232 diabetics on maintenance hemodialysis, only seven were employed, while 64.9% were unable to conduct routine daily activities without assistance [12]. Approximately 50% of diabetic patients begun on maintenance hemodialysis die within 2 years of their first dialysis session. Diabetic hemodialysis patients sustained more total, cardiac, septic, and cerebrovascular deaths than did nondiabetic patients. When initially applied to diabetic patients with ESRD in the 1970s, maintenance hemodialysis was associated with a first-year mortality in excess of 75%, with inexorable loss of vision in survivors. Until the at-first-unappreciated major contribution of type II diabetes to ESRD became evident, kidney failure was incorrectly viewed as predominantly limited to the last stages of type I (juvenile, insulin-dependent) diabetes. Illustrated here is a blind 30-year-old man undergoing maintenance hemodialysis after experiencing 20 years of type I diabetes. A diabetic renal-retinal syndrome of blindness and renal failure was thought to be inevitable until the salutary effect of reducing hypertensive blood pressure became evident. Without question, reduction of hypertensive blood pressure levels was the key step that permitted improvement in survival and reduction in morbidity.

Diabetic Nephropathy: Impact of Cormorbidity

FIGURE 1-3 Statistical increase in diabetes. In the past 20 years, since the diabetic patient with endstage renal disease (ESRD) is no longer excluded from dialytic therapy or kidney transplantation, there has been a steady increase in the proportion of all patients with ESRD who have diabetes. In the United States, according to the 1997 report of the United States Renal Data System (USRDS) for the year 1995, more than 40% of all newly treated (incident) patients with ESRD have diabetes. For perspective, the USRDS does not list the actual incidence of a renal disease but rather tabulates those individuals who have been enrolled in federally reimbursed renal programs. The distinction may be important in that a relaxation in policy for referral of diabetic kidney patients would be indistinguishable from a true increase in incidence.

Diabetes 40%

28,740

43,135 All other 60%

Prevalence of diabetes, %

25

Country of origin United States

20

18

15

5

PERCENTAGE OF PATIENTS WITH END-STAGE RENAL DISEASE WITH TYPE II DIABETES

23 19

18 16

15

15

14

10

7

Country Japan Germany United States Pima Indians

10

9

1.3

8

Percentage 99 90 95

5

4

0 Black Mexican Puerto Rican

Japanese Filipinos Chinese

Koreans

FIGURE 1-4 Prevalence of diabetes mellitus in minority populations. Attack rates (incidence) for diabetes are higher in nonwhite populations than in whites. Type II diabetes accounts for more than 90% of all patients with end-stage renal disease (ESRD) with diabetes. As studied by Carter and colleagues [13], the effect of improved nutrition on expression of diabetes is remarkable. The American diet not only induces an increase in body mass but also may more than double the expressed rate of diabetes, especially in Asians. (From Carter and coworkers [13]; with permission.)

Infrequent feeding

Insulin resistance

Overfeeding

Obesity

Fat in muscle NIDDM

FIGURE 1-6 Thrifty gene. In addition to the artificial increase in incident patients with end-stage renal disease (ESRD) and diabetes that followed relaxation of acceptance criteria, industrialized nations have experienced a real increase in type II diabetes that correlates with an increase in body mass attributed to overfeeding. Formerly

FIGURE 1-5 Percent of diabetic ESRD. Noted first in United States inner-city dialysis programs, type II diabetes is the predominant variety noted in those individuals undergoing maintenance hemodialysis. Our recent survey of hemodialysis units in Brooklyn, New York, found that 97% of the mainly African-American patients had type II diabetes. Thus, there has been a reversal of the previously held impression that uremia was primarily a late manifestation of type I diabetes. (From Ritz and Stefanski [14] and Nelson and coworkers [15]; with permission.)

termed non–insulin-dependent diabetes mellitus (NIDDM) or maturity-onset diabetes, the variety of diabetes observed in industrialized overfed populations is now classified as type II disease. According to the Thrifty Gene hypothesis, the ability to survive extended fasts in prehistoric populations that hunted to survive selected genes that in time of excess caloric intake are expressed as hyperglycemia, insulin resistance, and hyperlipidemia (type II diabetes). A study by Ravussin and colleagues of American and Mexican Pima Indian tribes illustrates the effect of overfeeding on a genetic predisposition to type II diabetes. Separated about 200 years ago, Indians with the same genetic makeup began living in different areas with different lifestyles and diets. In the Arizona branch of the Pimas, who were fed surplus food and restrained to a reservation that restricted hunting and other activities, the prevalence of type II diabetes progressively increased to 37% in women and 54% in men. In contrast, Pimas living in Mexico with shorter stature, lower body mass, and lower cholesterol had a lower prevalence of type II diabetes (11% in women and 6% in men). (From Shafrir [16] and Schalin-Jantti [17]; with permission.)

1.4

Systemic Diseases and the Kidney

Type I and Type II Classified Type II

Insulin requiring Type II decreased insulin secretion/sensitvity

C-PEPTIDE CRITERIA

Type I

Type I β-cell destruction

FIGURE 1-7 Type I and type II compared. Differentiating type I from type II diabetes may be difficult, especially in young nonobese adults with minimal insulin secretion. Furthermore, with increasing duration of type II diabetes, beta cells may decrease their insulin secretion, sometimes to the range diagnostic of type I diabetes. Shown here is a modification of the schema devised by Kuzuya and Matsuda [18] that suggests a continuum of diabetes classification based on amount of insulin secreted. Lacking in this construction is the realization of the genetic determination of type I diabetes (all?) and the clear hereditary predisposition (despite inconstant genetic analyses) of many individuals with type II diabetes. At present, classification of diabetes is pragmatic and will likely change with larger-population screening studies. IGT—impaired glucose tolerance. (From Kuzuya and Matsuda [18]; with permission.)

70 Proportion on insulin, %

IGT

60

60 50 40

33

30 20

Type I (90% concordence between clinical criteria and C-peptide testing) Basal C-peptide 4

3.5

3.5 3.0

3.0 Clinical nephropathy

2.5

2.5 2.0

2.0 1.5

1.5

Clinical nephropathy

1.0

1.0

12

0.5

0.5 Microalbuminuria

0 0

3

6

9

12 15 18 Hyperglycemia, y

24

Doubling of base-line creatinine, %

Placebo P=0.007

20 15 Captopril

0 0.0 Placebo 202 Captopril 207

0.5

1.0

1.5

184 199

173 190

161 180

2.0 2.5 Follow-up, y 142 167

99 120

6 4 2 15

30

45

60

75

90

105 120

135

150 165

Creatinine clearance, mL/min

50

10 5

Window for conservative management

8

0

27

FIGURE 1-22 Diabetic nephropathy in types I and II. Whereas microalbuminuria and glomerular hyperfiltration are subtle pathophysiologic manifestations of early diabetic nephropathy, transformation to overt clinical diabetic nephropathy takes place over months to many years. In this figure, the curve for loss of glomerular filtration rate is plotted together with the curve for transition from microalbuminuria to gross proteinuria, affording a perspective of the course of diabetic nephropathy in both types of diabetes. While not all microalbuminuric individuals progress to proteinuria and azotemia, the majority are at risk for end-stage renal disease due to diabetic nephropathy. GFR—glomerular filtration rate.

45 40 35 30 25

10

0

0 21

Serum creatinine, mg/dL

4.0 Urinary albumin, g/d

GFR, mL/min

>4 4.0

3.0

3.5

4.0

75 82

45 50

22 24

FIGURE 1-23 Clinical recognition of diabetic nephropathy. The timing of renoprotective therapy in diabetes is a subject of current inquiry. Certainly, hypertension, poor metabolic regulation, and hyperlipidemia should be addressed in every diabetic individual at discovery. Discovery of microalbuminuria is by consensus reason to start treatment with an angiotensin-converting enzyme inhibitor in either type of diabetes, regardless of blood pressure elevation. As is true for other kidney disorders, however, nearly the entire course of renal injury in diabetes is clinically silent. Medical intervention during this “silent phase,” however (comprising blood pressure regulation, metabolic control, dietary protein restriction, and administration of angiotensin-converting enzyme inhibitors), is renoprotective, as judged by slowed loss of glomerular filtration. FIGURE 1-24 Renoprotection with enzyme inhibitors. Streptozotocin-induced diabetic rats manifest slower progression to proteinuria and azotemia when treated with angiotensin-converting enzyme inhibitors than with other antihypertensive drugs. The consensus supports the view that angiotensin-converting enzyme inhibitors afford a greater level of renoprotection in diabetes than do other classes of antihypertensive drugs. Large long-term direct comparisons of antihypertensive drug regimens in type II diabetes are now in progress. In the study shown here by Lewis and colleagues [23], treatment with captopril delayed the doubling of serum creatinine concentration in proteinuric type I diabetic patients. Trials of different angiotensin-converting enzyme inhibitors in both types of diabetes confirm their effectiveness but not their unique renoprotective properties in humans. For patients who cannot tolerate angiotensin-converting enzyme inhibitors because of cough, hyperkalemia, azotemia, or other side effects, substitution of an angiotensin-converting enzyme receptor blocker (losartan) may be renoprotective, although clinical trials of its use in diabetes are uncompleted. (From Lewis and coworkers [23]; with permission.)

1.10

Systemic Diseases and the Kidney

Microalbuminuric

Normoalbuminuric

10

70

AER, µg/min

50 6

40

4

30

AER, µg/min

60

8

20 2

Lisinopril

0 n n

10

Placebo

0 6

0

12 18 24 0 6 12 Time from randomization, m

227 202 201 179 213 196 179 170

120

193 34 191 45

33 37

29 34

18

24

25 32

32 37

FIGURE 1-26 Restricting protein. Dietary protein restriction in limited trials in small patient cohorts has slowed renal functional decline in type I diabetes. Because long-term compliance is difficult to attain, the place of restricted protein intake as a component of management is not defined. A, Normal diet. B, Protein-restricted diet. Dashed line indicates trend line slope. (From Zeller and colleagues [25]; with permission.)

Normal diet

Glomerular filtration rate, mL/min/1.73 m2

100 80 60 40 20 0 0

10

20

A

30

40

50

40

50

Time, mo 120

Protein-restricted diet

Glomerular filtration rate, mL/min/1.73 m2

100 80 60 40 20 0 0

B

FIGURE 1-25 Albumin excretion rate. In the recently completed Italian Euclid multicenter study, both microalbuminuric and normalbuminuric type I diabetic patients showed benefit from treatment with lisinopril, an angiotensin-converting enzyme inhibitor. Although microalbuminuria, with or without hypertension, is now sufficient reason to start treatment with an angiotensin-converting enzyme inhibitor, the question of whether normalbuminuric, normotensive diabetic individuals should be started on drug therapy is unanswered. AER—albumin excretion rate. (From Euclid study [24]; with permission.)

10

20

30 Time, mo

1.11

Diabetic Nephropathy: Impact of Cormorbidity

125

80

Rate of change in AER, % /year

Rate of change in AER, % /year

100

75

50

25

0

60

40

20

0 0

A

10

12

14

6

8

10

B

Mean Hb A1, %

FIGURE 1-27 Metabolic regulation studies. Multiple studies of the strict metabolic regulation of type I and type II diabetes all indicate that reduction of hyperglycemic levels to near normal slows the rate of renal functional deterioration. In this study, the albumin excretion rate (AER)— another way of expressing albuminuria—correlates directly with

Function

Pathology

Hyperfiltration

Mesangial expansion

Microalbuminuria

12

14

Mean Hb A1, %

hyperglycemia, as indicated by hemoglobin A1 (Hb A1) levels in both type I (A) and type II (B) diabetes. As for other studies using different markers, the courses of both types of diabetes over time were found to be equivalent. (From Gilbert and coworkers [26]; with permission.) FIGURE 1-28 Stages of nephropathy. The interrelationships between functional and morphologic markers of the stages of diabetic nephropathy are shown. Additional pathologic studies are needed to time with precision exactly when glomerular basement membrane (GBM) thickening and glomerular mesangial expansion take place. ESRD—endstage renal disease.

GBM thickening

Proteinuria

Glomerulosclerosis

ESRD

DIABETIC NEPHROPATHY: COMPLICATIONS Rate of GFR Loss Course of proteinuria Nephropathology Comorbidity Progression to ESRD

FIGURE 1-29 Type I and II nephropathic equivalence. A summation about the equivalence of type I and type II diabetes in terms of nephropathy is listed. Both types have similar complications. ESRD—endstage renal disease; GFR—glomerular filtration rate.

Hyperglycemia Normotension Euglycemia Protein restriction

Glomerulosclerosis

FIGURE 1-30 Major therapeutic maneuvers to slow loss of glomerular filtration rate are shown. Recent recognition of the adverse effect of hyperlipidemia is reason to include dietary and, if necessary, drug treatment for elevated blood lipid levels.

1.12

Systemic Diseases and the Kidney

PROGRESSION OF COMORBIDITY IN TYPE II DIABETES* Complication Retinopathy Cardiovascular Cerebrovascular Peripheral vascular

Initial, %

Subsequent, %

50 45 30 15

100 90 70 50

COMORBIDITY INDEX Persistent angina or myocardial infarction Other cardiovascular problems Respiratory disease Autonomic neuropathy Musculoskeletal disorders Infections including AIDS Liver and pancreatic disease Hematologic problems Spinal abnormalities Vision impairment Limb amputation Mental or emotional illness

*Creatinine clearance declined from 81 mL/min over 74 (40—119) mo. Endpoint: dialysis or death.

FIGURE 1-31 Comorbidity in type II. In both type I and type II diabetes, comorbidity, meaning extrarenal disease, makes every stage of progressive nephropathy more difficult to manage. In the long-term observational study in type II diabetes done by Bisenbach and Zazgornik [27], the striking impact of eye, heart, and peripheral vascular disease was noted in a cohort over 74 months. (From Bisenbach and Zazgornik [27]; with permission.)

A

Score 0 to 3: 0 = absent; 1 = mild; 2 = moderate; 3 = severe. Total = Index.

FIGURE 1-32 Comorbidity index. We devised a Comorbidity Index to facilitate initial and subsequent evaluations of patients over the course of interventive studies. Each of 12 areas is rated as having no disease (0) to severe disease (3). The total score represents overall illness and can be both reproduced by other observers and followed for years to document improvement or deterioration.

B

FIGURE 1-34 Heart disease and renal transplants. A, Pretransplantation. B, Five years after kidney transplation. Experienced clinicians managing renal failure in diabetes rapidly reach the conclusion that quality of life following successful kidney transplantation is far superior to that attained during any form of dialytic therapy. In the most favorable series, as illustrated by a singlecenter retrospective review of all kidney transplants performed between 1987 and 1993, there is no significant difference in actuarial 5-year patient or kidney graft survival between diabetic and nondiabetic recipients overall or when analyzed by donor source. It is equally encouraging that no difference in mean serum creatinine levels at 5 years was noted between diabetic and nondiabetic recipients [28]. Remarkably superior survival following kidney transplantation compared with survival after peritoneal dialysis and hemodialysis is documented in the 1997

HEART DISEASE Hyperlipidemia Hypertension Volume overload ACE inhibitor Erythropoietin

FIGURE 1-33 Heart disease. Heart disease is the leading cause of morbidity and death in both type I and type II diabetes. Throughout the course of diabetic nephropathy, periodic screening for cardiac integrity is appropriate. We have elicited symptomatic improvement in angina and work tolerance by using erythropoietin to increase anemic hemoglobin levels. ACE—angiotensin-converting enzyme.

report of the United States Renal Data System (USRDS) [1]. Fewer than five in 100 diabetic patients with end-stage renal disease (ESRD) treated with dialysis will survive 10 years, while cadaver donor and living donor kidney allograft recipients fare far better. Rehabilitation of diabetic patients with ESRD is incomparably better following renal transplantation compared with dialytic therapy. The enhanced quality of life permitted by a kidney transplant is the reason to prefer this option for newly evaluated diabetic persons with ESRD who are younger than the age of 60. More than half of diabetic recipients of a kidney transplant in most series live at least 3 years: many survivors return to occupational, school, and home responsibilities. Failure to continue monitoring of cardiac integrity may have disastrous results, as in this relatively young type I diabetic recipient of a cadaver renal allograft for diabetic nephropathy Although her allograft maintained good function, coronary artery disease progressed silently until a myocardial infarction occurred We now perform annual cardiac testing in all diabetic patients who have ESRD and are receiving any form of treatment.

Diabetic Nephropathy: Impact of Cormorbidity

RETINOPATHY Hyperglycemia Hypertension Volume overload Photocoagulation Erythropoietin

1.13

FIGURE 1-35 Retinopathy. Blindness due to the hemorrhagic and fibrotic changes of diabetic retinopathy is the most dreaded extrarenal complication feared by diabetic kidney patients. The pathogenesis of proliferative retinopathy reflects release by retinal and choroidal cells of growth (angiogenic) factors triggered by hypoxemia, which is caused by diminished blood flow. The interrelationship among hyperglycemia, hypertension, hypoxemia, and angiogenic factors is now being defined. There is reason to hope that specifically designed interdictive measures may halt progression of loss of sight.

FIGURE 1-36 Retinopathic changes. Proliferative retinopathy, microcapillary aneurysms, and dot plus blot hemorrhages are present in this funduscopic photograph taken at the time of initial renal evaluation of a nephrotic 37-year-old woman with type I diabetes. After prescription of a diuretic regimen, immediate consultation with a laser-skilled ophthalmologist was arranged.

A FIGURE 1-37 Panretinal photocoagulation (PRP). A, PRP is the therapeutic technique performed for proliferative retinopathy using an argon laser to deliver approximately 1500 discrete retinal burns, avoiding the fovea and disk (IA10 y Diabetic complications Rehabilitation Patient acceptance

COMPLICATIONS IN PATIENTS UNDERGOING KIDNEY TRANSPLANTATION

CAPD/CCPD

Hemodialysis

Transplantation

75% 25% Slow progression Fair to excellent Good to excellent

FIGURE 1-56 Options in diabetes with ESRD. Comparing outcomes of various options for uremia therapy in diabetic patients with end-stage renal disease (ESRD) is flawed by the differing criteria for selection for each treatment. Thus, if younger, healthier subjects are offered kidney transplantation, then subsequent relative survival analysis will be adversely affected for the residual pool treated by peritoneal dialysis or hemodialysis. Allowing for this caveat, the table depicts usual outcomes and relative rehabilitation results for continuous ambulatory peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), hemodialysis, and transplantation.

Kidney transplant Karnofsky score

1.18

Hemodialysis 50

Peritoneal dialysis

Withdrawal 0

Death

FIGURE 1-57 Karnofsky scores in rehabilitation. Graphic depiction of rehabilitation in diabetic patients with end-stage renal disease (ESRD) as judged by Karnofsky scores. Few diabetic patients receiving hemodialysis or peritoneal dialysis muster the strength to resume fulltime employment or other gainful activities. Originally devised for use by oncologists, the Karnofsky score is a reproducible, simple means of evaluating chronic illness from any cause. A score below 60 indicates marginal function and failed rehabilitation.

Diabetic Nephropathy: Impact of Cormorbidity

1.19

FIGURE 1-58 Complications of the hemodialysis regimen are more frequent in diabetic than in nondiabetic patients. A, Axillary vein occlusion proximal to an arteriovenous graft used for dialysis access is shown. B, Balloon angioplasty proffers only temporary respite owing to a high rate (70% in 6 months) of restenosis in diabetic patients. The value of an intraluminal stent prosthesis is being studied.

A

B

76.2 75

USRDS 1996 PD + Hemo

74

Surviving, %

72.6

74.4

LIFE PLAN FOR DIABETIC NEPHROPATHY

73.1 Explore and endorse treatment goals Enlist patient as key team member Prepare patient for probable course Prioritize ESRD options

70.9 70 68.9 67.7 65.9

66.2

66.4

65 1983

1984 1985

1986

1987

1988 1989

1990

1991

1992

1993

FIGURE 1-59 Improving one year survival with dialysis. The summative effect of multiple incremental improvements in management of diabetic patients with end-stage renal disease (ESRD) is reflected in a continuing increase in survival. Shown here, abstracted from the 1977 report of the United States Renal Data System (USRDS), is the increasing first-year survival rates for hemodialysis (hemo) plus peritoneal dialysis (PD) patients with diabetes.

FIGURE 1-60 Life plan. Given the concurrent involvement of multiple consultants in the care of diabetic individuals with end-stage renal disease (ESRD), there is a need for a defined strategy, here termed a “Life Plan.” Switching from hemodialysis to peritoneal dialysis (or the reverse) and deciding on a midcourse kidney transplant are common occurrences that ought not to provoke anxiety or stress. Reappraisal and reconstruction of the Life Plan should be performed by patient and physician at least annually.

1.20

Systemic Diseases and the Kidney

References 1. United States Renal Data System: USRDS 1997 Annual Data Report. Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; April, 1997. 2. Zimmet PZ: Challenges in diabetes epidemiology—from West to the rest (Kelly West Lecture 1991). Diabetes Care 1992, 15:232–252. 3. Harris M, Hadden WC, Knowles WC, and colleagues: Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20-74 yr. Diabetes 1987, 36:523–534. 4. Stephens GW, Gillaspy JA, Clyne D, and colleagues: Racial differences in the incidence of end-stage renal disease in types I and II diabetes mellitus. Am J Kidney Dis 1990, 15:562–567. 5. Haffner SM, Hazuda HP, Stern MP, and colleagues: Effects of socioeconomic status on hyperglycemia and retinopathy levels in Mexican Americans with NIDDM. Diabetes Care 1989, 12:128–134. 6. National Diabetes Data Group: Diabetes in America. Bethesda, MD: NIH Publication No. 85-1468; August, 1985. 7. Mauer SM, Chavers BM: A comparison of kidney disease in type I and type II diabetes. Adv Exp Med Biol 1985, 189:299–303. 8. Melton LJ, Palumbo PJ, Chu CP: Incidence of diabetes mellitus by clinical type. Diabetes Care 1983, 6:75–86. 9. Biesenback G, Janko O, Zazgornik J: Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus. Nephrol Dial Transplant 1994, 9:1097–1102. 10. Wirta O, Pasternack A, Laippala P, Turjanmaa V: Glomerular filtration rate and kidney size after six years disease duration in noninsulin-dependent diabetic subjects. Clin Nephrol 1996, 45:10–17. 11. Cheigh J, Raghavan J, Sullivan J, and colleagues: Is insufficient dialysis a cause for high morbidity in diabetic patients [abstract]? J Am Soc Nephrol 1991, 317. 12. Lowder GM, Perri NA, Friedman EA: Demographics, diabetes type, and degree of rehabilitation in diabetic patients on maintenance hemodialysis in Brooklyn. J Diabet Complications 1988, 2:218–226. 13. Carter JS, et al.: Non-insulin-dependent diabetes mellitus in minorities in the United States. Ann Intern Med 1996, 125:221–232. 14. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J Kidney Dis 1996, 27:167–194. 15. Nelson RG, Pettitt DJ, Carraher MJ, et al.: Effect of proteinuria on mortality in NIDDM. Diabetes 1988, 37:1499–1504. 16. Shafrir E: Development and consequences of insulin resistance: lessons from animals with hyperinsulinemia. Diabetes Metab 1996, 22:122–131. 17. Schalin-Jantii C, et al.: Polymorphism of the glycogen synthase gene in hypertensive and normotensive subjects. Hypertension 1996, 27:67–71. 18. Kuzuya T, Matsuda A: Classification of diabetes on the basis of etiologies versus degree of insulin deficiency. Diabetes Care 1997, 20:219–220. 19. Clausson P, Linnarsson R, Gottsater A, et al.: Relationships between diabetes duration, metabolic control and beta-cell function in a representative population of type 2 diabetic patients in Sweden. Diabet Med 1994, 11:794–801. 20. Service FJ, Rizza RA, Zimmerman BR, et al.: The classification of diabetes by clinical and C-peptide criteria: a prospective populationbased study. Diabetes Care 1997, 20:198–201.

21. Humphrey LL, et al.: Chronic renal failure in non-insulin-dependent diabetes mellitus: a population-based study in Rochester, Minnesota. Ann Intern Med 1989, 111:788–796. 22. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J Kidney Dis 1996, 27:167–194. 23. Lewis EJ, et al.: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy: the Collaborative Study Group. N Engl J Med 1993, 329:1456–1462. 24. The Euclid Study Group: Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997, 349:1787–1792. 25. Zeller K, et al.: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 1991, 324:78–84. 26. Gilbert RE, Tsalamandris C, Bach LA, et al.: Long-term glycemic control and the rate of progression of early diabetic kidney disease. Kidney Int 1993, 44:855–859. 27. Biesenbach G, Zazgornik J: High mortality and poor quality of life during predialysis period in type II diabetic patients with diabetic nephropathy. Ren Fail 1994, 16:263–272. 28. Shaffer D, Simpson MA, Madras PN, et al.: Kidney transplantation in diabetic patients using cyclosporine. Five-year follow-up. Arch Surg 1995, 130:287–288. 29. Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: an overview. Diabetes 1997, 46 (suppl 2): S58–S61. 30 Spallone V, Menzinger G: Diagnosis of cardiovascular autonomic neuropathy in diabetes. Diabetes 1997, 46 (suppl 2):S67–S76. 31. Enck P, Frieling T: Pathophysiology of diabetic gastroparesis. Diabetes 1997, 46 (suppl 2):S77–S81. 32. Soykan I, et al.: The effect of chronic oral domperidone therapy on gastrointestinal symptoms, gastric emptying, and quality of life in patients with gastroparesis. Am J Gastroenterol 1997, 92:976–980. 33. Hebert LA, Bain RP, Verme D, Cattran Det al.: Remission of nephrotic range proteinuria in type I diabetes: Collaborative Study Group. Kidney Int 1994, 46:1688–1693. 34. Gault MH, Fernandez D: Stable renal function in insulin-dependent diabetes mellitus 10 years after nephrotic range proteinuria. Nephron 1996, 72:86–92. 35. Lindblad AS, Nolph KD, Novak JW, Friedman EA: A survey of the NIH CAPD Registry population with end-stage renal disease attributed to diabetic nephropathy. J Diabet Complications 1988, 2:227-232. 36. Legrain M, Rottembourg J, Bentchikou A, et al.: Dialysis treatment of insulin dependent diabetic patients: ten years experience. Clin Nephrol 1984, 21:72-81 37. Rubin J, Hsu H: Continuous anbulatory peritoneal dialysis: ten years at one facility. Am J Kidney Dis 1991, 17: 165-169. 38. Habach G, Bloembergen WE, Mauger EA, et al.: Hospitalization among United States dialysis patients: hemodialysis versus peritoneal dialysis. J Am Soc Nephrol 1995, 11:1940-1948.

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, HenochSchönlein Purpura) J. Charles Jennette Ronald J. Falk

T

he kidneys are affected by a variety of systemic vasculitides [1,2]. This is not surprising given the numerous and varied types of vessels in the kidneys. The clinical manifestations and even the pathologic expressions of vasculitis often are not specific for a particular diagnostic category of vasculitis. An accurate precise diagnosis usually requires the integration of many different types of data, including clinical signs and symptoms, associated diseases (eg, asthma, systemic lupus erythematosus, rheumatoid arthritis, hepatitis virus, polymyalgia rheumatica), vascular distribution (ie, types and locations of involved vessels), histologic pattern of inflammation (eg, granulomatous versus necrotizing), immunopathologic features (eg, presence and composition of vascular immunoglobulin deposits), and serologic findings (eg, cryoglobulins, hypocomplementemia, hepatitis B antibodies, hepatitis C antibodies, antineutrophil cytoplasmic autoantibodies, anti–glomerular basement membrane [GBM] antibodies, antinuclear antibodies). Specific diagnosis of a vasculitis is very important because the prognosis and appropriate therapy vary substantially among different types of vasculitis. A general overview of the major categories of vasculitis that affect the kidneys is presented. The focus is primarily on polyarteritis nodosa, Henoch-Schönlein purpura, Wegener’s granulomatosis, and microscopic polyangiitis.

CHAPTER

2

2.2

Systemic Diseases and the Kidney

Overview SELECTED CATEGORIES OF VASCULITIS Large vessel vasculitis Giant cell arteritis Takayasu arteritis Medium-sized vessel vasculitis Polyarteritis nodosa Kawasaki disease Small vessel vasculitis ANCA small vessel vasculitis Microscopic polyangiitis Wegener’s granulomatosis Churg-Strauss syndrome Immune complex small vessel vasculitis Henoch-Schönlein purpura Cryoglobulinemic vasculitis Lupus vasculitis Serum sickness vasculitis Infection-induced immune complex vasculitis Anti–GBM small vessel vasculitis Goodpasture’s syndrome

Distribution of renal vascular involvement Small vessel vasculitis

Large vessel vasculitis

Medium-sized vessel vasculitis

FIGURE 2-1 Many different approaches to categorizing vasculitis exist. We use the approach adopted by the Chapel Hill International Consensus Conference on the Nomenclature of Systemic Vasculitis [3]. The Chapel Hill System divides vasculitides into those that have a predilection for large arteries (ie, the aorta and its major branches), medium-sized vessels (ie, main visceral arteries), and small vessels (predominantly capillaries, venules, and arterioles, and occasionally, small arteries). However, there is so much overlap in the size of the vessel involved by different vasculitides that other criteria are very important for precise diagnosis, especially when distinguishing among the different types of small vessel vasculitis. ANCA—antineutrophil cytoplasmic antibody.

FIGURE 2-2 Predominant distributions of renal vascular involvement. This diagram depicts the predominant distributions of renal vascular involvement by large, medium-sized, and small vessel vasculitides [2]. Note that all three categories may affect arteries, although arteries are least often affected by the small vessel vasculitides and often are not involved at all by this category of vasculitis. By the Chapel Hill definitions, glomerular involvement (ie, glomerulonephritis) is confined to the small vessel vasculitides, which provides a concrete criterion for separating the diseases in this category from those in the other two categories [3].

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura)

RENAL INJURY CAUSED BY DIFFERENT CATEGORIES OF VASCULITIS Large vessel vasculitis Ischemia causing renovascular hypertension (uncommon) Medium-sized vessel vasculitis Renal infarcts (frequent) Hemorrhage (uncommon) and rupture (rare) ANCA small vessel vasculitis Pauci-immune crescentic glomerulonephritis (common) Arcuate and interlobular arteritis (occasional) Medullary angiitis (uncommon) Interstitial granulomatous inflammation (rare) Immune complex small vessel vasculitis Immune complex proliferative or membranoproliferative glomerulonephritis with or without crescents (common) Arteriolitis and interlobular arteritis (rare) Anti–GBM small vessel vasculitis Crescentic glomerulonephritis (common) Extraglomerular vasculitis (only with concurrent ANCA disease)

2.3

FIGURE 2-3 The type of renal vessel involved by a vasculitis determines the resultant renal dysfunction. Large vessel vasculitides cause renal dysfunction by injuring the renal arteries and the aorta adjacent to the renal artery ostia. These injuries result in reduced renal blood flow and resultant renovascular hypertension. Medium-sized vessel vasculitis most often affects lobar, arcuate, and interlobular arteries, resulting in infarction and hemorrhage. Small vessel vasculitides most often affect the glomerular capillaries (ie, cause glomerulonephritis), but some types (especially the antineutrophil cytoplasmic antibody vasculitides) may also affect extraglomerular parenchymal arterioles, venules, and capillaries. Anti-GBM disease is a form of vasculitis that involves only capillaries in glomeruli or pulmonary alveoli, or both. This category of vasculitis is considered in detail seperately in this Atlas.

Large Vessel Vasculitis NAMES AND DEFINITIONS FOR LARGE VESSEL VASCULITIS Giant cell arteritis

Takayasu arteritis

Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial branches of the carotid artery. Often involves the temporal artery. Usually occurs in patients older than aged 50 years and often is associated with polymyalgia rheumatica. Granulomatous inflammation of the aorta and its major branches. Usually occurs in patients younger than aged 50 years.

FIGURE 2-4 The two major categories of large vessel vasculitis, giant cell (temporal) arteritis and Takayasu arteritis, are both characterized pathologically by granulomatous inflammation of the aorta, its major branches, or both. The most reliable criterion for distinguishing between these two disease is the younger age of patients with Takayasu arteritis compared with giant cell arteritis [3]. The presence of polymyalgia rheumatica supports a diagnosis of giant cell arteritis. Clinically significant renal disease is more commonly associated with Takayasu arteritis than giant cell arteritis, although pathologic involvement of the kidneys is a frequent finding with both conditions [4,5].

2.4

Systemic Diseases and the Kidney

Medium-sized Vessel Vasculitis NAMES AND DEFINITIONS FOR MEDIUM VESSEL VASCULITIS Polyarteritis nodosa

Kawasaki disease

Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Arteritis involving large, medium-sized, and small arteries, and associated with mucocutaneous lymph node syndrome. Coronary arteries are often involved. Aorta and veins may be involved. Usually occurs in children.

FIGURE 2-5 The medium-sized vasculitides are confined to arteries by the definitions of the Chapel Hill Nomenclature System [3,6]. By this approach the presence of evidence for involvement of vessels smaller than arteries (ie, capillaries, venules, arterioles), such as glomerulonephritis, purpura, or pulmonary hemorrhage, would point away from these diseases and toward one of the small vessel vasculitides. Both polyarteritis nodosa and Kawasaki disease cause acute necrotizing arteritis that may be complicated by thrombosis and hemorrhage. The presence of mucocutaneous lymph node syndrome distinguishes Kawasaki disease from polyarteritis nodosa.

FIGURE 2-6 Photograph of kidneys showing gross features of polyarteritis nodosa. The patient died from uncontrollable hemorrhage of a ruptured aneurysm that bled into the retroperitoneum and peritoneum. The cut surface of the left kidney and external surface of the right kidney are shown. The upper pole of the left kidney has three large aneurysms filled with dark thrombus. These aneurysms are actually pseudoaneurysms because they are not true dilations of the artery wall but rather are foci of necrotizing erosion through the artery wall into the perivascular tissue. These necrotic foci predispose to thrombosis with distal infarction, and if they erode to the surface of a viscera they can rupture and cause massive hemorrhage. The kidneys also have multiple pale areas of infarction with hemorrhagic rims, which are seen best on the surface of the right kidney.

A

B

FIGURE 2-7 Antemortem abdominal CAT scans showing polyarteritis nodosa (A–E). These are the same kidneys shown in Figure 2-6. Demonstrated are echogenic oval defects in both kidneys corresponding to the

C aneurysms (pseudoaneurysms), and a perirenal hematoma adjacent to the right kidney (left sides of panels) that resulted from rupture of one of the aneurysms. (Continued on next page)

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura)

2.5

FIGURE 2-7 (Continued) Antemortem abdominal CAT scans showing polyarteritis nodosa.

D

E

FIGURE 2-8 (see Color Plate) Micrograph of transmural fibrinoid necrosis of an arcuate artery in acute polyarteritis nodosa. The fibrinoid necrosis results from lytic destruction of vascular and perivascular tissue with spillage of plasma constituents, including the coagulation proteins, into the zone of destruction. The coagulation system, as well as other mediator systems, is activated and fibrin forms in the zone of necrosis, thus producing the deeply acidophilic (bright red) fibrinoid material. Marked perivascular inflammation is seen, which is the basis for the archaic term for this disease, ie, periarteritis nodosa. Note that the glomerulus is not inflamed. (Hematoxylin and eosin stain, 200.)

FIGURE 2-9 Micrograph of extensive destruction and sclerosis of an arcuate artery in the chronic phase of polyarteritis nodosa. Severe necrotizing injury, probably with thrombosis as well, has been almost completely replaced by fibrosis. A few small residual irregular foci of fibrinoid material can be seen. Extensive destruction to the muscularis can be discerned. Infarction in the distal vascular distribution of this artery was present in the specimen. (Hematoxylin and eosin stain, 150.)

2.6

Systemic Diseases and the Kidney

Small Vessel Vasculitis NAMES AND DEFINITIONS FOR SMALL VESSEL VASCULITIS Henoch-Schönlein purpura Cryoglobulinemic vasculitis Wegener’s granulomatosis Churg-Strauss syndrome Microscopic polyangiitis

Vasculitis with IgA-dominant immune deposits affecting small vessels, ie, capillaries, venules, or arterioles. Typically involves skin, gut and glomeruli, and is associated with arthralgias or arthritis. Vasculitis with cryoglobulin immune deposits affecting small vessels, ie, capillaries, venules, or arterioles, and associated with cryoglobulins in serum. Skin and glomeruli are often involved. Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels, eg, capillaries, venules, arterioles, and arteries. Necrotizing glomerulonephritis is common. Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels, and associated with asthma and blood eosinophilia Necrotizing vasculitis with few or no immune deposits affecting small vessels, ie, capillaries, venules, or arterioles. Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs.

FIGURE 2-10 The small vessel vasculitides have the highest frequency of clinically significant renal involvement of any category of vasculitis. This is not surprising given the numerous small vessels in the kidneys and their critical roles in renal function. The renal vessels most often involved by all small vessel vasculitides are the glomerular capillaries, resulting in glomerulonephritis. Glomerular involvement in immune complex vasculitis typically results in proliferative or membranoproliferative glomerulonephritis, whereas ANCA disease usually causes necrotizing glomerulonephritis with extensive crescent formation. Involvement of renal vessels other than glomerular capillaries is rare in immune complex vasculitis but common in ANCA vasculitis.

Diagnostic categorization of small vessel vasculitis with glomerulonephritis Signs and symptoms of small vessel vasculitis (eg, nephritis, purpura, mononeuritis multiplex, pulmonary hemorrhage, abdominal pain, arthralgias, myalgias)

Pauci-immune crescentic glomerulonephritis on renal biopsy

Cryoglobulins in blood

IgA nephropathy on renal biopsy

Type 1 MPGN on renal biopsy

No granulomatous inflammation or asthma

Granulomatous inflammation but no asthma

Granulomatous inflammation, asthma, and eosinophilia

Henoch-Schönlein purpura

Cryoglobulinemic vasculitis

Microscopic polyangiitis

Wegener's granulomatosis

Churg-Strauss syndrome

FIGURE 2-11 Algorithm for differentiating among the major categories of small vessel vasculitis that affect the kidneys. In a patient with signs and symptoms of small vessel vasculitis, the type of glomerulonephritis is useful for categorization. Identification of IgA nephropathy is indicative of Henoch-Schönlein purpura. Type I membranoproliferative glomerulonephritis (MPGN) suggests cryoglobulinemia and/or hepatitis C infection, and pauci-immune necrotizing and crescentic glomerulonephritis suggest some form of ANCA-associated vasculitis [1,2]. The different forms of ANCA vasculitis are distinguished by the presence or absence of certain features in addition to the necrotizing vasculitis, ie, granulomatous inflammation in Wegener’s granulomatosis, asthma and blood eosinophilia in Churg-Strauss syndrome, and neither granulomatous inflammation nor asthma in microscopic polyangiitis. Approximately 80% of patients with active untreated Wegener’s granulomatosis or microscopic polyangiitis have ANCA, but it is important to realize that a small proportion of patients with typical clinical and pathologic features of these diseases do not have detectable ANCA.

2.7

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura)

APPROXIMATE FREQUENCY OF ORGAN SYSTEM INVOLVEMENT IN SMALL VESSEL VASCULITIS

Organ system Renal Cutaneous Pulmonary Gastrointestinal Ear, nose, and throat Musculoskeletal Neurologic

Henoch-Schönlein purpura, % 50 90 35 kg/m2 No

Consider weight reduction program Yes

Age >65? No

Yes

No

Additional risk acceptable?

Hypertension unresponsive to medical management?

No further evaluation

Native kidney nephrectomy

Yes

No Proceed with evaluation

*

90 80 70 60 50 40 30 20 10 0

100

*

*

*

*

*

*

90

*

80 70

* 0

Obese patients Nonobese patients Obese patient grafts Nonobese patient grafts

3

6

9

12

15

18

21

24

Time, mo

Graft survival, %

Survival, %

100

60 50 40 Age 0–5 6–18 19–45 46–60 >60

30 20

FIGURE 12-18 Effects of obesity on patient and graft survival. In this case-control study, 46 obese (body mass index > 30 kg/m2) recipients of cadaveric renal transplantation were compared with nonobese controls matched for the following after transplantation: age, gender, diabetes, panel reactive antibody status, graft number, cardiovascular disease, date of transplantation, and immunosuppression. Survival of patients and grafts was significantly less among obese patients compared with controls (P < 0.01 and P < 0.05, respectively). The following occurred more often in obese versus nonobese patients: delayed graft function, postoperative complications, wound complications, and new-onset diabetes. (From Holley and coworkers [7]; with permission.)

10

n 198 1144 14994 10933 3908

t1/2 15.1 8.7 9.4 9.9 8.0

0 0

1

2

3

4

5

Years after transplantation

FIGURE 12-19 Effects of the recipient’s age on renal allograft survival. Data from the United Network for Organ Sharing Scientific Registry indicate that recipients over the age of 60 have slightly less allograft survival compared with younger recipients. t1/2—graft survival half-life (in years) the first year after transplantation. (From Cecka [3]; with permission.)

12.9

Evaluation of Prospective Donors and Recipients Evaluation of diabetes and hyperparathyroidism in recipients

84.7

Consider simultaneous kidney-pancreas transplantation

Yes

Pancreas graft survival, %

Difficult to control diabetes?

100

No

Symptomatic hyperparathyroidism or uncontrolled hypercalcemia?

Yes

Consider parathyroidectomy

80

73.5

77.4

73.2 69.0

71.4

52.5

46.0 39.4

40

27.7 27.7

20

22.6 Previous kidney transplantation (n=273)

0.25

Proceed with evaluation

Yes

History of recurrent UTIs?

No

No

Yes

Yes

Proceed with evaluation

No Indications for native kidney nephrectomy?

No

No

Consider ureteral diversion or intermittent self-catheterization

Yes Yes Consider native kidney nephrectomy

3.0

4.0

5.0

FIGURE 12-22 Urologic evaluation of transplantation recipients. Patients without signs and symptoms of bladder dysfunction generally do not need additional urologic testing. However, patients with bladder dysfunction must be evaluated to ensure that the bladder is functional after transplantation and that potential sources of urinary tract infection (UTI) are eliminated. Such patients can be screened initially with voiding cystourethrography (VCUG). (From Kasiske and coworkers [1]; with permission.)

No Ultrasonography, cystoscopy, and/or retrograde pyelogram normal?

2.0

FIGURE 12-21 Pancreas graft survival in recipients of pancreatic transplantation with simultaneous, no previous, and previous kidney transplantation. Survival rates of pancreatic grafts are best when pancreatic and kidney transplantations are performed at the same time. (Data from the United Network for Organ Sharing Scientific Registry [8].)

Urologic evaluation in recipients Signs or symptoms of bladder dysfunction?

1.0

Years after transplantation

FIGURE 12-20 Diabetes and hyperparathyroidism. Patients with difficult to control diabetes may be candidates for simultaneous kidney-pancreas transplantation. However, patients with diabetes who have a living donor are generally better off undergoing transplantation with the living donor kidney alone. Patients with symptomatic hyperparathyroidism or uncontrolled hypercalcemia should be considered for parathyroidectomy before transplantation. Medications that interfere with the metabolism of immunosuppressive agents such as cyclosporine should be substituted with appropriate alternatives, if possible, before transplantation. (From Kasiske and coworkers [1]; with permission.)

VCUG normal?

No previous kidney transplantation

39.2

0

Discontinue or reduce risk

Yes

No

Yes

61.8

54.4

60

No

Need for medication that may jeopardize recipient or graft?

Simultaneous kidney transplantation (n=3336)

Bladder insufficiency?

12.10

Transplantation as Treatment of End-Stage Renal Disease PUD and pancreatitis

Evaluation of active colonic disease in recipients Signs or symptoms of active PUD?

Yes

History of diverticulitis?

Yes

No Severe diverticular disease on barium enema?

No

Yes

Consider partial colectomy

Endoscopic or radiographic confirmation? No

No Yes

Other active colonic disease?

Yes

Adequate response to medical management?

Defer transplantation until quiescent

FIGURE 12-23 Diverticulitis and inflammatory bowel disease. Patients with a history of symptomatic diverticulitis must be evaluated for partial colectomy before transplantation. Inflammatory bowel disease generally should be quiescent at the time of transplantation. (From Kasiske and coworkers [1]; with permission.)

No

Consider cadaveric donor

Yes Blood and tissue typing

ABO compatible?

No

Yes T-cell CDC X-match negative?

No

Assess likelihood of false-positive results

Yes Yes

HLA identical?

Presence of autoantibodies?

No

Yes No

Proceed with evaluation

Transplantation

History of pancreatitis?

Yes

Delay transplantation until evaluation and treatment

No Proceed with evaluation

FIGURE 12-24 Peptic ulcer disease (PUD) and pancreatitis. Patients with PUD or pancreatitis must undergo evaluation and treatment before transplantation. Both conditions may be exacerbated by corticosteroids used after transplantation. (From Kasiske and coworkers [1]; with permission.) FIGURE 12-25 Immunologic evaluation for living donor transplantation. Generally, transplantation donors and recipients must have compatible blood groups. Tissue typing is also carried out, and the degree of human leukocyte antigen (HLA) matching may be taken into account in selecting the best living donor when more than one donor is available. Just before transplantation, the recipient’s serum is tested against donor cells to be certain no preformed antibodies are present in the recipient that may cause a hyperacute rejection. A positive crossmatch (X-match) generally precludes transplantation from that donor. CDC—cell-dependent cytotoxicity. (From Kasiske and coworkers [1]; with permission.)

Evaluation of transplantation from a living donor Potential living donor?

Consider pretransplantation surgical treatment

Yes

No Proceed with evaluation

No

Consider other donor

12.11

Evaluation of Prospective Donors and Recipients Donor-specific transfusions in recipients

100 1y

P= 0.02

2444

40

3303

Transplantation

No

P= 0.04

50 15,087

X-match negative?

Yes

60

20,461

Yes

3164

Negative X-match, flow cytometry, or antiglobulin?

Consider DST

76.4%

70

4172

No

19,187

Yes

84%

80

26,585

No

5 y>1 y

90 Adjusted graft survival, %

First transplantation?

Consider other donor

0

1-5

6-10

>10

0

1-5

6-10

>10

0

FIGURE 12-26 Donor-specific transfusion (DST). When the living donor is non– human leukocyte antigen identical and it is the recipient’s first transplantation, some centers use donor-specific blood transfusions before transplantation to enhance graft survival. Unfortunately, donor-specific transfusions may induce the formation of antibodies against the donor that will preclude the transplantation. Most centers have abandoned the use of random blood transfusions as part of the preparation of recipients for cadaveric transplantation. X-match— cross-match. (From Kasiske and coworkers [1]; with permission.)

Immunologic evaluation for cadaveric transplantation No living donor

No First transplantation?

Review typing from previous grafts

Yes PRA ≥11%

No

Autologous X-match positive?

Yes

No

Yes

PRA after DTT or analogous cell adsorption

Identify HLA specificities

Waiting list

Periodic antibody screening

Yes Increasing PRA? No

No

Final CDC X-match negative?

Yes

Transplantation

Number of pretransplantation transfusions

FIGURE 12-27 Effects of random blood transfusions on first cadaveric renal allograft survival. Blood transfusions before transplantation had a small but statistically significant beneficial effect on 1-year graft survival. However, a small reduction occurred in 5-year graft survival (among patients who survived at least 1 year with a functioning kidney) that was attributable to random donor blood transfusions before transplantation (From Gjertson [9]; with permission.) FIGURE 12-28 Immunologic evaluation for cadaveric transplantation. Donors and recipients must have compatible blood groups. Tissue typing is carried out, and the degree of matching is used in the allocation of cadaveric organs. Some data suggest that the presence of human leukocyte antigen (HLA) mismatches that were also mismatched in a previous graft (especially at the DR locus) may lead to early graft loss. Thus, it may be wise to avoid these mismatches. When the percentage of panel reactive antibodies (PRA) is over 10%, tests may be carried out to determine whether some of the antibodies are autoreactive rather than alloreactive. Autoreactive antibodies may not increase the risk for graft loss as do alloreactive antibodies. The presence of high titers of alloreactive antibodies usually is due to previous pregnancies, transplantations, and blood transfusions. Determining antibody specificities may be useful in avoiding certain HLA antigens. In the highly sensitized patient (PRA > 50%) it may be difficult to find a complement-dependent cytotoxicity (CDC) cross-matched (X-match) negative donor. Avoiding blood transfusions may help the titer decrease over time. DTT—1, 4-dithiothreitol (DTT). (From Kasiske and coworkers [1]; with permission.)

12.12

Transplantation as Treatment of End-Stage Renal Disease

100

100

90 80

90

70

80

60

HLA-identical sibling donor (n= 1984) Spousal donor (n= 368) Parental donor (n= 3368) Living unrelated donor (n=129) Cadaveric graft (n= 43,341) Cadaveric graft, urine flow 1st day, no dialysis (n=32,281) Cadaveric graft, no urine 1st day, dialysis required in 1st week (n= 11,060)

50 40 30 20 10 0 0

70 Graft survival, %

Graft survival, %

Evaluation of Prospective Living Donors

3

1 2 Years after transplantation

P< 0.025

60 50 40 30 Graft: HLA-identical 1-haplotype Zero-haplotype

20

FIGURE 12-29 Effects of donor source on renal allograft survival. Data from the United Network for Organ Sharing Scientific Registry were used to compare 3-year graft survival rates between recipients of kidneys from different donor sources. The best graft survival was seen in recipients of human leukocyte antigen (HLA)–identical sibling donors. Grafts from spouses and other living unrelated donors, however, survived just as well as did grafts from parental donors and better than grafts from cadaveric donors. These data have encouraged centers to use emotionally related donors to avoid the long waiting times for cadaveric kidneys. (From Terasaki and coworkers [10]; with permission.)

Candidate for renal transplantation

Yes

Willing and available ABO-compatible living related donor?

No

Yes

No Evaluate for cadaveric transplantation

No

No

Willing and available ABO-compatible emotionally related donor?

Cross-match negative?

t1/2 25.5 16.0 11.9

0 0

1

2

3

4

5

Years after transplantation

FIGURE 12-30 Effects of human leukocyte antigen (HLA) matching on living related graft survival. Graft survival is best for HLA-identical grafts from siblings and next best for one-haplotype mismatched grafts. Importantly, the half-life (t1/2) of grafts that survived at least 1 year is proportional to the degree of matching. This information can be used along with other factors to select the most suitable among two or more living prospective donors. (From Cecka [3]; with permission.) FIGURE 12-31 Use of living donors. A suitable living donor is better than a cadaveric donor because graft survival is better and preemptive transplantation is possible. The best donor usually is a family member. Psychosocial and biological factors must be taken into account when choosing among two or more living prospective donors. Every effort must be made to ensure that the donation is truly voluntary. Caregivers should tell prospective donors that if they do not wish to donate, then friends and relatives will be told “the donor was not medically suitable.” (From Kasiske and coworkers [2]; with permission.)

Choice of living donor versus cadaveric transplantation

Willing to accept living donor?

10

n 2288 3082 808

Yes

Yes Proceed with evaluation

12.13

Evaluation of Prospective Donors and Recipients Preliminary evaluation for a living donor Yes

Economic risk acceptable?

Risk assessment for living donor

Psychosocial evaluation

No

No

Age and renal function acceptable? Yes

No

Voluntarism reasonably certain?

No

Yes

Yes Yes

Surgical risk acceptable?

Financial incentive?

Preliminary medical evaluation

No

No

Long-term risk acceptable?

Yes

Yes Yes

Consider alternative donor

Consider alternative donor

No No Risk acceptable?

Risk of recurrent disease?

HIV, hepatitis, or pregnancy test positive? No

Risk acceptable?

Yes

CMV titer positive or history of tuberculosis?

Yes

Yes

Proceed with evaluation

FIGURE 12-32 Preliminary evaluation of a living prospective donor. The prospective donor must be made aware of the possible costs associated with donation, including travel to and from the transplantation center and time away from work. The prospective donor must undergo a psychological evaluation to ensure the donation is voluntary. A preliminary medical evaluation should assess the risks of transmitting infectious diseases with the kidney, eg, infection with human immunodeficiency virus (HIV) and cytomegalovirus (CMV). (From Kasiske and coworkers [2]; with permission.)

27

Transplantation centers, %

22

20 15 13

13

10 6 3

No age exclusion

55

60

65

70

No

Screening for diabetes negative?

Yes

Proceed with evaluation

FIGURE 12-33 Assessing risks. Older age may place the living prospective donor at greater surgical risk and may be associated with reduced graft survival for the recipient. The prospective donor must be informed of both the short-term surgical risks (very low in the absence of cardiovascular disease and other risk factors) and the long-term consequences of having only one kidney. With regard to long-term risks, it should be considered whether there is a familial disease that the living donor may be at risk to acquire and whether having only one kidney would alter the natural history of renal disease progression. These questions are often most pertinent for relatives of patients with diabetes. (From Kasiske and coworkers [2]; with permission.) FIGURE 12-34 Donor age restrictions used by transplantation centers. Results of an American Society of Transplantation survey of the United Network for Organ Sharing centers showed that many centers either use no specific age exclusion criteria or have no policy. Among those that use an upper age limit, there appears to be a bell-shaped curve, with 65 years of age at the median. (From Bia and coworkers [11]; with permission.)

30

0

Risk of diabetes? No

Yes No

No

75–80

Exclude if age in years is greater than:

No policy or do not know

12.14

Transplantation as Treatment of End-Stage Renal Disease 100 90

90

Progressive effect (each 10 y) (0.3) (1.4) (2.5)

Static effect (–20.2) (–17.1) (–14.0)

88

80 Transplantation centers, %

-20

-15

70

0

5

61

60 (52)

50

Progressive effect (each 10 y) (76) (101)

46

40

0

25

30

50 Proteinuria, mg/d

75

Static effect (2.4)

(–0.3)

20

100

(5.1)

Progressive effect (each 10 y) (0) (1.1) (2.2)

10 0 Mildly elevated FBS

Normal FBS but abnormal GTT

Mild type II diabetes < 50y

0

Mild type II diabetes < 30y

FIGURE 12-35 Screening living prospective donors for diabetes. Results of the survey of the United Network for Organ Sharing centers showed that most centers exclude patients with a mildly elevated fasting blood sugar (FBS) and patients with normal FBS but an abnormal glucose tolerance test (GTT). Most centers exclude donors with mild type II diabetes. (From Bia and coworkers [11]; with permission.)

64 54

50

40

30 20

20 12

10

9

0 Persistently 130/90 mm Hg

2.0 3.0 4.0 Systolic blood pressure, mm Hg

5.0

FIGURE 12-37 Blood pressure (BP) criteria for excluding living prospective donors. Results of the survey of the United Network for Organ Sharing centers showed that most exclude prospective donors who require antihypertensive medication or whose BP is persistently elevated over 130/80 mm Hg. However, most centers do not exclude living prospective donors who occasionally have BP readings over 130/80 mm Hg or patients with so-called white coat hypertension. (From Bia and coworkers [11]; with permission.)

60

Controlled on one BP medication

1.0

FIGURE 12-36 Long-term risks of kidney donation. In a meta-analysis combining 48 studies of the long-term effects of reduced renal mass in humans, no evidence was found of a progressive decline in renal function after a 50% reduction in renal mass. Indeed, a small but statistically significant increase occurred over time in the glomerular filtration rate. A small increase in urine protein excretion occurred; however, the rate of increase per decade was less than that generally considered an abnormal amount of protein excretion, eg, 150 mg/d. A small increase in systolic blood pressure was noted; however, it was not enough to lead to an increase in the incidence of hypertension. Thus, it appears that the long-term risks of kidney donation are very small. Shown are multiple linear regression coefficients and 95% confidence intervals. Failure of the confidence interval to include zero indicates P < 0.05. (From Kasiske and coworkers [12]; with permission.)

70

Transplantation centers, %

-10 -5 Glomerular filtration rate, mL/min

Occasionally 130/90 mm Hg

130/90 mm Hg in doctor's office only

No policy or do not know

12.15

Evaluation of Prospective Donors and Recipients Evaluation of prospective donors with proteinuria, hypertension, or kidney stones

Evaluation of donor risks in recipients with familial renal diseases

No

Proteinuria or pyuria?

Relative with ADPKD? Yes

Yes Evaluation indicates low risk?

Yes Yes

No

Normal renal imaging and low risk for ADPKD?

Hypertension?

Blood pressure high normal? Yes No

Yes

Female with acceptable low risk?

Yes Proceed with evaluation

Evaluate

Yes

Risk acceptable?

FIGURE 12-38 Proteinuria, hypertension, or kidney stones in living prospective donors. Prospective donors with pyuria must be evaluated for possible infection and other reversible abnormalities. Proteinuria is generally a contraindication to donation. Hypertension also must be considered at least a relative contraindication to donation. Patients with a history of nephrolithiasis but no current or recent stones may be considered for donation after first undergoing urologic and metabolic evaluations for stones. (From Kasiske and coworkers [2]; with permission.)

Final evaluation of prospective living donors No

Yes Angiography results acceptable?

Yes

No

Yes Schedule transplantation surgery

Consider alternative donor

No

Yes

Proceed with evaluation

Yes

No

Yes

Cross-match negative?

Male with no hematuria? No

No

History of kidney stones

No

Male with No hematuria?

No

Donor-specific transfusion?

No

Yes

Risk acceptable?

No

Relative with hereditary nephritis?

Yes

No

No

Consider alternative donor

Consider alternative donor

No

Evaluation indicates low risk?

No Yes

Isolated hematuria

FIGURE 12-39 Risks to the related donor when the recipient has familial renal disease. Donors for relatives with autosomal dominant polycystic kidney disease (ADPKD) may be permitted to donate if over 25 years old and results on renal imaging are negative for cysts. Some younger persons may be permitted to donate if genetic studies indicate that the risk for subsequent ADPKD is very low. Male relatives of individuals with hereditary nephritis can be donors if they do not have hematuria. Male relatives with hematuria cannot be donors. Female relatives without hematuria may donate; however, women of child-bearing age who might be carriers must consider the possibility of someday donating a kidney to a child of their own with the disease. Female relatives with hematuria should not donate when other evidence of renal disease exists; however, in the absence of such evidence the exact risk of donation is unknown. Occasionally, donors with isolated microhematuria (not hereditary) and a negative evaluation may be suitable donors. (From Kasiske and coworkers [2]; with permission.) FIGURE 12-40 Final steps in evaluating a living prospective donor. Renal artery angiography is performed to define the anatomy of the renal artery system and exclude other previously undetected abnormalities. Recent studies have shown that spiral computerized tomography can replace angiography without loss of sensitivity or specificity and with less risk and inconvenience to the prospective donor. (From Kasiske and coworkers [2]; with permission.)

12.16

Transplantation as Treatment of End-Stage Renal Disease

Use of Marginal Cadaveric Donor Kidneys FIGURE 12-41 Donor age. When there are no suitable living donors, recipients are placed on the cadaveric waiting list. The transplantation center must always decide whether a particular cadaveric kidney being offered for transplantation is suitable for the individual recipient. The shortage of organs and long waiting times have caused many centers to accept kidneys from older donors and kidneys that may be damaged. Data from the United Network for Organ Sharing clearly demonstrate the decreased graft survival rates of kidneys from older donors. As a compromise, some advocate using kidneys from older donors for older recipients. In any case, so-called marginal kidneys should be offered to recipients with appropriate informed consent. (From Cecka [3]; with permission.)

100 90 80

Graft survival, %

70 60 50 40 Age 6–18 19–30 31–45 46–60 >60

30 20 10

n 6652 7354 7532 6476 1928

t1/2 10.9 11.7 9.8 6.9 5.2

0 0

1

2

3

4

5

Years after transplantation

References 1.

2.

3.

4.

5.

6.

7.

Kasiske BL, Ramos EL, Gaston RS, et al.: The evaluation of renal transplant candidates: clinical practice guidelines. J Am Soc Nephrol 1995, 6:1–34. Kasiske BL, Ravenscraft M, Ramos EL, et al.: The evaluation of living renal transplant donors: clinical practice guidelines. J Am Soc Nephrol 1996, 7:2288–2313. Cecka JM: The UNOS Scientific Renal Transplant Registry. In Clinical Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles: UCLA Tissue Typing Laboratory, 1997:1–14. Periera BJG, Wright TL, Schmid CH, Levey AS: The impact of pretransplantation hepatitis C infection on the outcome of renal transplantation. Transplantation 1995, 60:799–805. Manske CL, Wang Y, Rector T, et al.: Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 1992, 340:998–1002. Ramos EL, Kasiske BL, Alexander SR, et al.: The evaluation of candidates for renal transplantation: the current practice of U.S. transplant centers. Transplantation 1994, 57:490–497. Holley JL, Shapiro R, Lopatin WB, et al.: Obesity as a risk factor following cadaveric renal transplantation. Transplantation 1990, 49:387–389.

8. 1996 Annual Report of the U.S. Scientific Registry for Transplant Recipients and the Organ Procurement and Transplantation Network– Transplant Data: 1988–1995. UNOS, Richmond, VA, and the Division of Transplantation, Bureau of Health Resources Development, Health Resources and Services Administration, U.S. Department of Health and Human Services; 1996. 9. Gjertson DW: A multi-factor analysis of kidney graft outcomes at one and five years posttransplantation: 1996 UNOS Update. In Clinical Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles: UCLA Tissue Typing Laboratory. 1997: 343–360. 10. Terasaki PI, Checka M, Gjertson DW, Takemoto S: High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995, 333:333–336. 11. Bia MJ, Ramos EL, Danovitch GM, et al.: Evaluation of living renal donors. the current practice of US transplant centers. Transplantation 1995, 60:322–327. 12. Kasiske BL, Ma JZ, Louis TA, Swan SK: Long-term effects of reduced renal mass in humans. Kidney Int 1995, 48:814–819.

Medical Complications of Renal Transplantation Robert S. Gaston

W

ith long-term function of allografts increasingly the norm, detection and management of medical complications assume greater importance in the care of renal transplantation recipients. At least two trends in transplantation seem likely to make medical surveillance even more crucial. First, better control of adverse immunologic events early after transplantation has significantly reduced graft loss caused by rejection; the impact of later events (especially death with a functioning organ and chronic rejection) on graft and patient survival is proportionately larger. Second, with successful transplantation now fairly routine, it is being offered to a broader spectrum of candidates, including increasingly older patients with multiple coexisting medical problems. Because more patients with immunosuppression are now being cared for over increasingly longer periods of time, the impact of comorbid events on outcomes must be reduced. Medical complications in the renal allograft recipient represent the often overlapping impact of several variables. At the time of transplantation, significant comorbidity may already be present and can be of immediate concern. Other problems may have originated in the milieu of chronic renal failure, such as hyperparathyroid bone disease or hypertension, but may evolve differently after transplantation. Finally, new complications may result from specific toxicities of pharmaceutical agents, reflecting the overall impact of immunosuppression. In many cases, all of these elements contribute to overt clinical illness. For instance, cardiovascular disease is now the most common cause of death in renal allograft recipients [1]. Coronary disease may have predated transplantation (indeed, coronary disease is a common cause of death among all patients with end-stage renal disease). After transplantation, hypertension and hyperlipidemia, perhaps exacerbated by administration of cyclosporine and corticosteroids, result in accelerated atherosclerosis, further potentiating preexisting cardiac problems. To intervene appropriately requires a comprehensive understanding of all the variables involved: any decision to lessen the impact of one risk factor (eg, withdrawing steroids) may result in unintended consequences (eg, acute rejection).

CHAPTER

13

13.2

Transplantation as Treatment of End-Stage Renal Disease

An obvious prerequisite to caring for transplant recipients is a thorough understanding of immunosuppressive therapies [2]. Although acute rejection can occur at any time, the greatest risk is during the first 90 days after transplantation. Accordingly, immunosuppression is most intense during this time, and the chances of suffering its consequences are great (eg, drug toxicities, infection, and some malignancies [lymphoma]). In general, tapering to a less arduous regimen over time is done, with resulting reduction in the risks of toxicity and infection. With long-term survival, however, the duration rather than the intensity of immunosuppression becomes more critical and strongly influences the risks of other complications, including malignancies (skin), bone disease, and atherosclerosis. Current maintenance immunosuppressive therapy involves multidrug regimens (including azathioprine or mycophenolate mofetil [MMF] and corticosteroids) built around a cornerstone,

the calcineurin-inhibitor (either cyclosporine or tacrolimus) [2]. Therapeutic considerations in treating patients on either of the calcineurin inhibitors are remarkably similar in terms of both adverse effects and drug interactions (Figs. 13-1 and 13-2) [3–5]. Common azathioprine toxicities include bone marrow suppression and alopecia. Because azathioprine is metabolized by xanthine oxidase, concomitant use with allopurinol is problematic. MMF causes less bone marrow suppression than does azathioprine and does not interact with allopurinol, facilitating therapy of gout. However, gastrointestinal complaints (usually dose-related nausea, bloating, or diarrhea) are common. In addition, MMF may exacerbate the gastrointestinal toxicity of tacrolimus. Corticosteroid toxicities are well described; protocols designed to minimize corticosteroid exposure of transplantation recipients remain the ideal pursued by many physicians who treat these patients.

ADVERSE EFFECTS OF CYCLOSPORINE AND TACROLIMUS Renal

Gastrointestinal

Hypertension

Hepatotoxicity (abnormal transaminase levels) Nephrotoxicity (azotemia) Nausea, vomiting, diarrhea (FK > CyA)

Metabolic

Cosmetic

Glucose intolerance (FK > CyA)

Gingival hypertrophy Headache (CyA only, especially Paresthesias in combination with Seizures calcium antagonists) Tremor Hirsutism (CyA > FK)

Hyperkalemia Hyperlipidemia (CyA > FK) Hyperuricemia Hypomagnesemia

COMMON DRUG INTERACTIONS WITH CYTOKINE INHIBITORS Drugs that commonly increase blood levels of cyclosporine and tacrolimus Bromocryptine Cimetidine Clarithromycin Clotrimazole Diltiazem Erythromycin Fluconazole Itraconazole Ketoconazole Mefredil Methylprednisolone Nicardipine Verapamil Drugs that commonly decrease blood levels of cyclosporine and tacrolimus Carbamazepine Phenobarbital Phenytoin Rifampin

Neurologic

FIGURE 13-1 Despite differing structures, both cyclosporine and tacrolimus bind to intracellular receptors in T cells, forming a combination that then inhibits calcineurindependent pathways of cell activation. Although slight differences exist in sideeffect profiles between the two drugs, their overall impact is remarkably similar. In many cases, dose reduction may ameliorate the toxic effect; however, the benefit of dose reduction must be weighed against increasing the risk of acute rejection in each patient. CyA–cyclosporine; FK–tacrolimus.

FIGURE 13-2 Cyclosporine and tacrolimus are subject to remarkably similar interactions, owing in part to a common pathway of metabolic degradation, the cytochrome P-450 enzyme system. Although the drugs listed here predictably alter blood levels of the calcineurin inhibitors, other interactions may also occur.

Medical Complications of Renal Transplantation

FIGURE 13-3 Risk of acute rejection in cadaver kidney transplantation. This graph, derived from the parametric analysis techniques of Blackstone and coworkers [6], depicts the risk of acute rejection over time. Using an immunosuppressive protocol including cyclosporine, mycophenolate mofetil, and prednisone, the risk of acute rejection is greatest during the first 2 months after transplantation, diminishing significantly afterward. Because the risk of rejection is greatest, immunosuppressive therapy is most intense during this period. Correspondingly, complications related to immunosuppressive therapy (including infections and specific drug toxicities) also are most likely during this time.

1.0 0.8 Risk month

13.3

0.6 0.4 0.2 0.0 0

2 4 6 8 10 Months posttransplant

12

Incidence rate

1.0 Rejection Toxicity

0.8 0.6 0.4 0.2 0 5

7.5

10 12.5 15 17.5 20 Tacrolimus level (whole blood), ng/mL

22.5

25

FIGURE 13-4 Relationship between blood levels of tacrolimus, immunosuppressive efficacy, and toxicity [7]. As tacrolimus levels diminish, particularly during the early period after transplantation, the risk of toxicity is reduced accordingly. However, the risk of acute rejection increases. Toxicity still can occur at very low drug levels, as can rejection at high levels. The relationship between these variables beyond the first 6 to 12 months after transplantation is not well established. A similar plot could be constructed for cyclosporine. (Adapted from Kershner and Fitzsimmons [7].)

Complications of Immunosuppression Malignancy Kaposi's (6%)

Other (36%)

Lymphomas (24%)

Skin and lip (34%)

FIGURE 13-5 Types and distribution of malignancies among renal transplant recipients in the current era of cyclosporine use. In these patients the risk of malignancy is increased approximately fourfold when compared with the general population [8]. Malignancies likely to be encountered in the transplantation recipient differ from those most common in the general population [9,10]. Lymphomas and Kaposi’s sarcoma may evolve as a consequence of viral infections. Women are at an increased risk for cervical carcinoma, again related to infection (human papilloma virus). Surprisingly, the solid tumors most commonly seen in the general population (eg, of the breast, lung, colon, and prostate) do not occur with significantly greater frequency among transplant recipients. Nonetheless, long-term care of these patients should involve standard screening for these malignancies at appropriate intervals. (From Penn [9]; with permission.)

13.4

Transplantation as Treatment of End-Stage Renal Disease

FIGURE 13-6 Primary basal cell carcinoma. Cutaneous carcinomas (primarily basal cell and squamous cell) comprise the greatest percentage of tumors in transplant recipients. They tend to be most problematic in fair-skinned persons whose lifestyle includes significant sun exposure; the risk increases with duration of immunosuppression. In immunocompetent patients the risks of these lesions usually are limited; however, in transplant recipients these lesions can be very aggressive and metastasize locally or even systemically. The best management is aggressive prevention: exposure to ultraviolet radiation from the sun should be minimized through diligent use of protective clothing, hats, and sunscreen. When suspicious lesions develop, early recognition and removal are of utmost importance.

FIGURE 13-7 Posttransplantation lymphoproliferative disease (PTLD): histologic appearance of a renal allograft infiltrated by a monoclonal proliferation of B lymphocytes. Non-Hodgkin’s lymphomas, of which PTLD is a variant, occur in 1% to 3% of transplant recipients and in many cases are linked to an infectious cause. PTLD can be of either polyclonal or monoclonal B-cell composition, with lymphocytes driven to proliferate by infection with the Epstein-Barr virus [11–13]. Development of PTLD is strongly linked to the intensity of immunosuppression and may regress with its reduction. However, most often in the setting of splanchnic involvement and monoclonal proliferation, as depicted, PTLD can follow a more aggressive unrelenting course despite withdrawal of immunosuppressive therapy.

Hematologic Complications Serum erythropoietin level, U/L

200 1st peak

2nd peak

150 100 50 25 0

0

10

20

30 40 50 60 Days after transplantation

70

80

FIGURE 13-8 The course of normal erythropoiesis after renal transplantation showing mean serum erythropoietin levels of 31 recipients [14]. An initial burst of erythropoietin (EPO) secretion at the time of engraftment does not result in erythropoiesis. As excellent graft function is achieved, a second burst of EPO secretion is normally followed by effective production of erythrocytes. The hatched area

is the range of serum erythropoietin levels in normal persons without anemia. Anemia is a common complication. Many patients leave the dialysis population with diminished iron stores and are unable to respond to erythropoietin produced by the successful allograft. Iron replacement therapy successfully restores erythropoiesis in these patients. Another common cause of anemia after transplantation is bone marrow suppression owing to drug therapy with azathioprine or mycophenolate mofetil (MMF), an effect that is usually dose-related [15,16]. Other drugs, notably angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, may also inhibit erythropoiesis [17]. Neutropenia also is a common complication after transplantation. It can reflect dose-related bone marrow suppression owing to drug therapy with azathioprine or MMF or an idiosyncratic response to a number of drugs commonly used in this population (acyclovir, ganciclovir, sulfa-trimethoprim, H2 blockers). Alternatively, neutropenia can be a manifestation of systemic viral, fungal, or tubercular infections. The approach to the patient with neutropenia usually involves reducing the dose or discontinuing the potential offending agents, along with a careful search for infections. In some settings of refractory neutropenia, administration of filgrastim (granulocyte colonystimulating factor, Neupogen®) reduces the duration and severity of neutropenia. (From Sun and coworkers [14]; with permission.)

Hematocrit, %

Medical Complications of Renal Transplantation 62 60 58 56 54 52 50 48 46 44 42 40 PRE

1

2 3 4 5 6 9 Months on enalapril (mean 7±4.5 mo)

12

15

13.5

FIGURE 13-9 Posttransplant erythrocytosis (PTE). PTE (a hematocrit of >0.52) affects 5% to 10% of renal transplantrecipients, most commonly male recipients with excellent allograft function [17]. PTE usually occurs during the first year after transplantation. Although it may resolve spontaneously in some patients, PTE persists in many. It has been linked to an increased risk of thromboembolic events; however, our own experience is that such events are uncommon. Previous management involved serial phlebotomy to maintain the hematocrit at 0.55 or less (dashed line). More recently, hematocrit levels have been found to normalize in almost all affected patients with a small daily dose of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist. The pathogenetic mechanisms underlying PTE and its response to these therapies remain poorly understood; although elevated serum erythropoietin levels decrease with ACEI use, other pathways also appear to be involved.

Death rate per 1000 patient years

Cardiovascular Complications 8 Diabetic Nondiabetic

7 6 5 4 3 2 1 0

FIGURE 13-10 Causes of death in renal allograft recipients. Cardiovascular diseases are the most common cause of death, largely reflecting the high prevalence of coronary artery disease in this population [1]. The risks are particularly high among recipients who have diabetes, as many as 50% of whom, even if asymptomatic, may have significant coronary disease at the time of transplantation evaluation [18]. Effective management of cardiac disease after transplantation mandates documentation of preexisting disease in patients at greatest risk [19].

Malignancy Cardiac Infectious Stroke Cause of death in patients with functioning transplants

DEMOGRAPHIC VARIABLES HIGHLY PREDICTIVE OF CORONARY DISEASE IN RENAL TRANSPLANTATION CANDIDATES WITH INSULIN-DEPENDENT DIABETES MELLITUS Age > 45 y Electrocardiographic abnormality: nonspecific ST-T wave changes History of cigarette smoking Duration of diabetes > 25 y

FIGURE 13-11 Demographic variables highly predictive of coronary disease in renal transplantation candidates with insulin-dependent diabetes mellitus. Most transplant centers screen potential candi-

dates, particularly persons with diabetes, for coronary disease before transplantation. In patients with diabetes who have end-stage renal disease with none of the demographic characteristics listed, the risk for coronary disease is low. Conversely, in patients who are insulin-dependent and have any of these risk factors, the prevalence of coronary disease is sufficiently high to justify angiography. A randomized study of medical therapy versus revascularization in transplantation candidates who have insulin-dependent diabetes and coronary disease showed superior outcomes with prophylactic revascularization, even in the absence of overt symptomatology [20]. (Adapted from Manske and coworkers [18].)

13.6

Transplantation as Treatment of End-Stage Renal Disease

75

50

,

n=591

n=429

60

40

45

30

30

20 74%

15

63%

10

0

0 100

200

300

400

70

Cholesterol, mg/dL

130

190

310

LDL, mg/dL

75

40 n=588

,

250

n=430

60

32

45

24

30

16

15

FIGURE 13-12 Hypercholesterolemia and hypertriglyceridemia. Hypercholesterolemia and hypertriglyceridemia are common after kidney transplantation. Approximately two thirds of transplant recipients have low density lipoprotein (LDL) or total cholesterol levels signifying increased cardiac risk; 29% have elevated triglyceride levels 2 years after transplantation (Kasiske, Unpublished data). Not only is hyperlipidemia a clear risk factor for coronary disease (see Figs. 13-13 and 13-14), but it may also contribute to the progressive graft dysfunction associated with chronic rejection [21,22]. HDL—high density lipoprotein. (From Bristol-Myers Squibb [23]; with permission.)

10%

8

29%

0

0 100

200

300

400

0

Triglycerides, mg/dL

35

50

65

80

95

HDL, mg/dL

RISK FACTORS FOR CORONARY MORBIDITY IN RENAL ALLOGRAFT RECIPIENTS

GUIDELINES FOR LIPID-LOWERING THERAPY Diet therapy

Positive

Negative

Age: Male ≥ 45 y Female ≥ 55 y or premature menopause Family history of premature coronary heart disease Smoking Hypertension HDL cholesterol < 35 mg/dL Diabetes mellitus

HDL cholesterol ≥ 60 mg/dL

FIGURE 13-13 Risk factors for coronary morbidity in renal allograft recipients. In addition to elevated low density lipoprotein (LDL) cholesterol levels, risk factors known to contribute to coronary morbidity often are present in renal allograft recipients. About 40% of recipients are over 45 years old, and 23% have diabetes. Smoking, hypertension, and hyperlipidemia are among the risk factors most amenable to long-term modification. (For guidelines in instituting lipid-lowering therapy see Figure 13-14 [24].)

LDL cholesterol, mg/dL

Initiation

Goal

No CHD and