OS 214 E1 20150218 LEC 08 Pathology of Tubular Diseases

OS 214: Nephrology

EXAM

Lec 08: Pathology of Tubular Diseases

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February 18, 2015

Sonya Chicano, MD

TOPIC OUTLINE I.

Acute Tubular Necrosis  A. Causes of Acute Tubular Necrosis B. Ischemic Acute Tubular Necrosis C. Toxic Acute Tubular Necrosis D. Clinical Course of Acute Tubular Necrosis Necrosis II. Tubulointerstitial Tubulointerstitial Nephritis III. Pyelonephritis Pyelonephritis and Urinary Tract Infection Infection  A. Acute Pyelonephritis Pyelonephritis B. Polyomavirus (BK Virus Nephropathy) IV. Chronic Pyelonephritis V. Xanthogranulomatous Xanthogranulomatous Pyelonephritis Pyelonephritis VI. Drug-Induced Tubulointerstitial Tubulointerstitial Nephritis VII. Acute Drug-Induced Drug-Induced Interstitial Nephritis Nephritis VIII. Analgesic Analgesic Abuse Nephropathy IX. Nephropathy Associated with NSAIDS X. Chinese Herbs Nephropathy XI. Urate Nephropathy XII. Multiple Myeloma XIII. Vascular Diseases  A. Benign Nephrosclerosis Nephrosclerosis B. Malignant Nephrosclerosis C. Renal Artery Stenosis

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I. ACUTE TUBULAR NECROSIS A clinico-pathologic entity characterized by destruction of tubular epithelial cells and acute suppression of renal function Also known as Acute Kidney Injury (AKI) Acute Tubular Necrosis (ATN) is fairly common Common in hospital hospital setting, setting, patients patients present present with complicated history and clinical course Eventually the patient will develop oliguria or anuria Most common cause of Acute Renal Failure (ARF) o Rapid reduction of renal function and renal flow, falling within 24 hours to less than 400 mL per day Presents with increased increased serum creatinine, much like glomerular and vascular disease We must determine if it is a glomerula/vascular/tubuloglomerula/vascular/tubulointerstitial disease. A. Causes of Acute Tubular Necrosis Ischemia due Ischemia  due to decreased or interrupted blood flow o  Polyarteritisnodosa o Malignant Hypertension o Hemolytic-uremic Hemolytic-uremic syndrome Decreased effective circulating blood volume o Direct Toxic injury  injury  to the tubules (Proximal Tubule affected) o  Drugs o Radiocontrast dyes Myoglobin o  o  Hemoglobin o  Radiation Acute tubulointerstitial tubulointerstitial nephritis o Hypersensitivity Hypersensitivity reaction to drugs Disseminated intravascular coagulation (DIC) Urinary obstruction o  Tumors o Prostatic Hypertrophy o Blood Clots

Figure 1. Pathophysiology of Ischemia and Tubule Cell Injury.

C. Toxic Acute Tubular Necrosis 

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D. Clinical Course of Acute Tubular Necrosis

Figure 2. Acute tubular necrosis (L: necrosis (L: Tubule with no brush border cells, sloughing of the epithelial cell s, flattened cuboidal cells and widened lumen, with cell debris in the lumen [circle]; R:  Associated with with some interstitial interstitial infiltrates (circle) (circle) but most prominent is tubular damage (rectangle), calcification of cells (arrow) *note calcification is from the death of cells  Dystrophic calcification CLINICAL COURSE  

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B. Ischemic Acute Tubular Necrosis Focal tubular epithelial necrosis with skip areas (destruction is patchy) since it depends on blood supply  Interstitial edema Epithelial regeneration – regeneration – some cells appear reactive Rupture of Tubular Basement Membrane (TBM) and occlusion of tubular lumina by casts May manifest histologically as: o Sloughing of the epithelial cells, o Blebbing in the early stages o Calcifications or mitotic figures

Highly variable Treatment is supportive e.g. hydration and removal of cause (important to know causative agent to know the treatment)

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MINA, MINA, MIRAL

Affects the proximal convoluted tubules (because this is where most reabsorption takes place) May be non-specific Some agents have distinct findings (however we usually don’t see this)such as: Mercuric chloride  –   –  large acidophilic inclusions, o necrotic, desquamated or calcified o Carbon tetrachloride – tetrachloride – neutral  neutral lipids in injured cells o Ethylene glycol  –marked  –marked ballooning and hydropic or vacuolar degeneration Calcium oxalate crystals in lumen o Appear the same as ischemic necrosis, so differentiate clinically

Initiation Phase o Lasts for 36 hours o Inciting event o This phase is dominated by this event o E.g. surgery/obstetric surgery/obstetric shock Decline in urine output with increase BUN o o  Oliguria   Due to transient decrease in blood flow to kidneys Maintenance phase o Sustained decrease in urine output to between 40-400 ml/day (oliguria) o Salt and water overload  due to abnormality of the patients hemodynamics o Rising BUN, hyperkalemia, metabolic acidosis o  Dialysis   patient may need temporary dialysis until the kidney can recover

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Lec 08: Pathology of Tubular Diseases

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Recovery phase Steady rise in urine volume (up to 3L per day) o o Tubules still damaged (urine spillage of water Na and K) o Clue when you see glucosuria in non-diabetic patients o  Hypokalemia  Clinical problem Vulnerable to infections o o Recovery is variable Nephrosis may return to normal after several  months since it is an acute case Some cases have a repeat biopsy done and  results show similar clinical findings Treatment: removal of offending agent and supportive o therapy Prognosis o Depends on the underlying cause o Toxic (removal of offending agent) vs. Ischemic (address the underlying cause) Shock related to sepsis, extensive burns or other causes of mult-organ failure >50% mortality II. TUBULO-INTERSTITIAL NEPHRITIS (TIN) Involves the renal parenchyma Etiology of Primary Tubulointerstitial Nephritis o  Infections Acute bacterial pyelonephritis  Chronic pyelonephritis (including reflux  nephropathy) Other infections (e.g. Viruses, parasites)  o  Toxins Drugs   Acute hypersensitivity interstitial nephritis  Analgesic nephritis  Heavy metals  Lead, Cadmium  o Metabolic Diseases Uratenepropathy   Nephrocalcinosis (hypercalcemic nephropathy)  Hypokalemic nephropathy  Oxalate nephropathy  o Physical factors Chronic urinary tract obstruction  Radiaton nephritis  o  Neoplasms Multiple myeloma  o Immunologic Reactions Transplant rejection  Sjögren syndrome  o Vascular Diseases o  Miscellaneous Balkan nephropathy  Nephronophthisis – medullary cystic d isease   complex Other rare causes (sarcoidosis)  “idiopathic” interstitial nephritis  Etiology of Secondary Tubulointerstitial Nephritis o Secondary to a glomerular disease (e.g. Crescentic Glomerulonephritis   very active glomerulus   very active tubules  lots of inflammatory cells) May be acute or chronic Must be differentiated from glomerular diseases o Look at the glomeruli. If there are abnormalities/infiltrates that are out of proportion (too much infiltrates despite a normal looking glomeruli), think of possible Primary Acute Tubulointerstitial Nephritis o If there are overactive glomeruli, think of Secondary  Acute Tubulointerstitial Nephritis Infection is usually ascending Bacteria from the urethra adheres to the mucosa, going o up the bladder. Abnormality in vesicoureteral valve causes it to enter the ureter and eventually the kidney. o

From Ma’am:

Figure 3. Ascending vs Hematogenous Infection Most common cause is ascending through the urinary tract.

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A. Acute Pyelonepthritis Involves the renal pelvis (pyelo = pelvis) o Cannot be reached by renal biopsy because it’s too deep; thus, diagnosis is usually limited to acute tubuloinsterstital nephritis However, if perform nephrectomy (surgical removal of o the kidneys), and we see inflammation of the renal pelvis aside from the parenchyma, then we consider it as acute pyrlonephritis Acute suppurative inflammation  caused by bacterial infection Complications Papillary Necrosis – usually seen in diabetics o o  Pyonephrosis  –  purulent material in renal pelvis (pyo=pus) o Perinephric abscess  –  infection extends outside the kidneys, infecting surrounding fat and adjacent structures. Prompt diagnosis and treatment is required among suspected patients to avoid nephrectomy. This could be detected by urinalysis and urine culture o Predisposing conditions o Urinary obstruction o Instrumentation of urinary tract - catheterization o Vesicoureteral reflux (VUR) Pregnancy o  o Patinet’s sex and age – older patients, usually females o Preexisting renal lesions o Diabetes Mellitus o Immunosuppression and immunodeficiency Kidneys are larger than normal due to the infection

We do not like it when it reaches the

kidney. This is because there is permanent damage once it the infection resolves.

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III. PYELONEPHRITIS AND URINARY TRACT INFECTION Ascending Infection o Most common, more common than hematogenous o Colonization of the distal urethra and introitus by coliform bacteria o From the urethra to the bladder o Multiplication in the bladder o Vesicoureteral reflux (incompetence of vesicoureteral valve) o Intrarenal reflux

Mina, Mina, Miral

Figure 4.Acute Pyelonephritis. Microabscessces (circled) – pinpoint finely granular surface, neutrophils (dark spots, upper right image), Leukocyte casts (arrow) From Ma’am: You can suggest a c u t e p y e l o n e p h r it i s j u s t b y lookin g at a renal biopsy of a sm all cortical samp le if you see leukocy te casts within tubules.

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Manifestations o Pain at the costovertebral angle (kidney punch sign) o Fever and malaise o Dysuria, frequency, and urgency o Pyuria, leukocyte casts Urine culture o o E. coli and polyoma virus (common in transplant patients, viral titers for this are done)

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B. POLYOMAVIRUS (BK VIRUS NEPHROPATHY) Most common viral infection in kidney transplant patients Three variants o BK – common cause of infection o SV (Simian virus) & JC – rarely causes infection BK  –  initials of Sudanese patient who first diagnosed with the virus Came about due to the more aggressive immunosuppressive drugs given to transplant patients Diagnosis Urine decoy cell determination o o Freshly voided urine + special fixative   observe the nuclei of the cells from urine  Positive result: nuclear clearing with chromatin pushed to the sides o A positive urine decoy cell determination test indicates infection anywhere along the urinary tract Positive result is indication for graft biopsy (graft  – o transplanted organs) If graft biopsy indicates infection, treatment is by lowering immunosuppressive drugs and anti-viral agents

Figure 5. Polyomavirus (BK virus) nephropathy. Urine decoy cells (left) – screening test, and graft biopsy with infected cells (right). Note the nuclear clearing, ground glass appearance and chromatin pushed to the periphery (circle).

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Coarse, discrete, corticomedullary scar overlying a dilated, blunted, or deformed calyx Two forms Reflux nephropathy – child w ith recurrent infection! o More common  Occurs in early childhood as a result of infection  on congenital vesicoureteral and intrareal reflux o Chronic obstructive pyelonephritis Grossly appears as coarsely granular cortical surface with irregularity o Vs. acute pyelonephritis which presents with pinpoint microabscesses o Irregularities of the surfaces are due to the scars

Figure 6.Chronic Pyelonephritis (gross). Note the coarsely granular and irregular cortical surface.

Figure 7.Chronic Pyelonephritis (microscopic).Features similar to end stage renal disease; however, there is involvement of the renal pelvis. Note the ff: interstitial infiltrates, sclerosis (circle), and colloid casts/thryoidization (arrow)

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Diagnosis: 5 decoy cells per HPF, or 10 decoy cells per LPF. Then do kidney biopsy to confirm.

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Infects only tubular and parietal epithelial cells This is because parietal cells are connected to the o proximal convoluted tubule (PCT)

V. XANTHOGRANULOMATOUS PYELONEPHRITIS Unusual and rare Associated with Proteus infection and obstruction Yellow orange nodules Differential diagnosis with Renal Cell CA (similar foamy macrophages) o Sometimes, frozen section may lead to misdiagnosis because these appear as clear cells, wherein macrophages can resemble RCCA

Figure 8.Xanthogranulomatous Pyelonephritis. Note the yellow orange nodules (arrow) on gross specimen and foamy macrophages (circle) on microscopic specimen, you can see bubbly cytoplasm but not t he fibrous septate(?) that lines RCCA Figure 6.Polyoma virus infection imaging. (clockwise, from top left) 1. immunostaining with SV-40, infected epithelial cells - Take note of the nuclei, not the cytoplasm. 2. Infected cells (circled) with chromatin pushed to the side, and inclusion (virus) present. 3. Viral particles seen in a paracrystalline array. You can see more cells in an SV-40 stain.

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IV. CHRONIC PYELONEPHRITIS Chronic tubulointerstitial inflammation and renal scarring associated with pathologic involvement of the calyces and pelvis Hallmark

Mina, Mina, Miral

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VI. DRUG-INDUCED TUBULOINTERSTITIAL Produce renal in 3 ways o They may trigger an interstitial immunologic reaction (acute hypersensitivity reaction) o They may cause Acute Renal Failure o They may cause subtle but cumulative injury (CRI)  – more chronic VII. ACUTE DRUG-INDUCED INTERSTITIAL NEPHRITIS Penicillins (methicillins, ampicillins), synthetic antibiotics (rifampicin), diuretics (thiazides), NSAIDS (phenylbutazones) and miscellaneous drugs (cimetidine) Withdrawal of drug leads to full recovery

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Disease begins at about 15 days (2-40 days) after exposure to the drug Patients may present with fever, eosinophilia (may be transient),rash (25%) a nd renal abnormailities Hematuria, mild proteinuria, and leukocyturia A rising serum creatinine level or acute renal failure with oliguria develop in 50% One needs to review medications to determine which one causes the injury Figure 11.Papillary Necrosis (Gross and MIcroscopic).Gross finding shows necrotic material form papillae, filling the calyces. Microscopic features show necrotic material. 

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Figure 9.Acute Drug-Induced Interstitial Nephritis.Note eosinophils (Ma’am says it is a bonus, because sometimes you cannot see this). Make sure however that DIIN is still part of your Ddx.

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VIII. ANALGESIC ABUSE NEPHROPATHY A form of chronic renal disease caused by excessive intake of analgesic mixtures and characterized morphologically by CTIN Complications Transitional Cell CA (TCCA) of renal pelvis Large quantities of mixtures of at least 2 antipyretic analgesics Aspirin, caffeine and acetaminophen (a metabolite of phenacetin) Papillary Necrosis o Sloughing off of papillae o Not only seen in analgesic nephropathy, but also in other diseases (see Figure 10). o Mixture of aspirin and phenacetin o Combined with water depletion Papillary Necrosis occurs first Cortical tubulointerstitial nephritis is a secondary phenomenon

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More common in women, psychoneurotic patients and factory workers due to recurrent headaches and muscle pains Headache, anemia, and gastrointestinal symptoms accompany analgesic nephropathy X. CHINESE HERBS NEPHROPATHY Aristolochic acid – component associated with nephropathy Increased incidence of carcinoma in the kidney and urinary tract For those who are fond of drinking chinese herbs and other supplements – be careful! Sometimes very subtle, and persists for several months, and biopsy reveals chronic changes   only then the clinician elicited in the history the intake of chinese herbs XI. URATE NEPHROPATHY Three types o Acute uric acid nephropathy Caused by precipitation of uric acid crystals in the  renal tubules leading to obstruction of nephrons and development of acute renal failure Leukemias and lymphomas who are undergoing  chemotherapy Drugs increase the death of tumor cells and uric  acid is released as the nuclei of these cells disintegrate Chronic urate or gouty nephropathy o More protracted form of hyperuricemia  Deposition of nonsodiumurate crystals  Birefringent needle-like crystals in the tubules or  interstitium Tophus – consists of foreign body giant cell s,   mononuclear cells and a fibrotic reaction Subtle disease, slowly progressive  o  Nephrolithasis – large stones Uric acid stones present in 22% of patients with  gout Uric acid stones present in 42% of patients with  secondary hyperuricemia Very big stones 

Figure 10. Papillary Necrosis and ot her Associated Diseases. Note that in analgesic nephropathy, almost all papillae are affected. 

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Acetaminophen injures cells by both covalent binding and oxidative damage Aspirin induces its effect by inhibiting the vasodilatory effects of prostaglandin, predisposing the papillae to ischemia Injury due to a combination of direct toxic effects and ischemia Prone to development of transitional cell CA of the renal cell pelvis

Mina, Mina, Miral

Figure 12.Urate Nephropathy.Note white streaks i n gross (circles) which are crystals, and needle-like pattern in microscopic finding (spaces once occupied by crystals, which dissolves during slide preparation) surrounded by inflammatory cells

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XII. MULTIPLE MYELOMA Renal involvement by multiple myeloma is sometimes an ominous manifestation Renal damage is brought about by: o Bence-Jones proteinuria and cast nephropathy Bence-Jones tubular casts appear as pink to blue  amorphous masses, sometimes concentrically laminated, surrounded by multinucleated giant cells Some light chains are directly toxic to epithelial  cells Bence-Jones proteins combine with Tamm Horsfall protein to form casts that obstruct tubules and produce an inflammatory reaction. o  Amyloidosis Accumulation of light chains with predisposition to  form amyloid fibrils (6-24% of myeloma patients) o Light chain deposition disease Deposited in the glomerular basement membrane  and mesangium and tubular ba sement membrane o Hypercalcemia and hyperuricemia Acute renal failure or chronic renal failure Seen in older patients, has poor prognosis (few months-few years)

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Figure 14. Hyaline Deposition in Arterioles seen in Benign Nephrosclerosis

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B. Malignant Nephrosclerosis Renal disease associated with accelerated or malignant phase of hypertension Flea-bitten kidney Fibrinoid necrosis of arterioles Hyperplastic arteriolitis --- onion skinning Diastolic BP of >130 mmHg Papilledema retinopathy Encephalopathy Cardiovascular abnormalities Renal failure Hypertensive crises o Loss of consciousness and convulsions

Figure 15. a. Fibrinoid necrosis. RBCs may be seen within the vascular wall. b. Hyperplastic arteriolitis – onion skinning

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C. Renal Artery Stenosis Unilateral --- uncommon cause of HPN Most common cause is occlusion by atheromatous plaque at the origin of the renal artery Fibromuscular dysplasia --- fibrous or fibromuscular thickening of intima, media or adventitia

Figure 13.Multiple Myeloma.Note the casts inside t he tubules. Casts are laminated, resembling annular rings in a tree or appear fractured.

XIII. VASCULAR DISEASES A. Benign Nephrosclerosis 

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Kidney associated with sclerosis of renal areterioles and small arteries Two processes Medial and intimal thickening o Response to hemodynamic changes, aging,  genetic defects or a combination o Hyaline deposition in arterioles Caused partly by extravasation of plasma proteins  through injured endothelium and partly by increased deposition of basement membrane matrix

Figure 16. a. fibromuscular dysplasia; can be intimal, medial or adventitial. b. atheromatous plaque with the presence of cholesterol clefts.

One Eight, Dominate! End of Transcription

Mina, Mina, Miral

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