OS 214 E1 20150218 LEC 08 Pathology of Tubular Diseases

MINA, MINA, MIRAL Page 1 of 5

EXAM OS 214: Nephrology Lec 08: Pathology of Tubular Diseases Sonya Chicano, MD

February 18, 2015

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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 setting, patients 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 serum creatinine, much like glomerular and vascular disease

We must determine if it is a glomerula/vascular/tubulo-interstitial disease.

A. Causes of Acute Tubular Necrosis 1. Ischemia due to decreased or interrupted blood flow

o Polyarteritisnodosa o Malignant Hypertension o Hemolytic-uremic syndrome o Decreased effective circulating blood volume

2. Direct Toxic injury to the tubules (Proximal Tubule affected) o Drugs o Radiocontrast dyes o Myoglobin o Hemoglobin o Radiation

3. Acute tubulointerstitial nephritis o Hypersensitivity reaction to drugs

4. Disseminated intravascular coagulation (DIC) 5. Urinary obstruction

o Tumors o Prostatic Hypertrophy o Blood Clots

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 – 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

Figure 1. Pathophysiology of Ischemia and Tubule Cell Injury.

C. Toxic Acute Tubular Necrosis

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: o Mercuric chloride – large acidophilic inclusions,

necrotic, desquamated or calcified o Carbon tetrachloride – neutral lipids in injured cells o Ethylene glycol –marked ballooning and hydropic or

vacuolar degeneration o Calcium oxalate crystals in lumen

Appear the same as ischemic necrosis, so differentiate clinically

D. Clinical Course of Acute Tubular Necrosis

Figure 2. Acute tubular necrosis (L: Tubule with no brush

border cells, sloughing of the epithelial cells, flattened cuboidal cells and widened lumen, with cell debris in the lumen [circle]; R:

Associated with some interstitial infiltrates (circle) but most prominent is tubular damage (rectangle), calcification of cells

(arrow) *note calcification is from the death of cells Dystrophic

calcification CLINICAL COURSE

Highly variable

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

PHASES

Initiation Phase o Lasts for 36 hours o Inciting event o This phase is dominated by this event o E.g. surgery/obstetric shock o Decline in urine output with increase BUN 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

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

II. Tubulointerstitial Nephritis III. Pyelonephritis and Urinary Tract Infection

A. Acute Pyelonephritis B. Polyomavirus (BK Virus Nephropathy)

IV. Chronic Pyelonephritis V. Xanthogranulomatous Pyelonephritis VI. Drug-Induced Tubulointerstitial Nephritis VII. Acute Drug-Induced Interstitial Nephritis VIII. Analgesic Abuse Nephropathy IX. Nephropathy Associated with NSAIDS X. Chinese Herbs Nephropathy XI. Urate Nephropathy XII. Multiple Myeloma XIII. Vascular Diseases

A. Benign Nephrosclerosis B. Malignant Nephrosclerosis C. Renal Artery Stenosis

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Lec 08: Pathology of Tubular Diseases OS214

Recovery phase o Steady rise in urine volume (up to 3L per day) 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 o Vulnerable to infections 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

o Treatment: removal of offending agent and supportive 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 disease

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 o Bacteria from the urethra adheres to the mucosa, going

up the bladder. Abnormality in vesicoureteral valve causes it to enter the ureter and eventually the kidney.

o From Ma’am: We do not like it when it reaches the kidney. This is because there is permanent damage once it the infection resolves.

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

Figure 3. Ascending vs Hematogenous Infection

Most common cause is ascending through the urinary tract.

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

o However, if perform nephrectomy (surgical removal of 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 o Papillary Necrosis – usually seen in diabetics 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. o This could be detected by urinalysis and urine culture

Predisposing conditions o Urinary obstruction o Instrumentation of urinary tract - catheterization o Vesicoureteral reflux (VUR) o Pregnancy 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

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 acute pyelonephritis just by looking at a renal biopsy of a small cortical sample if you

see leukocyte 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 o Urine culture o E. coli and polyoma virus (common in transplant

patients, viral titers for this are done)

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 o Urine decoy cell determination 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

o Positive result is indication for graft biopsy (graft – 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).

Diagnosis: 5 decoy cells per HPF, or 10 decoy cells per LPF.

Then do kidney biopsy to confirm.

Infects only tubular and parietal epithelial cells o This is because parietal cells are connected to the

proximal convoluted tubule (PCT)

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.

IV. CHRONIC PYELONEPHRITIS

Chronic tubulointerstitial inflammation and renal scarring associated with pathologic involvement of the calyces and pelvis

Hallmark

Coarse, discrete, corticomedullary scar overlying a dilated, blunted, or deformed calyx

Two forms o Reflux nephropathy – child with recurrent infection!

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)

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 the fibrous septate(?)

that lines RCCA

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%) and 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 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.

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

Figure 10. Papillary Necrosis and other Associated

Diseases. Note that in analgesic nephropathy, almost all papillae are affected.

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

Figure 11.Papillary Necrosis (Gross and

MIcroscopic).Gross finding shows necrotic material form papillae, filling the calyces. Microscopic features show

necrotic material.

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

o Chronic urate or gouty nephropathy More protracted form of hyperuricemia Deposition of nonsodiumurate crystals Birefringent needle-like crystals in the tubules or

interstitium Tophus – consists of foreign body giant cells,

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 12.Urate Nephropathy.Note white streaks in 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 basement membrane

o Hypercalcemia and hyperuricemia

Acute renal failure or chronic renal failure

Seen in older patients, has poor prognosis (few months-few years)

Figure 13.Multiple Myeloma.Note the casts inside the tubules. Casts

are laminated, resembling annular rings in a tree or appear fractured.

XIII. VASCULAR DISEASES

A. Benign Nephrosclerosis

Kidney associated with sclerosis of renal areterioles and small arteries

Two processes o Medial and intimal thickening

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 14. Hyaline Deposition in Arterioles seen in Benign Nephrosclerosis

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

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 16. a. fibromuscular dysplasia; can be intimal, medial or

adventitial. b. atheromatous plaque with the presence of cholesterol clefts.

One Eight, Dominate!

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