Tubulointerstitial nephritis


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Tubulointerstitial nephritis

  1. 1. Tubulointerstitial nephritis
  2. 2. Tubulointerstitial disease • 1. Acute tubular necrosis. (ischaemic or toxic necrosis of tubular cells) • 2. Tubulointerstitial nephritis. (inflammatory reactions involving the tubules and/or interstitium)
  3. 3. • Primary TIN-  Inflammation is limited to tubules and interstitium, glomeruli or vessels are uninvolved or may show minor changes. • Secondary TIN-  Inflammation associated with a primary glomerular, vascular or systemic disease. • Idiopathic TIN-  Unknown pathology.
  4. 4. • Reactive TIN-  Tubulointerstitial inflammation from effects of systemic infections, where kidneys are usually sterile. • Infectious TIN-  Tubulointerstitial inflammation from the effects of localization, of live micro-organisms in the kidneys, from where they can be identified and can be cultured.
  5. 5. Acute tubular necrosis • It is a clinicopathologic entity characterized morphologically by destruction of tubular epithelial cells and clinically by acute diminution or loss of renal function. • Most commonly secondary to ischaemia, but can also be due to direct toxic cell damage and is potentially reversible, since tubular cells can regenerate given time.
  6. 6. • ATN due to ischaemia due to  Shock (rapid uncompensated fall in systemic BP)  e.g. in trauma, burns, falciparum malaria, pancreatitis, sepsis, DIC, blood transfusion reactions etc OR  Reduction in intrarenal blood flow (RPGN, acute interstitial nephritis, urinary obstruction).
  7. 7. • M/S- • Both PCT and DCT are affected in patchy manner. • Damage to tubular BM but regeneration is impaired.
  8. 8. • ATN due to toxins • Heavy metals. • Organic solvents – CCl4, chloroform. • Drugs – antibiotics (gentamicin), anti-viral agents, NSAIDs, mercurial, diuretics. • Iodinated contrast agents used for X rays. • Pesticides. • Glycols – ethylene glycol.
  9. 9. • M/S- • Proximal tubules are selectively damaged. • Tubular simplification- Dilated and lined by reactive appearing or flattened cells. • Disappearance of brush border of PCT. • Frank necrosis of tubular cells with sloughing into tubular lamina with loss of nuclei. • Interstitial oedema, hyaline cast and cast containing necrotic cellular debris inside. • Intact tubular BM and tubular regeneration is possible. • Pigmented cast with brownish orange color – Haemolytic conditions and rhabdomyolysis.
  10. 10. • In mercuric chloride poisoning-  Dead cells contain large acidophilic inclusions.  Later these cells become totally necrotic and are desquamated in lumen and may undergo calcification. • Carbon tetrachloride-  Accumulation of lipid in injured cells followed by necrosis. • Ethylene glycol-  Marked ballooning and hydropic degeneration of PCTs.  Calcium oxalate crystals in tubular lumen.
  11. 11. Clinical course • Clinically variable, but classically in 3 phases – • Initiation (~ 36 hrs) (often missed) – slight increase in urine output and rise in serum urea. • Oliguric/Maintenance – urine output 400 ml or less/day, so Na+, K+ & water retention, rising urea, metabolic acidosis –danger of pulmonary oedema & cardiac dysrhythmias. • Diuretic/Recovery – urine output above normal, so loss of water, Na & K – danger of dehydration.
  12. 12. Pathophysiology of 3 phases • Initiation– tubular cells begin to lose concentrating ability. • Oliguric – tubular epithelium lost, so there is reabsorption of most of the glomerular filtrate. • Diuretic – regenerating epithelium can’t yet concentrate, but does prevent much reabsorption. (once concentrating ability restored, complete return to normal)
  13. 13. Acute tubular necrosis Dilatation of tubules, epithelial flattening, brush border loss in proximal tubules, and shedding of cells in some of them.
  14. 14. Severe acute tubular necrosis. Masses of cells (“fallen”) are observed in the lumina of tubules; there is complete denudation of some of them and almost complete obstruction of their lumina.
  15. 15. Regenerative changes in a patient with acute tubular necrosis. Most of tubular cells present high N:C ratio, large nuclei with prominent nucleoli and mitosis.
  16. 16. Tubulointerstitial nephritis • Acute TIN- • Associated with ARF. • Develops over period of days to several weeks due to either acute infection of kidneys or delayed hypersensitivity reaction to medication. Chronic TIN- • Develops over months or years. • Associated with progressive loss of GFR over time and characterized by many syndromes of renal tubular dysfunction.
  17. 17. Causes of Acute Tubulointerstitial Nephritis Drugs- • Antibiotics- • Ciprofloxacin. • Ethambutol. • INH. • Rifampicin. • Anticonvulsants- • Carbamazepine. • Phenobarbitone. • Phenytoin. • Valproate. NSAIDs- • Diclophenac. • Ibruprofen. • Indomethacin. Diuretics- • Frusemide. • Thiazides.
  18. 18. Fungal- • Candida. Immunologic- • Cryoglobulinemia. • IgA nephropathy. • Renal transplant rejection. • Sarcoidosis. • SLE (rare). • Sjögren's syndrome. • Wegener's granulomatosis. Neoplastic • Lymphoma. • Myeloma. Metabolic- • Hyperoxalaturia (Ethylene glycol poisoning). • Hyperuricosuria (Tumor lysis syndrome). Bacterial- • Brucella. • Corynebacterium diphtheriae. • Legionella. • Leptospira. • Mycobacterium. • Mycoplasma. • Rickettsia. • Salmonella. • Streptococci. • Staphylococci. • Treponema pallidum. • Yersinia.
  19. 19. Causes of Chronic Tubulointerstitial Nephritis Cystic diseases- • Acquired cystic disease. • Medullary cystic disease. • Medullary sponge kidney. • Nephronophthisis. • Polycystic kidney disease. Drugs- • Analgesics. • The Antineoplastics. • The imunosuppressants. • Lithium. Granulomatous- • Inflammatory bowel disease. • Sarcoidosis. • TB. • Wegener's granulomatosis. Hematologic- • Aplastic anemia. • Leukemia. • Lymphoma. • Multiple myeloma. • Sickle cell anemia.
  20. 20. Immunologic- • Amyloidosis • Cryoglobulinemia • Goodpasture's syndrome • IgA nephropathy • Renal transplant rejection • Sarcoidosis • Sjogren's syndrome • SLE. Infection- • Renal parenchymal: pyelonephritis. • Hantavirus—Puumula type infection (nephropathia epidemica) • Systemic. Mechanical- • Obstructive uropathy. • Reflux nephropathy. Metabolic- • Chronic hypokalemia. • Cystinosis. • Fabry's disease • Hypercalcemia. • Hypercalciuria. • Hyperoxaluria. • Hyperuricemia. • Hyperuricosuria.
  21. 21. Toxins- • Aristocholic acid. • Heavy metals (arsenic, bismuth, cadmium, chromium, copper, gold, iron, lead, mercury, uranium). Vascular- • Atheroembolism. • Hypertension. • Renal vein thrombosis. • Radiation nephritis. • Hereditary nephropathy associated with hyperuricemia and gout. • Idiopathic .
  22. 22. Acute pyelonephritis • It is an acute suppurative inflammation of the kidney caused by bacterial and viral infections, whether haematogenous and induced by septicaemic spread or ascending and associated with VUR.
  23. 23. Causes • Urinary tract obstruction- Congenital/Acquired. • VUR. • Catheterization. • Pregnancy. • Diabetes mellitus. • BPH. • Immunospuppression and immunodeficiency.
  24. 24. Pathogenesis
  25. 25. The vesicoureteral junction. In normal individuals (A), the intravesical portion of the ureter is oblique, such that the ureter is closed by muscle contraction during micturition. The most common cause of reflux is congenital complete or partial absence of the intravesical ureter (B).
  26. 26. • C/F- • Fever, malaise, dysuria, urgency, frequency. • PS shows significant leukocytosis and bacteria are detectable in Gram-stained unspun urine. • Pyuria. • Leukocyte casts are present in the urine of some patients, and the detection of these casts is pathognomonic. • Hematuria may be demonstrated during the acute phase of the disease.
  27. 27. Acute pyelonephritis. Discrete, yellowish, raised abscesses are grossly apparent on the cortical surface .
  28. 28. • Microscopy- • Patchy interstitial suppurative inflammation. • Intratubular aggregates of neurtophils. • Tubular necrosis. • Collecting tubules in cortex and medulla are filled with neutrophils. • Early stages- Neutrophilic infiltration limited to interstitial tissues. • Later stages- Involvement of tubules and produces abscess with destruction of engulfed tubules. • Glomeruli are spared.
  29. 29. Acute pyelonephritis. Acute neutrophilic exudate with tubules and in the renal substance.
  30. 30. Complications of acute pyelonephritis • Papillary necrosis. • Pyonephrosis. • Perinephric abcess.
  31. 31. Papillary necrosis • Seen mainly in diabetics and with urinary tract obstruction. • Usually B/L. • One or all pyramids of affected kidney are involved.
  32. 32. Papillary necrosis. Tips or distal two thirds of the pyramids shows areas of grey white to yellow necrosis.
  33. 33. Pyonephrosis • When there is total or complete obstruction, particularly when it is high in the urinary tract. • Suppurative exudate is unable to drain and thus fills renal pelvis, calyces and ureters.
  34. 34. Chronic pyelonephritis • It is a chronic tubulointerstitial renal disorder in which chronic tubulointerstitial inflammation and renal scarring are associated with pathologic involvement of calyces and pelvis. • It is an important cause of end stage kidney disease. • It is divided in two forms-  Chronic reflux associated  Chronic obstructive.
  35. 35. Reflux nephropathy • More common form of chronic pyelonephrotic scarring. • Renal involvement occurs in early childhood as a result of superimposition of a urinary infection on congenital VUR and intrarenal reflux. • Reflux may be unilateral or bilateral. • It occasionally causes renal damage in the absence of infection but only if obstruction is severe.
  36. 36. Chronic obstructive pyelonephritis • Obstruction predisposes the kidney to infection. • Recurrent infections due to obstruction leads to recurrent bouts of renal inflammation and scarring. • Parenchymal atrophy. • Can be unilateral or bilateral.
  37. 37. • The kidneys have an irregular surface, with depressions and granular aspect. • In the nonobstructive pyelonephritis parenchymal involvement can be focal, leaving ample areas of spared parenchyma. • The collecting system usually is dilated and the parenchyma is narrowed in both types of pyelonephritis, but this dilatation and narrowing are more prominent in obstructive causes, sometimes giving a multicystic appearance.
  38. 38. • It is very important to determine, macroscopically, that these cavities are interconnected each to other and with the renal pelvis (hydronephrosis) to differentiate it from an actual multicystic kidney disease. • When the narrowing and loss of the parenchyma are prominent- Renal atrophy.
  39. 39. • Microscopically it is characterized by interstitial fibrosis with inflammatory infiltrates mainly lymphocytes and plasma cells, and tubular atrophy. • Similar changes can be caused by hypertensive nephropathy, chronic glomerulopathies, diabetic nephropathy, and many other alterations. • Therefore, to diagnose chronic pyelonephritis we must study very well all the renal compartments, evaluate medullary papillas, pelvis and calyces, and correlate with the clinical and radiological data.
  40. 40. • Collapsed tubules mixed with expanded tubules lined by flattened epithelium with cylinders of colloid give an aspect similar to the follicles in the thyroid gland called as thyroidization. • Deposits of Tamm-Horsfall’s protein may be present focally in the interstitium. • Periglomerular sclerosis or FSGS. • Hyaline arteriosclerosis.
  41. 41. Chronic pyelonephritis. Scars associated with VUR.
  42. 42. Chronic pyelonephritis. The cystic appearing structures are actually dilated calyces, reflecting hydronephrosis. The renal parenchyma between the dilated calyces show reduction in tissue when compared to the more normal renal parenchyma of the lower pole.
  43. 43. Chronic pyelonephritis. Contracted granular kidney
  44. 44. Chronic inflammatory infiltrate and fibrosis are present in the renal interstitium. Atrophic tubules with chronic inflammatory infiltrate in interstitium.
  45. 45. Chronic pyelonephritis. Referred to as “thyroidization”, this histopathological picture is due to dilation of tubules which contain eosin-staining proteinaceous material.
  46. 46. The glomerulus reveals collapse or solidification of tuft, and sclerosis change. Sclerosis of glomeruli with atrophic tubules.
  47. 47. Xanthogranulomatous pyelonephritis • Characterized by prominent granulomatous inflammation with abundant lipid loaded macrophages. • It is very frequently associated to obstruction and stones. • The etiology is not completely understood, but bacterial infections, mainly E. Coli and Proteus, Klebsiella, Pseudomonas and Staphylococcus aureus and urinary obstruction are very important in the pathogenesis. • The disease is usually unilateral and it is not associated with renal failure.
  48. 48. The renal parenchyma is showing presence of yellow nodules. Xanthogranulomatous pyelonephritis. Accumulation of foamy macrophages, intermingled with lymphocytes and PMN.
  49. 49. Acute interstitial nephritis • Variety of clinical manifestations with RF. • 2 types-  Hypersensitivity(Drug induced).  Related to systemic infections. • M/S- • Inflammatory interstitial process composed of lymphocytes, plasma cells with tubulitis.
  50. 50. • Hypersensitivity-  Due to antibiotics, diuretics and NSAIDs.  M/S- Eosinophils may comprise significant component of inflammatory infiltrate.  Granulomatous interstitial process with tubulitis may be seen. • Systemic infections-  AIN associated with systemic infections are not common.
  51. 51. Acute interstitial nephritis. The diagnosis is based on the active inflammatory infiltrate on the right with unaffected glomeruli. Interstitial edema and fibrosis are present on the left side of the field, where some tubules show thickened basement membrane.
  52. 52. Chronic tubulointerstitial nephritis • Very common in association with glomerular, interstitial and vascular conditions. • Multiple etiologies. • Use of lithium, exposure to lead, sarcoidosis and Sjogren’s syndromes, renal TB, chronic granulomatous infections are most common etiological agents.
  53. 53. Altered filtration Tubular ischemia Reabsorption of noxious macromolecules Vascular damage Glomerular disease Chronic tubular cell injury Release of cytokines, proteinases adhesion molecules, growth factors ΔCell balance Fibroblast proliferation ↑Matrix deposition ↑ Recruitment of antigenically activated cells Tubular atrophy Interstitial fibrosis Interstitial infiltrates Tubular dysfunction ↓ Capillary perfusion
  54. 54. Clinical features • Symtomps of renal insufficiency. • ARF. • Erythematous maculopapular skin rash, fever, arthralgias, peripheral eosinophilia(Drug induced). • Microscopic haematuria and pus cells. • Eosinophils > 1% of the cells- Characetristic of interstitial nephritis.
  55. 55. • Mild proteinuria < 1gm/24 hours. • If proximal tubules are effected- Renal glucosuria, aminoaciduria, phosphaturia and uricosuria. • If distal tubule is effected- Potassium secretion and sodium balance regulation suffer. • If both tubules are affected- Renal tubular acidosis. • Medullary inflammation- Inappropriate urinary concentration and polyuria.
  56. 56. • M/S- • Pathological findings in tubulointerstitial compartment. • Late stages all three compartments are affected. • Interstitial fibrosis, tubular atrophy. • Inflammatory cells (lymphocytes and plasma cells) are seen in between tubules with no tubulitis.
  57. 57. • Loss of glomeruli can occur indirectly from severe tubular damage in nephron segments of glomerulus or due to periglomerular fibrosis and segmental sclerosis eventually leading to global glomerular sclerosis. • Medullary microcysts from hypokalemia. • Cast formation (thyroidization) occurs. • In some cases granulomatous process are noted- Exclude Sarcoidosis. • Granuloma + necrosis- Exclude infections and whether patient is immunosuppressed.
  58. 58. Chronic tubulointerstitial nephritis. The interstitium is expanded by fibrosis, with distortion of tubules and periglomerular fibrosis. Glomeruli do not show pathologic changes.
  59. 59. Granulomatous interstitial nephritis. Ischemic glomerulus surrounded by isolated atrophic tubules and granulomatous inflammation with sheets of epithelioid histiocytes. On the right side of the picture is a well-formed granuloma.
  60. 60. Tubulointerstitial nephritis induced by drugs and toxins • 3 ways of renal injury- • Triggers an interstitial immunologic reaction. • May cause ARF. • Injury to tubules resulting in chronic renal insufficiency.
  61. 61. Acute drug induced interstitial nephritis • Antibiotics (penicillins, cephalosporins, sulfonamides, tetracyclines, vancomycin, ciprofloxacin). • NSAID (salicylic acid, ibuprofen, naproxen, indomethacin, sulindac, mefenamic acid). • Diuretics (thiazides, furosemide, triamterene, chlortalidone). • Others (acetaminophen, captopril, cimetidine, ranitidine, phenobarbital, phenytoin, lithium, interferon, acyclovir, cyclosporine).
  62. 62. • Disease begins about 15 days after the exposure of drug. • Fever, rash, malaise and pain. • Eosinophilia, oliguria, glucosuria, aminoaciduria, phosphaturia, raised urinary creatinine, renal acidosis and proteinuria.
  63. 63. • Interstitial oedema, mononuclear inflammatory infiltrate consisting of lymphocytes and macrophages. • Eosinophils and neutrophils may be present. • Multinucleated giant cells; in some cases there are non-caseous granulomas (Methicillin and Thiazides). • Tubulitis (Infiltration of tubules by lymphocytes). • Glomeruli and vessels typically appear normal in acute IN.
  64. 64. Drug induced interstitial nephritis. The mononuclear inflammatory infiltrate contains abundant eosinophils. Severe tubular damage is observed.
  65. 65. • Tubulointerstitial nephritis and uveitis syndrome (TINU/Dobrin syndrome). • It happens in children and adults and it is commonest in women. • The cause is unknown but it is related to an immunological mechanism. • The histologic picture shows interstitial inflammation by lymphocytes, plasma cells, monocytes, neutrophils, and sparse eosinophils, granulomas, tubular necrosis and epithelial regeneration. • There are no glomerular or vascular lesions. • Favourable prognosis.
  66. 66. Analgesic nephropathy • Caused by excessive intake of analgesics and characterized by chronic tubulointerstitial nephritis with renal papillary necrosis. • AN predominates in women . • AN was originally described in conjunction with overuse of combination analgesics containing phenacetin. • However, despite removal of phenacetin from the market, AN continued to occur.
  67. 67. • Acetaminophen, caffeine, codeine and other NSAIDs have been implicated. • The phenacetin metabolite injures cells by both covalent binding and oxidative damage. • Aspirin- Inhibits vasodilatory effects of prostaglandin, predisposing the papillae to ischaemia.
  68. 68. Pathogenesis • Morphologically, analgesic nephropathy is characterized by papillary necrosis and tubulointerstitial inflammation. • At an early stage, damage to the vascular supply of the inner medulla (vasa recta) leads to a local interstitial inflammatory reaction and, eventually, to papillary ischemia, necrosis, fibrosis, and calcification.
  69. 69. • Renal function usually declines gradually. • Occasionally, papillary necrosis may be associated with hematuria and even renal colic owing to obstruction of a ureter by necrotic tissue. • Unable to generate maximally concentrated urine, reflecting the underlying medullary and papillary damage. • An acquired form of distal RTA may contribute to the development of nephrocalcinosis. • Anaemia- Out of proportion due to damage to RBCs by phenacetin metabolites.
  70. 70. • A “ring sign” on the pyelogram is pathognomonic of papillary necrosis and represents the radiolucent sloughed papilla surrounded by the radiodense contrast material in the calyx. • CT may reveal papillary calcifications surrounding the central sinus complex in a “garland” pattern. • Transitional cell carcinoma may develop in the urinary pelvis or ureters as a late complication of analgesic abuse.
  71. 71. • Grossly kidneys are either normal or reduced in size. • Cortex exhibits depressed and raised areas, depressed areas exhibit cortical atrophy overlying necrotic papillae. • Papillae show necrosis, calcification, fragmentation and sloughing.
  72. 72. • M/S- • Papillary changes. • Early stages- patchy necrosis. • Later stages- • Entire papilla is necrotic, ghosts of tubules, foci of dystrophic calcification. • Cortical changes- Loss and atrophy of tubules, interstitial fibrosis and inflammation.
  73. 73. Nephropathy associated with NSAIDs • NSAIDs are commonly used drugs. • COX-2 inhibitors. • COX-2 has been detected in renal tissues, medullary interstitial cells, macula densa, thick ascending limb of Henle, smooth muscle cells and endothelial cells of arterioles and veins.
  74. 74. • Patient may present with- • Varying degrees of proteinuria. • Sodium retention, oedema. • Haematuria. • Renal insufficiency. • Oligohydramnios with congenital renal insufficiency may occur in inutero exposure of fetus to NSAIDs which may cause bleeding diathesis, premature closure of ductus arteriosus and ileal perforation. • Risk factors- • Chronic renal disease, Elderly patients, Dehydration, Decreased cardiac output, Liver cirrhosis.
  75. 75. Associated syndromes • Acute tubular necrosis. • Acute renal failure due to inhibition of PG sythesis by NSAIDs. • Interstitial nephritis and minimal change disease. • Membranous glomerulonephritis with nephrotic syndrome.
  76. 76. • C/F- • Headaches. • ARF/CRF. • Haematuria. • Significant proteinuria. • Defects of urinary concentration, acidification and sodium retention. • Useful criteria for diagnosis-  Shrinkage of renal mass.  Bumpy renal contours.  Papillary calcifications.
  77. 77. M/S- • Interstitial nephritis with mononuclear cell infiltrate. • Less interstitial infiltrate and eosinophils as compared to others. • Occasional granulomas can be seen.
  78. 78. Urate nephropathy • Three types- • Acute uric acid nephropathy. • Chronic urate nephropathy. • Nephrolithiasis.
  79. 79. Acute uric acid nephropathy • Acute overproduction of uric acid and extreme hyperuricemia often lead to a rapidly progressive renal insufficiency, so-called acute uric acid nephropathy. • Usually seen as part of the tumor lysis syndrome in patients given cytotoxic drugs for the treatment of lymphoproliferative or myeloproliferative disorders. • Drugs cause death of tumour cells and uric acid is released by disintegration of nuclei.
  80. 80. • Deposition of uric acid crystals in the kidneys and their collecting systems, leading to partial or complete obstruction of collecting ducts, renal pelvis, or ureter. • Since obstruction is often bilateral, patients typically follow the clinical course of acute renal failure, characterized by oliguria and rapidly rising serum creatinine concentration. • In the early phase uric acid crystals can be found in urine, usually in association with microscopic or gross hematuria.
  81. 81. • The finding of a urine uric acid/creatinine ratio>1 distinguishes acute uric acid nephropathy from other causes of renal failure.
  82. 82. Uric acid crystals
  83. 83. Chronic urate nephropathy/Gouty nephropathy • Patients with less severe but prolonged forms of hyperuricemia are predisposed to a more chronic tubulointerstitial disorder, often referred to as gouty nephropathy. • Histologically, the distinctive feature of gouty nephropathy is the presence of crystalline deposits of uric acid and monosodium urate salts in distal tubules, collecting duct and interstitium.
  84. 84. • These deposits not only cause intrarenal obstruction but also incite an inflammatory response, leading to lymphocytic infiltration, foreign-body giant cell reaction, and eventual fibrosis, especially of medullary and papillary regions of the kidney. • Since patients with gout frequently suffer from hypertension, arterial and arteriolar thickening is common.
  85. 85. Nephrolothiasis • Uric acid stones are present in 22% patients of gout and 42% with secondary hyperuricemia.
  86. 86. Chronic urate nephropathy. Pale yellowish tan tophaceous deposits in the medulla.
  87. 87. Urate crystals in the renal medulla. Note the giant cells and fibrosis around the crystals
  88. 88. Urate nephropathy. Chronic urate nephropathy leads to deposition of uric acid crystals in intersitium, forming tophi with surrounding foreign body inflammation, mononuclear cell infiltrates, and fibrosis. The long, needle-shaped crystals form the pale mass shown here at high magnification.
  89. 89. Hypercalcemic nephropathy • Chronic hypercalcemia, as occurs in primary hyperparathyroidism, sarcoidosis, multiple myeloma, vitamin D intoxication, or metastatic bone disease, can cause tubulointerstitial damage and progressive renal insufficiency. • Clinically, the most striking defect is an inability to concentrate the urine maximally, resulting in polyuria and nocturia. • Reduced collecting duct responsiveness to vasopressin and defective transport of NaCl in the ascending limb of Henle’s loop are responsible for this.
  90. 90. • Reductions in GFR and renal blood flow also occur, both in acute severe hypercalcemia and with prolonged hypercalcemia of lesser severity. • Eventually, uncontrolled hypercalcemia leads to severe tubulointerstitial damage and overt renal failure. • Abdominal x-rays may demonstrate nephrocalcinosis as well as nephrolithiasis, the latter due to the hypercalciuria that often accompanies hypercalcemia.
  91. 91. • The earliest lesion is a focal degenerative change in renal epithelia, primarily in collecting ducts, distal convoluted tubules, and loops of Henle. • Tubule cell necrosis leads to nephron obstruction and stasis of intrarenal urine, favoring local precipitation of calcium salts and infection. • Dilatation and atrophy of tubules eventually occur, as do interstitial fibrosis, mononuclear leukocyte infiltration, and interstitial calcium deposition (nephrocalcinosis). • Calcium deposition may also occur in glomeruli and the walls of renal arterioles.
  92. 92. Right nephrectomy with birefringent deposits of oxalate in the renal interstitium. These crystals (arrow 1), varying in size, were surrounded by foreign body giant cells. Note the presence of areas of tubular atrophy and fibrosis (arrow 2).
  93. 93. Plasma Cell Dyscrasias • Several glomerular and tubulointerstitial disorders may occur in association with plasma cell dyscrasias. • Infiltration of the kidneys with myeloma cells is infrequent. • When it occurs, the process is usually focal, so renal insufficiency from this cause is also uncommon. • The more usual lesion is myeloma kidney characterized histologically by atrophic tubules, with many eosinophilic intraluminal casts, and numerous multinucleated giant cells within tubule walls and in the interstitium.
  94. 94. • Bence-Jones proteins are thought to cause myeloma kidney through direct toxicity to renal tubule cells. • In addition, Bence-Jones proteins may precipitate within the distal nephron where the high concentrations of these proteins and the acid composition of the tubule fluid favour intraluminal cast formation and intrarenal obstruction. • Further precipitation of Bence-Jones proteins can be induced by dehydration, which should, therefore, be avoided.
  95. 95. Myeloma cast nephropathy. Many atrophic tubules filled with eosinophilic casts which are surrounded by giant cell reactions.
  96. 96. LEAD NEPHROPATHY • Lead intoxication may produce a chronic tubulointerstitial renal disease. • Children who repeatedly ingest lead-based paints (pica) may develop kidney disease as adults. • Significant occupational exposure may occur in workplaces where lead-containing metals or paints are heated to high temperatures, such as battery factories, smelters, salvage yards, and weapon firing ranges.
  97. 97. • Tubule transport processes enhance the accumulation of lead within renal cells, particularly in the proximal convoluted tubule, leading to cell degeneration, mitochondrial swelling, and eosinophilic intranuclear inclusion bodies rich in lead. • In addition, lead nephropathy is associated with ischemic changes in the glomeruli, fibrosis of the adventitia of small renal arterioles, and focal areas of cortical scarring. • Eventually, the kidneys become atrophic.
  98. 98. • Patients with chronic lead nephropathy are characteristically hyperuricemic a consequence of enhanced reabsorption of filtered urate. • Acute gouty arthritis (so-called saturnine gout) develops in about 50% of patients with lead nephropathy, in striking contrast to other forms of chronic renal failure in which de novo gout is rare. • Hypertension is also a complication.
  99. 99. • Therefore, in any patient with slowly progressive renal failure, atrophic kidneys, gout, and hypertension, the diagnosis of lead intoxication should be considered. • Features of acute lead intoxication (abdominal colic, anemia, peripheral neuropathy, and encephalopathy) are usually absent. • The diagnosis may be suspected by finding elevated serum levels of lead.
  100. 100. • However, because blood levels may not be elevated even in the presence of a toxic total-body burden of lead, the quantitation of lead excretion following infusion of the chelating agent calcium disodium edetate is a more reliable indicator of serious lead exposure. • Urinary excretion of >0.6 mg/d of lead is indicative of overt toxicity, but even lead burdens of 0.08–0.6 mg/d may cause progressive loss of renal function.
  101. 101. LITHIUM • Use of lithium salts for bipolar disorder is associated with chronic tubulointerstitial nephropathy. • Nephrogenic diabetes insipidus, which may occur alone or in association with the renal insufficiency, is common. • It manifests as polyuria and polydipsia and is due to lithium-induced down regulation of the vasopressin- regulated water channels in the collecting duct.
  102. 102. • Mild proteinuria and hypercalcemia due to lithium-induced hyperparathyroidism are common. • The predominant finding on renal biopsy is tubular atrophy and interstitial fibrosis out of proportion to the extent of glomerular or vascular disease. • Tubular cysts are common, and concomitant focal segmental glomerulosclerosis can be observed.
  103. 103. • Renal function should be followed in patients taking this drug, and caution should be exercised if lithium is employed in patients with underlying renal disease. • Once renal impairment occurs, lithium therapy should be stopped and an alternative agent substituted. • Despite discontinuation of lithium, chronic renal disease in such patients is often irreversible and can progress to end-stage renal failure.
  104. 104. Chinese herbs nephropathy • It is characterized by rapidly progressive interstitial renal fibrosis in young women due to ingestion of weight-reduction pills containing Chinese herbs; at least one of the culprit ingredients is aristolochic acid. • Clinically, patients present with progressive chronic renal insufficiency with sterile pyuria and anemia that is proportionately severe relative to the level of renal function.
  105. 105. Malacoplakia • Unusual inflammatory condition with very characteristic pathological finding. • Affects urinary tract as well as other organs. • Females>males. • E.coli is causative agent and this condition results from improper bacterial processing and clearance. • Gross- • Affected kidney is small, discrete, yellowish-brown nodules or patches.
  106. 106. • M/S- • Aggregates of histiocytes containing basophilic PAS positive lamellated inclusions, occasionaly with targetoid appearance in their cytoplasm, termed as Michaelis-Guttman bodies. • Inclusions are positive for calcium and can be highlighted by Von Kossa stain.
  107. 107. Malacoplakia. Collections of large histiocytes with granular eosinophilic cytoplasm: Von Hansemann cells. The cytoplasm contains abundant basophilic inclusions with a variable size: Michaelis-Gutmann bodies. Some of them are laminated and others have targetoid appearance (arrows).
  108. 108. Radiation Nephritis • Renal dysfunction can be expected to occur if ≥ 23 Gy (2300 rad) of x-ray irradiation is administered to both kidneys. • It can present acutely or chronically with renal failure, moderate to malignant hypertension, anemia, and proteinuria that may reach the nephrotic range. • M/S- Hyalinized glomeruli and arterioles, atrophic tubules, and extensive interstitial fibrosis.
  109. 109. BALKAN ENDEMIC NEPHROPATHY • Endemic in Europe. • Related to local toxin. • Clinically patients with chronic interstitial nephritis develop CRF.
  110. 110. Polyoma virus nephropathy • Polyoma virus (PV) can cause interstitial nephritis and lead to graft failure in renal transplant recipients. • Also termed as BK virus nephropathy. • It has been associated with premature loss of kidney function in renal transplant patients and should therefore be considered in the differential diagnosis of renal allograft dysfunction.
  111. 111. Polyoma virus nephropathy. Enlarged tubular epithelial cells with nuclear inclusions and interstitial inflammation.
  112. 112. References • Robins and Cotran pathologic basis of disease, 7th edition. • Heptinstall's pathology of the kidney, Volume 1 by J. Charles Jennette, Robert H. Heptinstall. • Silverberg’s principles and practice of surgical pathology and cytopathology, fourth edition. • Tubulointerstitial Diseases of the Kidney by Alan S. L. Yu, Barry M. Brenner. • Kelly CJ, Neilson EG: Tubulointerstitial diseases, in Brenner and Rector’s The Kidney 7th edition.