Tubulointerstitial nephritis involves inflammatory reactions in the renal tubules and interstitium. It can be primary, secondary to other renal diseases, idiopathic, reactive to infections, or infectious itself. Acute tubular necrosis is characterized by tubular epithelial cell death due to ischemia or toxins and can cause acute kidney injury. Chronic tubulointerstitial nephritis develops over months or years and is associated with progressive loss of kidney function. It has many etiologies including drugs, infections, obstructive nephropathy, and autoimmune diseases.

1. Tubulointerstitial nephritis

5. Tubulointerstitial disease
• 1. Acute tubular necrosis.
(ischaemic or toxic necrosis of tubular cells)
• 2. Tubulointerstitial nephritis.
(inflammatory reactions involving the tubules and/or
interstitium)

6. • 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.

7. • 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.

8. 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.

9. • 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).

10. • M/S-
• Both PCT and DCT are affected in patchy manner.
• Damage to tubular BM but regeneration is impaired.

11. • 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.

12. • 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.

13. • 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.

16. 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.

17. 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)

18. Acute tubular necrosis
Dilatation of tubules, epithelial flattening, brush border loss in
proximal tubules, and shedding of cells in some of them.

19. 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.

20. 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.

21. 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.

22. Causes of Acute Tubulointerstitial Nephritis
Drugs-
• Antibiotics-
• Ciprofloxacin.
• Ethambutol.
• INH.
• Rifampicin.
• Anticonvulsants-
• Carbamazepine.
• Phenobarbitone.
• Phenytoin.
• Valproate.
NSAIDs-
• Diclophenac.
• Ibruprofen.
• Indomethacin.
Diuretics-
• Frusemide.
• Thiazides.

23. 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.

24. 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.

25. 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.

26. 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 .

27. 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.

28. Causes
• Urinary tract obstruction- Congenital/Acquired.
• VUR.
• Catheterization.
• Pregnancy.
• Diabetes mellitus.
• BPH.
• Immunospuppression and immunodeficiency.

29. Pathogenesis

30. 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).

31. • 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.

32. Acute pyelonephritis.
Discrete, yellowish, raised abscesses are grossly apparent
on the cortical surface .

33. • 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.

34. Acute pyelonephritis.
Acute neutrophilic exudate with tubules
and in the renal substance.

35. Complications of acute pyelonephritis
• Papillary necrosis.
• Pyonephrosis.
• Perinephric abcess.

36. Papillary necrosis
• Seen mainly in diabetics and with urinary tract
obstruction.
• Usually B/L.
• One or all pyramids of affected kidney are
involved.

37. Papillary necrosis.
Tips or distal two thirds of the pyramids shows areas of grey white to yellow necrosis.

38. 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.

39. 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.

40. 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.

41. 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.

42. • 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.

43. • 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.

44. • 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.

45. • 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.

46. Chronic pyelonephritis.
Scars associated with VUR.

47. 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.

48. Chronic pyelonephritis.
Contracted granular kidney

49. Chronic inflammatory infiltrate
and fibrosis are present in the
renal interstitium.
Atrophic tubules with chronic
inflammatory infiltrate in
interstitium.

50. Chronic pyelonephritis.
Referred to as “thyroidization”, this histopathological picture is due
to dilation of tubules which contain eosin-staining proteinaceous
material.

51. The glomerulus reveals collapse
or solidification of tuft, and
sclerosis change.
Sclerosis of glomeruli with
atrophic tubules.

52. 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.

53. The renal parenchyma is showing presence
of yellow nodules.
Xanthogranulomatous
pyelonephritis.
Accumulation of foamy
macrophages, intermingled with
lymphocytes and PMN.

54. 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.

55. • 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.

56. 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.

57. 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.

58. 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

59. 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.

60. • 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.

61. • 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.

62. • 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.

63. Chronic tubulointerstitial nephritis.
The interstitium is expanded by fibrosis, with distortion of
tubules and periglomerular fibrosis. Glomeruli do not show
pathologic changes.

64. 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.

65. 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.

66. 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).

67. • 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.

68. • 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.

69. Drug induced interstitial nephritis.
The mononuclear inflammatory infiltrate contains abundant eosinophils.
Severe tubular damage is observed.

70. • 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.

71. 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.

72. • 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.

73. 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.

74. • 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.

75. • 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.

76. • 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.

77. • 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.

78. 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.

79. • 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.

80. 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.

81. • 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.

82. M/S-
• Interstitial nephritis with mononuclear cell infiltrate.
• Less interstitial infiltrate and eosinophils as
compared to others.
• Occasional granulomas can be seen.

83. Urate nephropathy
• Three types-
• Acute uric acid nephropathy.
• Chronic urate nephropathy.
• Nephrolithiasis.

84. 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.

85. • 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.

86. • The finding of a urine uric acid/creatinine ratio>1
distinguishes acute uric acid nephropathy from other
causes of renal failure.

87. Uric acid crystals

88. 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.

89. • 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.

90. Nephrolothiasis
• Uric acid stones are present in 22% patients of gout
and 42% with secondary hyperuricemia.

91. Chronic urate nephropathy.
Pale yellowish tan tophaceous deposits in the medulla.

92. Urate crystals in the renal medulla. Note the giant cells
and fibrosis around the crystals

93. 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.

94. 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.

95. • 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.

96. • 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.

97. 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).

98. 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.

99. • 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.

100. Myeloma cast nephropathy.
Many atrophic tubules filled with eosinophilic casts which are
surrounded by giant cell reactions.

101. 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.

102. • 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.

103. • 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.

104. • 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.

105. • 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.

106. 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.

107. • 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.

108. • 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.

109. 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.

110. 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.

111. • 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.

112. 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).

113. 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.

114. BALKAN ENDEMIC NEPHROPATHY
• Endemic in Europe.
• Related to local toxin.
• Clinically patients with chronic interstitial nephritis
develop CRF.

115. 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.

116. Polyoma virus nephropathy.
Enlarged tubular epithelial cells with
nuclear inclusions and interstitial
inflammation.

117. 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.