This document discusses tubulointerstitial disorders, which are diseases affecting the renal tubules and interstitium. Tubulointerstitial disorders are distinguished from glomerular diseases by the absence of nephritic or nephrotic syndrome and the presence of tubular dysfunction manifesting as defects in concentration ability, polyuria, nocturia, and metabolic acidosis. Common tubulointerstitial disorders discussed include acute tubular necrosis, tubulointerstitial nephritis, pyelonephritis, drug-induced tubulointerstitial nephritis, analgesic nephropathy, and diseases causing hypercalcemia and nephrocalcinosis.

1. Disease affecting the tubules
and Interstitium
Most disorders affecting tubules
also involve interstitium – grouped
as tubulo-interstitial disorders

2. Clinically, How are TI disorders
distinguished from glomerular
diseases?
• Early course – Absence of nephritic or nephrotic
syndrome
• Presence of Defects in tubular function
(concentration ability)
• Polyuria, nocturia, salt wasting, disturbance in
secretion of acid (metabolic acidosis)
• Late course : difficult to distinguish from
glomerular diseases

3. Tubulo-interstitial disorders
• Acute tubular necrosis(ATN)
• Tubulo-interstitial nephritis

4. Acute renal failure
• Acute suppression of renal function and
urine flow <400ml /24 hrs
• Causes : Pre-renal, intra-renal & Post
renal
• Most common cause is Acute tubular
necrosis

5. What is ATN?
• Clinico-pathologic entity characterized
morphologically by destruction of tubular
epithelial cells and clinically by ARF.
• It is important to recognize because by
early management, this condition is
reversible.
• 2 major causes – Ischemia & Toxins

7. Pathogenesis of ATN
• Tubular cell injury
Reversible Irreversible
Loss of polarity & detachment
Distal Na delivery Obstruction by casts Necrosis
Apoptosis
Vasoconstriction Reduced tubular flow
Reduced GFR ----------Oliguria

8. Acute Renal Failure

9. Pathogenesis

10. Morphology – Ischemic type ATN
– Focal tubular necrosis at multiple points
along the entire nephron (with long skip
areas)
– History of recent hemorrhage, hypotension,
surgery
– Urinalysis: Muddy (dirty)brown granular or
tubular epithelial cells casts

11. Acute tubular necrosis
• Tubules showing necrosis of lining
epithelial cells

12. Ischemic tubular necrosis
• Tubules in acute tubular necrosis are dilated and lined by atrophic
epithelium. Some contain characteristic pigment casts

13. Morphology – Nephrotoxic type
ATN
– Produces predominantly proximal tubule
damage (No skip segments) with sparing of
the distal tubules and basement membranes
– Mercury – Injured cells contain acidophilic
inclusions later calcify
– Ccl4 –accumulation of lipids with necrosis
– Ethylene glycol – Ca oxylate crystals in lumen
– Better prognosis than Ischemic Type

14. ATN-Nephrotoxic type -Ethylene glycol
• Tubular cells undergoing ballooning and vacuolar
degeneration

15. ATN - Ethylene glycol
• Ca Oxalate crystals in tubular lumen by
polarizing microscopy

16. ATN – Clinical course
– Initiation phase: (upto 36) Grossly the kidneys
are swollen and edematous.
– Slight decline in urine output & raise in BUN
– Maintenance phase: After 1-2 weeks, Urine
output the lowest(40-400ml/day) , electrolyte
imbalances, hyperkalemia & uremic
manifestations.
– Recovery phase: Tubular regeneration
occurs with normal renal function returning
after tubular cells mature (after three weeks).
Initially, there is polyuria until the tubular
cells mature
– Often there is hypokalemia

17. Tubulo - Interstitial Nephritis
• Infections – pyelonephritis
• Toxins
• Metabolic disorders
• Neoplasms
• Immunologic reactions
• Vascular diseases
• Radiation

18. Pyelonephritis
• Renal disorder affecting tubules, interstitium and renal
pelvis
• Etiology & Pathogenesis:
• 85% Gram negative bacilli – E.coli, proteus, klebsiella
• 2 routes
• Hematogenous route – Non-enteric organisms Ex-Staph
• Ascending infection :
• From urethra to bladder
• Multiplication in the bladder
• Vesico-ureteral reflux (incompetance of VU valve)
• Intra-renal reflux

19. VU reflux

20. Intra-renal reflux

21. Acute Pyelonephritis
• Suppurative bacterial infection (E. coli most
common organism)- grossly focal discrete
abscess in 1 or both kidneys
• Microscopically – Neutrophilic infiltration of
interstitium & tubules
• Clinical: most patients are young women
between the ages of 15 and 40 years

22. Acute Pyelonephritis
• Sudden onset of costovertebral angle
tenderness, fever, chills, nausea and vomiting,
and lower urinary tract signs of dysuria and
frequency of urination
• Laboratory-urinalysis
– Bacteriuria, WBCs (Pyuria), WBC casts (key finding –
casts are formed only in tubules)
• Complications: chronic pyelonephritis,
Pyonephrosis, perinephric abscess, papillary
necrosis, septicemia and endotoxin shock

23. Acute PN
• In the lower pole of this
kidney is a 1 cm pale
yellow abscess

24. Acute Pyelonephritis
• PMN in the
tubules
and
interstitium

25. Renal papillary necrosis
• Notice the pale
grey zones in the
papillae
surrounded by an
hyperemic zone.
These are actually
regions of
necrosis, so-
called renal
papillary necrosis.
• Seen in diabetics
and Acute PN

26. Chronic Pyelonephritis
• Progression of acute pyelonephritis
• 2 types:
• Reflux type is most common and relates to VUR
beginning in childhood
• Obstructive type due to obstruction in lower urinary tract
with infection
These result in large scarred areas of the kidney and distortion of
the pyramids
Clinical presentation may be silent, gradual onset renal
insufficiency, hypertension
Late stages – Present with proteinuria due to FSGS and end stage
renal failure
• Diagnosis: IVP-flattening of the calyces underlying
cortical scars

27. • Hall mark lesion: U-shaped Cortico-
medullary scar overlying a blunted, dilated,
deformed calyx

28. Chronic Pyelonephritis
• The typical large
“geographic “
scarring and the
distortion of the
pyramids is seen
here.(Asymmetric
scarring seen
here, Contrast
with CGN, which
is symmetric)

29. Chronic Pyelonephritis
• Chronic inflammatory cells in tubules & interstitium,
Arrows point to plasma cells

30. Chronic PN
• Hallmark micro feature:Thyroidization (colloid casts
in tubules) is typical of chronic pyelonephritis. This
will result in broad casts in the urine sediment.

31. Xanthogranulomatous
pyelonephritis
• Form of C. pyelonephritis
• Gross – large yellowish nodules
• Accumulation of foamy macrophages and
giant cells
• Associated with Proteus infection

32. Acute Drug-Induced Tubulointerstitial
Nephritis (hypersensitivity nephritis)
• Acute onset (approx. 15 days after drug exposure-
although most patients require several weeks of drug
exposure before developing renal injury) of azotemia,
oliguria, fever, EOSINOPHILIA , rash, mild to
moderate proteinuria, and hematuria on occasion
• Frequently occurs with synthetic antibiotics Ex-
Methicillin, Ampicillin
• An immunologic reaction involving type I or type IV
hypersensitivity
• Eosinophils in the urine are a good marker of a drug-
induced hypersensitivity reaction
• Renal failure occurs in 50% of patients
• Biopsy – Edema, infiltration of eosinophils and
inflammatory cells in interstitium. Sometimes
granuloma and giant cells can be seen

33. Drug induced TI nephritis
• Biopsy - Numerous
eosinophils

34. Analgesic Abuse Nephropathy
• Form of renal disease with intake of analgesic
mixtures presenting with chronic tubulo-
interstitial nephritis and renal papillary necrosis
• analgesic abuse - (aspirin + Phenacetin or
acetaminophen)
• Acetaminophen is the metabolite of
phenacetin that causes injury to cells by
forming free radicals;
• Aspirin inhibits prostaglandin synthesis and
when combined with acetaminophen, normal
vasodilatation effects of prostaglandins are
inhibited producing ischemic injury to the
renal papillae

35. Analgesic Abuse Nephropathy
• Papillary necrosis occurs first followed by
tubulointerstitial nephritis
• All papillae are affected but in different stages of
necrosis (contrast with diabetes where all
papillae are same stage of necrosis) with
dystrophic calcification, sloughing
• Micro – necrosis of papillae, In cortex- atrophy of
tubules, inflammation and fibrosis

36. Analgesic Abuse Nephropathy
• Clinical course:
• Common in women
• Early course: concentrating ability is lost
(Polyuria) later chronic renal insufficiency
• Anemia – due to phenacetin metabolites toxic to
RBCs
• Urine- Hematuria when there is sloughing of
papillae
• Renal colic – Obstruction by papillae
• Long term complication – Transitional cell
carcinoma of the renal pelvis

37. Papillary necrosis
• Acute tubulo-interstitial nephritis
• Analgesic nephropathy
• Diabetes
• Sickle cell anemia or trait
• Renal TB
• Urinary tract obstruction

38. NSAID associated Nephropathy
• ARF
• Acute hypersensitivity Tubulo-interstitial
nephritis
• Lipoid nephrosis (MCD)
• Membranous GN

39. Urate Nephropathy
• Uric acid nephropathy can produce three
lesions.
• acute uric acid nephropathy –Chemotherapy
• Chronic urate nephropathy – Gout
• Nephrolithiasis – Uric acid stones

40. Urate Nephropathy
• Note the typical finely fibrillar appearance of the uric
acid crystals with adjacent fibrosis and the atrophy
of the renal parenchyma.

41. Hypercalcemia & Nephrocalcinosis
• Causes : Hyperparathyroidism, multiple
myeloma, Vit D intoxication, metastatic
bone disease, milk-alkali syndrome
• Deposition of calcium in the tubular
basement membranes(metastatic
calcification)
• Results in polyuria due to a lack of
concentrating ability

42. Multiple Myeloma
• Cast Nephropathy: Bence-Jones proteins
combine with the urinary glycoprotein
(Tamm-Horsfall) under acidic conditions to
form large, histologically distinct tubular
casts that obstruct the tubular lumina and
induce granulomatous inflammation
• Amyloidosis
• Hypercalcemia & Hyperuricemia

43. Cast Nephropathy

44. Urinalysis in ARF
Causes of renal failure & Urinary findings
• ATN – Dirty brown casts and epithelial cells
• AGN – RBC casts and proteinuria
• Acute tubulo-interstitial nephritis – WBC
casts and pyuria (Pus cells in urine)

45. Disease of blood vessels

46. Kidney Complications in
Hypertension
• Benign Nephrosclerosis : Sclerosis of
renal arterioles and small arteries
• Pathogenesis : Medial and intimal
thickening (hemodynamic response)
• Hyaline deposition in arterioles
(Extravasation of plasma proteins)
• Clinically- mild reduction in GFR with mild
proteinuria

47. Benign Nephrosclerosis - Gross
• Size –normal or
reduced
• Surface has fine
granularity resembling
the grains of a leather
as shown in picture

48. Benign Nephrosclerosis (Hyaline
arteriolosclerosis) - Micro
• Shown in
picture is an
arteriole
with hyaline
deposition
and
thickening of
the walls

49. Malignant Nephrosclerosis
• Renal disease in accelerated phase of
hypertension (malignant HT)
• Pathogenesis : Related to damage to
vessels by long standing benign HT with
increased permeability to proteins,
endothelial injury and platelet deposition
• Leading to fibrinoid necrosis and
intravascular thrombosis

50. Malignant Nephrosclerosis
• Gross : ‘Flea-
bitten’ kidney –
small petechial
hemorrhages on
cortical surface
due to rupture of
arterioles and
capillaries

51. Malignant Nephrosclerosis
• Micro 1 –
Fibrinoid
necrosis of a
small vessel
with pink
fibrin in the
walls
• This feature
also called
Necrotizing
arteriolitis

52. Malignant Nephrosclerosis
 Micro 2 –
Hyperplastic
arteriolitis -
Thickening and
proliferation of
smooth muscle cells
of the arterial wall
and collagen
producing an "onion
skin"appearance.
 This finding is more
often seen than
fibrinoid necrosis

53. Renal artery stenosis(RAS)
• Important to recognize because HT can be
surgically cured
• Two types
– Occlusion by atheromatous plaque (older men)
– Fibromuscular hyperplasia (young females)
Pathogenesis – Hypertension result from abnormal
activity of the renin-angiotensin system in the
chronically ischemic kidney

54. RAS - Atherosclerosis
• Note the constriction of the renal artery

55. RAS - Fibromuscular Hyperplasia
• Middle aged females
• Due to smooth muscle hyperplasia
(Media) which reduces blood flow to the
kidney involves multiple segments
• Abnormal renal arteriogram-shows
“beading effect”

56. Fibromuscular Hyperplasia
• Note the beaded appearance of the
renal artery. The lumen is constricted
as seen on the right

57. Thrombotic Microangiopathies
• Group of disorder with thrombosis of capillaries and
arterioles thru out the body characterized clinically by
MAHA, thrombocytopenia and renal failure. Termed as
HUS/TTP syndrome
• HUS – renal symptoms predominate
• TTP – CNS symptoms predominate
• Classification :
• Classic childhood HUS
• Adult HUS – Infection, Anti-phospholipid antibodies,
pregnancy, Vascular disorders
• Idiopathic HUS/TTP
• Pathogenesis : Vascular obstruction and constriction
related to endothelial injury(toxin mediated) and platelet
aggregation

58. Classic (Childhood) HUS syndrome
• Main cause for renal failure in children
• Intestinal infection of Verocytotoxin producing E.coli
(type O157:H7) or shiga toxin of Shigella infection
• Epidemics – Intake of infected hamburger (ground meat)
• Clinical – Diarrhea, oliguria, hematuria and MAHA,
Hypertension, ARF
• Peripheral blood smear- MAHA with schistocytes &
thromocytopenia
• Kidney – Widespread cortical necrosis
• Micro – arterioles show fibrinoid necrosis and
Subendothelial deposits of fibrin in vessel walls &
occlusion by platelet thrombi

59. Thrombotic Microangiopathy
• In this case of Hemolytic-Uremic syndrome note
the platelet-fibrin thrombi in the glomerular
capillaries.

60. Diffuse Cortical Necrosis
• Cortical necrosis which is bilateral and
symmetrical
• ischemic in origin and arises from
conditions that result in disseminated
intravascular coagulation.
• Ex- Abruptio placentae - premature
separation of the placenta, hemolytic–
uremic syndrome and septic shock.

61. Cortical Necrosis
• Note the pale
change to the
cortex and the
columns of
bertini

64. Renal Infarction
• Renal infarcts MOST COMMONLY
develop from thromboemboli/vegetations
originating in the left heart
• Less common causes are vasculitis, sickle
cell disease
• Patients present with flank pain, fever,
leukocytosis, proteinuria, and hematuria
• Infarcts are anemic or pale, wedge-
shaped(base towards cortex)

65. Renal Infarct
• Gross – Pale, wedge
shaped infarct
• Micro – Normal area in
the Rt and infarcted area
with coagulative necrosis
on Lt

66. Obstructive Uropathy (Hydronephrosis)
• Causes :
• Congenital anomalies
• Urinary calculi
• BPH
• Tumours
• Inflammation
• Sloughed papillae & Blood clots
• Pregnancy
• Uterine prolapse with cystocele
• Functional disorders – Neurogenic bladder
• Complications : Susceptibility for infections,
stone formation and hydronephrosis

67. Hydronephrosis
• Term used to describe dilatation of renal
pelvis and calyces with atrophy of the
kidney due to obstruction to flow of urine
• C/F depends on Uni or Bilaterality and
partial or complete obstruction
- Partial obstruction – Polyuria
- Complete - Anuria
• Investigations – IVP & USG

68. Hydronephrosis

69. Hydronephrosis
• Severe case showing
marked cortical
thinning
• Dilatation of pelvis
and calyces