1. Tubulointerstitial diseases involve the tubules and interstitium of the kidney to a greater degree than the glomeruli and vasculature. They can be primary or secondary due to progressive glomerular or vascular injury. 2. The tubulointerstitial compartment consists of everything other than the glomeruli and makes up the majority of the mature kidney. Injury can result from toxic insults, infections, drugs, or immunological processes. 3. Acute interstitial nephritis is characterized by infiltration of inflammatory cells like T cells and monocytes into the interstitium, sparing the glomeruli. It is commonly caused by drugs but can also result

1. TUBULOINTERSTITIAL DISEASESTUBULOINTERSTITIAL DISEASES
OF KINDEYOF KINDEY

3. DEFINITION
Primary tubulointerstitial diseases are
characterised by histologic and functional
abnormalities that involve the tubules and
interstitium to a greater degree than the glomeruli
and renal vasculature.
Secondary tubulointerstitial disease occur as a
consequence of progressive glomerular or vascular
injury.

4. HISTORICAL PERSPECTIVE:
The tubulointerstitial compartment consists of
everything that is not glomeruli,mass of mature
kidney.
Some forms of injury to the tubulointerstitial
compartment are the result of toxic insult or
exposure to infections and drugs, much of the
inflammatory process is immunologic in
nature.

5. MECHANISMS OF TUBULOINTERSTITIAL INJURY:MECHANISMS OF TUBULOINTERSTITIAL INJURY:
A)A. Tubulointerstitial antigens:-
are derived from surrounding interstitial cells and their extracellular structure..
1. Antigens from renal cells and tubule basement membranes.
• Antibodies that react to cellular brush border have been observed

6. 2. Drug / Hapten conjugates as nephritogenic antigens
- Members of the penicillin family, with cephalosporins,phenytoin and
mercuric chloride
3. Antigens based on molecular mimicry:
- some antibodies to nephriotogenic streptococci cross – react with type IV
collagen.
4. Extra renal antigens in preformed or in situ immune deposits:
− Immune deposit formation in the tubulointerstitium can result in interstitial
nephritis e.g. SLE with DNA deposits, Ig A nephropathy, Sjogren's nephropathy,
cryoglobulinemia.

7. ACUTE INTERSTITIAL NEPHRITIS:
• ~1% of healthy persons who have a renal biopsy during a work up of
haematuria or proteinuria, will have primary interstitial nephritis.
• 1 to 15% will show acute interstitial nephritis in patients with apparent
renal disease (on renal biopsy)

8. Pathology:Pathology:
• The hallmark of acute primary interstitial nephritis is the infiltration of
inflammatory cells into the interstitial compartment with sparing of glomeruli.
• Infiltrating cells – mainly of T cells and monocytes, but plasma cells and
eosinophils may be seen. (T cells – preference for CD4 lymphocyte.

9. – Together with interstitial edema, this infiltrate causes the tubules to be
pushed away from each other. The TBM may be disrupted in more severe
cases.
– In acute granulomatous interstitial nephritis, the granulomas are sparse
and non necrotic, giants cells are rare.
Drugs and tuberculosis can also cause of granuloma formation.

10. Clinical features:
• Typical presentation – sudden decrement in renal function, most
commonly in an asymptomatic patient who has experienced an intervening
illness or who begun on a new medication.
• Occasionally, present as total renal failure.
• In case of infection, there often will be fever and localizing signs, and with
drug induced acute tubulointerstitial disease, the patient commonly exhibits
an allergic process, such as a maculopapular skin rash, fever or eosinophilia.

11. skin rash > 50% of patient.
Fever > 75% of patient.
Eosinophilia > 80% of patient.
– lumber pain (due to distention of the renal capsule from diffuse swelling of
the kidney )
– The course of renal failure in acute interstitial nephritis is most
commonly several days to weeks

12. Investigation
 reveal mild to moderate proteinuria and hematuria in over 75% of cases of
tubulointerstitial diseases.
 Gross haematuria reported in 44%
 The sediment, will show red and white blood cells.
 WBC casts occasionally.
 RBC castes have been reported in primary acute interstitial nephritis, but are
so infrequent that they should suggest on alternative glomerular diagnosis.
 Finding of eosinophils in the urine is suggestive of allergic interstitial nephritis.
 Serum creatinine levels- increase ( often first attention to the renal failure).

13.  Proteinuria- modest (nearly always <3gm/24hr).
 Oliguria (Severe interstitial inflammation- cause tubular obstruction and
impede urine flow)
 Electrolyte complication ( antibiotic therapies).
 Fanconi sundrome and renal tubular acidosis are rarely observed in acute
interstitial nephritis and more common in chronic tubulo interstitial diseases
 Kidney size - usually normal or slight increased (USG)
 Diagnosis can be established with certainty only by renal biopsy.

14. Etiology :
Drugs are the predominant etiologic agents today, followed by infection, particularly
in children, and the autoimmune idiopathic lesions. Actue interstitial Nephritis :
Causative factors.
A. A. Drugs
a) Antibiotics : Penicillins d) Miscellaneous Agents.
Rifampin Captopril
Sulfa Cimetidine
Vancomycin Ranitidine
Ciprofloxacin Phenolbarbital
Cephalosporins Nitro furantoin
Erythromycin Phenindione
Minocycline Phenytoin.
Trimethoprim- Allopurinol
Sulfamethoxazole interferon
Acyclovir Inter leukin 2
Ethambutol Antic CD4 antibody
Hairy vetch poisoing.
b) NSAIDS
c) Diuretics - Thiazides, Furosemide, Triamterene

15. B.Infectious Agents :
a) Bacteria- legionella, Brucella corny bacterium diptheriae.
Streptococcus, Staphylococcus, Yersinia, Salmonella , E.coli , Compylobacter
c) 0thter Agents - Mycoplasma, Rickettsia, Leptospira, Mycobacterium
tuberculosis , Toxoplasma, Chlamydia.
b) Virusesb) Viruses
• Epstein- Barr virus
• Cytomegalo Virus
• Hanta virus
• HIV
• Herpes Simplex
• Polyoma Virus
• Hepatitis B virus.

16. C. Idiopathic
Anti- tubule basement membrane disease
Tubulo interstitial nephritis and uveitis syndrome.
Kawasaki Diseases
Sarcoidosis.
A. Drugs:
Methicillin - Most common - Immune response
After methjcillin, generic penicilln and ampicillin commonly implicated
Four types of renal injury are associated with nasids
a) Acute renal ischemic renal insufficiency
b) Analgesic-associated nephropathhy
c) A flank pain - renal failure syndrome
d) Acute interstitial nephritis

17.  Acute interstitial nephritis appears in two forms.
B. Infection :
 Acute pyelonephrits is frequently associated with transient interstitial infiltrates
containing polymorphonuclear leukocytes.
 Acute interstitial nephritis and renal failure, however, frequently can be seen in
the setting of systemic infection.
 The HIV has not directly cause an isolated interstitial nephritis, however,
tubulointerstitial lesions are common in this disease because of a variety of factors.
These factors include opportunistic infections with cytomegalovirus, crytococcosis,
histoplasmosis, nephrocalcinosis, and sulfa derivatives.

18. C. Idiopathic :
Uncommon lesion
 The predominance of mononulcear cells in the interstitial infiltrate, the presence
of constitutional symptoms, and the spontaneous nature of the lesion all suggest a
possible immunologic basis.
 Linear deposition of anti-TBM antibodies have been observed in 70% of
patients with anti-GBM disease.
 Most commonly, however, anti- TBM antibodies appear in the setting of renal
transplantation.

19. Unlike drug-induced lesions, the idiopathic forms ofUnlike drug-induced lesions, the idiopathic forms of
interstitial nephritis are infrequently associated with rash orinterstitial nephritis are infrequently associated with rash or
eosinophilia, although fever is common.eosinophilia, although fever is common.
The patients with tubulointerstitial nephritis and uveitisThe patients with tubulointerstitial nephritis and uveitis
(TINU Syndrome) are usually adolescent girls, or(TINU Syndrome) are usually adolescent girls, or
occasionally adults, who present with constitutionaloccasionally adults, who present with constitutional
symptoms, reduced renal function and tubule dysfunction,symptoms, reduced renal function and tubule dysfunction,
bone marrow or lymphoid granulomas, and uveitis duringbone marrow or lymphoid granulomas, and uveitis during
some point in the course of disease. The etiology -some point in the course of disease. The etiology -
unknown; association with Chlamydia infection. Theunknown; association with Chlamydia infection. The
prognosis in children seems to be excellent with or withoutprognosis in children seems to be excellent with or without
treatment with steroids, whereas the course is moretreatment with steroids, whereas the course is more
guarded in adults. The adults are generally treated withguarded in adults. The adults are generally treated with
corticosteroids and partial recover of renal function maycorticosteroids and partial recover of renal function may

20. Course and Treatment :
 Removal of the offending agents.
 Complete recovery is inversely proportional to the duration of renal failure.
 Prognostic factor - duration
Active involvement or not
The extent to which interstitial involved.
 In the case of idiopathic acute interstitial nephritis, although spontaneous
resolution occurs, more than 50% of patients are left with residual renal dysfunction.
 The primary therapeutic principle in acute interstitial nephritis is to identify the
likely inciting factor and remove or treat it.
 Withdrawl of a drug or offending agent often results in improvement in renal
function within several days in many patients.

21. In the absence of a prompt response, early institution ofIn the absence of a prompt response, early institution of
chemotherapy may be appropriate.chemotherapy may be appropriate.
Trial of corticosteroids consists of a dose equivalent to 1 mg /kg/ dayTrial of corticosteroids consists of a dose equivalent to 1 mg /kg/ day
of prednisolone in patients with absent infection.of prednisolone in patients with absent infection.
Improvement in renal function should begin within 1 to 2 weeks ofImprovement in renal function should begin within 1 to 2 weeks of
initiation of treatment, in which case the course can be discontinuedinitiation of treatment, in which case the course can be discontinued
after 4 to 6 weeks.after 4 to 6 weeks.
If no improvement within the first 2 weeks, the addition of a secondIf no improvement within the first 2 weeks, the addition of a second
agent such as cyclophosphamide (2 mg/kg/d) may be considered.agent such as cyclophosphamide (2 mg/kg/d) may be considered.
Plasmapheresis.Plasmapheresis.

22. CHONIC INTERSTITAL NEPHNRITISCHONIC INTERSTITAL NEPHNRITIS
Pathology:-
 Include tubule cell atrophy with flattened epithelial
 Cells and tubule dilatation,interstitial fibrosis.
 Tubule basement membranes are frequently thickened.
 Cellular infiltrate is composed of lymphocytes with only occasional
neutrophils, plasma cells and eosinophils.
 Immunofluorescent- Reveals the presence of C3 or immunoglobulin along
the tubular basement membrance, typically in linear distribution.

23. Clinical Features:-Clinical Features:-
 Presents either because of systemic symptoms of a primary disease or
because of non specific symptoms of renal failure.
Non specific symptoms – lassitude . weakness, nausea, nocturia, and sleep
disturbances.
 Creatinine clearance at presentation < 50ml/min 75%
(<15ml/min 33% of them.)
 Included non nephrotic range proteinuria, microscopic hematuria and pyuria,
glycosuria(25%cases), and surprisingly, + urine cultures in 28% of patients.
 Decrease Serum uric acid
(because of tubular defects in the reabsorption of uric acid)
 Anaemia (because of early destruction of erythropoietin producing interstitial cell)
 Approximately 50% patients have HTN (>140/90mmhg)

24. Etiology:-
Causes of chronic Interstitial Nephritis.
A. Hereditary Diseases
 Autosomal dominant Polycystic kidney disease.
 Medullary cystic diseases- Juvenile nephronophthisis.
B. Metabolic disturbances
 Hypercalcemia/ nephrocalcinosis
 Hyperoxaluria.
 Hypokalemia
 Hyperuricemia
 Cystinosis
 Methylmalonic acidemia

25. C. Drugs and Toxins
Analgesics
Cadmium
Lead
Nitrosourea
Cyclosporine
Lithium
Cyclosporine
Cisplatin
Chinese herbs used in slimming regiment
D. Immune –mediated disorders
Renal allograft rejection
Wegener granulomatosis
Sjogren syndrome
SLE
Vasculitis
Sarcoidosis

26. F. Hematologic disturbances
multiple myeloma
light chain deposition disease
sickle cell disease
paroxysmal nocturnal hemoglobinuria
lymphoma
G. Infections
Direct infection
Malacoplakia
Xanthogranulomatous pyelonephritis
H. Obstructive and Mechanical Disorders
Tumor
Stones
Outlet obstruction
Vesicoureteral reflux

27. H. MIscellanceous
Endemic nephropathy.
Radiation nephritis
Progressive glomerular disease
Extracorporeal shock wave lithotripsy
Aging
HTN
Ischemia.

28. Sarcoidosis
 Affect the kidney through disordered calcium metabolism.
 10 to 15%- have hypercalcemia which can lead to concentrating defects,
depress glomerular filtration, or result in nephrocalcinosis or nephrolithiasis.
 Granulomatous interstitial nephritis predominantly occur in men.

29.  The pathologic finding in renal sarcoidosis consist ofThe pathologic finding in renal sarcoidosis consist of
interstitial non caseating granulomas composed of giantinterstitial non caseating granulomas composed of giant
cell, histiocytes, and lymphocytescell, histiocytes, and lymphocytes
 Impressive therapeutic response to corticosteroid therapy.Impressive therapeutic response to corticosteroid therapy.
 Cyclophosphamide is occasionally used in refractory cases.Cyclophosphamide is occasionally used in refractory cases.

30. MULTIPLE MYELOMAMULTIPLE MYELOMA
 Acute and chronic renal failure common .
 Classic pathologic change include the presence of proteinaceous casts in
dilated, atrophic distal nephron segments with surrounding multinucleated giant
cells, probably of monocyte-macrophage origin. cast typically contain both tamm-
horsfall protein and the pathologic light chain)
 Bence Jones proteinuria.
 Current consensus is that light chains are nephrotoxic.

31.  The physicochemical factors important for lightThe physicochemical factors important for light
chain precipitation include light chainchain precipitation include light chain
concentration, the acidic intraluminal PH of theconcentration, the acidic intraluminal PH of the
distal nephron, tubular flow rate, and thedistal nephron, tubular flow rate, and the
presence of Tamm – Horsfall protein.presence of Tamm – Horsfall protein.

32. Analgesic nephropathy:
Long term ingestion of large quantities of analgesics has been associated with
chronic interstitial nephritis and papillary necrosis.
Patients frequently have nocturia (decreased concentrating ability), sterile
pyuria, and HTN.
Anaemia is frequently seen.

33. Uric acid nephropathyUric acid nephropathy
 Overproduction of uric acid and hyperuricemia (especially inOverproduction of uric acid and hyperuricemia (especially in
acutely treated myeloproliferative disease) can cause acute renalacutely treated myeloproliferative disease) can cause acute renal
failure.failure.
 Historically, chronic hyperuricemia associated with chronicHistorically, chronic hyperuricemia associated with chronic
interstitial disease was called "gouty nephropathy.interstitial disease was called "gouty nephropathy.
 Histologically, presence of crystalline deposits of uric acid andHistologically, presence of crystalline deposits of uric acid and
monosodium urate salts in kidney parenchyma..Bacteriuria andmonosodium urate salts in kidney parenchyma..Bacteriuria and
pyelonephritis occurs in the one fourth of cases.pyelonephritis occurs in the one fourth of cases.

34.  GFR may be near normal, proteinuria, and diminished urinaryGFR may be near normal, proteinuria, and diminished urinary
concentrating ability.concentrating ability.
 Rx,Rx,
–– Allopurinol 200 to 800 mg /d.Allopurinol 200 to 800 mg /d.
–– Increasing urine volume with potent diuretics (Furosemide orIncreasing urine volume with potent diuretics (Furosemide or
mannitol) effectively lower intratubular uric acid concentrationmannitol) effectively lower intratubular uric acid concentration
–– Alkalinization of the urine to pH7 or greater with NaHco3Alkalinization of the urine to pH7 or greater with NaHco3
and/or acetazolamide (carbonic anhydrase inhibitor) enhancesand/or acetazolamide (carbonic anhydrase inhibitor) enhances
uric acid solubility.uric acid solubility.

35. Hypokalemic NephropathyHypokalemic Nephropathy
RareRare
Both inherited and acquired forms of hypokalemic nephropathy.Both inherited and acquired forms of hypokalemic nephropathy.
Pathologic characteristic of both acquired and inherited forms isPathologic characteristic of both acquired and inherited forms is
the finding of vacuoles in the proximal convoluted tubules.the finding of vacuoles in the proximal convoluted tubules.
Hypokalemia stimulates ammoniagenesis (Because of theHypokalemia stimulates ammoniagenesis (Because of the
associated intracellular acidosis), which then elicits complementassociated intracellular acidosis), which then elicits complement
activation, initiating the influx of immune cells into theactivation, initiating the influx of immune cells into the
interstitium.interstitium.

36. Obstructive nephropathyObstructive nephropathy
Complete or partial urinary tract obstructionComplete or partial urinary tract obstruction
Pathologic changes in both the tubulointerstitium and glomeruli,Pathologic changes in both the tubulointerstitium and glomeruli,
consisting of interstitial fibrosis, tubular atrophy and occasionallyconsisting of interstitial fibrosis, tubular atrophy and occasionally
focal glomerular sclerosis.focal glomerular sclerosis.
In both chronic and acute ureteral obstruction there areIn both chronic and acute ureteral obstruction there are
mononuclear cells in the interstitium. They are most evidentmononuclear cells in the interstitium. They are most evident
surrounding distal tubular cells but are present throughout thesurrounding distal tubular cells but are present throughout the
cortex and medulla.cortex and medulla.
Chinese herbs nephropathy is characterized by rapidlyChinese herbs nephropathy is characterized by rapidly
progressive interstitial renal fibrosis in young women due toprogressive interstitial renal fibrosis in young women due to
ingestion of slimming pills containing chinese herbs. At least oneingestion of slimming pills containing chinese herbs. At least one
of the culprint ingredients is aristolochic acid.of the culprint ingredients is aristolochic acid.

37. Lead nephropathyLead nephropathy
Sources : from old water pipes, pottery, crystal, and lead basedSources : from old water pipes, pottery, crystal, and lead based
paint in older dwellings.paint in older dwellings.
The diagosis is suggested by an augmented (>0.6mg) 24-hourThe diagosis is suggested by an augmented (>0.6mg) 24-hour
urinary excretion of lead after two 1-g doses of disodium EDTAurinary excretion of lead after two 1-g doses of disodium EDTA
In adults, lead nephropathy is pathologically a chronic interstitialIn adults, lead nephropathy is pathologically a chronic interstitial
nephritis, with interstitial fibrosis, atrophy and nephrocalcinosis.nephritis, with interstitial fibrosis, atrophy and nephrocalcinosis.
Rx- chelating agent such as calcium disodium edetate.Rx- chelating agent such as calcium disodium edetate.

38. Course and Treatment :Course and Treatment :
General therapeutic principles includeGeneral therapeutic principles include
Treating primary diseases.Treating primary diseases.
Identifying and eliminating any exogenous agents (drugs, heavyIdentifying and eliminating any exogenous agents (drugs, heavy
metals) or conditions (obstruction, infection) associated with themetals) or conditions (obstruction, infection) associated with the
chronic interstitial lesionchronic interstitial lesion
Good control of blood pressure (particularly ACE inhibition)Good control of blood pressure (particularly ACE inhibition)
Treatment of electrolyte disturbances (particularly metabolicTreatment of electrolyte disturbances (particularly metabolic
acidosis, byperuricemia, and hyper phosphatemia).acidosis, byperuricemia, and hyper phosphatemia).
More specific therapies Such as chelation in lead nephropathy andMore specific therapies Such as chelation in lead nephropathy and
corticosteroids in sarcoidosis.corticosteroids in sarcoidosis.