TUBULOINTERSTITIAL DISEASES TUBULOINTERSTITIAL DISEASES OF KINDEYOF KINDEY

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.

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.

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

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.

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)

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.

– 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.

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.

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

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).

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.

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 CaptoprilSulfa CimetidineVancomycin RanitidineCiprofloxacin PhenolbarbitalCephalosporins Nitro furantoinErythromycin PhenindioneMinocycline Phenytoin.Trimethoprim- AllopurinolSulfamethoxazole interferonAcyclovir Inter leukin 2Ethambutol Antic CD4 antibody

Hairy vetch poisoing. b) NSAIDSc) Diuretics - Thiazides, Furosemide, Triamterene

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.

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

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.

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.

Unlike drug-induced lesions, the idiopathic forms of Unlike drug-induced lesions, the idiopathic forms of interstitial nephritis are infrequently associated with rash or interstitial nephritis are infrequently associated with rash or eosinophilia, although fever is common.eosinophilia, although fever is common.

The patients with tubulointerstitial nephritis and uveitis The 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 constitutional occasionally 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 during bone 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. The unknown; association with Chlamydia infection. The prognosis in children seems to be excellent with or without prognosis in children seems to be excellent with or without treatment with steroids, whereas the course is more treatment with steroids, whereas the course is more guarded in adults. The adults are generally treated with guarded in adults. The adults are generally treated with corticosteroids and partial recover of renal function may corticosteroids and partial recover of renal function may occur over several weeks. occur over several weeks.

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.

In the absence of a prompt response, early institution of In 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/ day Trial 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 of Improvement in renal function should begin within 1 to 2 weeks of

initiation of treatment, in which case the course can be discontinued initiation 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 second If 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.

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.

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)

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

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 granulomatosisSjogren syndromeSLEVasculitisSarcoidosis

F. Hematologic disturbances multiple myeloma

light chain deposition disease

sickle cell disease

paroxysmal nocturnal hemoglobinuria

lymphoma

G. InfectionsDirect infection

Malacoplakia

Xanthogranulomatous pyelonephritis

H. Obstructive and Mechanical DisordersTumor

Stones

Outlet obstruction

Vesicoureteral reflux

H. MIscellanceous

Endemic nephropathy.

Radiation nephritis

Progressive glomerular disease

Extracorporeal shock wave lithotripsy

Aging

HTN

Ischemia.

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.

The pathologic finding in renal sarcoidosis consist of The pathologic finding in renal sarcoidosis consist of

interstitial non caseating granulomas composed of giant interstitial 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.

MULTIPLE MYELOMA MULTIPLE 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.

The physicochemical factors important for light The physicochemical factors important for light

chain precipitation include light chain chain precipitation include light chain

concentration, the acidic intraluminal PH of the concentration, the acidic intraluminal PH of the

distal nephron, tubular flow rate, and the distal nephron, tubular flow rate, and the

presence of Tamm – Horsfall protein.presence of Tamm – Horsfall protein.

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.

Uric acid nephropathyUric acid nephropathy Overproduction of uric acid and hyperuricemia (especially in Overproduction of uric acid and hyperuricemia (especially in

acutely treated myeloproliferative disease) can cause acute renal acutely treated myeloproliferative disease) can cause acute renal

failure.failure.

Historically, chronic hyperuricemia associated with chronic Historically, 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 and Histologically, presence of crystalline deposits of uric acid and

monosodium urate salts in kidney parenchyma..Bacteriuria and monosodium urate salts in kidney parenchyma..Bacteriuria and

pyelonephritis occurs in the one fourth of cases.pyelonephritis occurs in the one fourth of cases.

GFR may be near normal, proteinuria, and diminished urinary GFR 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 or Increasing 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 NaHco3 Alkalinization of the urine to pH7 or greater with NaHco3

and/or acetazolamide (carbonic anhydrase inhibitor) enhances and/or acetazolamide (carbonic anhydrase inhibitor) enhances

uric acid solubility.uric acid solubility.

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 is Pathologic 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 the Hypokalemia stimulates ammoniagenesis (Because of the

associated intracellular acidosis), which then elicits complement associated intracellular acidosis), which then elicits complement

activation, initiating the influx of immune cells into the activation, initiating the influx of immune cells into the

interstitium.interstitium.

Obstructive nephropathyObstructive nephropathyComplete 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 occasionally consisting of interstitial fibrosis, tubular atrophy and occasionally focal glomerular sclerosis. focal glomerular sclerosis.

In both chronic and acute ureteral obstruction there are In both chronic and acute ureteral obstruction there are mononuclear cells in the interstitium. They are most evident mononuclear cells in the interstitium. They are most evident surrounding distal tubular cells but are present throughout the surrounding distal tubular cells but are present throughout the cortex and medulla.cortex and medulla.

Chinese herbs nephropathy is characterized by rapidly Chinese herbs nephropathy is characterized by rapidly

progressive interstitial renal fibrosis in young women due to progressive interstitial renal fibrosis in young women due to

ingestion of slimming pills containing chinese herbs. At least one ingestion of slimming pills containing chinese herbs. At least one

of the culprint ingredients is aristolochic acid.of the culprint ingredients is aristolochic acid.

Lead nephropathyLead nephropathy

Sources : from old water pipes, pottery, crystal, and lead based Sources : 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-hour The 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 interstitial In 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.

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, heavy Identifying and eliminating any exogenous agents (drugs, heavy metals) or conditions (obstruction, infection) associated with the metals) 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 metabolic Treatment of electrolyte disturbances (particularly metabolic acidosis, byperuricemia, and hyper phosphatemia).acidosis, byperuricemia, and hyper phosphatemia).

More specific therapies Such as chelation in lead nephropathy and More specific therapies Such as chelation in lead nephropathy and corticosteroids in sarcoidosis.corticosteroids in sarcoidosis.