Tubulointristitial Tubulointristitial NephritisNephritis

Dr. Hamed ShakhatrehDr. Hamed Shakhatreh

Consultant nephrologestConsultant nephrologest

Head of nephrology department,Al-basher Head of nephrology department,Al-basher hospital. M.O.Hhospital. M.O.H

Primary interstitial nephropathies make up a diverse group of diseases that elicit interstitial inflammation associated with renal tubular cell damage.

Traditionally, interstitial nephritis has been classified morphologically and clinically into: acute and chronic forms.

Acute Interstitial Acute Interstitial NephritisNephritis

70% Drug hypersensitivity70% Drug hypersensitivity 30% Antibiotics: 30% Antibiotics: PCNs (Methicillin), PCNs (Methicillin),

Cephalosporins, CiproCephalosporins, Cipro Sulfa drugsSulfa drugs NSAIDsNSAIDs Allopurinol...Allopurinol...

15% Infection15% Infection Strep, Legionella, CMV, other bact/virusesStrep, Legionella, CMV, other bact/viruses8% Idiopathic8% Idiopathic6% Autoimmune Dz6% Autoimmune Dz (Sarcoidosis, Tubulointerstitial (Sarcoidosis, Tubulointerstitial

nephritis/Uveitis)nephritis/Uveitis)

Drug Causes of Drug Causes of AINAIN

AntibioticsAntibiotics Cephalosporins, Ciprofloxacin, Cephalosporins, Ciprofloxacin, Ethambutol, Isoniazid, Macrolides, Ethambutol, Isoniazid, Macrolides, Penicillins, Rifampin, Sulfonamides, Penicillins, Rifampin, Sulfonamides, Tetracycline, Vancomycin Tetracycline, Vancomycin

NSAIDsNSAIDs Almost all agents, including selective Almost all agents, including selective COX-2 inhibitorsCOX-2 inhibitors

DiureticsDiuretics Furosemide, Thiazides, Triamterene Furosemide, Thiazides, Triamterene

MiscellaneoMiscellaneousus

Acyclovir, Allopurinol, Amlodipine, Acyclovir, Allopurinol, Amlodipine, Azathioprine, Captopril, Carbamazepine, Azathioprine, Captopril, Carbamazepine, Clofibrate, Cocaine, Diltiazem, Clofibrate, Cocaine, Diltiazem, Famotidine, Indinavir, Mesalazine, Famotidine, Indinavir, Mesalazine, Omeprazole, Phenteramine, Phenytoin, Omeprazole, Phenteramine, Phenytoin, Pranlukast, Propylthioruacil, Quinine, Pranlukast, Propylthioruacil, Quinine, RanitidineRanitidine

AIN from DrugsAIN from DrugsRenal damage is NOT dose-dependentRenal damage is NOT dose-dependentMay take weeks after initial exposure to drugMay take weeks after initial exposure to drug More common is seen several months to a year after useMore common is seen several months to a year after useBut as early as 1 week after medication is begunBut as early as 1 week after medication is begun Fever (27%)Fever (27%) Serum Eosinophilia (23%)Serum Eosinophilia (23%) Maculopapular rash (15%)Maculopapular rash (15%)

Bland sediment or WBCs, RBCs, non-nephrotic proteinuriaBland sediment or WBCs, RBCs, non-nephrotic proteinuria WBC Casts are pathognomonic!WBC Casts are pathognomonic! Urine eosinophilsUrine eosinophils on Wright’s or Hansel’s Stain on Wright’s or Hansel’s Stain

Also see urine eos in RPGN, renal atheroemboliAlso see urine eos in RPGN, renal atheroemboli Leukocytoclastic vasculitisLeukocytoclastic vasculitis

Interstitial nephritisInterstitial nephritis

Acute allergic IN- presents with Acute allergic IN- presents with fever, maculopapular rash, fever, maculopapular rash, arthralgia, eosinophilia with use of arthralgia, eosinophilia with use of certain drugs or systemic infectioncertain drugs or systemic infection

UA_ microscopic hematuria, pyuria, UA_ microscopic hematuria, pyuria, non nephrotic proteinuria, non nephrotic proteinuria, eosinophiluriaeosinophiluria

Usually resolves after d/c of Usually resolves after d/c of offending drug and steroidsoffending drug and steroids

Clinical Clinical PresentationPresentation

NauseaNauseaVomitingVomitingMalaiseMalaise

•Rash 15%

•Fever 27%

•Eosinophilia 23%

•Triad 10%

AIN of any AIN of any causecause

Drug-Induced AINDrug-Induced AIN

Laboratory ManifestionsLaboratory Manifestions

Acute rise in plasma creatinine Acute rise in plasma creatinine

concentrationconcentration

Eosinophilia and eosinophiluriaEosinophilia and eosinophiluria

Urine sediment: wbcs, rbcs, white Urine sediment: wbcs, rbcs, white

cell castscell casts

Proteinuria (< 1 g/day)Proteinuria (< 1 g/day)

Infectious Causes Infectious Causes of AINof AIN

BacterialBacterial Corynebacterium Corynebacterium diphtheriae, diphtheriae, legionella, legionella, staphylococci, staphylococci, streptococci, yersinia streptococci, yersinia

ViralViral CMV, EBV, HIV, HCV, CMV, EBV, HIV, HCV, HSV, hantaviruses, HSV, hantaviruses, mumps, polyoma virusmumps, polyoma virus

OtherOther Leptospira, mycobacterium, Leptospira, mycobacterium, mycoplasma, rickettsia, mycoplasma, rickettsia, syphilis, toxoplasmosis syphilis, toxoplasmosis

Acute bilateral pyelonephritisAcute bilateral pyelonephritis Flank pain, toxic, febrileFlank pain, toxic, febrile U/A : pyoria, hematuria, proteinuria, U/A : pyoria, hematuria, proteinuria,

bacteriuriabacteriuria B/C & U/C help to diagnosis B/C & U/C help to diagnosis

Infiltrative/Infiltrative/Autoimmne Autoimmne

Causes of AINCauses of AINSarcoidosisSarcoidosisSjogren’s SyndromeSjogren’s SyndromeLeukemiaLeukemiaLymphomaLymphomaSystemic lupus erythematosus Systemic lupus erythematosus TINU SYNDROMETINU SYNDROME

Acute Kidney Acute Kidney InjuryInjury

PrerenalPrerenal HypovolemiaHypovolemia

Decreased cardiac outputDecreased cardiac output

Renal vasoconstrictionRenal vasoconstriction

IntrinsicIntrinsic Acute Tubular NecrosisAcute Tubular Necrosis

GlomerulonephritisGlomerulonephritis

Vascular disordersVascular disorders

PostrenalPostrenal Bladder NeckBladder NeckUreteral Ureteral TubularTubular

Renal biopsyRenal biopsy

Uncertainty of Uncertainty of

diagnosisdiagnosis

Advanced renal Advanced renal

failurefailure

Lack of Lack of

spontaneous spontaneous

recovery following recovery following

removal of removal of

offending drugoffending drug

IndicationsIndications

TreatmentTreatment

Discontinuation of offending agentDiscontinuation of offending agent

CorticosteroidsCorticosteroids

Prednisone 1 mg/kg to a max of 40-60 Prednisone 1 mg/kg to a max of 40-60 mg x 1-2 weeksmg x 1-2 weeks

IV Methylprednisolone 0.5 – 1 g/day x 3 IV Methylprednisolone 0.5 – 1 g/day x 3 daysdays

AIN PROGNOSISAIN PROGNOSIS

Most patients recover full kidney Most patients recover full kidney function in 1 yearfunction in 1 year

Poor prognostic factorsPoor prognostic factors AKI > 3 weeksAKI > 3 weeks Advanced age at onsetAdvanced age at onset

Chronic Tubulointerstitial Chronic Tubulointerstitial Disease Disease

chronic interstitial nephritis (CIN) chronic interstitial nephritis (CIN) follows a more indolent course and is follows a more indolent course and is characterized by tubulointerstitial characterized by tubulointerstitial fibrosis and atrophy associated with fibrosis and atrophy associated with interstitial mononuclear cell infiltration. interstitial mononuclear cell infiltration.

Over time, glomerular and vascular Over time, glomerular and vascular structures are involved, with structures are involved, with progressive fibrosis and sclerosis within progressive fibrosis and sclerosis within the kidney the kidney

Causes of chronic interstitial Causes of chronic interstitial nephritisnephritis

Toxins( analgesic nephropathy, lead Toxins( analgesic nephropathy, lead nephropathy)nephropathy)

InfectionInfection(chronic pyelonephritis)(chronic pyelonephritis) Autoimmune( Sjogren syndrome, SLE, Autoimmune( Sjogren syndrome, SLE,

renal rejection)renal rejection) Metabolic( hyperuricemia, hypercalcemia)Metabolic( hyperuricemia, hypercalcemia)

RadiationRadiation Neoplastic infiltration( leukemia, Neoplastic infiltration( leukemia,

lymphoma, multiple myeloma)lymphoma, multiple myeloma) Hereditary renal Hereditary renal

diseases(ADPKD,MCD,MSK)diseases(ADPKD,MCD,MSK)

Analgesic abuse Analgesic abuse nephropathynephropathy

chronic interstitial nephritischronic interstitial nephritis Result from excessive Result from excessive

consumption consumption

(NSAID & Aspirin)(NSAID & Aspirin) Dose dependent (at least 1 kg)Dose dependent (at least 1 kg) Being responsible for 1% to 3% Being responsible for 1% to 3%

of ESRD casesof ESRD cases

Bacterial infectionBacterial infection bacterial infection of the renal bacterial infection of the renal

parenchyma causes interstitial nephritisparenchyma causes interstitial nephritis infection without anatomical abnormality infection without anatomical abnormality

seldom produces permanent damageseldom produces permanent damage obstruction (stones, prostate etc) in obstruction (stones, prostate etc) in

combination with infection can cause combination with infection can cause progressive diseaseprogressive disease

tuberculosis causes extensive tuberculosis causes extensive destruction from granulomata, fibrosis destruction from granulomata, fibrosis and caseationand caseation

At first, interstitial edema and At first, interstitial edema and PMN infiltration, then formation of PMN infiltration, then formation of irregular abscesses and eventually irregular abscesses and eventually scarsscars

Risk factors:Risk factors:

diabetes mellitusdiabetes mellitus

obstructionobstruction

delayed antimicrobial therapydelayed antimicrobial therapy

severe infection with ATNsevere infection with ATN

reflux nephropathyreflux nephropathy

papillary necrosispapillary necrosis

Urinary tract obstructionUrinary tract obstruction

Consequences of urinary tract Consequences of urinary tract obstructionobstruction

Reduced glomerular filtration rateReduced glomerular filtration rate Reduced renal blood flow (after initial Reduced renal blood flow (after initial

rise)rise) Impaired renal concentrating abilityImpaired renal concentrating ability Impaired distal tubular functionImpaired distal tubular function

Nephrogenic diabetes insipidusNephrogenic diabetes insipidus Renal salt wastingRenal salt wasting Renal tubular acidosisRenal tubular acidosis Impaired potassium concentrationImpaired potassium concentration

Reduced RBF leads to renal ischemia Reduced RBF leads to renal ischemia tubular atrophytubular atrophy

Intraluminal Intraluminal

pressurepressureRBFRBF GFRGFR

Phase APhase A ——... due to... due to

obstructionobstruction

PeristalsisPeristalsis

——... due to... due to

VasodilationVasodilationProstacyclinProstacyclinProstraglandiProstraglandin En E22

˜̃...... due todue to

Intratubular Intratubular pressurepressure

Phase BPhase B ˜̃...... due todue to

Disorganised Disorganised peristalsis peristalsis dilation of dilation of tubules and tubules and ureterureter

˜̃...... due todue to

VasoconstrictiVasoconstrictiononAngiotensin IIAngiotensin IIThromboxanThromboxane Ae A22

˜̃...... due todue toContinuing Continuing obstructionobstructionvasoconstrictvasoconstrictionion

Acute urinary tract Acute urinary tract obstructionobstruction

Functional consequencesFunctional consequences

0 6 12 18

Ureteric and tubular pressure

Renal blood flow (RBF)

GFR

Hours

baseline

myelomamyeloma Bence-Jones protein (light chains from Bence-Jones protein (light chains from

malignant plasma cell clone) causes malignant plasma cell clone) causes interstitial nephritis, tubular interstitial nephritis, tubular obstruction(cast nephropathy) and obstruction(cast nephropathy) and amyloid depositionamyloid deposition

Myeloma kidney :the classic pathologic Myeloma kidney :the classic pathologic include THP+LC casts in dilated, include THP+LC casts in dilated, atrophic distal tubuls with infiltration atrophic distal tubuls with infiltration monocyte & macrophage & plasma monocyte & macrophage & plasma cells that produce giant cellscells that produce giant cells

LCs are nephrotoxic through direct LCs are nephrotoxic through direct injury of tubular epithelial cells & injury of tubular epithelial cells & intrarenal obstruction from cast intrarenal obstruction from cast formation formation

Predisposing factors: Predisposing factors:

LC concentrationLC concentration

LC isoelectric pointLC isoelectric point

intraluminal PHintraluminal PH

tubular flow rate tubular flow rate

presence of Tamm-Horsfall Prpresence of Tamm-Horsfall Pr

Hypercalcemic Hypercalcemic NephropathyNephropathy

Chronic hypercalcemia is seen inChronic hypercalcemia is seen in

HyperparathyroidismHyperparathyroidism

SarcoidosisSarcoidosis

Multiple myelomaMultiple myeloma

Vitamin D toxicityVitamin D toxicity

Metastasis bone diseaseMetastasis bone disease

Hypercalcemia decrease GFR Hypercalcemia decrease GFR through renal vasoconstrictionthrough renal vasoconstriction

Calcium deposition in distal Calcium deposition in distal nephron and interstitial that leads nephron and interstitial that leads to mononeuclear cell infiltration to mononeuclear cell infiltration and tubular necrosisand tubular necrosis

Defective concentration ability, Defective concentration ability, poliuria, nocturia poliuria, nocturia

Nephrocalcinosis & nephrolitiasis Nephrocalcinosis & nephrolitiasis

WBC CastsWBC Casts

Cells in the cast have Cells in the cast have nucleinuclei

(unlike RBC casts)(unlike RBC casts)

Pathognomonic for Acute Pathognomonic for Acute Interstitial NephritisInterstitial Nephritis

Match:Match:

1. hyaline casts1. hyaline casts 2. muddy brown casts2. muddy brown casts 3. RBCs3. RBCs 4. RBC casts4. RBC casts 5. Oval fat bodies5. Oval fat bodies 6. eosinophils6. eosinophils

A. ATNA. ATN B. prerenal azotemiaB. prerenal azotemia C. glomerulonephritisC. glomerulonephritis D. nephrolithiasisD. nephrolithiasis E. interstitial diseaseE. interstitial disease F. nephrotic F. nephrotic

syndromesyndrome

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