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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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