Tubulointerstitial nephritis Dr F. MOEINZADEH

Case 1  A 34 y/o female is evaluated for Cr rising.  She has low back pain from 15days ago and consume Iboprofen tab 4times /day.  Nausea +, no vomiting, no oliguria  PH.Ex: T=37.1°C RR=18/min PR= 85/min  Other finding is unremarkable

Case 2  A 74 years old man with low back pain and anemia referred to nephrology clinic due to Cr rising.  Lab data: Cr= 3.2 mg/dL Ca= 11.7mg/dL Alb= 3.8 g/dL Hb= 9.3g/dL MCV=85fl PLT=143000/mm3  Kidney sonography: RT kidney= 120mm LT kidney= 115mm and some calcifications in both kidneys.

Tubulointerstitial Nephritis  A group of clinical disorders that affect principally the renal tubules and interstitium with relative sparing of glomeruli and renal vasculature

Classification: 1. AIN: acute IN 2. CIN: chronic IN

Acute Interstitial Nephritis AIN is a clinicopathologic syndrome of:  ARF  Associated with interstitial edema and cellular infiltrate

Acute Interstitial Nephritis  Etiology Idiopathic Secondary

Secondary Causes of ATIN  Drugs : Antibiotics: Penicillins, Cephalosporins, Sulfa drugs, Ciprofloxacin, Acyclovir NSAIDS Diuretics: Thiazides, Furosemide, Triamterene Others: Cimetidine, Omeprazole, Phenytoin, Allopurinol  Systemic infection : Legionnaires disease, Leptospirosis, Streptococcal infection, CMV infection  Primary kidney infections : Acute bacterial pyelonephritis.  Autoimmune disorders : Sarcoidosis, Sjogrene syndrome

Pathophysiology – drug induced AIN  Drug-induced AIN is secondary to immune reaction  AIN occurs only in a small percentage of individuals taking the drug  AIN is not dose-dependent  Association with extrarenal manifestations of hypersensitivity  Recurrencence after re-exposure to the drug

TYPICAL CLINICAL MANIFESTATION OF ACUTE INTERSTITIAL NEPHRITIS  History of drug hypersensitivity or recent infection and taking antibiotics  Sudden onset of fever lasting several days to weeks  Variable degrees of hypertension  Triad: fever, rash, eosinophilia: typical but unusual presentation

 Flank pain due to capsule distention  Most presentation: any of this features  Hypertension, edema is uncommon in AIN  A particularly severe and rapid-onset AIN may occur upon reintroduction of rifampin after a drug-free period

Laboratory Findings in AIN  Acute rise in plasma cr  Eosinophilia  Sterile pyuria  Positive Hansel stain (>1% total WBCs are eos): rarely

Laboratory Findings in AIN  Active urine sediment with WBC, RBC, and WBC casts  Normal or mildly increased protein excretion (usually no more than 1g/day)  Renal tubular acidosis  Rise in creatinine with FENa >1.0; no expected acute tubular necrosis or glomerulonephritis  Kidney size normal or increased

Eosinophiluria Other conditions associated with Eosinophiluria  Prostatitis  Upper & lower UTI  Bladder Cancer  Renal Atheroembolic disease

Diagnostic Studies  CBC  Urinalysis  Hansel stain  Renal ultrasound  Gallium scan

Renal biopsy  Gold standard is renal biopsy. Indications are: Uncertainty of diagnosis Advanced RF Lack of spontaneous recovery after cessation of offending drug If immunosupressive therapy is considered  Renal biopsy is generally not required for diagnosis but reveals extensive interstitial and tubular infiltration of leukocytes, including eosinophils.

Algorithm for the treatment of allergic and other immune-mediated AIN

Prognosis  Most cases of AIN resolve completely after offending factor has been removed.  The longer the patient remains in renal failure, the less likely it is that complete recovery of renal function will occur.

Chronic interstitial nephritis  A clinicopathologic entity defined as slowly progressive renal insufficiency due to tubular cell atrophy and progressive interstitial fibrosis caused by a chronic interstitial mononuclear cell infiltrate.  CTIN is responsible for 15-30% of all cases of ESRD.

Conditions assiciated with CTIN  Hereditary: ADPKD, Alport  Metabolic disturbances: hypercalcemia, hyperoxaluria, hyperuricemia, hypokalemia, cystinosis  Drugs & toxins: NSAIDS, lead, lithium, cisplatin, cyclosporine, tacrolimus, Chinese herbs.  Immune mediated: Wegener granulomatosis, sjogrene, SLE, sarcoidosis, vasculitis

 Hematologic & malignancies: MM, Sickle cell anemia, lymphoma  Infections: chronic pyelonephritis, xanthogranulomatous pyelonephritis  Obstruction: tumors, stones, bladder outlet obstruction, vesicoureteral reflux.  Others: radiation nephritis, hypertensive atherosclerosis, renal ischemic disease

Clinical manifestations  Usually asymptomatic until develop CKD eg: malaise, nausea, nocturia, sleep disturbances  Is sometimes found incidentally on routine Lab work: decreased GFR (Cr rise), U/A: PU. Microscopic hematuria, pyuria.

Clinical findings that suggest chronic TIN  Hyperchloremic metabolic acidosis  Hyperkalemia (out of proportion of RF)  Reduced maximal urinary concentrating ability (polyuria, nocturia)  Partial or complete fanconi syndrome( phosphaturia, bicarbonaturia, Aauria, uricosuria, glycosuria)  Modest proteinuria (<2 gr/day)

 RTA II( proximal RTA) : lead poising MM  RTA I( Distal): chronic urinary obstruction  Polyuria: analgesic nephropathy, sickle cell disease, PKD.

Etiologies  Metabolic disturbances  Analgesic nephropathy  Lead nephropathy  Chinese herb nephropathy  Sarcoidosis  MM

Metabolic disturbances  Hyperclcemia: can lead to nephrocalcinosis ( deposition around tubules and collecting ducts)  Acute hyperphosphatemia, sodium phosphate solution lead to nephrocacinosis ( incompletely reversible after hypercalcemia resolve)  Prolong hyperuricemia  Hyperoxaluria (in jojenoileal bypass)

Analgesic nephropathy  Medication contain: aspirin, acetaminophen, phenacetin, caffeine, codeine.  Acetaminophen: 1. is concentrate in the papillary tips 2. its reactive metabolites can injure cells in the renal papilla, papillary necrosis.  This effect can exagerate with concomitant NSAIDs use.

Analgesic nephropathy  Usually occur in young women who had co- morbidities of emotional stress, neuropsychiatric problem, GI disturbances.  Plain CT: papillary calcification, abnormal renal cortex contour.  Tx: cessation of drug  BUT: progression of renal function loss is usually slowed or even arrested with drug discontinuation.

Lead nephropathy  Lead taken up by PCT that cause aminoaciduria, glycosuria, CIN.  Triad: HTN, gout (saturnine gout) and chronic renal insufficiency.  Dx: elevated 24h urinary excretion of lead after administration of 2, 1g doses of EDTA.  Tx: chelation therapy with EDTA that arrest or even reverse the CKD.

Chinese herb nephropathy  Silent renal insufficiency  Fanconi syndrome or fatigue from anemia  Rapidly progressive CIN with accelerated interstitial fibrosis, lead to ESRD.  Tx: cessation of herbs  Note: urothelia malignancy monitoring

Sarcoidosis  The most common cause of renal dysfunction: hypercalcemia.  Cause noncaseating granolomatous interstitial nephritis.  RTA II  CIN respond to corticosteroid therapy: loss of granolomatous & lymphocytic infiltrate.

Multiple myeloma  Induce acute & chronic renal dysfunction.  Tubulointerstitial pathology: light chain cast nephropathy: most common complication. hypercalcemia with nephrocalcinosis hyperuricemia amyloid deposition

MM  light chain cast nephropathy: cast clogging the tubule initiate a multinucleated giant cell inflammatory reaction.  Tx: chemotherapy to reduce excess production, volume repletion and alkalization of the urine.

Urinary tract obstruction  Acute & chronic urinary tract obstruction are associated with a mononuclear cell infiltrate.  Obstruction cause: CIN Impaired excretion of H+& K vasopressin- resistant concentrating defect.  Tx: relief of the obstruction

Radiation nephritis  In radiation more than: 2300cGy  Acute and severe injury within 1 year of radiation: HTN, anemia, edema  Insidious chronic form: mild renal insufficiency, HTN, mild proteinuria.  Pathogenesis: injury to the vascular endothelium, vascular occlusion, tubular atrophy, interstitial fibrosis.

Hypertensive arterionephrosclerosis  Arteriopathy in the afferent arterioles leading to interstitial & glomerular changes related to ischemia.  Prominent cause of the loss of renal function: Tubular atrophy & interstitial fibrosis.