TUBULOINTERSTITIAL DISEASES Al-Absi, M.D.

TUBULOINTERSTITIAL DISEASES Tubulointerstitial nephritis: Primary - Inflammation limited to tubules & with uninvolved or minimally involved glomeruli/vessels. Acute - Sudden onset & rapid decline in renal function associated with interstitial edema Chronic - Protracted onset and slow decline in renal function associated with interstitial fibrosis Secondary - Tubulointerstitial inflammation associated with primary glomerular/vascular diseases Infectious – Tubulointerstitial inflammation associated with presence of live microorganism Idiopathic – Tubulointerstitial nephritis where etiological agents or causes are not known Reactive – Tubulointerstitial inflammation from the effects of systemic inflammation. Kidney is sterile.

TUBULOINTERSTITIAL DISEASES Urinary tract infection colonization of excretory system by live microorganism Pyelonephritis: tubulointerstitial nephritis with pelvis and calyceal involvement Acute - usually suppurative inflammation involving pelvi-calyceal system and parenchyma Chronic - involvement of pelvi-calyceal system and parenchyma with prominent scarring

Tubulointerstitial Nephropathy Two distinct clinical presentations and course of development: (1) acute (2) chronic Immunologic mechanisms often involved in pathogenesis regardless of underlying cause Histologic changes evident on microscopy are not specific for a given etiology

Immunologic Mechanisms in Tubulointerstitial Nephropathy Drug acting as hapten binding to tubulointerstitial parenchyma, making the latter immunogenic Drug-induced damage through toxic mechanisms, producing nephritogenic neo-antigens Molecular mimicry by infectious agents inducing cross-reactive immune response

Acute Tubulointerstitial Nephropathy Drug-induced acute renal failure allergic tubulointerstitial nephritis nephrotoxic tubular injury Acute bacterial pyelonephritis Metabolic disorders hypercalcemia hyperuricosuria Environmental factors

Morphologic Features of Drug-Induced ATIN Increased interstitial volume due to: mononuclear cell infiltration lymphocytes, plasma cells, macrophages, granulomatous reaction, eosinophiles interstitial edema Tubular injury characterized by: disruption of tubular basement membranes epithelial cell necrosis

Chronic Tubulointerstitial Nephropathy Drug-induced analgesics, cyclosporine, antineoplastic agents Infection-related chronic bacterial pyelonephritis vesicoureteral reflux obstructive uropathy Autoimmunity SLE, Sjogren’s Disease

Morphologic Features of Chronic TIN Interstitial fibrosis with less prominence of cellular infiltrates Decreased vascularity due to reduced volume of capillaries Tubular atrophy Secondary glomerulosclerosis

Clinical Evidence of Tubular Dysfunction in TIN Renal glucosuria and amino aciduria Hypophosphatemia Hyperchloremic acidosis Hypokalemia Hyperkalemia Reduced urine concentrating ability Sodium wasting Pyuria and urine epithelial cells

UTI and Pyelonephritis Acute versus Chronic Ascending versus Hematogenous Bacterial Adhesion Vesicoureteral reflux

UTI and Pyelonephritis Asymptomatic & symptomatic Pathology: Interstitial edema, and inflammation Chronic Pyelonephritis and Reflux

Clinical Aspects of TIN Related to Specific Drugs or Other Causes beta lactam derivative antibiotics NSAIDS analgesics aminoglycosides Environmental agents Alternative medications Bacteria

Acute Tubulointerstitial Nephritis Induced by Beta-Lactam Derivatives Duration of drug administration may vary from few days to several weeks; not dose-dependent Clinical manifestations: fever, rash, eosinophilia, oliguric or non-oliguric renal failure Urinary findings: hematuria (microscopic or gross), pyuria, proteinuria, eosinophiluria

Acute Tubulointerstitial Nephritis Induced by Beta-Lactam Derivatives Pathogenesis: possible immune-medicated Pathology: Enlarged kidney, IS inflammation Clinical Course

Tubulointerstitial Nephritis Induced by Non-steroidal Anti-inflammatory Drugs Usually occurs after prolonged drug administration and may present as: Acute impairment of renal function with non-nephrotic range proteinuria, hyperkalemia and other evidence of tubular dysfunction Clinical manifestations similar to those above, but with nephrotic range proteinuria Nephrotic syndrome without other evidence of renal impairment

Analgesic Abuse Nephropathy Initial occurrence reported in association with phenacetin abuse Has been associated with long term use of analgesic mixtures containing phenacetin (?acetaminophen) and aspirin or other non-steroidal anti-inflammatory drugs Drug accumulates and is highly concentrated in the renal medullary interstitium

Analgesic Abuse Nephropathy Clinical features: Slow progressive impairment of renal function Tubular dysfunction characterized by the development of hyperkalemic, hyperchloremic renal tubular acidosis and nephrogenic diabetes insipidus Impairment of sodium reabsorption May progress to the development of papillary necrosis Uro-epithelia cancer

Aminoglycoside Nephrotoxicity Recognized potential for causing acute renal failure in hospitalized patients Drug enters the tubular lumen by glomerular filtration and is reabsorbed by proximal tubules where tubule cell injury leading to necrosis may occur. Manifested clinically by progressive increase in serum creatinine, renal K+ and Mg++ wasting, renal glucosuria

Cystic Diseases Cyst Formation: large fluid-filled pouches Causes PKD

PKD Autosomal dominant or recessive Prevalence ADPKD1, and ADPKD2

PKD Pathology Other organs involvment Prognosis: ADPKD2 is worse

Acquired cystic disease Pathogenesis Organs involved Long term risks

Balkan Endemic Nephropathy: Clinical Features Slowly progressive renal insufficiency Urine sediment usually unremarkable Proteinuria usually <1.0 g/day Renal tubular dysfunction Hypertension in <25% of patients Gross hematuria: may be a sign of uroepithelial tumor

Chinese Herbs Nephropathy Rapidly progressive interstitial nephropathy attributed to weight-reducing diets containing Chinese herbs Renal pathology closely resembling the characteristic lesions of Balkan Endemic Nephropathy Multiple foci of cellular atypia in the renal pelvis and ureters Aristolochic acid, a known carcinogen and suspected etiologic agent