TUBULOINTERSTITIAL DISEASES Terminology

1. TUBULOINTERSTITIAL DISEASESTerminology • 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.

2. TUBULOINTERSTITIAL DISEASETerminology ( cont.) • 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

3. Tubulointerstitial nephritisCauses • Infections: (1) Reactive (2) Infectious • Drug reaction • Obstruction: (1) with infection: pyelonephritis / pyonephrosis (2) without infection : hydronephrosis • Non-obstructive : vesicoureteral reflux • Immune mediated : (1) with anti TBM antibodies, can be 10 or 20 (2) with IC deposition which can be 10 or 20

4. Tubulointerstitial nephritisPathogenetic mechanisms • Antibody mediated • Anti-TBM-antibody disease • Immune-complex disease • T-cell mediated • Associated with infections • Reactive • Infectious

5. Tubuluinterstitial nephritis • Primary anti-TBM-antibody nephritis • IgG antibodies directed against tubular basement membrane • Linear staining on immunofluorescence microscopy • Edema and mononuclear cells in interstitium • Glomeruli and blood vessels are unremarkable • Secondary anti-TBM-antibody disease • 20 to 10 glomerulonephritidies, allograft nephropathy

6. Tubulointerstitial nephritis with immune complexes • Primary immune complex disease • granular staining on IF microscopy on tubular basement membrane • Primary – Rare • Secondary – Usually associated with primary glomerulonephritidies involving TBM and interstitium • e.g SLE, MPGN, Membranous GN etc.

7. Cell-mediated mechanism • Delayed-type hypersensitivity reaction • Activated CD4+ T and monocyte / macrophage cells releases cytokines which modulates inflammatory reactions and fibrogenesis • Cytotoxic T-cell injury in which CD4+ T and CD8+ T play important role

8. Pathology of primary IN • bilaterally symmetrical enlargement of kidney • edema • inflammatory cells in interstitium • tubular change including tubulitis, breaks in TBM, necrosis of tubular epithelial cells etc.

9. Pathology of renal failure acute chronic

10. Acute renal failure (ARF) • Rapid deterioration of renal function in a relatively short period of time • Sudden inability to maintain normal fluid and electrolyte homeostasis • Marked decrease in renal output • May be of glomerular, tubular, interstitial or vascular origin

11. Causes of ARF • acute tubular necrosis • infarction & cortical necrosis • organic diseases of renal vessels • severe forms of glomerulonephritis • severe infection • acute tubulointerstitial nephritis • outflow obstruction (post-renal) • impairment of blood flow (pre-renal)

12. Acute tubular necrosis (ATN) • commonest cause of acute renal failure • develops due to : • direct poisoning of tubules (nephrotoxic lesions) • renal ischemia (tubulorrhexic lesions)

13. Acute tubular necrosisEtiology & Pathogenesis • Ischemic in origin (Tubulorrhexic lesion) Prolonged ischemia due to: Shock: postoperative, intra-operative, post-traumatic, septic, hypotensive Hemorrhage:postpartum hemorrhage, abruptio placentae Other: severe burns, transfusion accidents, dehydration, heat stroke, crushing injuries, non-traumatic rhabdomyolysis, paroxysmal hemoglobinuria etc.

14. Acute tubular necrosisEtiology and Pathogenesis • Direct effects of toxins (Nephrotoxic lesion) Therapeutic agents : • Antibiotics : Aminoglycosides, NSAIDs, chemotherapeutic agents, etc. • Heavy metals: mercury, lead, gold etc. • Radiocontrast agents • Multiple bee stings, scorpion bites etc.

15. Gross pathology • bilaterally enlarged & swollen kidney due to edema • Cut surface bulges and has a flabby consistency • widened & pale cortex • dark & congested medulla

18. Light microscopy • dilated lumen with flattened epithelial cells • Greatest change in proximal tubules, varies in two forms • loss of brush borders- proximal tubules • evidence of regeneration of epithelial cells • hyaline, granular and pigmented casts • interstitial edema & inflammation • Intra-vascular collection of nucleated red blood cells

20. ATN- Prognosis • depends upon underlying cause, over all mortality rate  50% • post-traumatic (62%), post-operative (56%), medical (46 %), obstetric (17 %) • Higher in older debilitated pts. & in pts.with multiple organ disease • good for uncomplicated and younger patients

21. Chronic renal failure • Occurs in all cases of end-stage renal disease of whatever etiology • GFR falls below 20% of normal • End result of all chronic renal disease which can be glomerular, tubulointerstitial or vascular in origin • Characterized by prolonged signs and symptoms of uremia • Is a major cause of death in renal disease

22. Chronic renal failure • Systemic (visceral) manifestations • Enlarged heart & pericarditis • Uremic pneumonitis & pleuritis • Uremic colitis • Uremic encephalopathy • Hypoplastic anemia

23. TUBULO-INTERSTITIAL DISEASE • Urinary tract infection • colonization of excretory system by live microorganism • Most caused by gram negative enteric organism • Most common form of renal involvement is: • Pyelonephritis: bacterial infection of the kidney that affects parenchyma, calyces and pelvis • Acute -usually suppurative inflammation involving • pelvi-calyceal system and parenchyma • Chronic -involvement pelvi-calyceal system and parenchyma with prominent scarring

24. Pyelonephritis • Acute: usually suppurative, often associated (1) with / without obstruction (2) ascending infection through vesicoureteral reflux (3) from hematogenous dissemination. • Chronic: inflammation with prominent scarring; may be (1) obstructive with recurrent infection (2) non-obstructive with vesicoureteral reflux → reflux nephropathy

25. Acute PyelonephritisPredisposing factors • Urinary obstruction: congenital or acquired • Instrumentation of urinary tract • Vesicoureteral reflux • Pregnancy: 4-6% develops bacteriuria • Gender and age • Preexisting renal lesions • Diabetes mellitus, immunosuppression & immunodeficiency

26. Acute pyelonephritis • route of invasion : • via blood stream • ascending route • obstructive • non-obstructive role of vesicoureteral reflux and infected urine

32. Chronic pyelonephritis • It is a chronic tubulointerstitial inflammation involving renal parenchyma, pelvis and calyces associated with scarring • non-obstructive • reflux nephropathy • obstructive