Acute Tubular Injury (ATI): AKI Causes, Pathology & Progn...

--- TUBULAR & INTERSTITIAL DISEASES --- ACUTE TUBULAR INJURY (ATI) Definition & Importance Characterized by acute renal failure with tubular epithelial necrosis "ATI" preferred over "ATN" — necrosis is often absent Most common cause of AKI — 50% of AKI in hospitalized patients Clinically important because it is potentially reversible --- Causes Ischemic ATI Hypovolemic shock, sepsis, burns, trauma, acute pancreatitis Vascular: microscopic polyangiitis, HUS, TTP Nephrotoxic ATI Endogenous: myoglobin (crush injury), hemoglobin (mismatched transfusion), monoclonal light chains, bile Exogenous: gentamicin, radiocontrast dyes, mercury, carbon tetrachloride Combined ischemic + nephrotoxic Mismatched blood transfusions (hemoglobinuria) Crush injuries (myoglobinuria) The toxic iron content of these globin molecules directly causes ATI --- Pathogenesis Tubular Cell Injury Proximal tubule cells are most vulnerable because they have: Large surface area for reabsorption Active transport systems High metabolic rate and oxygen consumption Ability to concentrate toxins What happens in ischemia: Na,K-ATPase redistributes from basolateral to luminal surface This causes abnormal ion transport and increased sodium delivery to distal tubules Triggers tubuloglomerular feedback, causing vasoconstriction and reduced GFR Ischemic cells release cytokines and adhesion molecules, recruiting leukocytes Injured cells detach, causing luminal obstruction and rising intratubular pressure Filtrate leaks back into interstitium causing interstitial edema and further damage Disturbances in Blood Flow Intrarenal vasoconstriction is the main mechanism Reduces glomerular blood flow and oxygen delivery to the outer medulla Causes: activated renin-angiotensin system, increased endothelin release, decreased nitric oxide and prostacyclin production from sublethal endothelial injury Possibly a direct reduction in glomerular ultrafiltration coefficient --- Morphology Ischemic ATI Patchy, focal tubular necrosis with large skip areas Mainly affects: straight portion of proximal tubule and thick ascending limb of medulla Tubulorrhexis (basement membrane rupture) Casts occlude tubular lumens Interstitial edema, leukocytes in dilated vasa recta Regenerating epithelium: flattened cells, hyperchromatic nuclei, mitotic figures Toxic ATI Necrosis mainly in proximal convoluted tubules — diffuse, not patchy Mercury chloride: large acidophilic inclusions, then necrosis and calcification Ethylene glycol: ballooning/vacuolar degeneration of PCT + calcium oxalate crystals in tubular lumens Key distinction: Ischemic = patchy, multifocal; Toxic = diffuse, mainly proximal tubule --- Clinical Phases Initiation Phase (about 36 hours) Dominated by the precipitating event (trauma, surgery, etc.) Slight decline in urine output, slight rise in BUN Easily overlooked clinically Maintenance Phase Oliguria: urine output 40–400 mL/day Salt and water overload Rising BUN and creatinine Hyperkalemia — life-threatening Metabolic acidosis Full uremia may develop Patient can survive with proper management Recovery Phase Urine volume rises, may reach 3 L/day Tubules still dysfunctional — large losses of water, sodium, potassium Hypokalemia replaces hyperkalemia (opposite of maintenance phase) Increased vulnerability to infection BUN and creatinine gradually normalize Most patients recover completely; subtle tubular impairment may persist for months --- Prognosis Nephrotoxic ATI without other organ damage: 95% recover with supportive care Ischemic ATI with multi-organ failure (sepsis, burns): mortality exceeds 50% Recovery depends on intact basement membrane and ability of tubular cells to regenerate Re-epithelialization driven by growth factors from tubular cells and local inflammatory cells --- TUBULOINTERSTITIAL NEPHRITIS (TIN) How to Distinguish from Glomerular Disease No nephritic syndrome, no nephrotic syndrome Tubular dysfunction is the hallmark: Impaired urine concentration causing polyuria and nocturia Salt wasting Metabolic acidosis (impaired acid excretion) Isolated defects in tubular reabsorption or secretion --- Causes Category Examples --- --- Infections Acute/chronic pyelonephritis, reflux nephropathy, viruses, parasites Drugs/Toxins Methicillin, NSAIDs, analgesics, lead, cadmium Metabolic Urate nephropathy, nephrocalcinosis, oxalate nephropathy Physical Chronic obstruction, neoplasms, multiple myeloma (light-chain cast nephropathy) Immunologic Transplant rejection, Sjögren syndrome, sarcoidosis Miscellaneous Nephronophthisis, idiopathic interstitial nephritis --- Acute vs Chronic TIN Feature Acute TIN Chronic TIN --- --- --- Onset Rapid Insidious Edema Present Absent Infiltrate Neutrophils prominent Predominantly mononuclear Fibrosis Absent Prominent Tubular changes Injury and regeneration Atrophy --- PYELONEPHRITIS General Inflammation of tubules, interstitium, and renal pelvis One of the most common kidney diseases Two forms: acute and chronic Causative Organisms More t