--- TUBULAR & INTERSTITIAL DISEASES --- ACUTE TUBULAR INJURY (ATI) Definition & Importance - Characterized by acute renal failure with tubular epithelial necros
--- 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 than 85% are gram-negative enteric bacilli - In order of frequency: E. coli, Proteus, Klebsiella, Enterobacter - Others: Streptococcus faecalis, staphylococci - Fungi (Candida): granulomatous interstitial inflammation - Immunocompromised: polyomavirus, CMV, adenovirus Routes of Infection 1. Ascending — most common route 2. Hematogenous — less common Why ascending infection is more common in females: - Shorter urethra - No antibacterial prostatic fluid - Hormonal changes increasing bacterial adherence - Urethral trauma during intercourse Bacterial virulence: P-fimbriae (pili) with adhesins bind urothelial cell receptors Conditions that promote ascent to the kidney: - Urinary tract obstruction - Vesicoureteral reflux (VUR) - Intrarenal reflux --- ACUTE PYELONEPHRITIS Definition Suppurative inflammation of the kidney caused by bacterial (sometimes viral) infection Morphology - Patchy interstitial suppurative inflammation - Intratubular aggregates of neutrophils (pus casts — diagnostic of renal origin) - Neutrophilic tubulitis and tubular injury - Glomeruli are relatively resistant — important exam point - Extensive disease can eventually destroy glomeruli - Fungal infection causes granulomatous interstitial inflammation Three Major Complications 1. Papillary Necrosis - Classic settings: diabetes mellitus, sickle cell disease, urinary tract obstruction - Usually bilateral; may be unilateral - Gray-white to yellow necrosis of pyramid tips or distal two-thirds - Histology: ischemic coagulative necrosis, tubule outlines preserved - Leukocytes at junction of preserved and necrotic tissue 2. Pyonephrosis - Occurs with complete or near-complete obstruction - Pus fills the renal pelvis, calyces, and ureter entirely 3. Perinephric Abscess - Suppurative inflammation extends through the renal capsule into perinephric fat Healing After Acute Pyelonephritis - Neutrophils replaced by macrophages, plasma cells, lymphocytes - Inflammatory foci replaced by fibrous scars visible on cortical surface - Scars show tubular atrophy, interstitial fibrosis, lymphocytic infiltrate in patchy "jigsaw" pattern with preserved parenchyma in between - Scars are almost always associated with underlying calyceal fibrosis and deformation Clinical Features - Sudden onset of costovertebral angle pain - Fever and malaise (systemic infection) - Bladder irritation: dysuria, frequency, urgency - Pyuria (leukocytes in urine) - Leukocyte casts rich in neutrophils (pus casts) — confirm renal origin - Diagnosis confirmed by quantitative urine culture - Uncomplicated cases resolve within days with appropriate antibiotics Predisposing Factors for Acute Pyelonephritis - Urinary tract obstruction (congenital or acquired) - Urinary instrumentation/catheterization - Vesicoureteral reflux - Pregnancy (4–6% develop bacteriuria; 20–40% progress to symptomatic infection if untre