Tubulointerstitial & Acute Kidney Injury

AKI framework and urinary indices

Definition. Acute kidney injury (AKI) is an abrupt fall in GFR over hours to days, with rising serum creatinine and BUN (azotemia) and often oliguria. By KDIGO criteria, a creatinine rise of ≥0.3 mg/dL within 48 hours, a rise to ≥1.5× baseline within 7 days, or urine output <0.5 mL/kg/h for 6 hours qualifies. Localize it as prerenal (hypoperfusion), intrinsic/renal (tubules, interstitium, glomeruli, or vessels), or postrenal (obstruction); urinary indices sort them.

Prerenal azotemia. Reduced renal perfusion (hypovolemia, heart failure, hypotension, renal artery stenosis) with structurally intact tubules. Low flow activates RAAS and ADH, so the tubules avidly reclaim sodium and water: FENa <1%, urine sodium <20 mEq/L, and concentrated urine (osmolality >500 mOsm/kg). Urea is passively reabsorbed along with that sodium and water while creatinine is not, so BUN rises out of proportion to creatinine (BUN:Cr >20:1). It reverses when perfusion is restored; if prolonged, it can progress to ischemic ATN.

Postrenal AKI. Obstruction lowers GFR only if it is bilateral or blocks a single functioning kidney: BPH, stones, tumor (e.g., cervical cancer compressing both ureters), or neurogenic bladder. Early on, back-pressure lowers GFR while the tubules still work, so indices mimic prerenal (FENa <1%); prolonged back-pressure damages the tubules and FENa rises above 2%. Ultrasound shows hydronephrosis. Relieve the obstruction, then watch for post-obstructive diuresis with volume and electrolyte losses.

Calculating FENa. FENa = (U_Na × P_Cr) ÷ (P_Na × U_Cr) × 100. Diuretics force natriuresis and can push FENa up in a truly prerenal patient; a fractional excretion of urea <35% still points to prerenal physiology.

Acute tubular necrosis

Most common intrinsic AKI. ATN is necrosis of tubular epithelial cells. Dead cells slough into the lumen, obstruct flow, and let filtrate leak back across the denuded basement membrane; increased sodium delivery to the macula densa also triggers afferent vasoconstriction through tubuloglomerular feedback. Damaged tubules can neither reclaim sodium nor concentrate urine, hence FENa >2%, urine osmolality <350, and BUN:Cr <15. The sloughed cells aggregate into muddy brown granular casts, the sediment signature of ATN.

Ischemic ATN. Sepsis, shock, hypotension, or prolonged prerenal azotemia. The most vulnerable segments are the proximal straight tubule (S3) and the medullary thick ascending limb: both have high metabolic demand and sit in the relatively hypoxic outer medulla. Injury is patchy.

Nephrotoxic ATN. Toxins mainly injure the proximal tubule, which concentrates what it reabsorbs.

• Drugs: aminoglycosides, amphotericin B, cisplatin, IV contrast.
• Pigments: myoglobin from rhabdomyolysis (crush injury, seizures, statins) and hemoglobin from hemolysis. In rhabdomyolysis the dipstick is positive for blood, but microscopy shows few or no RBCs.
• Ethylene glycol: envelope-shaped calcium oxalate crystals with an anion-gap metabolic acidosis.

Clinical course. ATN is usually reversible because tubular epithelium regenerates along an intact basement membrane. It runs three phases:

Interstitial nephritis and papillary necrosis

Acute interstitial nephritis (AIN). An immune-mediated drug hypersensitivity reaction in the interstitium, appearing days to weeks after exposure. Histology shows interstitial edema with lymphocytes, macrophages, and characteristically eosinophils (sometimes granulomas); glomeruli are spared. Clinically: fever, rash, arthralgia, peripheral eosinophilia, and eosinophiluria, with sterile pyuria and WBC casts. It usually reverses when the drug is stopped.

• Drug culprits: NSAIDs, penicillins and cephalosporins, sulfonamides (including sulfa diuretics), rifampin, PPIs, allopurinol.
• Non-drug causes: systemic infections and autoimmune disease (sarcoidosis, SLE, Sjögren syndrome).

The "5 Ps" of AIN: Pee (diuretics), Pain-free (NSAIDs), Penicillins, Proton-pump inhibitors, rifamPin. NSAID-induced AIN often lacks fever and rash and may come with nephrotic-range proteinuria.

Renal papillary necrosis. Ischemic sloughing of the renal papillae, the tips of the medullary pyramids at the end of the low-flow, hypoxic vasa recta circulation. It causes gross hematuria, flank pain (colic if a sloughed papilla lodges in the ureter), and sometimes passage of tissue in the urine. Remember SAAD:

• Sickle cell disease or trait: sickling in the hypoxic, hypertonic medulla.
• Analgesics: NSAIDs (loss of vasodilatory medullary prostaglandins) and phenacetin, which also raises the risk of urothelial carcinoma of the renal pelvis.
• Acute pyelonephritis.
• Diabetes mellitus.

Renal tubular acidoses

Normal-gap acidosis from tubular defects. RTAs cause a normal-anion-gap (hyperchloremic) metabolic acidosis from defective tubular handling of H⁺ or HCO₃⁻, not from GFR loss. Three types are tested: 1 (distal), 2 (proximal), and 4 (hypoaldosteronism). Serum potassium is the fastest sorter, urine pH the second.

Type 1 (distal). α-Intercalated cells of the collecting duct fail to secrete H⁺, so urine pH stays >5.5 despite systemic acidosis. Potassium is wasted, causing hypokalemia. Alkaline urine, bone buffering of acid (hypercalciuria), and low urinary citrate favor calcium phosphate stones and nephrocalcinosis. Causes: amphotericin B, autoimmune disease (Sjögren syndrome), and congenital forms.

Type 2 (proximal). The proximal tubule cannot reclaim HCO₃⁻ normally, so bicarbonate spills into the urine until serum HCO₃⁻ falls below the lowered threshold; after that, the intact distal nephron acidifies urine (pH <5.5). Increased distal sodium delivery drives hypokalemia. It often accompanies Fanconi syndrome, a generalized proximal defect with glucosuria (normal serum glucose), aminoaciduria, and phosphaturia leading to hypophosphatemic rickets or osteomalacia. Causes: multiple myeloma, Wilson disease, lead, acetazolamide, tenofovir.

Type 4 (hypoaldosteronism). Aldosterone deficiency or resistance reduces collecting-duct K⁺ and H⁺ secretion, making this the only hyperkalemic RTA. Hyperkalemia in turn suppresses proximal ammoniagenesis, so less NH₄⁺ buffer is available and acid is retained even though urine pH stays <5.5. Causes: diabetic hyporeninemic hypoaldosteronism, ACE inhibitors/ARBs, NSAIDs, heparin, spironolactone; also amiloride, trimethoprim, and calcineurin inhibitors.

Sort any normal-gap acidosis by potassium first: high K⁺ = type 4. If K⁺ is low, urine pH >5.5 = type 1 and urine pH <5.5 = type 2. A positive urinary anion gap [(U_Na + U_K) − U_Cl] reflects poor NH₄⁺ excretion (types 1 and 4); diarrhea gives a negative gap.