Urinary Tract Infection & Pyelonephritis (Pathology)

How infection reaches the kidney

Ascending infection. Nearly all UTIs begin when fecal gram-negative flora colonize the vaginal introitus and periurethral skin, enter the bladder through the urethra and, if urine flow or the vesicoureteral valve fails, climb the ureters to the renal pelvis. At the renal poles, compound papillae have open duct orifices that allow intrarenal reflux of infected urine into the parenchyma, which is why pyelonephritic scars cluster there. Host factors that favor ascent:

• Short female urethra: UTI is far more common in women; in older men, prostatic obstruction raises the risk.
• Intercourse and spermicides: intercourse pushes periurethral bacteria into the bladder, and spermicides disrupt protective vaginal lactobacilli.
• Urinary catheters: the leading cause of hospital-acquired UTI; biofilm shields the organisms.
• Obstruction and stasis: BPH, stones, tumors, neurogenic bladder.
• Vesicoureteral reflux in children: a short intravesical ureteral segment lets urine reflux upward during voiding.
• Pregnancy: progesterone relaxes ureteral smooth muscle and the enlarging uterus compresses the ureters (right more than left), so asymptomatic bacteriuria is screened for and treated to prevent pyelonephritis.
• Diabetes: glycosuria, impaired neutrophil function and neuropathic bladder stasis.

Hematogenous infection. Less often, bloodborne S. aureus (injection drug use, endocarditis) or Candida (candidemia) lodges in the well-perfused cortex, producing multiple microabscesses or a larger cortical abscess (renal carbuncle). S. aureus in the urine of a patient without a catheter should prompt blood cultures to look for bacteremia.

Uropathogens

Uropathogenic E. coli. E. coli causes about 80% of community-acquired UTIs. Type 1 fimbriae bind mannose residues on bladder urothelium and mediate cystitis; P fimbriae bind Gal-Gal glycolipids (the P blood group antigen) of the upper tract and are the key virulence factor for pyelonephritis. Other E. coli factors belong to other diseases: the K1 capsule to neonatal meningitis, heat-labile toxin to traveler's diarrhea and Shiga-like toxin to hemorrhagic colitis and HUS. E. coli ferments lactose and reduces nitrate to nitrite.

A negative nitrite test does not exclude UTI: gram-positive organisms such as S. saprophyticus and Enterococcus do not convert nitrate to nitrite, and urine that has spent little time in the bladder allows too little conversion.

Proteus and urease. Proteus mirabilis urease splits urea into ammonia, raising urine pH above 7 so that magnesium ammonium phosphate (struvite) precipitates, seen as coffin-lid crystals. Stones can branch to fill the pelvis and calyces (staghorn calculi) and harbor bacteria beyond the reach of antibiotics, so infection recurs until the stone is removed. Klebsiella and S. saprophyticus also make urease.

Cystitis and acute pyelonephritis

Cystitis. Infection confined to the bladder produces dysuria, frequency, urgency and suprapubic discomfort, sometimes hematuria, without fever or flank pain. Urinalysis shows pyuria with positive leukocyte esterase (an enzyme of neutrophils) and often a positive nitrite (Enterobacterales reduce nitrate); a clean-catch culture classically grows ≥100,000 CFU/mL of a single organism.

Acute pyelonephritis. Upper-tract infection adds fever, chills, flank pain, costovertebral angle tenderness, nausea, vomiting and leukocytosis, with or without cystitis symptoms. White blood cell casts are the key clue: casts are molded in renal tubules, so they localize the inflammation to the kidney. Bacteremia and urosepsis are the dangerous extensions.

Pathology. The kidney is swollen, with yellow-white abscesses on the cortical surface. Microscopically, patchy suppurative inflammation fills the interstitium and neutrophils pack tubular lumens, the source of WBC casts. Glomeruli are characteristically spared, so proteinuria stays modest; pyelonephritis is a tubulointerstitial disease.

• Papillary necrosis: ischemic necrosis of the papillary tips, favored by diabetes and obstruction (also sickle cell disease and analgesic abuse); sloughed papillae cause gross hematuria and colic and can obstruct the ureter.
• Pyonephrosis: pus fills an obstructed collecting system.
• Perinephric abscess: infection ruptures through the renal capsule; suspect it when fever persists despite appropriate antibiotics.
• Urosepsis: bacteremia and septic shock, especially in elderly, obstructed or immunocompromised patients.

Chronic pyelonephritis and special variants

Chronic pyelonephritis. Repeated infection of a kidney that cannot drain or protect itself, from vesicoureteral reflux (reflux nephropathy, beginning in childhood) or chronic obstruction, produces coarse, irregular, asymmetric corticomedullary scars, concentrated at the poles, each overlying a dilated, blunted calyx. Tubules are atrophic or dilated and filled with eosinophilic colloid-like casts that resemble thyroid follicles ("thyroidization"), set in interstitial fibrosis with lymphocytes and plasma cells. Late consequences are hypertension, proteinuria from secondary FSGS and CKD. In children, voiding cystourethrography grades the reflux and a DMSA scan shows scars.

The calyceal deformity beneath each scar separates chronic pyelonephritis from vascular disease: benign nephrosclerosis causes smooth, symmetric, finely granular shrinkage, and malignant hypertension a "flea-bitten" petechial surface.

Sterile pyuria

Neutrophils in the urine with no growth on routine culture mean either an organism that routine media miss or noninfectious inflammation:

• Urethritis from Chlamydia trachomatis (an obligate intracellular organism) or Neisseria gonorrhoeae in a sexually active patient; diagnose by nucleic acid amplification testing.
• Renal tuberculosis: hematogenous seeding from the lungs; requires acid-fast culture of early-morning urine specimens.
• Acute interstitial nephritis: drug hypersensitivity with fever, rash, WBC casts and urine eosinophils.
• Other causes: a partially treated UTI, stones and urothelial tumors.