Pyelonephritis

1. Etiology and Pathogenesis

Routes of Infection

• Ascending route (most common): Fecal flora (especially E. coli) colonize the urethra and bladder, then ascend to the kidney. This is facilitated by a short female urethra, which explains the much higher incidence in women of reproductive age.
• Hematogenous route (less common): Bacteremia seeds the kidney; more likely with Staphylococcus aureus and gram-negative organisms in septicemic patients.

Causative Organisms

• E. coli - by far the most common (uropathogenic strains with P-fimbriae that adhere to uroepithelium)
• Klebsiella, Proteus, Enterobacter, Pseudomonas
• Enterococcus (especially in nosocomial/complicated cases)
• Fungi and mycobacteria cause granulomatous interstitial inflammation rather than the usual neutrophilic response

Predisposing Factors

2. Pathology

Acute Pyelonephritis - Gross Appearance

Robbins, Cotran & Kumar Pathologic Basis of Disease

Acute Pyelonephritis - Microscopy

• Neutrophil-rich inflammation initially limited to tubules, then spreading to the interstitium
• Neutrophils extend into collecting ducts - producing WBC (pus) casts in urine (pathognomonic of upper tract disease - casts only form in tubules)
• Glomeruli typically spared in uncomplicated cases
• With obstruction: pus fills the renal pelvis and ureter = pyonephrosis

Complications of Acute Pyelonephritis

• Papillary necrosis: Ischemic + suppurative necrosis of papillary tips. Classic triad of predisposing conditions: diabetes, urinary tract obstruction, sickle cell anemia. Sloughed papillae can obstruct the ureter.
• Renal/perinephric abscess: Liquefaction of parenchyma; may require drainage if ≥3 cm
• Emphysematous pyelonephritis: Gas-forming infection in diabetics (usually E. coli or Klebsiella); life-threatening; diagnosed on CT
• Septicemia/urosepsis: ~10-19% of sepsis cases have a genitourinary source

Healing

Chronic Pyelonephritis

• Chronic tubulointerstitial inflammation and calyceal/pelvic scarring - the hallmark that distinguishes it from other chronic interstitial nephritides
• Reflux-associated (most common): Recurrent ascending infections via VUR; predominantly affects upper and lower poles where intrarenal reflux is highest
• Obstructive: Bilateral when from congenital urethral anomalies; may affect the entire kidney
• Microscopically: "thyroidization" of tubules (colloid-like eosinophilic casts), periglomerular fibrosis, glomerulosclerosis secondary to loss of renal mass
• End result: progressive CKD

3. Clinical Features

Acute Pyelonephritis

• Sudden onset of flank pain / costovertebral angle (CVA) tenderness
• Fever, chills, rigors
• Nausea, vomiting, malaise (systemic symptoms)
• May or may not have concomitant lower urinary tract symptoms (dysuria, frequency, urgency)
• Urine culture: ≥10⁵ CFU/mL (positive urine culture required for diagnosis)

A missed diagnosis of cystitis is unlikely to lead to patient deterioration; in contrast, missed pyelonephritis could lead to untreated sepsis. - Tintinalli's Emergency Medicine

Special Populations - Watch for Atypical Presentations

• Spinal cord injury: No flank pain; may manifest as increased spasticity, autonomic dysreflexia, sense of unease
• Elderly: Altered mental status, weakness, malaise (fever/pain may be absent)
• Immunocompromised: Signs of infection may be blunted

4. Diagnosis

Urinalysis / Dipstick

• WBC casts (pus casts) on microscopy = upper tract disease (formed only in tubules) - this differentiates pyelonephritis from cystitis
• Urine culture is the diagnostic gold standard; negative nitrite does NOT exclude infection

Blood Tests

• CBC: leukocytosis with left shift
• Blood cultures: obtain in hospitalized/severe cases (bacteremia in 15-30%)
• Creatinine/BMP: AKI occurs in up to 25% of gestational pyelonephritis cases

Imaging

• Not routinely required for uncomplicated cases
• CT (non-contrast then contrast): Best for complications - renal/perinephric abscess, emphysematous pyelonephritis, papillary necrosis, obstruction
• Ultrasound: For pregnancy (avoids radiation); identifies obstruction, hydronephrosis, abscess; less sensitive than CT for early parenchymal changes
• Indications: failure to improve after 48-72h of antibiotics, recurrent pyelonephritis, suspected abscess, diabetes

5. Treatment

Decision: Inpatient vs. Outpatient

• Severely ill (high fever, rigors, prostration)
• Unable to tolerate oral fluids/medications
• Pregnancy
• Diabetes or immunocompromise
• Suspected complication (abscess, obstruction, emphysematous pyelonephritis)
• Unclear diagnosis

Antibiotic Regimens

• Ciprofloxacin 500 mg twice daily × 5-7 days ← first choice where resistance <20%
• Levofloxacin 750 mg once daily × 5-7 days
• If fluoroquinolone resistance suspected: TMP-SMX DS, cefpodoxime, or amoxicillin-clavulanate × 7-14 days
• Note: nitrofurantoin and fosfomycin do NOT achieve adequate renal tissue levels and are not appropriate for pyelonephritis

• Initial empiric IV: aminoglycoside (gentamicin) ± ampicillin; or IV ceftriaxone
• Transition to oral at 24-48h once clinically improved
• Total duration: 7-14 days (5-7 days adequate for fluoroquinolones)
• Severe complicated: IV meropenem 1g q8h, or piperacillin-tazobactam, or IV plazomicin 15 mg/kg once daily - Goldman-Cecil Medicine

Pregnancy-Specific Treatment

• Hospital admission recommended (outpatient management acceptable only for mild cases)
• IV antibiotics until afebrile, then oral to complete 14 days
• Safe choices: cephalosporins, penicillins (avoid fluoroquinolones and tetracyclines in pregnancy)
• Prophylactic suppressive antibiotics until delivery to prevent recurrence and reduce risk of preterm labor
• Recurrence rate: 6-8%; AKI complicates up to 25% of gestational pyelonephritis
• Associated with IUGR, premature labor, sepsis - NKF Primer on Kidney Diseases, 8e

Complicated Pyelonephritis / Abscesses

• Renal/perinephric abscesses ≥3 cm should be drained
• 4-6 weeks total antibiotics for abscess
• If obstructed + infected and not responding to antibiotics: percutaneous nephrostomy
• Emphysematous pyelonephritis: usually requires nephrectomy in addition to antibiotics

6. Chronic Pyelonephritis and Reflux Nephropathy

• Asymmetric, coarse, irregular scarring (especially at poles) on imaging
• Clubbing/blunting of calyx underlying each scar (calyceal deformity is required to diagnose chronic pyelonephritis radiologically)
• May progress to hypertension and CKD
• "Thyroidization" of tubules on histology (colloid-like casts)

7. Summary Table: Acute vs. Chronic Pyelonephritis