How does leptospirosis cause Acute Kidney Injury (AKI)?

Mechanisms of Leptospirosis-Induced Acute Kidney Injury

Leptospirosis causes AKI through multiple interconnected mechanisms: direct bacterial invasion and nephrotoxicity via outer membrane proteins binding to renal tubular cells, tubulointerstitial inflammation with immune cell infiltration, hypovolemia from capillary leak and fluid shifts, rhabdomyolysis, hyperbilirubinemia, and systemic inflammatory responses with cytokine-mediated injury. 1, 2

Direct Bacterial Mechanisms

Tubular Invasion and Cellular Damage

• Leptospires directly infiltrate kidney cells via the renal tubules and interstitium, establishing infection by circumventing the immune system 1
• The bacterial outer membrane protein LipL32 binds to toll-like receptor-2 (TLR-2) expressed on renal tubular epithelial cells (TECs), triggering intracellular inflammatory signaling pathways 1
• This binding activates tumor necrosis factor (TNF)-α production and nuclear factor kappa activation, resulting in both acute and chronic kidney injury 1

Histopathological Changes

• The major histological findings include acute interstitial nephritis and acute tubular necrosis 2
• Tubulointerstitial nephritis develops with marked inflammatory infiltration in the tubules and interstitium, predominantly CD68-positive monocytes/macrophages of M1 phenotype 3
• Chronic infection can lead to tubulointerstitial nephritis with fibrosis, particularly in susceptible hosts 4

Inflammatory and Immune-Mediated Injury

Cytokine and Chemokine Dysregulation

• Pro-inflammatory cytokines IL-1β and IL-10 are significantly upregulated in kidneys during leptospirosis 4
• Chemokines MIP-1α/CCL3 and IP-10/CXCL-10 are elevated, promoting inflammatory cell infiltration and maintaining inflammatory processes 4
• Sustained inflammatory responses can persist even after bacterial clearance, contributing to ongoing renal dysfunction 3

Immune Cell Infiltration

• Inflammatory cell infiltration occurs in response to bacterial carriage, with predominance of M1 phenotype macrophages 3, 4
• The maintenance of inflammatory processes results in progressive alterations of renal tissues and potential progression to chronic kidney disease 4

Hemodynamic and Metabolic Factors

Volume Depletion and Hypoperfusion

• Hypovolemia develops from capillary leak syndrome and fluid shifts, contributing to prerenal azotemia 2
• Capillary fragility leads to hemorrhage, which can worsen volume depletion 5

Rhabdomyolysis

• Muscle injury with myoglobin release contributes to tubular toxicity and AKI development 2
• This mechanism is particularly relevant in severe cases with significant myalgia 5

Hyperbilirubinemia

• Direct nephrotoxic effects of elevated bilirubin levels contribute to kidney injury in severe leptospirosis (Weil's disease) 2
• Severe cholestasis may further impair renal function by worsening inflammation and macrocirculatory dysfunction 5

Tubular Dysfunction Patterns

Unique Clinical Features

• Leptospirosis-induced AKI is characteristically nonoliguric and hypokalemic, distinguishing it from other causes of AKI 2
• Tubular function abnormalities precede decline in glomerular filtration rate, explaining the high frequency of hypokalemia 2
• Proximal tubular injury can manifest as Fanconi syndrome with hypokalaemia, hypophosphataemia, normal anion gap metabolic acidosis, and hypovolaemia from salt wasting 5

Progression to Chronic Kidney Disease

Sustained Inflammation

• Survivors of severe leptospirosis can progress to chronic kidney disease due to sustained tubulointerstitial inflammation 3, 4
• Even after antibiotic resolution of infection, moderate renal dysfunction may persist from ongoing inflammatory processes 3
• Pro-fibrotic TGF-β expression and chronic inflammatory cell infiltration contribute to renal fibrosis development 4

Clinical Implications

Severity Stratification

• AKI severity correlates with mortality: RIFLE classification shows mortality of 2% for "risk," 8% for "injury," and 23% for "failure" 6
• AKIN classification demonstrates similar mortality patterns: 2% for AKIN 1,8% for AKIN 2, and 23% for AKIN 3 6
• Overall mortality in leptospirosis-associated AKI is approximately 22%, with 86% of non-survivors classified as RIFLE "failure" or AKIN 3 2, 6

Common Pitfalls

• Do not assume oliguria is present—leptospirosis AKI is typically nonoliguric, which may delay recognition 2
• Monitor potassium closely—hypokalemia rather than hyperkalemia is the expected electrolyte abnormality due to tubular dysfunction 2
• Consider corticosteroids for persistent inflammation—sustained tubulointerstitial nephritis after infection clearance may respond to intermediate-dose oral corticosteroids 3
• Recognize the biphasic course—initial bacteremic phase (4-7 days) followed by immune phase (1-3 days later) with hepatorenal syndrome and hemorrhage 5