What is the pathophysiology of kidney disease?

Pathophysiology of Kidney Disease

Kidney disease pathophysiology fundamentally involves maladaptive bidirectional organ cross-talk where initial injury triggers a cascade of hemodynamic, neurohormonal, and inflammatory mechanisms that perpetuate progressive nephron loss, fibrosis, and irreversible functional decline regardless of the original etiology. 1

Core Pathophysiological Mechanisms

Hemodynamic Alterations

• Renal hypoperfusion represents a primary mechanism where decreased blood flow to the outer medulla compromises tubular function and viability, particularly in acute settings 2
• In heart failure with kidney dysfunction, venous congestion is more pathophysiologically important than low cardiac output in determining worsening kidney function, as systemic venous congestion decreases venous return and increases left filling pressures, impairing perfusion of kidneys, liver, lungs, and gut 1
• Splanchnic and systemic vasodilation in cirrhosis causes effective arterial underfilling, leading to compensatory vasoconstrictor system activation (renin-angiotensin-aldosterone and sympathetic nervous systems) that results in kidney vasoconstriction, initially conserving sodium and water, then ultimately reducing kidney blood flow to levels that impair GFR 1

Neurohormonal Activation

• Hyperactivity of the renin-angiotensin-aldosterone system (RAAS) occurs in response to perceived low cardiac output or renal hypoperfusion, initially serving as a compensatory mechanism but becoming deleterious with disease progression 1, 3
• The renal response to impaired glomerular perfusion increases tubular sodium reabsorption and activates the renin-angiotensin-aldosterone axis, resulting in further volume overload and compromised diuretic effectiveness 1
• Aldosterone specifically exacerbates oxidative stress and cellular changes that promote fibrosis, creating a cascade leading to progressive renal fibrosis 4

Inflammatory Pathways

• Both innate and adaptive immune responses contribute significantly to kidney injury, with endothelial cells upregulating adhesion molecules that have counterreceptors on leukocytes during ischemia/reperfusion 2
• Tubule epithelial cells generate proinflammatory and chemotactic cytokines that perpetuate local inflammation 2
• Inflammatory markers are elevated in CKD patients, and chronic elevation of inflammatory mediators like CRP is associated with higher prevalence of complications 1
• Bacterial products and cytokines have vasodilatory properties that promote further splanchnic and systemic vasodilation, worsening circulatory dysfunction, while also altering kidney peritubular microcirculation and causing oxidative stress that affects cellular metabolism and induces apoptosis 1

Cellular and Molecular Mechanisms

• Oxidative stress plays a central role, with hyperglycemia-induced inflammation and oxidative stress leading to tubular damage and eventual kidney fibrosis 5
• Mitochondrial dysfunction triggers maladaptive repair mechanisms that accelerate progression from acute to chronic disease 4
• Cellular senescence of renal cells contributes to progressive functional decline 4
• Key signaling pathways including Wnt/β-catenin, TGF-β/SMAD, and Hippo/YAP/TAZ promote fibrosis and impact renal function, representing common final pathways regardless of initial etiology 4

Progression from Acute to Chronic Disease

The AKI-AKD-CKD Continuum

• AKI represents the acute phase (≤7 days) characterized by abrupt decrease in kidney function, while AKD captures the subacute recovery or progression phase (7-90 days), existing within a broader continuum of kidney injury 6, 7
• Maladaptive repair mechanisms following AKI accelerate progression to CKD, with renal injury triggering pathophysiological mechanisms including renal hypoperfusion, sepsis, nephrotoxicity, and immune responses 4
• Various molecules play pivotal roles in inflammation and hypoxia, triggering maladaptive repair, mitochondrial dysfunction, immune system reactions, and cellular senescence of renal cells during the transition from acute to chronic disease 4

Common Final Pathway

• Regardless of etiology (diabetes, hypertension, infection, reduced blood supply, obstruction, or genetic alterations), CKD develops through common mechanisms leading to a progressive, shared renal phenotype 8
• The pathophysiology involves more than a dozen identified pathways including hyperactivity of RAAS, osmotic sodium retention, endothelial dysfunction, dyslipidemia, RAS/RAF/extracellular-signal-regulated kinase pathway, modification of the purinergic system, PI 3-kinase-dependent signaling pathways, and inflammation, all leading to histomorphological alterations 3

Specific Disease Contexts

Diabetic Kidney Disease

• DKD involves hyperglycemia-induced inflammation, oxidative stress, and tubular damage eventually leading to kidney damage and fibrosis 5
• The tight cellular and molecular interactions between the renal, diabetic, and cardiovascular systems in acute or chronic disease settings create complex bidirectional pathophysiology 3

Cardiorenal Syndrome

• The pathophysiology is represented by maladaptive bidirectional pathways wherein acute or chronic dysfunction of one organ drives acute or chronic dysfunction in the other organ, extending across hemodynamic, neurohormonal, and inflammatory axes 1
• Suboptimal decongestion, diuretic resistance, and low use rates of guideline-directed medical therapy contribute to poor cardiovascular and kidney outcomes 1

Hepatorenal Syndrome

• Bacterial infection is the most common insult precipitating kidney failure in cirrhosis, with bacterial products and cytokines inducing vasodilation that worsens circulatory dysfunction while directly inflicting kidney damage 1

Clinical Implications

• Early identification of kidney dysfunction using standardized criteria (KDIGO defines AKI as rise in serum creatinine >0.3 mg/dL within 48 hours or 50% increase within 7 days) allows for prompt intervention, as even small increases in serum creatinine are independently associated with approximately fourfold increase in hospital mortality 6
• Understanding these common cellular and molecular mechanisms is key to successful identification of new therapeutic targets, with present therapy primarily based upon renin-angiotensin inhibition, and future perspectives including anti-inflammatory, anti-fibrotic approaches, and drugs targeting specific signaling pathways 8
• Efficient and personalized strategies to achieve decongestion while optimizing implementation of evidence-based therapies that modify disease trajectory are essential to reduce adverse outcomes and premature death 1