What is the pathogenesis of Chronic Kidney Disease (CKD)?

From the Guidelines

The pathogenesis of chronic kidney disease (CKD) involves a complex interplay of factors, including primary causes like diabetes and hypertension, which trigger adaptive responses that become maladaptive over time, ultimately leading to progressive nephron loss and declining kidney function. The most recent and highest quality study on this topic is from 2025, which provides an updated commentary on the evaluation and management of CKD 1. According to this study, CKD is estimated to affect 37 million people in the United States alone, with hypertension and diabetes mellitus being the most common risk factors. Key factors in the pathogenesis of CKD include:

• Glomerular hyperfiltration and systemic and intraglomerular hypertension, which accelerate injury through mechanical stress on glomerular structures
• Proteinuria, which develops as damaged glomeruli leak proteins into tubules, causing tubular inflammation and fibrosis
• Chronic inflammation from immune cell infiltration and cytokine release, which promotes ongoing tissue damage
• Overactivation of the renin-angiotensin-aldosterone system, causing vasoconstriction, sodium retention, and fibrosis
• Progressive tubulointerstitial fibrosis, which represents the final common pathway of CKD, with myofibroblasts depositing excessive extracellular matrix that replaces functional tissue
• Metabolic abnormalities like uremia, acidosis, and mineral imbalances, which further damage kidneys. As noted in a recent study from 2022, the management of CKD has evolved to include newer classes of glucose-lowering agents, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, which have been shown to reduce the risk of kidney failure, kidney function decline, death due to kidney disease, and cardiovascular disease in adults with CKD and type 2 diabetes mellitus 1. Overall, the pathogenesis of CKD is a complex and multifactorial process, and understanding these factors is crucial for the development of effective prevention and treatment strategies.

From the Research

Pathogenesis of Chronic Kidney Disease (CKD)

The pathogenesis of CKD is a complex process involving multiple factors and mechanisms. Some of the key factors include:

• Systemic and glomerular hypertension, which can lead to progressive scarring and fibrosis in the kidney 2
• Activation of the renin-angiotensin-aldosterone system (RAAS), which plays a crucial role in regulating blood pressure and electrolyte balance 2, 3
• Podocyte loss and dyslipidemia, which can contribute to the progression of CKD 2
• Proteinuria, which is associated with increased risk of progression of CKD and death 4
• Tubulointerstitial fibrosis, which can occur independently of glomerulosclerosis 2

Underlying Causes of CKD

The underlying causes of CKD can vary, but some of the most common causes include:

• Diabetes, which is a major cause of CKD in high-income and middle-income countries 5, 4
• Hypertension, which can lead to deteriorating renal function and progressive CKD 3, 5
• Chronic glomerulonephritis, particularly IgA nephropathy, which is a major cause of end-stage kidney disease in Japan 5
• Type 2 diabetic nephropathy, which involves both genetic and environmental factors, including persistent hyperglycemia, reactive oxygen species, and systemic and/or glomerular hypertension 5

Complications of CKD

CKD can lead to several complications, including:

• Anaemia due to reduced production of erythropoietin by the kidney 4
• Mineral bone disease caused by disturbed vitamin D, calcium, and phosphate metabolism 4
• Increased risk of death from cardiovascular disease, cancer, and other causes 4
• Reduced health-related quality of life, which falls as kidney function worsens 4

Treatment and Management of CKD

Treatment and management of CKD typically involve:

• Angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), which can slow the progression of CKD 6
• Blood pressure control, which is essential to slow the progression of CKD 3
• Lifestyle modifications, such as dietary changes and increased physical activity, which can help to manage CKD 4
• Early intervention and access to healthcare services, which can help to prevent or delay the progression of CKD 4