Chronic Kidney Disease (N18)

Causes

The etiology of chronic kidney disease (CKD) is multifactorial and involves progressive, irreversible loss of nephron function resulting from a wide range of metabolic, vascular, inflammatory, autoimmune, genetic, and obstructive disorders. The most common causes worldwide are diabetes mellitus and hypertension, both of which produce chronic injury to the glomerular and vascular structures of the kidney through hyperglycemia, hemodynamic stress, oxidative damage, and fibrosis. Additional causes include glomerulonephritides such as IgA Nephropathy, polycystic kidney disease, chronic pyelonephritis, obstructive uropathy, autoimmune diseases such as lupus nephritis, and drug- or toxin-induced nephropathy. Persistent renal injury activates inflammatory and fibrotic pathways that gradually replace functional nephron tissue with scar tissue, leading to declining glomerular filtration rate, proteinuria, electrolyte disturbances, and progressive renal insufficiency. Environmental factors, aging, cardiovascular disease, obesity, and genetic susceptibility further influence disease progression and long-term renal outcomes.

Pathophysiology

The pathophysiology of chronic kidney disease (CKD) involves progressive nephron loss accompanied by maladaptive hemodynamic, inflammatory, and fibrotic responses that ultimately lead to irreversible renal dysfunction. Initial injury from conditions such as diabetes, hypertension, autoimmune disease, or chronic inflammation damages glomerular, tubular, vascular, or interstitial structures within the kidney. As functional nephrons are lost, the remaining nephrons undergo compensatory hyperfiltration and increased intraglomerular pressure in an attempt to maintain overall renal function. Over time, this adaptive response becomes maladaptive, promoting further glomerular injury, proteinuria, oxidative stress, endothelial dysfunction, and activation of inflammatory and profibrotic pathways including transforming growth factor-beta (TGF-β), renin-angiotensin-aldosterone signaling, and cytokine-mediated fibrosis. Progressive glomerulosclerosis and tubulointerstitial fibrosis reduce filtration capacity and impair electrolyte, acid-base, endocrine, and fluid regulation. As kidney function declines, accumulation of uremic toxins, anemia from reduced erythropoietin production, disturbances in calcium-phosphate metabolism, hypertension, cardiovascular disease, and systemic inflammation contribute to the widespread multisystem complications of advanced CKD.

Clinical features

The clinical features of chronic kidney disease (CKD) often develop gradually and may remain asymptomatic during the early stages despite progressive nephron loss. As renal function declines, patients commonly develop fatigue, weakness, decreased exercise tolerance, anorexia, nausea, edema, nocturia, and hypertension due to impaired fluid and electrolyte regulation. Proteinuria and abnormalities in urine concentration may be detected early, while worsening kidney dysfunction can lead to electrolyte disturbances such as hyperkalemia, metabolic acidosis, and volume overload. Progressive accumulation of uremic toxins may produce pruritus, cognitive impairment, sleep disturbances, peripheral neuropathy, muscle cramps, and a metallic taste. CKD also disrupts endocrine functions of the kidney, contributing to anemia from reduced erythropoietin production and abnormalities in calcium-phosphate metabolism that promote renal osteodystrophy and vascular calcification. In advanced disease, patients may develop severe cardiovascular complications, pulmonary edema, pericarditis, or symptoms of uremic syndrome requiring dialysis or kidney transplantation.

Diagnosis

The diagnosis of chronic kidney disease (CKD) is based on evidence of persistent kidney damage or reduced renal function lasting at least three months. Diagnostic evaluation typically includes measurement of serum creatinine and estimation of glomerular filtration rate (eGFR), along with urinalysis to assess for proteinuria, hematuria, or other urinary abnormalities. Quantification of albuminuria using the urine albumin-to-creatinine ratio is particularly important because persistent proteinuria is both a marker of kidney damage and a predictor of disease progression. Additional laboratory studies may reveal electrolyte disturbances, metabolic acidosis, anemia, or abnormalities in calcium-phosphate metabolism associated with declining renal function. Renal ultrasound is commonly performed to evaluate kidney size, cortical thickness, obstruction, or structural abnormalities, while kidney biopsy may be indicated when the underlying cause is uncertain or specific glomerular diseases are suspected. CKD is staged according to eGFR and degree of albuminuria, which helps guide prognosis, monitoring, and therapeutic management.

Mechanism of action videos

• Semaglutide: Renal Protection
• Aldosterone Drives Fibrosis in Chronic Kidney Disease

Biological pathways

• Vasopressin regulates renal water homeostasis via Aquaporins
• Signaling by PDGFR in disease
• Kidney development
• Formation of the ureteric bud
• Formation of the nephric duct
• Formation of intermediate mesoderm
• Nuclear Receptor transcription pathway
• Peptide hormone metabolism
• Cellular hexose transport

Clinical trials

• Sevoflurane-induced Prevention of Ischemia-reperfusion Lesions in Renal Allograft Transplants Recipients
• A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Event-Driven Study to Investigate the Effect of Orforglipron on the Incidence of Major Adverse Cardiovascular Events in Participants With Established Atherosclerotic Cardiovascular Disease and/or Chronic Kidney Disease
• A Phase 3, Open-label, Uncontrolled Study to Evaluate the Activity, Safety, Pharmacokinetics and Pharmacodynamics of Roxadustat for the Treatment of Anemia in Pediatric Participants With Chronic Kidney Disease
• Adia Med of Winter Park LLC Chronic Kidney Disease Research Study
• Safety of Finerenone Versus Alternate-Day Spironolactone in Patients With Heart Failure and Diabetic Kidney Disease at High Risk for Hyperkalemia: The SAFE-K Randomized Trial
• A Phase III, Randomised, Double-Blind Study to Assess the Efficacy, Safety and Tolerability of Baxdrostat in Combination With Dapagliflozin Compared With Dapagliflozin Alone on Chronic Kidney Disease (CKD) Progression in Participants With CKD and High Blood Pressure
• Anakinra for the Treatment of Recurrent Postprandial Hypoglycemia After Total Gastrectomy in a Patient With End-Stage Renal Disease
• A Phase II Randomised, Double-blind, Parallel-group, Multicentre, International Trial to Investigate the Safety and Efficacy of Vicadrostat and Empagliflozin Administered With Simultaneous vs Staggered Initiation in Participants With Chronic Kidney Disease at Risk of Kidney Disease Progression
• An 18-month, Open-label, Single-arm Safety Extension Study of an age-and Bodyweight-adjusted Oral Finerenone Regimen, in Addition to an ACEI or ARB, for the Treatment of Children and Young Adults From 1 to 18 Years of Age With Chronic Kidney Disease and Proteinuria
• A Phase 1, 3-Part, Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of CTX001 in Healthy Adult Participants.
• A Pilot Randomized Clinical Trial to Assess Feasibility, Safety, and Efficacy of Rapid, Simultaneous Therapy Initiation in Chronic Kidney Disease and Type 2 Diabetes: RAPID-CKD
• Tirzepatide Study of Renal Function in People With Overweight or Obesity and Chronic Kidney Disease With or Without Type 2 Diabetes: Focus on Kidney Hypoxia in Relation to Fatty Kidney Disease Using Multiparametric Magnetic Resonance Imaging
• A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody-Mediated Interleukin-6 Inhibition in Japan
• A Multicenter Rollover Extension Program (REP) to Evaluate the Long-term Safety and Tolerability of Open Label Iptacopan in Adult Participants With Primary IgA Nephropathy Who Have Completed Study CLNP023X2203 or CLNP023A2301
• A Multicenter Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of Zigakibart in Adults With Primary IgA Nephropathy.
• Randomized Cross-over Trial of Sodium Bicarbonate on Muscle Mitochondrial Energetics and Physical Endurance in Chronic Kidney Disease and Metabolic Acidosis
• CANagliflozin In DIALysis Patients
• Bleeding Reduction in Acute and Chronic KidnEy patienTs Having Surgery (BRACKETS) Pilot Trial
• Randomized Clinical Study to Analyse the Effects of Dapagliflozin on Renal Morphology and Renal Perfusion in Patients With Impaired Renal Function One Year After Kidney Transplantation
• A Controlled, Open-label PA Efficacy and Safety Study in Imlifidase Desensitised Kidney Tx Patients With Positive XM Against a Deceased Donor Prior to Imlifidase Treatment, Including Non-comparative Registry and Concurrent Reference Cohorts
• A Participant- and Investigator--Blinded, Placebo- Controlled, Randomized, Multipart, Single and Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of OJR520 in Healthy Volunteers and Participants With Chronic Kidney Disease
• A Phase 2b, Open-label Study to Evaluate the Efficacy and Safety of Inaxaplin in Subjects With Proteinuric APOL1-mediated Kidney Disease With or Without Comorbidities That May Independently Contribute to Chronic Kidney Disease
• A Prospective Cohort Study of Tenofovir Alafenamide Switching Therapy in Kidney or Liver Transplant Recipients With Chronic Hepatitis B Virus Infection
• Safety and Efficacy of a Phased Transition From Epogen to Three Times Weekly Oral Vadadustat for the Treatment of Anemia in Subjects Receiving In-Center Hemodialysis
• A Randomized, Placebo-Controlled, Multicenter, Phase 1/2a Study to Investigate the Safety, Tolerability, and Pharmacokinetics of IGT-303 in Healthy Volunteers and Participants With Chronic Kidney Disease
• A Phase 1, Randomized, Placebo-Controlled, Single Ascending Dose First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of VIS649 Administered Intravenously in Healthy Subjects
• A Phase 3, Randomised, Double-blind, Parallel-group, Event-driven, Cardiovascular Safety Study With BI 456906 Administered Subcutaneously Compared With Placebo in Participants With Overweight or Obesity With Established Cardiovascular Disease (CVD) or Chronic Kidney Disease, and/or at Least Two Weight-related Complications or Risk Factors for CVD
• KOR-PED-202 An Open-label, Single-arm Study to Evaluate the Safety and Tolerability of Intravenous Difelikefalin in Adolescents Aged 12 to 17 Years on Haemodialysis With Moderate-to-Severe Pruritus
• A Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Nemolizumab in Subjects With Chronic Kidney Disease With Associated Moderate to Severe Pruritus
• A Phase I/IIa Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Pharmacokinetics of AZD7760 in Healthy Participants and in Patients With End-stage Kidney Disease Receiving Hemodialysis Through a Central Venous Catheter
• Prospective Analysis of Immunogenicity of the Nonavalent Human Papillomavirus Vaccination (GARDASIL 9) in Patients Post Solid Organ Transplant
• A Single Arm, Open Label, Pilot Study to Evaluate the Safety and Efficacy of Once Daily 25mg Empagliflozin in Patients on Peritoneal Dialysis With Residual Kidney Function
• A Phase 2b / 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Combined Dose-Finding and Cardiovascular Outcome Study to Investigate the Efficacy and Safety of CSL300 (Clazakizumab) in Subjects With End Stage Kidney Disease Undergoing Dialysis
• A Phase III, Randomised, Double-blind, Placebo-controlled, Event-driven Study to Assess the Efficacy, Safety and Tolerability of Baxdrostat in Combination With Dapagliflozin Compared With Dapagliflozin Alone on Renal Outcomes and Cardiovascular Mortality in Participants With Chronic Kidney Disease and High Blood Pressure
• A Phase 1, Open-Label Study to Assess the Safety and Pharmacokinetics of INCB123667 When Administered Orally to Adult Participants With Severe Renal Impairment or End Stage Renal Disease
• Effects of Glucocorticoid Therapy on Renal Function in Patients With Primary Aldosteronism Complicated by Chronic Kidney Disease After Adrenalectomy: A Multicenter Randomized Controlled Trial
• Effect of JATENZO® Therapy on Testosterone and Hemoglobin Concentrations in Hypogonadal Men With Chronic Kidney Disease
• An Open-label, Mass Balance Study to Investigate the Absorption, Metabolism and Excretion of [14C]HRS-1780 After a Single Oral Dose to Healthy Male Subjects
• A Multicenter, International, Randomized, Double-blind, Placebo-controlled Clinical Trial of the Aldosterone Synthase Inhibitor BI 690517 in Combination With Empagliflozin in Patients With Chronic Kidney Disease
• A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamic Effects of ANGPTL3 Inhibition With Either Small-Interfering RNA Alone or in Combination With an ANGPTL3 Antibody in Participants With Diabetic Kidney Disease