Chronic Kidney Disease

Chronic kidney disease is a general term for heterogeneous disorders affecting kidney structure and function, classified by stages of severity assessed from glomerular filtration rate (GFR) and albuminuria together with the clinical diagnosis (cause and pathology). ^[1] Defined as a low estimated GFR (eGFR) or albuminuria, chronic kidney disease affects approximately 14% of adults in the US. ^[2] The global estimated prevalence of chronic kidney disease is 13.4%, and a systematic review found the majority of cases in stage 3. ^{[3] [4]} A recent Lancet review estimates approximately 850 million cases worldwide and projects chronic kidney disease to become the fifth leading underlying cause of death by 2050. ^[5] Chronic kidney disease is irreversible and progressive, and patients remain asymptomatic most of the time, with complications of renal dysfunction appearing only in more advanced stages. ^[6] Risk of premature cardiovascular disease is particularly high, as most patients develop a disability or die from cardiovascular disease before ever progressing to kidney failure, which makes chronic kidney disease a major contributor to cardiovascular risk. ^{[5] [4]} In advanced stages, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. ^[7]

Hypertension and diabetes are the most common etiologies of chronic kidney disease in the United States, and large cohort studies identify high blood pressure as an important risk factor for it. ^{[8] [9]} Diabetic kidney disease is the most common cause of chronic kidney disease in the United States and develops in approximately 30% to 40% of individuals with diabetes mellitus. ^[10] The global increase in chronic kidney disease is mainly driven by rising prevalence of diabetes mellitus, hypertension, obesity and aging, while infection and herbal or environmental toxins remain common causes in some regions. ^[3] Obesity drives chronic kidney disease progression through hemodynamic changes, inflammation, oxidative stress and activation of the renin-angiotensin-aldosterone system, and obesity-related kidney disease is characterized by glomerulomegaly, often with segmental glomerulosclerosis. ^[11]

For individuals at high risk of chronic kidney disease, estimated glomerular filtration rate, urine albumin-creatinine ratio and blood pressure should be measured regularly, because early-stage disease is asymptomatic and most people with it remain undiagnosed. ^[16] GFR is most commonly estimated from serum creatinine, and confirmatory tests for a more accurate assessment include cystatin C-based equations and urinary or plasma clearance of exogenous filtration markers. ^[17] Urine albumin-creatinine ratio (ACR) is the preferred measure of albuminuria for defining and staging chronic kidney disease, with screening positivity at ACR ≥30 mg/g, stage A2 at an ACR of 30 to 299 mg/g and stage A3 at ACR ≥300 mg/g. ^[18] By eGFR stage, a global prevalence meta-analysis used stage 1 as eGFR >90 with ACR >30, stage 2 as eGFR 60-89 with ACR >30, stage 3 as eGFR 30-59, stage 4 as eGFR 15-29 and stage 5 as eGFR <15. ^[4] In a KDIGO-funded meta-analysis of general population cohorts, an eGFR below 60 mL/min/1.73 m2 and an ACR of 10 mg/g or more were independent predictors of mortality, and the two measures were multiplicatively associated with risk. ^[19] An individual-participant meta-analysis of 114 cohorts found lower eGFR (from creatinine alone or creatinine with

Blood glucose and blood pressure control are described as the only primary prevention measures for chronic kidney disease. ^[21] Clinical practice guidelines now recommend a sodium-glucose co-transporter 2 (SGLT2) inhibitor alongside a renin-angiotensin-aldosterone system inhibitor as foundational therapy in people with chronic kidney disease, with or without type 2 diabetes. ^[16] A collaborative meta-analysis of 13 placebo-controlled trials (90 413 participants) found that SGLT2 inhibitors reduced the risk of kidney disease progression by 37% and of acute kidney injury by 23%, with similar effects in patients with and without diabetes. ^[22] In the SMART-C meta-analysis of 10 randomized trials, SGLT2 inhibitors reduced the risk of CKD progression (HR 0.62) irrespective of baseline eGFR and albuminuria, including at an eGFR below 30 mL/min/1.73 m2 (HR 0.71). ^[23] A meta-analysis of 8 randomized trials found clear absolute benefits of SGLT2 inhibitors on kidney, hospitalization and mortality outcomes irrespective of diabetes status and level of urine albumin to creatinine ratio. ^[24]