End-stage renal disease (ESRD) — also termed end-stage kidney disease (ESKD) or kidney failure — is defined as eGFR <15 mL/min/1.73 m², at which point kidney function can no longer sustain life without kidney replacement therapy (dialysis or transplantation) or conservative management.
Over 750,000 individuals in the United States have ESRD, accounting for approximately 7–10% of Medicare fee-for-service spending, with a 5-year survival rate of approximately 40% after dialysis initiation.
Incidence and prevalence expected to increase by 44% and 85%, respectively, from 2000 to 2115 (Gilbertson).
Currently, ore than 800,000 patients with kidney failure have Medicare coverage.
Incidence rising steadily for the past 15 years, to greater than 308 cases per million population.
The U.S. Renal data System reports that in 2006, the adjusted incidence of end-stage renal diseae increased to 360 cases per million people.
The incident rate of ESRD cases at the initiation of hemodialysis is higher for males, with 415.1 per million population compared with 256.6 for females.
Patients with ESRD account for less than 1% of Medicare population, but they account for 5.8% of the expenses.
The onset of ESRD substantially alters a patient’s lifestyle and imposes increased mobility and mortality.
New cases are growing fastest among people aged older than 75 years.
Average cost for a patient with end-stage renal disease is $70,000 per year.
Diabetes and hypertension are the two leading causes, accounting for 47% and 29% of incident ESRD cases in the US, respectively.
The Global Burden of Disease 2023 analysis identified the five leading attributable risk factors for CKD disability-adjusted life years as high fasting plasma glucose (31.9%), high systolic blood pressure (24.5%), high BMI (23.5%), diet (17.6%), and non-optimal temperature (4.4%).
Additional risk factors include:
Black, Hispanic, and American Indian/Alaska Native race/ethnicity
Proteinuria, obesity, smoking, elevated triglycerides, and family history of kidney disease
Glomerulonephritis, polycystic kidney disease, and APOL1 gene risk variants, a major contributor to excess CKD risk in individuals of Black ethnicity.
Clinical Manifestations-Uremic Syndrome
ESRD produces a multisystem syndrome resulting from retained uremic toxins, loss of renal endocrine function, and electrolyte/volume dysregulation.
Cardiovascular: Hypertension, fluid overload, heart failure, accelerated vascular calcification, pericarditis, sudden cardiac death is the leading cause of mortality.
Hematologic: Anemia (from erythropoietin deficiency and low iron bioavailability), immune dysfunction, bleeding tendency.
Neurologic: Uremic encephalopathy, peripheral neuropathy, cognitive dysfunction, asterixis
Endocrine/Metabolic: Secondary hyperparathyroidism, CKD-mineral bone disorder, insulin resistance, metabolic acidosis.
Gastrointestinal: Nausea, vomiting, anorexia, metallic taste.
The following figure illustrates the complex pathobiology underlying the dramatically increased cardiovascular risk in ESRD patients:
Kidney Replacement Therapy
The decision to initiate dialysis is based on symptoms rather than eGFR alone — a randomized trial showed no mortality benefit to starting dialysis at higher eGFR (10–14) versus lower eGFR (5–7 mL/min/1.73 m²).
Urgent indications include uremic encephalopathy, pericarditis, and pleuritis.
Kidney transplantation is the optimal therapy, with living donor transplantation performed preemptively (before dialysis) yielding the best outcomes.
Referral to a transplant program is advised when eGFR falls below 30 mL/min/1.73 m², though the median wait time is approximately 4 years.
Dialysis modalities include in-center hemodialysis (~90% of US dialysis patients), home hemodialysis, and peritoneal dialysis.
Observational data suggest no significant difference in 5-year mortality between hemodialysis and peritoneal dialysis.
Conservative management without dialysis is a reasonable alternative for patients with limited life expectancy, severe comorbidities, or those who wish to avoid medical interventions, emphasizing symptom management and quality of life.
ESRD Complications
Anemia: Managed with iron supplementation (oral or IV) and erythropoiesis-stimulating agents (ESAs), initiated when hemoglobin falls to 9–10 g/dL with a target of 10–11.5 g/dL.
Complete correction with ESAs increases cardiovascular risk and should be avoided.
Hypoxia-inducible factor prolyl hydroxylase inhibitors (roxadustat) are an oral alternative but have not demonstrated superior cardiovascular safety.
CKD-Mineral Bone Disorder: Dietary phosphate restriction, phosphate binders (calcium acetate, sevelamer, iron-based binders), vitamin D analogues, and calcimimetics (cinacalcet) are used to manage hyperphosphatemia, hypocalcemia, and secondary hyperparathyroidism.
Cardiovascular disease: CVD is the leading cause of death in ESRD, with unique pathophysiology including medial arterial calcification.
Notably, statin trials in dialysis populations have been negative, which may be partly explained by the distinct vascular pathology.
Blood pressure control through adequate dialysis and sodium restriction improves mortality.
Vaccination (influenza, pneumococcal, hepatitis B, tetanus) is advised.
Insulin is preferred for glycemic management in ESRD.
Medication dosing adjustments are critical across analgesics, antimicrobials, and anticoagulants.
Therapies:
Several drug classes have transformed the management of CKD to delay or prevent progression to ESRD:
SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin) are first-line therapy, reducing kidney disease progression by ~37–38% and cardiovascular events in patients with CKD with or without diabetes.
They can be initiated at eGFR ≥20 mL/min/1.73 m² and continued until dialysis.
GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) reduce major adverse kidney events and cardiovascular risk.
The FLOW trial demonstrated that semaglutide reduced major kidney disease events in patients with type 2 diabetes and CKD.
SGLT2 inhibitors appear more effective than GLP-1 RAs specifically for preventing eGFR decline and kidney failure.
Finerenone (nonsteroidal MRA) reduces risk of eGFR decline, ESKD, cardiovascular death, and heart failure hospitalization in adults with CKD associated with type 2 diabetes (eGFR ≥25 mL/min/1.73 m²), though hyperkalemia risk requires monitoring.
RAS inhibitors (ACE inhibitors/ARBs) remain foundational for patients with CKD and albuminuria or hypertension.
The STOP-ACEi trial showed no benefit to discontinuing RAS inhibitors in advanced CKD.
The following figure compares renal outcomes across these drug classes:
Guideline emphasizes that kidney-protective agents (RASi, SGLT2i, finerenone, GLP-1 RAs) should be continued even after eGFR declines below initiation thresholds, as several major trials demonstrated ongoing cardiovascular benefit without increased adverse effects.
Independent risk factors include older age, proteinuria, diabetes mellitus, hypertension, African-American race, elevated serum creatinine, obesity, lower hemoglobin, elevated uric acid self-reported nocturnal and family history of kidney disease (Hsu).
The mortality from kidney failure is estimated to be approximately 18% per year, and is a higher mortality rate than observed among patients with heart failure, diabetes, or many cancers.
For most patients ESRD is managed by in-center hemodialysis, that obligates the placement and functionality of vascular access, they need to travel three times a week to the dialysis center, three times weekly hemodialysis treatment lasting three hours or more, tolerance to recurrent lassitude and generalized lack of well-being often experienced after each hemodialysis treatment, restricted intake o fluids, and assorted dietary restrictions.
Most important causes are diabetic nephropathy and hypertension and the incidence increases each year.
Results in a substantial escalation in the progression of coronary artery disease.
Cardiovascular disease leading cause of death, accounting for 40 to 50% of deaths.
Cardiovascular disease mortality is 10-20 times greater than in the general population.
Blacks are overrepresented in the end-stage renal disease population.
More than 500,000 people with end-stage renal disease in the US, approximately 1/3 are black, and the relative incidence of end-stage renal disease is 3.6 times higher among black than white individuals.
Blacks with chronic kidney disease are less likely to be under the care of a nephrologist, have a referral for peritoneal dialysis or kidney transplantation.
Two common variants of the APOL1 gene accounts for much of the excess of non-diabetic chronic kidney disease risk among black individuals in the US.
Black patients are less likely to receive adequate dialysis dosing, to have a fistula placed, to achieve target hemoglobin levels.
Black patients survive longer than white patients on dialysis, with a 13-45% lower mortality.
The overall survival advantage for black patients on dialysis applies only to older adults, while those younger than 50 years have a higher risk of death (Kucirka LM et al).
Cardiovascular mortality in patients on hemodialysis or on peritoneal dialysis have a 10 to 20 times greater risk than in the general population.
Kidney transplantation as a treatment for ESRD offers a better quality of life, and on average 10 extra years of life for recipients of the first deceased donor kidney transplant compared with treatment with dialysis (Wolfe RA et al).
Patients who received renal transplants have a 68% lower mortality rate in patients eligible for transplant who continue to receive hemodialysis.
Among patients aged 65 years or older who have ESRD, mortality rates are 6 times higher than in the general population.
The most common cause of sudden death in patients with ESRD is hyperkalemia, which often follows missed dialysis or dietary indiscretion.
Greater than 20% annual mortality.
At every age, patients with ESRD on dialysis have significantly increased mortality when compared with nondialysis patients and individuals without kidney disease.
Patients at increased risk for non-cardiovascular morbidity and mortality, including that caused by infection.
Hospitalization with major infection is an independent factor in the subsequent risk of ESRD.
Bacteremia second leading cause of death with end stage renal disease requiring dialysis.
30% of patients on dialysis have cholesterol level higher than 200 mg/dL
Cardiac troponin T has been found to be falsely elevated in patients with end-stage renal disease.
25-40% of diabetic patients develop end-stage renal disease.
Not shown to be associated with elevated cardiac troponim-I levels.
Patients older than 75 years represent about 17.8% of hemodialysis patients.
Patients with ESRD, the activity of the 1-alpha-hydroxylase enzyme is substantially diminished, and this enzyme is primarily expressed in the kidney and converts 25-hydroxyvitamin D to active 1, 25 dihydroxyvitamin D.
As a consequence of a low 1, 25 dihydroxyvitamin D, parathormone is stimulated to restore its level and incorrect abnormal calcium and phosphate levels.
As a result, avlow 1-alpha–hydroxylase enzyme activity results in severe secondary or tertiary hyperparathyroidism, which is associated with skeletal complications, including fracture, deformity, and growth failure in children.
To interrupt this process, 1, 25 dihydroxyvitamin D is often prescribed to patients with ESRD in the form of vitamin D receptor agonists.
18-26% of elderly patients fail to survive the first 90 days on hemodialysis.
Hospitalizations average 12-15 days per patient per year.
Better survival of European patients with ESRD compared with those in the U.S.
Patients on regular hemodialysis or continuous ambulatory peritoneal dialysis have a prevalence of malnutrition of 27% in the 18-40-year age group, 31% in the 41-64-year group and 51% in the 65-year-and older group.
Despite a high prevalence of malnutrition, it is cited as a cause of death in such patients only 1-2% of the time.
Albumin levels strongly associated with mortality risk.
Hypothyroidism may develop in end-stage renal disease, due to metabolic derangements associated with progressive uremia.
There is a threefold higher risk for end-stage renal disease during follow-up of overweight adolescents and an almost sevenfold higher risk for obese youth (Vivante A et al).
Severity and prevalence of anemia closely associated with kidney dysfunction as the frequency of anemia increases from 27% to 76% with a decline in glomerular filtration rate from more than 60 mL/min1.73m2 to less than 15mL/min1.73m2.
During persistent metabolic acidosis the body loses its ability to block amino acid and protein degradation.
Metabolic acidosis exerts a negative inotropic effect of the myocardium.
Children with end-stage renal disease have a long-tem survival of 79% at 10 years and 66 years at 20 years.
Mortality rates 30 times that of children without end-stage renal disease.
Treatment with dialysis in children associated with a four fold risk for death compared with those children receiving renal transplantation.
Occurs in 5-10 children per million each year.
In children the most common causes of death are cardiovascular disease and infection.
Transplant is the treatment of choice in children, to maximize survival, growth, and development, but 75% of children will require treatment with dialysis prior to receiving a kidney transplant.
The all cause mortality rates in children receiving maintenance dialysis is at least 30 times higher than the general pediatric population.
There is a significant decrease in mortality rates over time among children and adolescents initiating dialysis treatment between 1990 and 2010 (Mitsnefes MM et al).
The older a child is when renal-replacement is needed the better the chance for long-term survival.
Children younger than 5-6 years have the highest risk of death.
Mortality risk increases with decreasing age less than 5 years and increases with increasing age beyond 10 years.
Causes of death in children with ESRD are cardiovascular disease and infections.
Such patients usually have hypocalcemia and as a result of treatment for renal osteodystrophy it is not uncommon to see hypercalcemia.