End-stage renal disease (ESRD) happens when the kidneys lose so much function that they can no longer sustain life without dialysis or a transplant. It’s defined by a glomerular filtration rate (GFR) below 15 mL/min, meaning the kidneys are filtering less than 15% of what healthy kidneys handle. In the United States, over 831,000 people were living with kidney failure in 2023, an all-time high. The causes range from chronic conditions like diabetes and high blood pressure to genetic disorders, infections, and physical blockages in the urinary tract.
Diabetes Is the Leading Cause
Diabetes is responsible for more cases of ESRD than any other condition. Persistently high blood sugar damages every type of cell in the kidney’s filtering units, called glomeruli. The damage follows a predictable chain: excess glucose gets funneled into metabolic pathways that produce harmful byproducts, including molecules called reactive oxygen species. These act as a common thread linking several destructive processes in the kidney. They trigger scarring in the tiny filters and the surrounding tissue, thickening the membranes that blood passes through and gradually choking off the kidney’s ability to do its job.
High blood sugar also causes the kidneys to overwork early on, a state called hyperfiltration. While this sounds like the kidneys are performing well, the increased pressure inside the glomeruli actually accelerates the structural damage already being caused by metabolic stress. Over years or decades, this combination of chemical injury and mechanical strain leads to widespread scarring (glomerulosclerosis), progressively reducing kidney function until it reaches end-stage levels. African Americans develop diabetes-related ESRD at four times the rate of European Americans, reflecting both genetic susceptibility and disparities in disease management.
High Blood Pressure and Blood Vessel Damage
Hypertension is the second most common cause. Healthy kidneys have a built-in safeguard: they can regulate internal blood flow so that elevated pressure in the rest of the body doesn’t get transmitted directly into the delicate filtering structures. In people with certain risk factors, this autoregulatory mechanism breaks down. When that happens, high systemic blood pressure reaches the glomeruli unchecked, gradually damaging the small blood vessels and the surrounding tissue. This process, called nephrosclerosis, hardens and narrows the renal arteries over time.
A related vascular cause is renal artery stenosis, where the arteries supplying the kidneys become physically narrowed, most often by atherosclerosis (plaque buildup). This accounts for 60% to 90% of renal artery stenosis cases and primarily affects men over 45. The narrowing starves the kidney of blood, and the resulting damage eventually becomes irreversible. Once that threshold is crossed, restoring blood flow through surgery or stenting no longer recovers kidney function.
Glomerular Diseases
Glomerulonephritis refers to a group of conditions where the kidney’s filtering units become inflamed. IgA nephropathy is the most common form worldwide. In this condition, an antibody called IgA accumulates in the glomeruli, triggering chronic inflammation and scarring. Most cases of glomerulonephritis that aren’t effectively treated will progress to chronic kidney disease and eventually ESRD.
Lupus nephritis, a kidney complication of the autoimmune disease lupus, is another significant contributor. The immune system attacks the kidney tissue directly, causing inflammation that can be difficult to control. Other forms of glomerular disease involve abnormal protein deposits. In one type (AL amyloidosis), progression to kidney failure can happen in as little as two to three years. In another (AA amyloidosis), treating the underlying condition that triggers the protein deposits can sometimes halt the damage.
Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of ESRD. Fluid-filled cysts grow throughout both kidneys over decades, gradually compressing and replacing healthy tissue. Because cyst growth is slow, most people with ADPKD don’t reach kidney failure until middle age. The average age at which patients start dialysis or receive a transplant is around 56, and the majority (68%) are between 40 and 64 years old when they reach that point.
ADPKD follows a predictable inheritance pattern: a child of an affected parent has a 50% chance of inheriting the condition. In the early 2000s, roughly 4,300 Americans per year began renal replacement therapy because of ADPKD, a rate of about 7.5 cases per million people annually. Rates were highest among those aged 40 to 64 and among non-Hispanic white and African American populations.
Urinary Tract Obstruction
When urine can’t drain properly, pressure builds backward from the bladder into the kidneys. This condition, called obstructive nephropathy, can result from kidney stones, an enlarged prostate, bladder tumors, or congenital abnormalities of the urinary tract. The increased pressure first affects the collecting ducts (where urine is concentrated), then spreads to the rest of the kidney’s tubular system.
How much permanent damage occurs depends on three factors: how long the blockage lasts, how complete it is, and where it’s located. A partial obstruction caught early may cause little lasting harm. A complete blockage left untreated for weeks or months triggers a cascade of inflammation and scarring (interstitial fibrosis) that can destroy enough tissue to cause kidney failure. The rising pressure also squeezes the tiny blood vessels that supply the kidney, compounding the injury.
Medications and Toxins
Certain drugs damage the kidneys directly, and repeated exposure over time can push someone with already-reduced kidney function toward ESRD. Common culprits include NSAIDs (ibuprofen, naproxen), some antibiotics, and certain diuretics. One study found that 96% of patients with chronic kidney disease had received at least one prescription for a nephrotoxic drug. Patients aged 60 and older were eight times more likely to receive contraindicated medications compared to younger patients, highlighting how routine prescribing can inadvertently accelerate kidney decline in vulnerable people.
Genetic and Demographic Risk Factors
Beyond ADPKD, several genetic factors influence who progresses to ESRD and how quickly. The risk of kidney failure is four times higher among African Americans, three times higher among Native Americans, and two times higher among Hispanic Americans compared to white Americans. These disparities aren’t explained by diabetes and hypertension alone.
A gene called MYH9 plays a significant role. Variants of this gene are found in about 60% of African Americans but only 4% of European Americans, and they’re strongly associated with kidney failure attributed to hypertension and certain forms of kidney scarring (focal segmental glomerulosclerosis, or FSGS). Another genetic variant, in the GCK1 gene, appears to make African Americans susceptible to developing ESRD at a younger age. Variations in genes that control inflammation, including those involved in immune signaling, also influence how quickly kidney disease progresses regardless of the original cause.
How Multiple Causes Overlap
In practice, ESRD rarely has a single neat cause. Someone with diabetes often develops high blood pressure, and the two conditions damage the kidneys through overlapping but distinct mechanisms. A person with mild genetic susceptibility might tolerate years of moderate hypertension, while someone carrying high-risk gene variants may progress to kidney failure from the same blood pressure levels. Obesity, smoking, and recurrent kidney infections add further stress to kidneys already under strain.
The adjusted rate of new ESRD cases in the U.S. has actually fallen 21% over the past two decades, dropping from 456 to 362 per million people between 2003 and 2023. Better management of diabetes and blood pressure likely explains much of this decline. But because the population is aging and growing, the absolute number of new cases rose 28% over the same period, reaching 131,564 in 2023. The total number of Americans living with kidney failure continues to climb, underscoring that prevention and early management of the root causes remain the most effective tools against this disease.