Chronic Kidney Disease

Chronic kidney disease (CKD) refers to abnormalities of the kidneys in structure or function that persist for at least three months and have consequences for health. The kidneys filter waste from the blood, balance water, salts and acids, and regulate blood pressure and red blood cell production, so a gradual loss of this work affects nearly every organ system. CKD is classified by its cause, by the level of glomerular filtration rate (GFR), and by the amount of albumin in the urine. This classification guides diagnosis, prognosis and treatment.

CKD matters because it is common, often silent until late, and strongly linked to cardiovascular disease. Estimates of its global prevalence run into the hundreds of millions, and the burden has grown since 1990, driven mainly by type 2 diabetes and hypertension. Advanced disease can end in kidney failure, which requires dialysis or kidney transplantation, or in conservative care. Slowing progression with blood pressure control, glucose control and newer drugs is therefore a central goal of public health and clinical medicine.

This entry first defines CKD and explains its staging system, then describes how kidney function declines and what causes the disease. It goes on to cover global epidemiology, complications, detection, treatment strategies and the care of kidney failure, before reviewing how the concept developed and the questions that remain open.

Definition and Diagnostic Criteria

Core definition

Under the KDIGO nomenclature, clinicians recognise CKD when a structural or functional kidney problem has lasted beyond three months and bears on a person's health. CKD is classified by cause, glomerular filtration rate (GFR) category (G1–G5), and albuminuria category (A1–A3), but the diagnosis itself rests on the presence of damage or dysfunction, not on a particular cause. The 2024 guideline emphasises that the definition covers many kinds of kidney damage beyond a reduced glomerular filtration rate and albuminuria (the definition includes many different markers of kidney damage).

The three-month window is a working convention rather than a biological boundary, but it serves a clear purpose: it separates injuries that are still resolving from those that have settled into a lasting state. Acute kidney injury is defined as an abrupt decrease in kidney function occurring over seven days or less. Kidney disorders persisting up to three months are classed as acute kidney disease, which sits between the acute and chronic categories. The threshold also matters because recovery can be incomplete. Patients whose serum creatinine returns fully to baseline after AKI still face higher risk of later CKD, which suggests persistent subclinical damage. For this reason, in patients who have recovered from AKI, the diagnosis of CKD should wait for 3 months after discharge.

Diagnostic markers

A person can meet the criteria by either of two routes: a reduced filtration rate or evidence of kidney damage, present for more than three months. The filtration threshold is an eGFR below 60 mL/min per 1.73 m². Without markers of kidney damage, a GFR above 60 is insufficient to classify CKD. The main damage markers include albuminuria with an albumin-to-creatinine ratio of 30 mg/g or more, urine sediment abnormalities, electrolyte and other abnormalities due to tubular disorders, histological abnormalities, structural abnormalities detected by imaging, and a history of kidney transplantation. Persistent abnormalities on urinalysis are also informative: urine abnormalities such as white cells, red cells, non-hyaline casts, or protein even with eGFR at or above 60 suggest kidney disease. Albuminuria itself is discussed in more detail in the staging section, where it is treated as a separate axis of risk, see albuminuria.

Two caveats apply. First, eGFR is calculated from serum markers and is an estimated value that assumes a steady state of the biomarker, so it is less reliable when kidney function is changing quickly. Second, the 60 threshold is contested for older adults. KDIGO 2024 keeps it in place even when albuminuria is absent, but a significant part of the healthy population older than 65 years has a GFR below 60, which has led some researchers to argue for age-calibrated cut-offs.

Confirming chronicity

A single abnormal value is rarely enough, because transient illness, dehydration, or acute injury can depress kidney function briefly. Small fluctuations in GFR are common and are not necessarily a sign of progression. KDIGO therefore asks clinicians to review past history and earlier measurements to determine how long the abnormality has been present, and if the duration is not clearly beyond three months, CKD is not confirmed, and the patient may have CKD, acute kidney disease, or both, so tests should be repeated. Some systems formalise this further. The UK framework, for example, requires an eGFR below 60 on at least two occasions 90 days apart.

A typical clinical illustration is a 75-year-old man whose first eGFR is 40 with otherwise normal urinalysis. He is not labelled as having CKD until repeat testing three months later confirms the value (the eGFR is still below 60). Where confirmation is needed in people whose eGFR is between 45 and 59 and who have no other damage markers, KDIGO suggests measuring cystatin C, which reduces the influence of muscle mass on the estimate.

Distinction from related terms

Acute kidney injury is characterised by speed. It is more commonly reversible than chronic kidney failure, and it is usually triggered by an event such as serious infection, major surgical blood loss, or certain medicines (it is usually caused by an event that leads to kidney malfunction). The clinical challenge is that AKI can occur in someone who already has CKD. In that setting, acute-on-chronic deterioration should be suspected when a patient with known CKD experiences a sudden rise in serum creatinine above their established baseline. Comparing current results with earlier ones is therefore central to telling the two apart, as the doctor compares these levels to previous tests to find out if the kidney problem is acute or chronic.

The term kidney failure has a different meaning depending on context. KDIGO applies it to chronic disease that persists beyond three months, whereas in acute injury it refers to AKI stage 3 lasting three months or less (in a chronic setting, kidney failure is defined as lasting more than three months, whereas in an acute setting it is reserved for AKI stage 3 with a duration of three months or less). Within CKD, kidney failure denotes the most advanced stage, at which replacement therapy becomes necessary. CKD is a state of progressive loss of kidney function that ultimately requires renal replacement therapy, such as dialysis or transplantation. Older literature used the phrase chronic renal failure, and in most instances it means the same as CKD, although in some cases it refers specifically to end-stage renal disease or stage 5 CKD.

Staging and the CGA Classification

Current staging of chronic kidney disease uses two numerical axes, which is why the framework is often described as two-dimensional. Under the KDIGO 2024 guideline, a patient is classified by the cause of the disease, a glomerular filtration rate (GFR) category, and an albuminuria category, and this combined system is abbreviated CGA. The GFR category runs from G1 to G5 and the albuminuria category from A1 to A3. The cause is recorded alongside these two axes rather than folded into them, so the stage describes function and damage, while the etiology guides treatment. The two axes are then read together on a grid, the KDIGO heat map, rather than being used as separate labels.

GFR categories G1 to G5

The G categories divide eGFR into bands measured in mL/min per 1.73 m². G1 covers values of 90 and above, G2 covers 60 to 89, and G3 is split into G3a (45 to 59) and G3b (30 to 44). G4 covers 15 to 29, and G5 covers values below 15. G5 is defined as below 15 or on dialysis, which is why G5 is equated with kidney failure rather than with a numerical value alone. The 60 mL/min per 1.73 m² boundary is the familiar cut-off for CKD, but it is only meaningful when the reduction persists: an eGFR below 60 that lasts at least three months indicates CKD.

The cut-points were not chosen to mark a physiological break point. The eGFR thresholds used to define and stage CKD are based on risk, which means each boundary reflects how outcomes change across the band. The split of G3 into two sub-categories follows the same logic, since the risk of progression and complications rises noticeably between about 45 and 30 mL/min per 1.73 m².

Albuminuria categories A1 to A3

Albuminuria is measured mainly as the urine albumin-to-creatinine ratio (UACR), expressed in mg/g. A1 is under 30 mg/g (normal to mildly increased), A2 is 30–300 mg/g (moderately increased), and A3 is over 300 mg/g (severely increased). A2 corresponds to the older term microalbuminuria, and A3 to macroalbuminuria. Where only a 24-hour urine protein measurement is available, A2 and A3 are expressed as protein excretion of roughly 0.5 to 3.5 g/day and above 3.5 g/day, respectively.

Albuminuria carries prognostic weight in its own right. An elevated UACR marks renal dysfunction and independently predicts cardiovascular disease. Because of this, the A category adds information that eGFR cannot supply. A patient with a G2 eGFR and A3 albuminuria is at higher risk of progression and cardiovascular events than a patient with a lower eGFR and no albuminuria, which is the core reason the two-axis approach is preferred.

The KDIGO heat map

The heat map places G and A categories in a grid and assigns each cell a risk level from low to very high. It grades the risk of CKD progression by combining GFR categories with albuminuria categories, running from green for low risk through red for very high risk. The practical value lies in separating people with the same eGFR. Two people with the same eGFR can sit at very different risk depending on how much albumin is in their urine. The grid is also tied to outcomes beyond progression: the heat map is associated with all-cause and cardiovascular mortality, kidney failure, and acute kidney injury, independent of eGFR alone. Colour names and cell boundaries differ between reproductions of the grid, so clinical use should follow the original guideline.

Creatinine-based versus cystatin C-based estimation

Most eGFR values are calculated from serum creatinine. Creatinine is the first-line test, and confirmatory testing with serum cystatin C is recommended when creatinine-based eGFR is considered less accurate because of deviant muscle mass. Creatinine is produced by muscle, so its limitations follow directly from that origin. People with reduced muscle mass, such as those with sarcopenia from prolonged bed rest, tend to have an eGFR that is overestimated. Conversely, athletes with large muscle mass tend to have an eGFR that is underestimated. Diet, exercise and renal tubular secretion also shift serum creatinine. In a large comparison of outcomes, the creatinine-based eGFR had the weakest association with death from any cause among the three GFR estimates.

Cystatin C is a protein produced by nearly all nucleated cells and handled by the kidney in a way that is largely independent of muscle. It is not affected by body habitus and muscle mass, which makes it attractive for patients whose creatinine is unreliable. Its own limitations are important. Its levels are influenced by thyroid function, smoking, inflammation, fat mass, pregnancy and immunosuppressants. Cost is another barrier to routine use. The two markers also disagree in measurable ways: in one pooled analysis, the prevalence of an eGFR below 60 was 9.7% with the creatinine equation and 13.7% with the cystatin C equation. A combined creatinine–cystatin C equation, the CKD-EPI creatinine-cystatin equation, improves accuracy, especially for individuals with eGFR values of 45–59. In practice, cystatin C is most useful when muscle mass is atypical, in older adults, in people with extreme diets, and when drugs or disease are likely to alter creatinine handling.

Kidney Physiology and Mechanisms of Progression

The nephron and kidney function

The nephron is the functional unit of the kidney. Each one couples a glomerulus, where plasma is filtered, to a tubule that reclaims most of that filtrate while secreting wastes and drugs into urine. Net urine output therefore reflects the balance between reabsorption and secretion along the tubule. The kidney also functions as an endocrine organ. It produces erythropoietin, which signals the bone marrow to make red cells, and it converts vitamin D into its active hormonal form, which governs calcium and phosphate balance. Because the kidney's total filtering capacity is the sum of its nephrons, the loss of nephrons is central to the disease. In CKD, CKD leads to irreversible loss of nephrons, with a progressive, silent deterioration of renal function, which is why function can fall for years before symptoms appear.

Adaptive hyperfiltration

When nephrons are destroyed, the survivors compensate. Each remaining nephron increases its own filtration rate, a process called adaptive hyperfiltration, so total glomerular filtration rate can remain close to normal even as nephron mass shrinks. The remaining nephrons compensate by increasing single-nephron GFR, so total GFR is preserved, which is why a normal-looking GFR does not exclude ongoing damage.

This compensation carries a cost. Higher glomerular capillary pressure and enlarged glomeruli strain podocytes, the cells that form the filtration barrier. Their loss drives albuminuria and proximal tubular overload, contributing to CKD progression. The proximal tubule must also reabsorb a larger filtrate load, which raises its oxygen demand in tissue that is already vulnerable. Reduced nephron endowment at birth, along with obesity, diabetes and hypertension, can speed this cycle. These factors accelerate the decline in nephron number through glomerular hyperfiltration, making CKD more likely to develop.

The hyperfiltration model is not the whole story. It does not account for patients whose GFR declines without albuminuria, even in the presence of substantial vascular disease. Some decline in GFR therefore appears to follow other routes, such as reduced perfusion of the nephron.

Inflammation, fibrosis and a shared final pathway

Diverse injuries converge on a common endpoint. The pathogenic mechanisms of CKD converge on progressive interstitial fibrosis, peritubular capillary loss with hypoxia, and destruction of functioning nephrons through tubular atrophy. Even when the original disease is inactive or has been cured, progression can continue through intrinsic hemodynamic factors and other mechanisms such as chronic inflammation, reduced regenerative capacity of the kidney, and fibrosis. Fibrosis itself is driven by myofibroblasts and inflammatory cells, with transforming growth factor β (TGF-β) being of particular importance among the molecular pathways. Inflammatory leukocytes accumulate in the interstitium early in kidneys that go on to scar (interstitial recruitment of inflammatory leukocytes and myofibroblasts occurs early), and hypoxia appears to contribute before structural damage becomes visible.

This convergence is the basis of the concept of a shared final pathway. Glomerulosclerosis, vascular sclerosis and tubulointerstitial fibrosis are seen across many diseases, suggesting a common final pathway of progressive injury. A practical consequence is that serum creatinine and proteinuria, which primarily reflect glomerular health, may underestimate the tubulointerstitial scarring that drives long-term loss.

Proteinuria and blood pressure as accelerators

Proteinuria is both a marker and a driver of progression. Filtered proteins are toxic to proximal tubular cells, and this toxicity promotes tubular atrophy and interstitial fibrosis. Proteinuria can also cause damage through increased reactive oxygen species, autophagy dysfunction, lysosomal membrane permeabilization, endoplasmic reticulum stress and complement activation. The quantitative link is substantial. In one analysis of non-glomerular disease, every doubling of baseline urine protein-to-creatinine ratio was associated with a 0.3 ml/min/1.73m² reduction of GFR per year.

Blood pressure acts on the same mechanism. Hyperfiltration raises glomerular capillary pressure, and maneuvers that decreased hyperfiltration, such as low-protein diet, angiotensin I converting enzyme inhibitors, lipid-lowering agents, or heparin, were effective in ameliorating glomerular sclerosis. This is the rationale for reducing intraglomerular pressure and albuminuria in management, although the evidence is strongest for specific interventions rather than for any single mechanism.

Patterns of eGFR decline over time

The absolute eGFR is only part of the picture, because the rate of change carries prognostic information. Some decline is simply age-related. Age-related GFR decline reflects the normal loss of nephrons with aging, without adaptive hyperfiltration to compensate. Pathological decline is different. Over ten years, the rate of reaching kidney failure or a 50% decline in eGFR ranged from around 10% (nonglomerular CKD) to around 40% (glomerular CKD). Clinical guidance also treats short-term change as meaningful. Initial eGFR declines of more than 30% are rare and should prompt review of volume status, blood pressure and other causes, as well as repeat testing.

Slope may also be more informative than a single measurement. Researchers have noted that a single time point may not capture fibrosis, which represents years of progression, and that the slope of eGFR over time might show a better correlation. For this reason, trials of therapies for CKD often assess whether they change the rate of decline, not just the level of kidney function. Rapid progression has been associated with factors including blood pressure control, anemia, diabetes, albuminuria and disease stage. These factors are linked to rapid CKD progression in a real-world cohort.

Causes and Risk Factors

Most cases of CKD trace back to a few conditions that damage the glomeruli, the blood vessels, the tubules, or the urinary outflow tract. The mix differs by region. In high-income countries, diabetes and hypertension dominate, while in some other settings a large share of cases never receives a clear cause.

Diabetes

Diabetes is the leading cause of CKD in many high-income countries. Both type 1 diabetes and type 2 diabetes can produce diabetic kidney disease. Sustained hyperglycemia damages the kidney through several routes. Excess glucose binds proteins in a process called non-enzymatic glycation, which alters the structure and function of cells in the filter. Mesangial cells in the glomerulus multiply and enlarge, the basement membrane thickens, and extracellular matrix accumulates. In advanced disease this produces nodular glomerulosclerosis, the lesion historically known as Kimmelstiel–Wilson syndrome. The small arterioles supplying the glomeruli also thicken and become hyalinized. Protein begins to leak through the damaged filter, so albuminuria often appears years before filtration falls. This sequence makes urine albumin testing important in people with diabetes.

Hypertension

Hypertension acts as both a cause and an accelerator of CKD, and the relationship runs in both directions. Healthy kidneys protect their capillaries through autoregulation: preglomerular arterioles constrict when systemic pressure rises. When chronic pressure exceeds the range this mechanism can absorb, afferent arterioles develop hyalinosis and narrowing, and the glomeruli are exposed to pressure they cannot withstand. The result is benign nephrosclerosis, in which reduced perfusion leads to ischemic scarring. Severe or malignant hypertension can cause acute injury on top of this. The feedback runs the other way too. As functioning nephrons are lost, the kidney retains sodium and water and activates the renin–angiotensin–aldosterone system, pushing blood pressure higher and making control harder. This loop is one reason blood pressure management is central to slowing progression.

Glomerulonephritis and Primary Glomerular Disease

Glomerulonephritis is inflammation of the glomeruli. It was once the leading cause of CKD worldwide and remains important in many regions, although in wealthier countries diabetes and hypertension have overtaken it. Many forms are immune-mediated. Antibodies or immune complexes can deposit in the glomerulus, activating the complement system and recruiting inflammatory cells, which damages podocytes and produces proteinuria. Examples include IgA nephropathy, membranous nephropathy, and lupus nephritis in systemic lupus erythematosus. In other forms, autoantibodies attack the glomerular basement membrane or neutrophil proteins, as in anti-GBM disease and ANCA-associated vasculitis. Some cases follow infection. Because the specific type often can only be determined by kidney biopsy, many cases remain unclassified where biopsy is rarely available. In one Iranian series of 1,000 patients with end-stage kidney disease, about a quarter had no determined cause, which was attributed partly to late referral.

Hereditary and Structural Causes

Autosomal dominant polycystic kidney disease is the most common inherited cause of kidney failure. Variants in PKD1 account for roughly 85% of cases and variants in PKD2 for about 15%. Both genes encode polycystin proteins, and cysts gradually expand and replace functional tissue. Disease caused by PKD1 variants generally reaches kidney failure earlier. In one European comparison, the median age at kidney failure was about 54 years for PKD1 and about 74 years for PKD2. Congenital anomalies, such as hypoplasia, dysplasia, or agenesis, reduce the number of nephrons from birth and can lead to CKD in early adulthood. Urinary tract obstruction, caused by stones, prostatic enlargement, tumours, or congenital valves, raises pressure in the renal pelvis and tubules, and it increases the risk of infection and reflux.

Drug-Related and Environmental Exposures

Long-term use of nephrotoxic medicines is a recognized cause. Common culprits include prolonged analgesic use, nonsteroidal anti-inflammatory drugs (especially in people who are dehydrated or older), lithium, aminoglycoside antibiotics, calcineurin inhibitors, and iodinated contrast agents. Certain herbal preparations containing aristolochic acid have caused tubular damage and fibrosis. Heat stress and repeated dehydration have been proposed as contributors to CKD among outdoor and agricultural workers in Central America and South Asia, where the evidence remains contested and is discussed separately.

Genetic Risk Variants

Some people carry genetic variants that substantially raise their risk. The best-characterized example is APOL1, encoding apolipoprotein L1, which carries the G1 and G2 risk variants. These variants are concentrated in people of recent West and Central African ancestry. Under the classic model, two copies are needed to confer strong risk, although a West African study found that a single copy also carried a lower but measurable increase in risk. The variants are thought to have persisted because they offered protection against trypanosome infection. APOL1 is expressed in podocytes and functions in innate immune defense, and risk variants are thought to injure podocytes. In a UK cohort of people of African ancestry living with HIV, high-risk genotypes were strongly associated with end-stage kidney disease.

Modifiers: Age, Obesity and Smoking

Age reduces nephron number and the kidney's reserve, so the risk of CKD and the consequences of injury both rise in older people. Obesity increases risk through glomerular hyperfiltration, insulin resistance, and higher blood pressure, and it often compounds the effects of diabetes and hypertension. Smoking damages blood vessels, increases albuminuria, and is associated with faster decline in kidney function, particularly among people who already have diabetes or hypertension.

Epidemiology and Global Burden

Why prevalence estimates differ

Published global counts of CKD vary widely. One Global Burden of Disease (GBD) 2021 analysis reported a global CKD prevalence of 359 million in 2021, with 11.13 million new cases, while another GBD 2021 summary counted 673.7 million people worldwide. A Lancet summary gives approximately 850 million cases, and a later Lancet review puts the number of affected adults at 788–844 million. The sources I reviewed do not fully document why the GBD outputs differ, but the usual drivers are the case definition, the data, and the modelling. The definition sets the threshold: the Lancet seminar ties premature cardiovascular risk to a GFR below 60 mL/min per 1.73 m² or an albumin-to-creatinine ratio above 3 mg/mmol (about 30 mg/g), and analyses that include or exclude albuminuria, dialysis patients, or the adult-only population will produce different totals. Methods also matter. GBD 2021 re-extracted European dialysis registry data for 1998–2017 and used global sex-specific coefficients and finer dialysis staging. Finally, data are thin in many countries, so one Lancet review notes that estimates are limited by ascertainment bias and inadequate access to testing, particularly in low-income and middle-income countries.

Trends from 1990 to 2021

Across GBD analyses, the burden grew substantially. In the 359-million analysis, prevalence rose 92% since 1990, incident cases rose 156%, deaths rose 176%, and DALYs rose 114%. Age-standardised rates rose more slowly: the mortality trend was an AAPC of 0.745, and the DALY trend an AAPC of 0.322. Attribution shows that type 2 diabetes and hypertension dominate. The rise in mortality was driven mainly by type 2 diabetes (31.24%, 477,273 of 1,527,639 deaths) and hypertension (29.74%, 454,359 deaths), and for DALYs type 2 diabetes accounted for 25.37% and hypertension for 24.41%. Hypertension's share has grown as well; its attributable prevalence increased from over 11 million in 1990 to over 24 million in 2021. For glomerulonephritis, the excerpts I reviewed do not give a clear 2021 share. They do show a declining trend in its burden, both in pediatric CKD-related mortality and DALYs and in projections, so I have not assigned it a share here.

Regional and income-related disparities

The burden follows development levels. Regions with a higher Socio-demographic Index generally have a lower burden of CKD, while less developed regions show the opposite pattern. Age-standardised mortality and DALY rates are highest in low SDI regions. Trends are not uniform, however: low- and low-middle SDI areas show the fastest escalation in burden, while some high-income countries have achieved reductions. Cause-specific analyses show similar contrasts. For CKD attributable to low physical activity, the highest age-standardised mortality was in Andean Latin America, followed by Central Sub-Saharan Africa and North Africa and the Middle East, while Eastern Europe had the lowest. These patterns sit alongside the diagnostic gaps noted above, which means recorded burden in poorer settings may understate true need.

Age, sex and population aging

Burden rises steeply with age. DALY rates were lowest in the 5–9 age group for both sexes and rose thereafter with age. Most of the CKD burden falls on people aged 50 and older. Sex differences depend on the measure: incidence and prevalence rates were higher among women, while men had higher mortality and DALY rates. In the high-BMI analysis, males showed earlier onset of burden, while older females experienced a higher overall burden. Population aging is a major driver of rising case counts. Researchers attribute the roughly 40% increase in prevalence and incidence over three decades to global population growth and aging, and a GBD decomposition is designed to separate the effects of aging, population growth, and socioeconomic disparities.

Projections to 2030 and 2045

Projections differ by model and horizon. A Bayesian age-period-cohort model projects that by 2030 the number of CKD cases will reach about 25 million, with an age-standardised rate of 297.62 per 100,000. That model expects the highest rates among women, people with type 2 diabetes and hypertension, people over 60, and residents of high and upper-middle SDI countries. For 2045, a GBD-based study expects that without effective public-health interventions, CKD incidence due to type 2 diabetes and hypertension will keep rising sharply, while CKD linked to type 1 diabetes and glomerulonephritis is expected to decline. That study adds that the increase will be more pronounced in males and in aging populations of low- and middle-income countries. The horizon also changes the headline message. The Lancet summary expects CKD to become the fifth leading underlying cause of death worldwide by 2050, whereas the later review gives 2040. These projections mainly extrapolate past trends, population growth and aging, and the assumed continuation of current risk-factor patterns, so they are sensitive to changes in diabetes and hypertension control.

Complications and Comorbidity

Cardiovascular disease is the complication with the greatest effect on survival. Cardiovascular disease is prevalent in patients with chronic kidney disease and may account for 50% of all deaths. Cardiac changes begin early. Left ventricular hypertrophy occurs early in CKD and reaches a prevalence of 70–80% in patients with kidney failure. Retained sodium and water, together with anemia, create a hyperdynamic circulation that loads the heart. As CKD advances, heart failure and sudden cardiac death make up a growing share of fatal events, while atherosclerotic events become relatively less important. The key features of CKD-associated cardiomyopathy are increased left ventricular mass and left ventricular hypertrophy, diastolic and systolic left ventricular dysfunction, and profound cardiac fibrosis on histology. Arterial stiffness and a marked tendency toward vascular calcification add to the burden. Kidney-related factors such as iso-osmotic and non-osmotic sodium retention, volume expansion, anaemia, inflammation, malnutrition, sympathetic overactivity, mineral bone disorders are considered to accelerate cardiovascular disease in intermediate and late stages.

Disorders of mineral and bone metabolism, now grouped as CKD-MBD, involve calcium, phosphate, PTH, FGF23, and the vitamin D hormonal system, which function as an interlinked regulatory network. These abnormalities emerge early. In chronic kidney disease (CKD) stage 3, approximately 40%–50% of patients exhibit abnormalities in calcium, phosphorus and parathormone (PTH) levels. Phosphate retention drives parathyroid hormone upward, and this hormone normally promotes phosphate excretion while releasing minerals from bone. Persistent secondary hyperparathyroidism can produce high bone turnover, known as osteitis fibrosa cystica, whereas abnormal bone turnover (ie, renal osteodystrophy) that can manifest as osteitis fibrosa cystica and adynamic bone disease describes the spectrum. Mineral imbalance also promotes calcium-phosphate deposition in arteries and heart valves, and vascular calcification (ie, calcium-phosphate crystal deposition), the leading cause of mortality in CKD is one of the most consequential outcomes. Anemia has a related but partly separate basis: the failing kidney produces less erythropoietin, and iron deficiency and inflammation further suppress red cell production. The value of proactively administered intravenous iron for safely treating anaemia in dialysis patients has been shown.

Electrolyte and acid-base disturbances become more frequent as filtration declines. Laboratory studies may show metabolic complications, such as hyperkalemia, hyperphosphatemia, hypocalcemia, and metabolic acidosis. Acid accumulates when the body generates more net acid than the kidney can excrete. Chronic metabolic acidosis is common in later stages: studies suggest 12-20% of patients with CKD stage G3b and 27-38% with G4-5 CKD have chronic metabolic acidosis. Acidosis contributes to muscle wasting and bone loss, which is why treatment guidance aims to keep serum bicarbonate above 18 mmol/L. Some researchers argue that acidosis also drives progression rather than only reflecting it. Potassium handling is similarly impaired, and caution should be exercised in individuals with eGFR < 30 mL/min/1.73 m^2, for whom potassium intake may need to be restricted. Mild to moderate hyperkalemia is managed with dietary restriction, correction of acidosis and potassium-lowering agents, whereas severe hyperkalemia (> 6 mmol/L or mEq/L) warrants urgent treatment. Sodium and water retention produces fluid retention and edema, and alkali therapy given to correct acidosis can itself worsen edema and blood pressure because of sodium loading.

Symptom burden rises substantially in advanced stages. In a European cohort of older adults with stage 4–5 CKD not yet on dialysis, the 1396 patients included in the study had a mean of 13±6 symptoms at baseline. In dialysis patients, elevated parathyroid hormone has been linked to weight loss, impaired appetite, pain, and sleep disorders. Malnutrition arises from reduced appetite, protein-energy wasting, metabolic acidosis and chronic inflammation, and it is closely tied to frailty and poorer outcomes. Uremia impairs immune function, and vascular access devices used for dialysis provide routes for infection, so infection is a significant cause of hospitalization and death in this population. Cognitive slowing, fatigue and depression are also common and erode quality of life, although their mechanisms are less well defined than those of the cardiovascular and mineral complications.

Because the kidney clears many drugs and their metabolites, falling GFR prolongs drug exposure and raises the risk of drug toxicity. Many medicines require dose reduction, longer dosing intervals or avoidance as GFR declines; examples include some antibiotics, anticoagulants and metformin. Nephrotoxic agents such as NSAIDs and iodinated contrast add further risk. Medication errors commonly occur when standard doses are continued after kidney function has dropped, when the most recent eGFR is outdated, or when over-the-counter analgesics are used without review. Such errors can cause bleeding, neurotoxicity, lactic acidosis or hyperkalemia, which is why regular prescription review, often with pharmacist involvement, is part of routine care.

Detection, Screening and Diagnosis

Why CKD is often found late

CKD is usually silent in its early stages, and this is the main reason it goes undiagnosed. Early-stage (stages 1–3) CKD has an asymptomatic presentation, so most patients remain unaware of their disease status. Symptoms such as nausea, muscle cramps, swelling of the feet and ankles, itchy skin and sleep disturbance tend to appear later, and they are usually seen in advanced stages, but they can also occur in other disorders, so they should not be read as proof of kidney disease. One US estimate noted that 9 in 10 adults do not know they have CKD, and of those, 1 in 3 have severe CKD. Late recognition therefore limits the window in which progression can be slowed, and it is the reason that routine laboratory testing matters more than symptom review.

Who should be tested

Testing is targeted at people at increased risk. KDIGO 2024 advises that people at risk for and with CKD be tested using both urine albumin measurement and assessment of glomerular filtration rate (GFR). The groups emphasised in guidance include people with diabetes, and for type 1 diabetes screening is recommended commencing 5 years after diagnosis. Hypertension and cardiovascular disease are also priority groups, since CKD is associated with multiple long-term conditions, the most common being cardiovascular disease, hypertension, and type 2 diabetes. Other high-risk groups include people with recent AKI or acute kidney disease (AKD), particularly multiple episodes of AKI, and those who have been partially diagnosed with CKD by either eGFR or albuminuria but cannot be fully staged. Where a familial form is suspected, the diagnosis in one person may allow detection in other family members. Whether the whole adult population should be screened remains debated. One analysis concluded that population-based screening effectively diagnoses albuminuria, but a more impactful and cost-effective approach may involve identifying at-risk populations.

Core tests and urinalysis

The standard pairing is eGFR, calculated from serum creatinine, and the urine albumin-to-creatinine ratio (ACR). Albuminuria is preferred to total proteinuria because it is more sensitive in detecting glomerular injuries and is easier to standardize. The first-morning midstream sample is preferred in adults and children. Both measures are useful because they are standardized, readily available, related to prognosis, and actionable. Neither, however, identifies the cause: albuminuria and eGFR are not specific for any particular cause of CKD. Routine urinalysis adds information. In one rural South African screening cohort, abnormalities other than albuminuria were detected in 240 (34.3%) of the samples, including haematuria, leucocytes, nitrites and glycosuria.

Point-of-care testing

KDIGO 2024 suggests that point-of-care testing (POCT) may be used for creatinine and urine albumin measurement where access to laboratories is limited. Such testing may facilitate access to earlier diagnosis and care and can be implemented in rural and remote locations. Devices should ideally measure both blood creatinine and urine albumin and creatinine, and be standardized and calibrated with similar rigour as laboratory tests. Accuracy varies by device and setting. In the South African cohort, sensitivity was 0.79 and specificity 0.84, with a positive predictive value of 0.39 and a negative predictive value of 0.97, so the authors concluded that the test has good negative predictive value and could be used to rule out albuminuria when screening for CKD. A primary-care study of an instrument-read strip reached a similar conclusion, describing it as a poor rule-in test for albuminuria at the point of care, as evidenced by the low positive predictive value, but a reasonable rule-out test. Thus a positive screen is typically confirmed by a laboratory ACR.

Confirming chronicity and evaluating cause

A single abnormal result does not establish the diagnosis. A single abnormal GFR or UACR level is not diagnostic for CKD. Following an incidental finding of elevated ACR, haematuria or low eGFR, repeat tests to confirm presence of CKD are recommended. In adults, a random urine sample with an ACR above 30 mg/g is generally confirmed on a first-morning void midstream sample. Chronicity itself is judged by persistence beyond three months.

Once CKD is confirmed, the cause is sought through clinical history, blood and urine tests, and imaging. Structural abnormalities seen on imaging, such as those in polycystic kidney disease, and histological abnormalities on biopsy can both serve as markers of kidney damage. Biopsy is usually reserved for cases where the picture is unclear, and genetic testing is considered when a familial form is suspected.

Limits of screening programmes

Screening faces several practical obstacles. Cost is central, since screening must be safe, cost-effective and widely available to be justified. Access is uneven, and point-of-care tools are one way to reach underserved populations. False positives are a further problem: transient albuminuria, for example during fever, after strenuous exercise or with postural change, can produce an abnormal result that resolves on retesting, which is why repeat measurement is essential before labelling a person as having CKD.

Slowing Progression and Management

Management of CKD has two aims: slowing the loss of kidney function and reducing cardiovascular events, which often matter more to survival than kidney failure does. Most of the strongest interventions are drugs or measures that act on the same risks that drive kidney damage, so their use depends on the cause, the GFR category and the degree of albuminuria.

Blood pressure control and renin-angiotensin system (RAS) inhibition form the oldest pillar. The 2021 KDIGO blood pressure guideline proposes a systolic target below 120 mm Hg for most people with CKD not receiving dialysis, provided the target is tolerated and measured with a standardized office technique. The justification rests on cardioprotective and survival benefit, not on renoprotective effects. Whether intensive control also slows kidney function loss is far less settled. For RAS inhibition, the guideline recommends starting an ACE inhibitor or angiotensin II receptor blocker in people with severely increased albuminuria (G1–G4, A3) without diabetes, and in those with moderately-to-severely increased albuminuria (G1–G4, A2 and A3) with diabetes. Treatment is generally continued even as eGFR declines, with the guideline advising that these drugs be continued even when the eGFR falls below 30 ml/min per 1.73 m².

Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) have moved from diabetes drugs to a core kidney therapy. For adults with type 2 diabetes, CKD and an eGFR of at least 20, the guideline recommends treatment, and it extends the recommendation to people with eGFR ≥20 ml/min per 1.73 m² with urine ACR ≥200 mg/g (≥20 mg/mmol), or heart failure, irrespective of the level of albuminuria. For eGFR 20–45 with ACR below 200 mg/g, the recommendation is weaker: it is only a suggestion, largely because of the limited evidence available for this group. Pooled trial data indicated a 37% reduction in the risk of kidney disease progression compared with placebo, irrespective of diabetes status. Once started, treatment is usually continued, and the guideline suggests that it can be maintained even if the eGFR falls below 20 ml/min per 1.73 m², unless it is not tolerated, until dialysis or transplantation.

Other newer agents extend this framework. A nonsteroidal mineralocorticoid receptor antagonist is suggested for adults with type 2 diabetes, an eGFR above 25, normal potassium and albuminuria despite the maximum tolerated dose of RAS inhibitor. Recent evidence has also supported finerenone in type 2 diabetes and glucagon-like peptide-1 receptor agonists for kidney protection (New evidence supports the use of finerenone in patients with type 2 diabetes and CKD, and GLP-1 receptor agonists for their kidney-protective effects.). Statins are recommended for adults with CKD aged 50 and older, with evidence supporting their role in preventing cardiovascular disease in this high-risk population.

Comprehensive care also includes glycemic control, lipid management, diet, physical activity, smoking cessation and weight management. These measures address the metabolic and vascular conditions that accelerate kidney damage, and they are usually tailored to the patient's eGFR, since some glucose-lowering and lipid-lowering options need dose changes or are not suitable at lower levels of kidney function.

Avoiding nephrotoxins is another central task. The guideline stresses nephrotoxin stewardship and prevention of acute kidney injury through patient education on sick day medication management. Dose adjustment matters because reduced clearance can lead to accumulation: adjusting doses by eGFR avoids further nephrotoxicity or potential overdosing due to decreased kidney clearance. Errors are common in practice. Antimicrobials are the most common dosing error while managing CKD patients, and in hospitals around 25%-77% of drugs are adjusted inappropriately. Where creatinine may mislead, for example in people with muscle loss, pharmacists are expected to know which patients may need alternative kidney function biomarkers to estimate glomerular filtration rate.

Pharmacists are central to implementing these measures. They can help delay chronic kidney disease progression by improving glycemic and blood pressure control by increasing use of RAASi, SGLT2i, GLP1RA, and finerenone, and they take part in medication reconciliation and nephrotoxin review. Guidance treats interprofessional care teams as essential to good outcomes. However, the evidence for multidisciplinary models is more heterogeneous than for drugs. Their benefits are usually measured through blood pressure control, medication safety, adherence or timely referral, rather than through hard kidney endpoints, so their effect on delaying kidney failure is harder to isolate.

Kidney Failure: Dialysis, Transplantation and Conservative Care

When to start kidney replacement therapy

Kidney replacement therapy (KRT) is the umbrella term for dialysis and transplantation. In practice, the decision to start rests mainly on symptoms, complications such as fluid overload or persistent electrolyte and acid-base disturbance, and the trajectory of kidney function, rather than on one fixed number. No specific eGFR value for starting dialysis in the absence of symptomatic kidney failure has been established. The IDEAL trial did not show a clinical benefit from starting at higher eGFR levels, and the variability in measurement of eGFR in CKD G5 is such that it should not be considered to reliably reflect kidney function. Guidance therefore generally does not endorse preemptive dialysis, although a 2011 European guideline is an exception. Actual practice varies by country: registry averages for the eGFR at dialysis start range from about 5 in Taiwan to about 11 in the United States.

Planning is guided by prediction as well as by the current level. One KDIGO 2024 practice point suggests that a 2-year kidney failure risk threshold of >40% can be used to determine the modality education, timing of preparation for kidney replacement therapy (KRT) including vascular access planning or referral for transplantation. In children, poor growth refractory to optimized nutrition, growth hormone, and medical management is an indication for initiating KRT. Most people in earlier stages never reach this point: in one retrospective cohort from a university hospital in Thailand, only 19.9% of stage 4 CKD patients required KRT over a five-year observation period.

Hemodialysis and peritoneal dialysis

Hemodialysis pumps blood through an external dialyzer, where solutes and excess water are removed by diffusion and ultrafiltration. The usual schedule is about three sessions per week, each lasting several hours, most often in a dialysis center. Reliable access is the critical technical problem. An arteriovenous fistula is preferred for durability and lower infection risk, while synthetic grafts and tunneled central venous catheters are used when a fistula is not feasible; catheters carry higher rates of bloodstream infection and thrombosis. Common complications include low blood pressure during treatment, cramps, access failure, infection and cardiovascular strain.

Peritoneal dialysis uses the lining of the abdomen as the filtering membrane. Dialysate is introduced through a catheter, either by manual exchanges several times a day or by an automated cycler overnight. It can be done at home and tends to preserve residual kidney function better in early years, but it requires training, a suitable home environment and vigilance against peritonitis and catheter exit-site infection. Patterns of use differ widely: in 2021 in the United States, in-center HD use accounted for 83.8% of all KRT while PD, pre-emptive kidney transplantation, and home HD accounted for 12.7%, 3.1%, and 4%, respectively.

Kidney transplantation

Transplantation can come from a living donor or a deceased donor. Living-donor transplants are often performed preemptively, before dialysis is needed, and generally avoid long waits. Deceased-donor kidneys are allocated through national or regional waiting lists using criteria such as waiting time, blood group, tissue matching and urgency; waits of several years are common in many systems. Recipients take lifelong immunosuppression, usually a calcineurin inhibitor combined with an antiproliferative drug and sometimes corticosteroids, which lowers the risk of rejection but raises the risk of infection, malignancy and drug toxicity. Rejection may be acute, antibody-mediated or chronic, and is monitored with serum creatinine, antibody testing and biopsy when needed.

The survival advantage is substantial. One UCSF-affiliated summary reports that fewer than 65% of people on dialysis in the U.S. live longer than five years, whereas transplantation is associated with a five-year survival rate greater than 80%. Access, however, is uneven. In a survey of developing countries, transplantation was available in only a small share of low-income settings, and LICs had the lowest availability of kidney transplant services (12%), with living donor transplants as the only organ source.

Conservative and palliative care

Conservative kidney management (CKM) is care for kidney failure that deliberately does not include KRT. The guiding principle in CKM is that all active treatment is aligned with the individual's preferences, goals, and prognosis and is usually aimed at optimizing quality of life. Its components typically include treating complications such as anemia, acidosis and mineral-bone disorder, advance care planning, and attention to symptoms and spiritual needs. For some older patients with multiple conditions, CKM improves symptom burden and aligns with quality-of-life goals, with modest or no loss of longevity.

Shared decision-making is central to this choice. It is defined as a collaborative process in which clinicians and patients work together to make health care decisions that align with the patient's values, goals, and preferences. Despite this, CKM is often underused. More than 80% of patients start in-center hemodialysis instead of home therapies, and patients are rarely informed about conservative kidney management as a viable option. Experts recommend starting these conversations early and spreading them across several consultations, with CKM can be provided by a nephrologist alone but ideally is managed through partnership with a dedicated supportive or palliative care service.

Global inequalities

Access to KRT depends heavily on income and health-system capacity. In a survey of 165 countries, chronic haemodialysis was available in 162 (98%) of 165 countries, chronic peritoneal dialysis in 130 (79%), and kidney transplantation in 116 (70%). Yet 74 (45%) of 166 countries allocated public funding to provide free haemodialysis at the point of delivery; use of this funding scheme increased with country income level. Human resources are an equally strong constraint: the median global prevalence of nephrologists was 11·8 per million population (IQR 1·8–24·8) with an 80-fold difference between low-income and high-income countries. Financial barriers also shape transplant services, since globally, 64% of all countries provide full coverage for kidney transplantation, with 43% charging fees at the point of delivery.

Trends reflect these gaps. While access to dialysis has been increasing globally, fewer people have access to kidney transplantation today compared to five years ago. Across regions, the disparities are also reflected in drug funding, with public support for dialysis and transplant medications available in only a minority of countries worldwide.

History and Evolution of the Concept

The modern idea of chronic kidney disease (CKD) grew out of nineteenth-century clinical observation. Richard Bright, a physician at Guy's Hospital in London, showed in the late 1820s that patients with generalized edema and albumin in the urine tended to have diseased kidneys when they were examined after death Bright showed that when dropsy was accompanied by albumin in the urine, it indicated kidney disease in those who came to autopsy. His 1827 Reports of Medical Cases linked edema to kidney damage and identified swelling and proteinuria as the main clinical features of the serious kidney disorder that bears his name. Bright also recognized milder, more indolent forms of the disease, and his 1836 series extended the work to observations on renal disease in general in 1836 he published his final and most extensive series on observations on renal disease. The 1827 case count is reported inconsistently: one account gives 25 cases of dropsy, while another gives 23 patients studied between 1825 and 1827. Bright's name was attached to the whole group of conditions, which were later classified as acute or chronic nephritis Bright's disease is a historical classification of kidney diseases that are described in modern medicine as acute or chronic nephritis. In 1850, Owen Rees, Bright's assistant, added a raised concentration of urea in the blood to the clinical picture a raised concentration of urea in the blood was reported as a feature to include in the constellation of clinical and post-mortem characteristics of renal disease. The term remained in use well into the twentieth century.

Clinical terminology changed slowly. For much of the twentieth century, the phrase chronic renal failure (CRF) was used for all long-term kidney impairment, although it was most naturally applied to the more severe degrees. The 2002 guideline from the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) changed this by proposing a definition that did not depend on the cause. The workgroup developing this guideline provided a new conceptual framework for a diagnosis of CKD independent of cause, and developed a classification scheme of kidney disease severity based on the level of glomerular filtration rate (GFR). The new term replaced the older term chronic renal failure (CRF), which referred to more severe degrees of CKD. KDIGO endorsed the definition in 2004 and endorsed by the Kidney Disease: Improving Global Outcomes (KDIGO) in 2004. KDIGO later issued updated guidance, and the most recent update was in 2024 the most recent KDIGO update was in 2024. The classification was intended to give clinicians, patients, researchers and policymakers a shared vocabulary Defining chronic kidney disease and classifying the stages of severity would provide a common language for communication among providers, patients and their families, investigators, and policy-makers.

Measurement of GFR also changed over time. Reference methods such as inulin clearance were accurate but too laborious for routine use, and creatinine-based estimates became the practical alternative. The Modification of Diet in Renal Disease (MDRD) equation of 1999 and the CKD-EPI equations of 2009 and 2012 were then widely adopted. These equations included a race coefficient, because adults of African ancestry were observed to have higher serum creatinine levels. For over 20 years, the equations used to estimate eGFR have employed a race variable in their calculation, and critics argued that this coefficient amounted to race-based medicine.

In 2021, a joint task force from the National Kidney Foundation and the American Society of Nephrology reviewed more than 20 approaches and recommended the CKD-EPI 2021 equation, which uses creatinine without race and expands the use of cystatin C recommended the implementation of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) equation for eGFR using creatine and expanded utilization of cystatin C testing. The change had uneven effects. Most people of non-Black race see slightly higher eGFR values, while those who identify as African American see slightly lower values in general those self-identifying as African American will have slightly lower eGFR and all other racial groups will have slightly higher eGFR. In one cohort of patients with autosomal dominant polycystic kidney disease, the change lowered the baseline eGFR of African American patients from 89.3 to 80.3 mL/min/1.73 m², while it raised values in Caucasian patients Among Caucasian patients, the median baseline eGFR increased from 85.0 to 88.6 mL/min/1.73 m^2 and the final eGFR from 63.1 to 66.1 mL/min/1.73 m^2 using the 2021 equation (p < 0.001). Because eGFR thresholds guide staging and treatment eligibility, such shifts can affect clinical decisions. Adoption has also been uneven internationally. The race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 estimated glomerular filtration rate-creatinine (eGFRcr) equation is being adopted in the United States. Elsewhere there is debate regarding its validation and adoption.

Recognition of CKD as a public health problem has developed alongside these technical changes. Chronic kidney disease (CKD) is a worldwide public health problem, with adverse outcomes of kidney failure, cardiovascular disease (CVD), and premature death. Public awareness campaigns followed. World Kidney Day, which draws attention to kidney health, was one of the main vehicles for this advocacy, and by 2011 it had been held five times, with the 2011 observance focusing on chronic kidney failure as a growing problem The World Kidney Day was announced for the fifth time in 2011, that calls attention to chronic renal failure as it attains the title of endemic.

Open Questions and Controversies

Race coefficients in eGFR equations

For years, creatinine-based equations such as the 2009 CKD-EPI equation raised the estimate for people identified as Black. Critics argued that this adjustment treated a social category as a biological variable and could hide differences in muscle mass, diet and environmental exposure. In 2021 a joint task force of the National Kidney Foundation and the American Society of Nephrology recommended dropping race from the equations. The refitted CKD-EPI 2021 creatinine equation and the combined creatinine–cystatin C equation omit race. In the derivation study, the race-free creatinine equation underestimated measured GFR in Black participants by a median of about 3.6 mL/min/1.73 m² and overestimated it in non-Black participants by about 3.9 mL/min/1.73 m². The combined creatinine–cystatin C equation performed better and narrowed the gap between groups. The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative endorsed immediate use of the 2021 creatinine equation, wider use of cystatin C where available, and continued validation of filtration markers.

The change is not clinically neutral. A retrospective analysis in the US Military Health System, using data from 2016 to 2019, found that the number of Black adults with CKD stages 3–5 rose by 58.1% under the 2021 equation, while the count among non-Black adults fell by 30.4%. Across the thresholds that alter management, about 45.8% of Black adults were reclassified to more advanced stages, and 44.0% of non-Black adults to less severe ones. Because diagnosis, staging and eligibility for drugs, referral or transplantation often depend on fixed eGFR cut-offs, these shifts raise practical questions about who receives care. Validation work continues. A Danish cohort with measured GFR showed that bias and accuracy vary across GFR strata, so local validation remains necessary.

Chronic kidney disease of unknown etiology

Chronic kidney disease of unknown etiology (CKDu) has been reported in several regions, most prominently Mesoamerican nephropathy in Central America, where cases have been recorded since about 2000. In Central America it mainly affects young male agricultural workers, often in hot coastal areas. It is not linked to the classic risk factors of older age, diabetes, hypertension, glomerulonephritis or obesity. Its clinical picture is nonspecific, and a diagnosis commonly requires a kidney biopsy showing tubulointerstitial nephritis, usually at a chronic stage. Estimates of deaths in the region run into the tens of thousands.

The competing hypotheses include heat stress and dehydration, agrochemicals and pesticides, heavy metals, repeated use of nephrotoxic drugs such as NSAIDs, muscle injury, infections such as leptospirosis and hantavirus, and genetic susceptibility. Many investigators regard heat stress with repeated dehydration as the central driver, proposing that recurrent subclinical acute kidney injury gradually erodes function, and animal studies have reported chronic kidney damage after recurrent heat exposure. Other reviews judge that studies of pesticides and infections have largely been negative, while noting that no consensus exists and that several factors may combine. Some researchers now group these cases, including parts of Sri Lankan nephropathy, under the broader label of heat stress nephropathy. For affected communities, the only measures with some demonstrated effect are preventive, such as avoiding heat stress and maintaining hydration, because no specific treatment has been established.

Treatment gaps in CKD without diabetes or albuminuria

Most large trials of kidney-protective drugs enrolled people with high levels of albuminuria, leaving people with low or absent albuminuria, and those without diabetes, less well studied. The DAPA-CKD trial included 1398 participants without diabetes, and EMPA-KIDNEY included 3569, with benefits seen in that group. A real-world cohort of 1480 patients without type 2 diabetes, with a mean age of about 75, found similar eGFR slopes across low and high urine albumin-to-creatinine ratios after dapagliflozin treatment. That study is observational, so it cannot establish causation. Reviews describe SGLT2 inhibitors as a cornerstone therapy that slows progression regardless of albuminuria, but data in advanced CKD (G4/G5) remain limited.

Non-albuminuric CKD carries its own uncertainty. In hypertensive patients without diabetes, the cardiovascular risks of this phenotype have been studied rarely, and a post hoc analysis of the SPRINT trial was designed to address that gap. Ongoing trials are testing newer agents in these populations. The FIND-CKD trial is evaluating finerenone in about 1600 people with non-diabetic CKD, nearly 60% of whom have an underlying glomerular disease, with total eGFR slope over 32 months as the primary outcome. Other work, such as the SELECT trial of semaglutide, enrolled people with obesity and cardiovascular disease but without diabetes, and in that low-kidney-risk population the findings are less applicable to people at high risk. Pooled trial data have been used in cost-effectiveness models suggesting value across a wider range of eGFR and albuminuria, but such models do not replace prospective outcome data.

Early detection and risk prediction

Current risk tools combine eGFR, its rate of change and albuminuria, yet most people with CKD progress slowly, and identifying the minority who decline rapidly would allow more intensive monitoring. Machine learning models built on laboratory and electronic health record data are being explored for this purpose, as are biomarkers beyond creatinine and albumin. These approaches face substantial obstacles: models must be validated externally, must remain calibrated across populations, and must be transparent enough for clinicians to trust. The race-free eGFR transition illustrates the broader problem, since a change in an input variable can alter the predicted risk for entire groups. CKDu adds another challenge, because affected young workers often lack the traditional markers that prompt screening.

Equity in access

Access to diagnosis, specialist care, dialysis and transplantation depends heavily on health-system organization and income. Laboratory testing and cystatin C assays are not uniformly available, and the race-free equation transition has exposed how fragile diagnostic thresholds can be when they are applied across diverse populations. CKDu affects workers in low-income agricultural settings whose exposures are shaped by labor conditions, so occupational protections such as rest, shade and drinking water access are proposed as preventive measures. Health policy responses discussed in the literature include expanding screening and laboratory capacity, improving drug coverage, and reducing financial barriers to kidney replacement therapy. These measures are closely tied to universal health coverage, social determinants of health and income inequality.

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