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Causes and aetiology

TL;DR — Aetiology is not a decorative label: it changes prognosis, family screening, disease-specific treatment and recurrence risk. Diabetes and vascular disease dominate coded CKD, but glomerular, tubulointerstitial, obstructive, cystic, congenital, drug-related and unknown-cause disease require active consideration (KDIGO CKD Work Group 2024, PMID 38490803). Genetic testing can resolve diagnoses left uncertain after conventional evaluation, but yield depends heavily on selection: a 227-gene panel applied to 50 clinically unscreened patients referred for native renal biopsy produced a molecular diagnosis in only 2 (4%), against yields of up to 18% previously reported in cohorts selected for suspected genetic disease, and the authors concluded testing is most valuable when a heritable form is already suspected (Benson 2020, PMID 32723786). CKD of unknown aetiology in agricultural communities is a distinct epidemiological problem whose causal mixture remains unsettled (Rao 2023, PMID 37403003).

A cause-first framework

Start with tempo, albuminuria pattern, urine sediment, imaging, systemic disease, exposures and family history. The same eGFR can arise from different diseases and therefore imply different treatment (KDIGO CKD Work Group 2024, PMID 38490803).

Common attributed causes

Diabetes and hypertension are frequently recorded together, but attribution without urinalysis, imaging or longitudinal context can hide glomerular and inherited disease. Kidney outcome synthesis for diabetes is in the dedicated page.

Glomerular and systemic disease

Haematuria, high-grade proteinuria, rapid decline or systemic inflammatory features raise the value of serology and biopsy. Targeted IgA-nephropathy trials show why a cause can now alter therapy (Lafayette 2023, PMID 37591292) (Rovin 2023, PMID 37931634).

Structural and obstructive disease

Ultrasound identifies hydronephrosis, asymmetry, cystic disease and congenital abnormalities. Reversible obstruction should not be classified as unexplained CKD without evaluation.

Inherited disease

Family history, early onset, syndromic features, cysts or a biopsy pattern can trigger genomic testing. Adult-onset monogenic disease is missed when family history is not elicited (Granhoj 2022, PMID 34515170).

CKD of unknown aetiology

Mesoamerican and other endemic nephropathies combine occupational heat, dehydration and possible toxic exposures; inconsistent definitions block causal comparison (Sanchez Polo 2020, PMID 33116757).

Aetiologic pattern table

Pattern Causes to prioritize Test that changes the branch
Heavy albuminuria, bland sediment Diabetic, membranous, FSGS, amyloid Quantification, serology, paraprotein testing, biopsy context
Haematuria + albuminuria IgA, vasculitis, lupus, hereditary basement-membrane disease Microscopy, serology, biopsy/genomics
Low albuminuria + falling eGFR Vascular, tubulointerstitial, obstructive, genetic Medication/exposure history, imaging, tubular indices
Enlarged cystic kidneys ADPKD and cystic phenocopies Imaging pattern, family history, genomics
Small asymmetric kidneys Reflux, vascular or chronic obstruction Imaging and historical records
Young onset or family clustering Monogenic disease Genomic testing with counselling — yield is selection-dependent, ~4% unscreened versus up to 18% in suspected-genetic cohorts (Benson 2020, PMID 32723786)
Hot-region manual-worker cluster CKD of unknown aetiology Harmonized occupational and exposure assessment (Rao 2023, PMID 37403003)

APOL1: the variant that reorganized "hypertensive nephrosclerosis"

Two coding variants in APOL1 (G1 and G2), common on African chromosomes and absent from European ones, are associated with focal segmental glomerulosclerosis (OR 10.5, 95% CI 6.0–18.4) and hypertension-attributed ESKD (OR 7.3, 5.6–9.5) in African Americans; both sit within haplotypes bearing signatures of positive selection, and only the disease-associated variants lyse Trypanosoma brucei rhodesiense in vitro (Genovese 2010, PMID 20647424). The evolutionary explanation — a trypanosome-resistance allele carried to high frequency — is the reason a "racial disparity" in kidney disease had a genetic component that is not a property of race.

Population-based genotyping puts the effect in absolute terms. In the Dallas Heart Study (1,825 African American and 1,042 European American participants), among people without diabetes, microalbuminuria was present in 2.3% of European Americans, 6.0% of African Americans with no or one risk allele, and 16.5% of those with two risk alleles; eGFR below 60 was present in 1.5%, 1.7% and 6.7% respectively (Friedman 2011, PMID 21997396). Two findings follow and both matter for attribution. First, African Americans without the high-risk genotype had non-diabetic CKD rates indistinguishable from European Americans — so ancestry alone does not carry the risk. Second, APOL1 genotype showed no association with CKD among participants with diabetes, so it does not explain diabetic kidney disease (Friedman 2011, PMID 21997396). This is why much CKD historically coded as "hypertensive nephrosclerosis" in Black patients is better understood as APOL1-mediated kidney disease with hypertension as consequence rather than cause. See race and the eGFR equation for what this implies about using race as a clinical variable.

Genomic yield, calibrated

The 4% yield in unscreened biopsy referrals quoted above (Benson 2020, PMID 32723786) is one end of a range whose other end is much higher. Exome sequencing of 3,315 adults with CKD across two cohorts gave a diagnostic variant in 307 (9.3%), spanning 66 distinct monogenic disorders, of which 39 (59%) appeared in only a single patient (Groopman 2019, PMID 30586318). Yield was strongly category-dependent: 23.9% (127/531) in congenital or cystic kidney disease and 17.1% (48/281) in nephropathy of unknown origin. A further 1.6% (34/2,187 assessed) carried medically actionable findings unrelated to their nephropathy that would nonetheless alter renal management (Groopman 2019, PMID 30586318). Two operational conclusions: the long tail of ultra-rare disorders means panel design will always lag, and "nephropathy of unknown origin" is the phenotype with the highest yield-per-test after cystic disease.

Environmental and occupational nephropathies

Aristolochic acid. Balkan endemic nephropathy — a slowly progressive tubulointerstitial disease around Danube tributaries, frequently accompanied by upper-tract urothelial carcinoma — was attributed after decades to aristolochic acid from Aristolochia clematitis contaminating home-milled wheat. The same toxin caused the rapidly progressive fibrosis outbreak in Belgium after ingestion of Aristolochia fangchi root extract. Aristolactam–DNA adducts in kidney and tumour tissue link the two, and they induce a characteristic A:T→T:A transversion signature in TP53 and other cancer genes, detected also in Taiwanese cases (Jelaković 2019, PMID 31054628). This is one of the few CKD aetiologies with a molecular fingerprint that can be read retrospectively from tissue.

Heat and volume depletion. In 284 Nicaraguan sugarcane workers sampled before and near the end of a six-month harvest, mean baseline eGFR was 113 mL/min/1.73 m² and fewer than 5% had albuminuria — so this is not an albuminuric glomerular disease. Field workers had increases in urinary NGAL and IL-18 of 1.49 (95% CI 1.06–2.09) and 1.61 (1.12–2.31) times those of non-field workers, greatest among cane cutters and irrigators; workers with the largest NGAL and NAG rises had eGFR declines of 4.6 (1.0–8.2) and 3.1 (−0.6–6.7) mL/min/1.73 m² across a single harvest (Laws 2016, PMID 26454687). Electrolyte solution consumption was associated with lower injury markers in some job categories but had no overall effect — which is the honest state of the hydration-intervention evidence.

Drug-associated CKD, with the effect sizes attached

Exposure Best available estimate Design limit
Proton pump inhibitors Incident CKD HR 1.50 (95% CI 1.14–1.96) adjusted, in 10,482 ARIC participants with baseline eGFR ≥60, replicated in 248,751 Geisinger patients; H2-blockers used as active comparator (Lazarus 2016, PMID 26752337) Observational; confounding by indication and by comorbidity remains plausible despite the active-comparator design
Lithium Incidence of CKD 0.012 cases per exposed patient-year in 1,012 patients over 2000–2015; mean eGFR decline 1.8 mL/min/year among those reaching stage G3; stage G4 incidence 0.0004/patient-year; no ESKD observed (Van Alphen 2021, PMID 33392830) Single-centre; survivor and prescribing-selection effects; competing benefit of lithium not modelled
Aristolochic acid Causative for Balkan endemic nephropathy and associated upper-tract urothelial carcinoma; adduct and TP53 signature confirm exposure (Jelaković 2019, PMID 31054628) Historical cohorts; dose–response poorly quantified

The PPI and lithium literatures illustrate opposite failure modes: a large relative risk on a very common exposure that may be confounded, and a well-characterized mechanism whose absolute event rate turns out to be low.

Among 10,093 native kidney biopsies at a single Chinese centre between 2002 and 2006, obesity-related glomerulopathy (BMI ≥28 kg/m², proteinuria ≥0.4 g/24 h, glomerulomegaly with or without FSGS) accounted for 90 cases (0.89%), rising from 0.62% to 1.0% over five years (p = 0.02). Patients were young (mean 37.5 ± 9.3 years), 67% male, mean BMI 31.2 ± 3.3, and all had visceral obesity; mean proteinuria was 1.48 ± 1.2 g/24 h and only 10% were nephrotic-range, while 42% had a creatinine clearance above 120 mL/min/1.73 m² (Chen 2008, PMID 18423814). The hyperfiltering, sub-nephrotic phenotype is the diagnostic trap: it does not look like a glomerular disease at presentation, and biopsy series systematically undercount it because such patients are rarely biopsied.

Monoclonal gammopathy of renal significance

A non-malignant B-cell or plasma-cell clone that does not meet myeloma criteria can nonetheless cause severe kidney disease through the immunoglobulin it secretes. MGRS spans AL amyloidosis, proliferative glomerulonephritis with monoclonal immunoglobulin deposits and C3 glomerulopathy with monoclonal gammopathy, among others; diagnosis requires kidney biopsy interpreted with light microscopy, immunofluorescence and electron microscopy — sometimes with isotype-specific staining, immunoelectron microscopy or proteomics — alongside serum and urine protein electrophoresis, immunofixation and serum free light chains (Bridoux 2015, PMID 25607108). It belongs on any CKD aetiology list because clone-directed chemotherapy often improves kidney outcomes, so the haematological threshold for treatment is set by the kidney, not by the tumour burden (Bridoux 2015, PMID 25607108).

Sickle cell trait: a second common ancestry-linked variant

APOL1 is not the only haemoglobin- or ancestry-linked contributor to kidney disease risk in people of African ancestry. In the REGARDS population-based cohort, 9,909 self-reported Black participants included 739 with sickle cell trait and 243 with haemoglobin C trait. Incident ESRD occurred in 40/739 (5.4%) with sickle cell trait, 6/243 (2.5%) with haemoglobin C trait and 234/8,927 (2.6%) of non-carriers; incidence rates were 8.5 versus 4.0 per 1,000 person-years, giving a hazard ratio of 2.03 (95% CI 1.44–2.84). Haemoglobin C trait was associated with neither prevalent CKD nor ESRD. Critically, in the same cohort the ESRD incidence rate for APOL1 high-risk genotypes was 6.6 per 1,000 person-years with HR 1.77 (95% CI 1.31–2.38) — so sickle cell trait conferred risk of a magnitude similar to the APOL1 high-risk genotype (Naik 2017, PMID 28280138).

Sickle cell trait is usually communicated as a carrier state without health consequences, and this result — comparable in effect size to a variant that reorganised the attribution of "hypertensive nephrosclerosis" — is the strongest published argument that the counselling framing needs revision.

CKD of unknown aetiology: what the biopsies show

The epidemiological literature on CKDu is large; the histological literature is small, which is why a prospective biopsy series matters. Among 600 new patients presenting to a tertiary nephrology clinic serving endemic areas of Sri Lanka over one year, 87 underwent kidney biopsy and 43 (49%) had primary tubulointerstitial kidney disease. On detailed review, 13 (30%) showed moderate-to-severe active disease and 6 (15%) moderate-to-severe chronic tubulointerstitial disease. All affected patients were born in endemic provinces and 91% had spent most of their lives there; they were more likely to be men and farmers (RR 2.0, 95% CI 1.2–2.9), tobacco users (RR 1.7, 1.0–2.3) and well-water drinkers (RR 1.5, 1.1–2.0). Age, urine dipstick protein and serum albumin together predicted tubulointerstitial disease on biopsy with 79% sensitivity and 84% specificity, and — importantly — patients referred despite comorbid diabetes or hypertension were not less likely to have tubulointerstitial disease (Anand 2019, PMID 30659059).

That last point undermines the standard exclusion-based case definition: having diabetes or hypertension did not reduce the probability of the endemic tubulointerstitial lesion, so defining CKDu as CKD without those comorbidities systematically misclassifies cases. The presence of active disease in 30% of affected biopsies also argues that at least some of this is an ongoing exposure rather than a burnt-out historical injury.

Decision and interpretation matrix

Dimension Question Guardrail
Diagnostic axis Cause + G category + A category Avoid treating eGFR as the diagnosis
Time axis Chronicity and trajectory Separate acute change from persistent disease
Risk axis Kidney failure + cardiovascular events + death Show competing events
Treatment axis Eligibility, absolute benefit, harm, burden Do not rank drugs by relative effect alone
Measurement axis Assay, equation, repeatability State what was actually measured
Equity axis Testing, referral, access, affordability Audit downstream care, not labels only
Patient axis Symptoms, function, life participation Include outcomes patients prioritize
Evidence axis RCT, cohort, model, guideline Do not collapse designs

Evidence ledger

This ledger makes the page’s evidentiary mix inspectable. It does not imply that every source answers every question.

PMID Record used Role and boundary
38490803 KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. (KDIGO CKD Work Group 2024, PMID 38490803) Guideline or commentary; recommendation evidence depends on its review.
32723786 Diagnostic utility of genetic testing in patients undergoing renal biopsy. (Benson 2020, PMID 32723786) Observational or conceptual evidence; association is not treatment effect.
37403003 Chronic kidney disease of unknown aetiology: a global review. (Rao 2023, PMID 37403003) Observational or conceptual evidence; association is not treatment effect.
37591292 Targeted-release budesonide in primary IgA nephropathy: NefIgArd 2-year results. (Lafayette 2023, PMID 37591292) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
37931634 Sparsentan versus irbesartan in IgA nephropathy: PROTECT 2-year results. (Rovin 2023, PMID 37931634) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
34515170 Family History is Important to Identify Patients with Monogenic Causes of Adult-Onset CKD. (Granhoj 2022, PMID 34515170) Observational or conceptual evidence; association is not treatment effect.
33116757 Mesoamerican Nephropathy: What We Know so Far. (Sanchez Polo 2020, PMID 33116757) Observational or conceptual evidence; association is not treatment effect.
38519239 Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns. (Levin 2024, PMID 38519239) Guideline or commentary; recommendation evidence depends on its review.
32061315 Global, regional, and national burden of chronic kidney disease, 1990-2017. (GBD CKD Collaboration 2020, PMID 32061315) Modelled projection; the estimate follows from the model inputs and assumptions, not from observed randomized follow-up.
22038337 A population-based approach for the definition of chronic kidney disease: CKD Prognosis Consortium. (Cirillo 2012, PMID 22038337) Synthesis; heterogeneity and included-study definitions constrain transport.
23243116 Cohort profile: the chronic kidney disease prognosis consortium. (Matsushita 2013, PMID 23243116) Observational or conceptual evidence; association is not treatment effect.
37787795 Estimated GFR, Albuminuria, and Adverse Outcomes: individual-participant data meta-analysis. (CKD Prognosis Consortium 2023, PMID 37787795) Synthesis; heterogeneity and included-study definitions constrain transport.
30348535 Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities. (Inker 2019, PMID 30348535) Synthesis; heterogeneity and included-study definitions constrain transport.
34554658 New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. (Inker 2021, PMID 34554658) Observational or conceptual evidence; association is not treatment effect.
34563581 A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. (Delgado 2022, PMID 34563581) Guideline or commentary; recommendation evidence depends on its review.
26757465 Multinational assessment of equations predicting kidney failure. (Tangri 2016, PMID 26757465) Synthesis; heterogeneity and included-study definitions constrain transport.
36857500 Kidney Failure Risk Equation evaluation with novel inputs in 59 cohorts. (Grams 2023, PMID 36857500) Observational or conceptual evidence; association is not treatment effect.
26028594 eGFR and albuminuria for prediction of cardiovascular outcomes: individual-participant meta-analysis. (Matsushita 2015, PMID 26028594) Synthesis; heterogeneity and included-study definitions constrain transport.
32970396 Dapagliflozin in Patients with Chronic Kidney Disease. (Heerspink 2020, PMID 32970396) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
36331190 Empagliflozin in Patients with Chronic Kidney Disease. (EMPA-KIDNEY Collaborative Group 2023, PMID 36331190) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
30990260 Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. (Perkovic 2019, PMID 30990260) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
41205219 Chronic Kidney Disease Prevalence and Awareness Among US Adults. (Gong 2026, PMID 41205219) Observational or conceptual evidence; association is not treatment effect.
38213490 Cost-effectiveness of screening for chronic kidney disease: evidence and gaps. (van Mil 2024, PMID 38213490) Guideline or commentary; recommendation evidence depends on its review.
39137037 Screening for chronic kidney disease: change of perspective and novel developments. (van Mil 2024, PMID 39137037) Observational or conceptual evidence; association is not treatment effect.
38186904 Cost-effectiveness of screening for CKD in the general adult population: systematic review. (Yeo 2024, PMID 38186904) Synthesis; heterogeneity and included-study definitions constrain transport.
40227684 Balancing Efficiency and Equity in Population-Wide CKD Screening. (Cusick 2025, PMID 40227684) Modelled projection; the estimate follows from the model inputs and assumptions, not from observed randomized follow-up.
18161745 Cellular and molecular mechanisms of fibrosis. (Wynn 2008, PMID 18161745) Observational or conceptual evidence; association is not treatment effect.
7246778 Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. (Hostetter 1981, PMID 7246778) Observational or conceptual evidence; association is not treatment effect.
24522492 Relative risks of CKD for mortality and end-stage renal disease across races are similar. (Wen 2014, PMID 24522492) Observational or conceptual evidence; association is not treatment effect.

What can and cannot be concluded

  • Risk associations do not by themselves establish that changing the marker changes risk.
  • A relative effect must be paired with baseline risk, follow-up and the exact endpoint.
  • Albuminuria, acute eGFR change, chronic eGFR slope and kidney failure are not interchangeable.
  • Subgroup consistency is not evidence that every subgroup had adequate power.
  • Guideline recommendations combine evidence with values, feasibility, cost and service capacity.
  • Older adults require competing-mortality and treatment-burden framing.
  • Dialysis and transplantation comparisons are vulnerable to eligibility and immortal-time bias.
  • Modelled lifetime benefit is not a randomized observed benefit.
  • A biochemical response without a patient-important outcome remains a surrogate result.
  • This page is research synthesis, not individualized medical advice.

Research-design checklist

  • Define CKD cause, G category, A category and chronicity at baseline.
  • Report the creatinine or cystatin C equation and laboratory calibration.
  • Prespecify acute and chronic eGFR slopes when haemodynamic effects are expected.
  • Keep sustained GFR decline, kidney failure and replacement therapy separable.
  • Report absolute event risks, follow-up and confidence intervals with relative effects.
  • Treat death as a competing event where it can preclude kidney failure.
  • Measure hyperkalaemia, acute kidney injury and treatment discontinuation consistently.
  • Include symptoms, function, life participation and treatment burden.
  • Describe background RAS, SGLT2, MRA and GLP-1 therapy explicitly.
  • Prespecify albuminuria and cause strata without over-reading underpowered interactions.
  • Record screening, prescribing, persistence and monitoring as separate implementation steps.
  • Report representation, access and affordability variables needed for equity analysis.

Open questions

  • At what pre-test probability does a broad gene panel earn its place? Yield fell to 4% in unscreened biopsy referrals against up to 18% in suspected-genetic cohorts, and no prospective study reports the downstream treatment, family and cost consequences (Benson 2020, PMID 32723786) (Granhoj 2022, PMID 34515170). → OQ-17
  • How often does a recorded cause of “diabetes” or “hypertension” survive contact with urinalysis, imaging and longitudinal review? Attribution without those inputs can hide glomerular and inherited disease.
  • Would a harmonised occupational and exposure instrument make endemic CKDu cohorts comparable enough to separate heat from toxin from infection? Current definitions block causal comparison (Rao 2023, PMID 37403003).

  • Does establishing a precise cause change outcomes, or only labels? Cause-specific therapy now exists for IgA nephropathy, ADPKD and glomerular disease, which makes this newly testable (Lafayette 2023, PMID 37591292) (Rovin 2023, PMID 37931634).

  • How much CKD currently attributed to hypertension in people of African ancestry is APOL1-mediated disease with hypertension as consequence rather than cause? The genotype carries no excess CKD risk in diabetes and none in single-allele carriers (Friedman 2011, PMID 21997396) (Genovese 2010, PMID 20647424).

  • What is the true incidence of obesity-related glomerulopathy? Every estimate comes from biopsy series, and the hyperfiltering sub-nephrotic phenotype is precisely the one least likely to be biopsied (Chen 2008, PMID 18423814).
  • Does hydration or work-rest scheduling prevent CKD of unknown aetiology in heat-exposed workers? Electrolyte-solution intake lowered injury biomarkers in some job categories but had no overall effect in the only longitudinal harvest-season cohort with biomarkers (Laws 2016, PMID 26454687).

  • Is the PPI–CKD association causal? An active-comparator design and replication cohort support it (HR 1.50, 1.14–1.96) but cannot exclude confounding by indication (Lazarus 2016, PMID 26752337).

  • Should sickle cell trait be communicated as a kidney disease risk factor? Its ESRD hazard ratio of 2.03 (1.44–2.84) is similar to that of APOL1 high-risk genotypes (1.77, 1.31–2.38) in the same cohort (Naik 2017, PMID 28280138).

  • Is the exclusion-based case definition of CKD of unknown aetiology valid? Patients with comorbid diabetes or hypertension were no less likely to have the endemic tubulointerstitial lesion on biopsy (Anand 2019, PMID 30659059).
  • What is the ongoing exposure in CKDu, given that 30% of affected biopsies show moderate-to-severe active disease rather than established scarring (Anand 2019, PMID 30659059)?

References

  1. KDIGO CKD Work Group et al. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314. PMID 38490803
  2. Benson et al. Diagnostic utility of genetic testing in patients undergoing renal biopsy. Cold Spring Harb Mol Case Stud. 2020;6(5). PMID 32723786
  3. Rao et al. Chronic kidney disease of unknown aetiology: a global review. Trop Med Int Health. 2023;28(8):588-600. PMID 37403003
  4. Lafayette et al. Targeted-release budesonide in primary IgA nephropathy: NefIgArd 2-year results. Lancet. 2023;402(10405):859-870. PMID 37591292
  5. Rovin et al. Sparsentan versus irbesartan in IgA nephropathy: PROTECT 2-year results. Lancet. 2023;402(10417):2077-2090. PMID 37931634
  6. Granhoj et al. Family History is Important to Identify Patients with Monogenic Causes of Adult-Onset CKD. Nephron. 2022;146(1):49-57. PMID 34515170
  7. Sanchez Polo et al. Mesoamerican Nephropathy: What We Know so Far. Int J Nephrol Renovasc Dis. 2020;13:261-272. PMID 33116757
  8. Levin et al. Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns. Kidney Int. 2024;105(4):684-701. PMID 38519239
  9. GBD CKD Collaboration et al. Global, regional, and national burden of chronic kidney disease, 1990-2017. Lancet. 2020;395(10225):709-733. PMID 32061315
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