Causes of Chronic Kidney Disease
The two dominant causes of CKD globally are diabetes mellitus and hypertension/atherosclerosis, accounting for the majority of cases in high-income, middle-income, and many low-income countries 1, 2. However, the etiology of CKD is often multifactorial and in many patients remains unidentified 3.
Primary Causes
Diabetic Kidney Disease
Diabetic kidney disease is the single largest cause of CKD and end-stage renal disease in the United States and most developed nations 4, 3. It affects 20-40% of patients with diabetes 5, 6. In diabetes, CKD can manifest in several patterns:
- Classical diabetic nephropathy: Characterized by mesangial expansion, diffuse or nodular glomerulosclerosis with Kimmelstiel-Wilson lesions, and arteriolar sclerohyalinosis 7
- Non-classical presentations: Up to half of diabetic patients with reduced kidney function have normal urinary protein levels, representing alternative causes such as hypertensive nephrosclerosis or diffuse microvascular atherosclerosis 7
Hypertension and Vascular Disease
Hypertension is both a cause and complication of CKD 3. Kidney damage from hypertension or diffuse microvascular atherosclerosis commonly presents with reduced renal function and urinary protein in the normal or microalbumin range 7.
Secondary and Less Common Causes
Glomerular Diseases
- Primary glomerulonephritis (e.g., membranous nephropathy, IgA nephropathy)
- Secondary glomerular diseases from systemic conditions (e.g., lupus nephritis) 7
Genetic/Hereditary Conditions
- Autosomal dominant polycystic kidney disease (ADPKD) 8
- Autosomal dominant tubulointerstitial kidney disease caused by mutations in:
- UMOD (uromodulin)
- MUC1 (mucin-1)
- REN (renin)
- HNF1B (hepatocyte nuclear factor 1b) 8
Tubulointerstitial Diseases
- Chronic interstitial nephritis
- Obstructive uropathy
- Reflux nephropathy 3
Vascular Diseases
- Renal artery stenosis
- Ischemic nephropathy 3
Modifiable Risk Factors
Beyond the primary disease causes, several modifiable factors contribute to CKD development and progression:
- Smoking 9
- Obesity 9
- Metabolic syndrome 9
- Hyperlipidemia 9
- Exposure to nephrotoxins: Heavy metals, excessive alcohol, analgesic medications 9
- Acute kidney injury history 9
Emerging and Regional Causes
CKD of Unknown Etiology (CKDu)
Increasingly reported from agricultural communities in Central America, Sri Lanka, and India, particularly affecting young male adults of lower socioeconomic status. Potential contributing factors include:
- Silica, arsenic, and fluoride exposure
- Heat stress and dehydration
- Mycotoxins (aflatoxins, ochratoxins)
- Pesticides (HCH, Endosulfan, Alachlor, Pendimethalin)
- Infections (Hantavirus, Leptospirosis) 10
Infectious Causes
- Hepatitis C virus
- HIV infection 9
Clinical Pearls for Identifying Etiology
When evaluating CKD etiology, establish the cause using clinical context, personal and family history, social and environmental factors, medications, physical examination, laboratory measures, imaging, and genetic and pathologic diagnosis 11.
Red Flags Suggesting Non-Diabetic Causes in Diabetic Patients:
- Diabetes duration <5 years (especially type 1)
- Active urine sediment (red or white blood cell casts)
- Persistent hematuria
- Rapidly falling eGFR (≥5 mL/min/1.73 m² loss per year)
- Low eGFR with little or no proteinuria
- Extreme proteinuria (>6 g/day)
- Absence of diabetic retinopathy
- Family history of non-diabetic renal disease 7, 6
These atypical presentations warrant nephrology referral and consideration of kidney biopsy 7, 6.
Sociodemographic Considerations
Race, gender, age, and family history significantly influence CKD risk:
- African-American descent confers higher risk
- Older age increases susceptibility
- Low birth weight is a risk factor
- Family history of kidney disease 9
The poorest populations globally face the highest CKD risk, with substantial disparities in access to care and treatment 2.