What are the potential causes of chronic kidney disease (CKD) in a patient without hypertension or diabetes?

Causes of CKD in Patients Without Hypertension or Diabetes

In patients without hypertension or diabetes, the most important causes to consider are glomerulonephritis, autoimmune diseases, genetic/hereditary kidney diseases (including polycystic kidney disease), chronic tubulointerstitial nephritis from medications or toxins, obstructive uropathy, and chronic kidney disease of unknown etiology (CKDu). 1, 2

Primary Non-Diabetic, Non-Hypertensive Causes

Glomerular Diseases

• Glomerulonephritis represents a significant cause of CKD, particularly in certain populations, with chronic glomerulonephritis accounting for a substantial proportion of CKD cases globally 1
• Primary focal segmental glomerulosclerosis (FSGS) can cause progressive CKD with normal-sized kidneys, especially in early stages 1
• Minimal change disease can cause significant proteinuria and kidney dysfunction while maintaining normal kidney morphology on imaging 1

Genetic and Hereditary Conditions

• Autosomal dominant tubulointerstitial kidney diseases lead to progressive tubulointerstitial fibrosis and progression to end-stage renal disease 1
• Polycystic kidney disease can cause kidney function decline with relatively normal-appearing kidneys in early stages 1

Toxic and Environmental Causes

• Chronic kidney disease of unknown etiology (CKDu) affects predominantly rural agricultural communities in low-to-middle income countries, characterized by absence of significant proteinuria and hypertension, with chronic tubulointerstitial nephritis on biopsy 2
• Nephrotoxin exposure including nonsteroidal anti-inflammatory drugs, heavy metals, agrochemicals, and contaminated drinking water can cause CKD 3, 2, 4
• Analgesic medications used excessively constitute a risk factor for chronic kidney disease 4

Other Systemic Conditions

• Cardiovascular disease history is a risk factor for CKD development even without hypertension 4
• Hepatitis C virus and HIV infection are established risk factors for chronic kidney disease 4
• Malignancy can be associated with kidney disease development 4

Diagnostic Approach for Atypical Presentations

Red Flags Requiring Kidney Biopsy

When CKD presents without the typical diabetic or hypertensive etiology, consider biopsy if any of the following are present:

• Rapidly declining GFR suggests alternative glomerular disease 5
• Active urinary sediment with red blood cells, white blood cells, or cellular casts strongly suggests non-diabetic glomerular disease 5
• Hematuria with dysmorphic red blood cells indicates glomerulonephritis and necessitates urgent evaluation 5
• Rapidly increasing proteinuria or nephrotic syndrome warrants biopsy, as approximately 40% of patients with kidney injury may have alternative diagnoses 5
• Evidence of systemic disease requires biopsy to diagnose conditions like MGRS-associated lesions 5

Initial Diagnostic Workup

• Measure both eGFR and UACR at baseline, as CKD can be diagnosed by either abnormality 1, 6
• Urinalysis with microscopy to detect red blood cells, white blood cells, and casts is essential 6
• Ultrasound findings of normal-sized kidneys do not exclude CKD, particularly in infiltrative disorders and certain glomerular diseases 1

Risk Factors Beyond Diabetes and Hypertension

Demographic and Genetic Factors

• African-American descent is a strong risk factor for chronic kidney disease 4
• Older age increases CKD risk 3, 4
• Family history of kidney disease is highly important 3, 4
• Low birth weight is considered a strong risk factor 4
• Male gender is associated with higher risk, particularly in CKDu 2

Modifiable Risk Factors

• Smoking can lead to kidney disease 4
• Obesity is a risk factor for CKD development 3, 4
• Excessive alcohol consumption constitutes a risk 4
• Acute kidney injury history increases risk of subsequent CKD 4

Common Pitfalls to Avoid

• Do not assume diabetes or hypertension are the cause without confirming typical features—approximately 40% of patients presumed to have diabetic kidney disease may have alternative diagnoses on biopsy 5
• Do not delay biopsy when atypical features are present, as the risk of complications from percutaneous kidney biopsy is no greater than 4% 5
• Do not rely solely on kidney size to exclude CKD—many causes including diabetic kidney disease, minimal change disease, and FSGS maintain normal kidney size 1
• Do not overlook occupational and environmental exposures, particularly in patients from agricultural communities or those with heat stress exposure 2
• Confirm persistent abnormalities with repeat testing over 3 months before establishing CKD diagnosis, as single measurements can be falsely positive 3, 5

Nephrology Referral Indications

Refer to nephrology when: 3, 1, 6

• eGFR <30 mL/min/1.73 m²
• Continuously increasing urinary albumin levels
• Continuously decreasing eGFR
• Persistent proteinuria >1,000 mg/24 hours
• Red cell casts or dysmorphic RBCs (>80%)
• Rapidly declining eGFR despite treatment