What are the causes of kidney failure?

Causes of Kidney Failure

Diabetes and hypertension are the two leading causes of kidney failure in developed countries, together accounting for the majority of cases, while glomerulonephritis remains a significant cause in certain regions of Asia and sub-Saharan Africa. 1, 2

Primary Causes

Diabetes

• Diabetic kidney disease is the single largest cause of kidney failure in the United States, accounting for more than 30-40% of end-stage renal disease cases in many countries 1, 2
• In type 1 diabetes, diabetic kidney disease typically develops after 10 years of disease duration, whereas in type 2 diabetes it may already be present at the time of diagnosis 2
• Diabetic patients have approximately 50% higher risk of progressing to end-stage renal disease compared to patients with similar GFR from other causes 1

Hypertension

• Hypertension is one of the most frequent causes of chronic kidney disease in developed countries 1, 2
• Hypertension creates a dangerous bidirectional relationship: it both causes kidney damage AND results from kidney disease, creating a cycle that accelerates kidney function decline 2, 3
• Uncontrolled hypertension dramatically accelerates CKD progression, with GFR decreasing at rates greater than 10 mL/min/year in patients with poorly controlled hypertension and macroalbuminuria 2

Glomerulonephritis

• Glomerulonephritis is a significant cause of CKD, particularly in certain Asian countries and sub-Saharan Africa where it is more common than in Western nations 1
• In China specifically, chronic glomerulonephritis and diabetes together account for more than 50% of CKD cases 1, 2

Acute Kidney Injury Causes

Prerenal Causes (Reduced Blood Flow)

• Hypotension from any cause including hypovolemia, decreased cardiac output, or shock 1, 3
• Renal artery occlusion or bilateral renal artery stenosis 1, 3
• Heart failure causing renal hypoperfusion through direct effects and neurohumoral activation 1

Intrinsic Renal Causes (Kidney Parenchymal Damage)

• Acute tubular necrosis 1
• Vasculitis 1
• Interstitial nephritis (often drug-induced) 1
• Renal infection or infiltration 1
• Drug and toxin-related injury 1, 4

Postrenal Causes (Obstruction)

• Ureteral, bladder, or urethral obstruction 1
• Note: Obstruction accounts for less than 3% of acute kidney injury cases, with prerenal and intrinsic renal causes accounting for more than 97% 1

Drug-Induced Kidney Failure

Hemodynamic Mechanisms

• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause kidney failure by reducing renal prostaglandins, thereby decreasing renal blood flow and glomerular filtration rate 4, 5, 6
• Risk factors for NSAID-induced renal insufficiency include: advanced age (mean 76 years), concurrent diuretic use, renal vascular disease from long-standing hypertension, diabetes, atherosclerotic cardiovascular disease, volume depletion, and pre-existing chronic kidney disease 5, 6
• The combination of ACE inhibitors/ARBs, diuretics, and NSAIDs ("triple whammy") significantly increases risk of acute kidney injury 3, 7

ACE Inhibitors and ARBs

• In patients with bilateral renal artery stenosis or severe heart failure, ACE inhibitors can cause acute kidney failure because renal function depends on angiotensin II-mediated efferent arteriolar constriction 8
• Increases in blood urea nitrogen and serum creatinine with ACE inhibitors are usually reversible upon discontinuation 8

Direct Tubular Toxicity

• Antiviral agents (cidofovir, adefovir, tenofovir) cause direct epithelial cell damage 4
• Bisphosphonates like pamidronate can cause tubular toxicity 4

Crystal Nephropathy

• Sulfadiazine, acyclovir, and indinavir can cause crystal deposition in the kidney leading to renal failure 4

Osmotic Nephrosis

• Intravenous immunoglobulin and hydroxyethyl starch can cause swollen, vacuolated proximal tubular cells 4

Other Contributing Causes

Genetic and Structural

• Autosomal dominant tubulointerstitial kidney diseases lead to progressive fibrosis and end-stage renal disease 2
• Polycystic kidney disease causes progressive kidney function decline 2
• Congenital dysplastic or hypoplastic kidneys 1

Secondary Factors

• Renal scarring from recurrent infections or reflux 1
• Infiltrative disorders (amyloidosis, sarcoidosis) 2

Clinical Risk Assessment

High-Risk Populations Requiring Screening

• All patients with diabetes should be screened immediately at diagnosis (type 2) or after 5 years (type 1) using urinary albumin-to-creatinine ratio and estimated GFR 1, 2
• Patients with hypertension require regular kidney function monitoring 1, 2
• Family history of diabetic kidney disease, hypertension, or cardiovascular disease increases risk 1

Warning Signs of Evolving Kidney Failure

• Rising serum urea nitrogen, creatinine, and potassium levels 5
• Weight gain with low fractional excretion of sodium suggests evolving acute kidney injury 5
• Persistent albuminuria (≥30 mg/g) for at least 3 months indicates chronic kidney damage 2, 7

Critical Pitfalls to Avoid

• Never assume normal-sized kidneys on imaging exclude chronic kidney disease—diabetic kidney disease, minimal change disease, and early FSGS all present with normal kidney size despite significant dysfunction 2
• Do not use NSAIDs in patients with volume depletion, even moderate dehydration, as this dramatically increases acute kidney failure risk 6
• Avoid the "triple whammy" combination of ACE inhibitors/ARBs, diuretics, and NSAIDs, especially in elderly patients 3, 7, 5
• In acute myocardial infarction patients, initiate ACE inhibitors with caution if baseline creatinine exceeds 2 mg/dL 8