What are the causes of proteinuria and ketonuria?

Causes of Proteinuria and Ketonuria

Proteinuria Causes

Proteinuria results from either benign physiological conditions that resolve spontaneously or pathological kidney damage requiring further evaluation, with the distinction made through quantitative testing and assessment of persistence. 1

Benign/Transient Causes (Resolve Without Intervention)

• Fever causes temporary elevation in urinary protein excretion 1
• Intense physical activity or exercise within 24 hours before urine collection produces transient proteinuria 1, 2
• Orthostatic proteinuria occurs with upright posture and normalizes when recumbent—this is a benign condition with excellent long-term prognosis 1, 3
• Dehydration concentrates urine and may elevate dipstick readings 4
• Emotional stress can cause temporary proteinuria 5
• Acute illness may produce transient protein excretion 5
• Marked hyperglycemia can cause transient elevations 1
• Congestive heart failure temporarily increases protein excretion 1

Pathological Causes (Require Evaluation and Management)

Glomerular Diseases (Usually >2g/24hr proteinuria)

• Diabetic nephropathy is the most common cause of persistent proteinuria in adults, often presenting first as microalbuminuria (30-299 mg/g creatinine) 1, 4
• Hypertensive nephrosclerosis, especially in patients with type 2 diabetes, damages the glomerular filtration barrier 1
• Lupus nephritis—dipstick ≥2+ warrants quantification in SLE patients 4
• IgA nephropathy and other primary glomerulonephritides 6
• Membranoproliferative glomerulonephritis 6

Tubulointerstitial Diseases

• Drug-induced interstitial disease or analgesic nephropathy may present with hematuria and proteinuria 6
• Tubular proteinuria results from failure of proximal tubular uptake and catabolism of small proteins (15-40,000 molecular weight) that are normally filtered and reabsorbed 7

Systemic Diseases

• Multiple myeloma should be considered in patients >50 years with unexplained proteinuria, causing overflow proteinuria from excess light chains 4
• Obesity activates the local renin-angiotensin system, causing mesangial hypertrophy and glomerular hyperfiltration 1

Urinary Tract Conditions

• Urinary tract infection causes transient proteinuria that resolves after treatment 1, 4
• Hematuria (blood in urine) can cause false positive protein results on dipstick 1, 8

False Positives (Technical Issues)

• Alkaline, dilute, or concentrated urine 5
• Gross hematuria (≥3+ blood on dipstick) 8
• Presence of mucus, semen, or white blood cells 5
• High specific gravity (≥1.020) is the strongest predictor of false positives 8
• Menstrual contamination 4
• Ketonuria, urobilinogen, bilirubin, bacteria, or epithelial cells increase false positive rates 8

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Ketonuria Causes

Ketonuria indicates increased production of ketone bodies from fatty acid metabolism, occurring in states of insulin deficiency, prolonged fasting, or metabolic stress. 6

Pathological Causes (Require Immediate Action)

• Diabetic ketoacidosis (DKA) in type 1 diabetes—a medical emergency resulting from absolute insulin deficiency and increased counterregulatory hormones (cortisol, epinephrine, glucagon, growth hormone) 6
• SGLT2 inhibitor use in patients with diabetes increases risk of euglycemic DKA 6
• History of previous DKA identifies ketosis-prone individuals 6
• Alcoholic ketoacidosis alters hepatic mitochondrial redox state, shifting equilibrium toward β-hydroxybutyrate production 6

Physiological/Metabolic Causes

• Prolonged fasting or starvation increases ketone production from triglyceride breakdown 6
• Very-low-carbohydrate (ketogenic) diets for weight loss or diabetes control 6
• Hypoxia shifts the equilibrium toward β-hydroxybutyrate formation 6

Clinical Action Required

• Individuals prone to ketosis should measure ketones in urine or blood if they have unexplained hyperglycemia or symptoms of ketosis (abdominal pain, nausea) and implement sick day rules and/or seek medical advice if ketones are increased 6
• Urine ketones have high sensitivity and negative predictive value for DKA, making them useful for ruling out DKA 6
• Blood ketone testing is superior to urine testing—children with type 1 diabetes randomized to blood ketone testing had almost half the number of emergency department visits or hospitalizations compared to urine testing 6

Important Caveat

Standard urine dipstick methods detect acetoacetate but not β-hydroxybutyrate, which predominates in DKA and other ketotic states—this may underestimate total ketone body concentration and provide misleading clinical information 6