Kidney Function Tests & Urinalysis Interpretation

Serum markers of kidney function

Creatinine physiology. Creatinine is a breakdown product of muscle creatine and is released at a fairly constant rate. It is freely filtered, and proximal tubular transporters (OCT2 and MATE) secrete another 10–20%, so measured creatinine clearance slightly overestimates GFR. The secreted fraction grows as GFR falls.

Creatinine lags behind GFR. After an abrupt fall in GFR, creatinine accumulates gradually over days until a new steady state is reached. A normal value hours after an ischemic or toxic insult therefore does not exclude AKI. The relationship is hyperbolic: halving GFR doubles creatinine. Early GFR loss barely moves the number, whereas at low GFR small further losses make it climb steeply.

Muscle mass distorts it. Low muscle mass means low creatinine production. In older and frail patients, cirrhosis (less muscle and less hepatic creatine synthesis), amputation, malnutrition, and paralysis, a "normal" creatinine hides a reduced GFR. Muscular patients, creatine supplements, and a large cooked-meat meal raise creatinine without any kidney injury. Ketoacids such as acetoacetate in DKA can also falsely raise creatinine measured by the older Jaffe method.

Drugs that block secretion. Trimethoprim, cimetidine, dolutegravir, bictegravir, cobicistat, and ritonavir inhibit tubular creatinine secretion. They cause a small, early, stable, reversible rise in creatinine while true GFR, BUN, cystatin C, and the urine sediment stay unchanged, so the drug can be continued. Trimethoprim also blocks the collecting-duct sodium channel (ENaC), as amiloride does, and can cause hyperkalemia.

Cystatin C. All nucleated cells produce cystatin C at a steady rate. It is freely filtered, then reabsorbed and degraded by the proximal tubule without being secreted, so it is independent of muscle mass and tubular secretion. It is used to confirm CKD when creatinine is unreliable (sarcopenia, cirrhosis, amputation, extremes of body size); the combined creatinine–cystatin C equation is the most accurate estimate. Corticosteroids, hyperthyroidism, and inflammation raise cystatin C.

Equations. The race-free 2021 CKD-EPI equation reports eGFR in mL/min/1.73 m² and is used to diagnose and stage CKD. Every creatinine-based equation assumes a steady state, so none is valid during AKI; follow urine output and the creatinine trend instead. The Cockcroft-Gault equation, (140 − age) × weight ÷ (72 × creatinine), multiplied by 0.85 for women, estimates creatinine clearance in mL/min. Many drug labels, including DOACs and antimicrobials, still base dosing on it. Using total body weight overestimates clearance in obesity.

BUN and the BUN:creatinine ratio

Urea handling. The liver makes urea from protein, and part of the filtered urea is reabsorbed. In volume depletion, ADH and slow tubular flow increase urea reabsorption, so BUN rises out of proportion to creatinine, with a ratio above 20:1. Other causes of a high ratio:

• upper GI bleeding (digested blood is a protein load)
• corticosteroids
• catabolic states such as sepsis and burns
• high-protein tube feeds or TPN

Intrinsic AKI such as ATN keeps the ratio near 10–15:1. BUN runs low in liver disease, malnutrition, and SIADH. Rhabdomyolysis lowers the ratio because it releases large amounts of creatinine from muscle.

The urine dipstick

Protein. The pad responds mainly to albumin and reads concentration, not daily excretion: dilute urine underestimates and concentrated urine overestimates protein. Immunoglobulin light chains are missed, and the pad usually misses moderately increased albuminuria (30 to 300 mg/g), which is why UACR, not the dipstick, screens for diabetic kidney disease. A negative or trace dipstick alongside a high protein-to-creatinine ratio, or a positive sulfosalicylic acid test (which precipitates all proteins), suggests overflow proteinuria from myeloma. The next steps are urine protein electrophoresis with immunofixation and serum free light chains.

Heme. The heme pad reacts with intact RBCs, free hemoglobin, and myoglobin, so hematuria is confirmed only by microscopy (≥3 RBC/hpf). A strongly positive dipstick with few or no RBCs means pigmenturia:

• myoglobin from rhabdomyolysis (CK often above 5,000 U/L)
• hemoglobin from intravascular hemolysis (low haptoglobin, high LDH, falling hematocrit)

Hemoglobin binds haptoglobin and tints the plasma pink, while small myoglobin is cleared quickly and leaves the plasma clear. Both pigments can cause AKI. Red or orange urine with a negative heme pad is pseudohematuria from beets, rifampin, phenazopyridine, or porphyria.

Other pads. Leukocyte esterase marks pyuria. Nitrite marks Enterobacterales that convert nitrate; it is often negative with Enterococcus, S. saprophyticus, or urine that sat only briefly in the bladder. Glycosuria with normal blood glucose points to proximal tubule dysfunction (Fanconi syndrome) or an SGLT2 inhibitor. A specific gravity fixed near 1.010 (isosthenuria) marks advanced CKD. A persistently alkaline pH above 7 suggests urease-producing infection.

Urine microscopy: cells, casts, and crystals

Red cells. Dysmorphic RBCs (acanthocytes with membrane blebs) and RBC casts mean bleeding through the glomerular basement membrane, the signature of a nephritic glomerulonephritis: post-infectious, IgA, lupus, ANCA vasculitis, or anti-GBM disease. Uniform (isomorphic) RBCs or clots point to the collecting system (stones, tumor, cystitis) and call for urologic evaluation instead.

Casts. Every cast has a matrix of Tamm-Horsfall protein (uromodulin), secreted by the thick ascending limb. Whatever the cast traps reveals where the injury is.

White cells. WBC casts show that pyuria comes from the kidney, whether from pyelonephritis (fever, flank pain, bacteriuria) or acute interstitial nephritis (new drug, rash, fever). Cystitis and urethritis cause pyuria without casts. Urine eosinophils are neither sensitive nor specific for AIN; they also appear in pyelonephritis and atheroembolic disease.

Nephrotic lipiduria. Heavy glomerular protein loss brings oval fat bodies (lipid-laden tubular cells) and fatty casts. Their cholesterol-ester droplets show Maltese crosses under polarized light. Lipiduria is typical of minimal change disease, membranous nephropathy, FSGS, and diabetic nephropathy, usually with an otherwise bland sediment.

Envelope- or needle-shaped calcium oxalate crystals in a confused patient with high anion and osmolal gaps mean ethylene glycol: give fomepizole and arrange hemodialysis. Cystinuria is a defect in proximal reabsorption of cystine and the dibasic amino acids ("COLA": cystine, ornithine, lysine, arginine).

Sterile pyuria. White cells with a negative routine culture have a short list of causes:

• a recently treated UTI
• urethritis from Chlamydia or gonorrhea (send NAAT)
• genitourinary tuberculosis (acidic urine and hematuria; send three early-morning urine AFB cultures)
• acute interstitial nephritis
• nephrolithiasis
• interstitial cystitis
• urothelial tumors
• Kawasaki disease in children

Quantifying and classifying proteinuria

Spot ratios. The urine albumin-to-creatinine ratio (UACR) screens patients with diabetes or CKD. Values under 30 mg/g are normal, 30–300 mg/g is moderately increased, and over 300 mg/g is severely increased. The protein-to-creatinine ratio (UPCR) in g/g roughly equals grams of protein excreted per day. The 24-hour collection remains the reference standard but is cumbersome and often incomplete.

Mechanisms. Glomerular proteinuria is mostly albumin and can reach nephrotic levels. Tubular proteinuria consists of low-molecular-weight proteins such as β2-microglobulin that the damaged proximal tubule fails to reclaim, usually under 2 g/day. Overflow proteinuria occurs when a filtered protein, classically light chains, exceeds tubular capacity.

Transient and orthostatic proteinuria. Fever, strenuous exercise, seizures, acute illness, and decompensated heart failure cause transient, usually low-grade proteinuria that disappears on recovery. Orthostatic proteinuria affects adolescents and young adults, often tall and thin, who spill protein (usually under 1 g/day) only when upright. It is benign, and with normal blood pressure, eGFR, and sediment it needs no biopsy, medication, or ongoing workup.