Kidney function, two complimentary evaluations Serum and urine testing Robert L. Stout, Ph.D.

Tests of kidney function Measured glomerular filtration rate. Urinalysis Serum creatinine and blood urea nitrogen. Estimated glomerular filtration rate, eGFR.

Measured glomerular filtration rate Only on patients with known kidney disease to determine severity. Requires injection of a tag; radioactive, non-metabolizable sugar or dye. Collect samples and determine clearance rate.

Urine protein and urine creatinine The kidneys filter the blood to remove metabolites, waste material(s), salts, and water. The kidneys also recover water, glucose, salts and amino acids from the forming urine. This process concentrates the urine while recovering important building material for the body.

Proteinuria The kidneys loose about mg of protein per day. On average about 1.0 to 1.5 gram of creatinine is produced per day depending on your muscle mass. Depending on your hydration state most people produce about 1 to 1.5 liters of urine per day.

Protein creatinine ratio It is both inconvenient and impractical to collect all the urine produced during a day. Urine concentration varies widely depending on the hydration state. The urine protein creatinine ratio allows an accurate measure of the average protein loss per day and is reported by all laboratories. Fulks M, Stout RL, Dolan VF. Urine Protein/Creatinine Ratio as a Mortality Risk Predictor in Non-Diabetics with Normal Renal Function. J. Insurance Medicine. 2012;43:76-83

Serum creatinine a measure of renal function Serum creatinine values are the result of 2 opposing factors –Production is driven by muscle mass; men have higher creatinine values than women of the same age. –Elimination is driven by filtration in the kidneys; as we age the kidneys have decreased capacity for filtration.

Aging and serum creatinine Normal aging is accompanied by a decrease in muscle mass. Normal aging is also accompanied by a decrease in kidney filtration and elimination of creatinine. Insurance product pricing accounts for the increasing mortality associated with normal aging. Underwriters need an objective measure of “age based normal renal function”.

Sex, age and mean serum creatinine

Upper range of expected value for creatinine

The samples A blood sample and urine may be collected anytime that is convenient for an applicant and paramedical examiner. The serum sample is allowed to clot and then centrifuged to separate the liquid portion (serum) from the clot, trapped cells and fibrin.

Things that can go wrong. For the urine, the only big problem is sample mix-up. In contrast, if the serum sample is not centrifuged within 2 hours there is a risk for, –Glycolysis, the catabolism of glucose in the sample –Hemolysis, the rupture of red cells and release of hemoglobin into the serum.

Hemolysis and glycolysis How do these effect the serum creatinine value? Which is the best indicator that something has gone wrong? If there was a problem can the underwriter still reliably proceed with the review?

Serum glucose (glycolysis) and creatinine Glycolysis

Hemolysis and serum creatinine

Serum creatinine set at 1.45mg/dL GLUCOSE GlycolysisTotal <= Serum <= %93.90%96.75%97.56%98.59%98.88%99.16%99.09% Creatinine %6.10%3.25%2.44%1.41%1.12%0.84%0.91%4849 % high 1.04%0.12%0.07% 0.05%0.06%0.09%0.62%2.11% % total 5.80%2.00%2.20%2.80%3.70%5.50%10.20%67.80%229433

Serum creatinine set at 1.45mg/dL GLUCOSE GlycolysisTotal <= Serum<= %93.90%96.75%97.56%98.59%98.88%99.16%99.09% Creat %6.10%3.25%2.44%1.41%1.12%0.84%0.91%4849 % high 1.04 % 0.12%0.07% 0.05%0.06%0.09%0.62% 2.11% % TOTAL 5.80%2.00%2.20%2.80%3.70%5.50%10.20%67.80%229433

Enzymatic and Jaffe creatinine

Jaffe serum creatinine>1.5 evaluated by 2 methods

Estimated glomerular filtration rate Half a dozen different equations. –The Mayo equation (Rule) and the CKD- EPI equations are the most common. They both work, however, they do not have the same mortality risk ranges. –If you use the tables from reinsurance most use the Mayo. National Kidney Disease Education Program 2014

Be wary of Trojan horses In the insurance industry all current assessments of kidney function rely on a serum creatinine. Jaffe serum creatinine results in samples with low glucose values are not reliable. You can directly substitute an enzymatic creatinine into the eGFR calculation.

Case study Female 62yo, non-smoker, chemistry all normal except glucose is 0 and creatinine is 1.4mg/dL. –eGFR = 38 ml/min/1.73m 2 Enzymatic creatinine was 0.9mg/dL –eGFR=69 ml/min/1.73m 2

Case study Male 62yo, 6’4”, 340lb, all normal except glucose is 0 and creatinine is 1.4mg/dL, urine 0.25pro/creatinine Enzymatic creatinine was 1.4mg/dL – Both eGFR is 51ml/min/1.73m 2 –Corrected for body surface area 71ml/min 25% of applicants with proteinuria have normal eGFR

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