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Protein in Urine Presages More Severe Problems - free full text link below
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"patients with heavy proteinuria but without overtly abnormal eGFR appeared to have worse clinical outcomes than those with moderately reduced eGFR but without proteinuria.....These findings are important because current guidelines for the classification and staging of CKD are based on eGFR without explicit consideration of the severity of concomitant proteinuria.....a patient with an eGFR of 80 mL/min/1.73 m2 and 3+ proteinuria on dipstick reading (or ACR of 400 mg/g) would be assigned to stage 1 CKD under the current system-even though his or her age-adjusted risks of death and the need for renal replacement therapy would be approximately 2 and 10 times higher, respectively, than an otherwise similar patient with an eGFR of 50 mL/min/1.73 m2 but no evidence of proteinuria (stage 3 disease)."
MedPage Today
February 02, 2010
Action Points
* Explain to interested patients that excessive protein in the urine is a sign of kidney dysfunction, but the more typical test is the estimated glomerular filtration rate.
* Explain that this study was based on a records review, normally a relatively weak form of evidence, but it also featured a large number of participants, which strengthens the findings somewhat.
The three-year risk of death, heart attack, and kidney failure was markedly increased in patients with baseline proteinuria, regardless of their estimated glomerular filtration rate (eGFR), researchers said.
In a population-based study of nearly 1 million people, mortality was approximately doubled with heavy proteinuria among individuals stratified according to their eGFR, reported Brenda R. Hemmelgarn, MD, PhD, of the University of Calgary in Canada, and colleagues.
Rates of myocardial infarction were increased by about 50% with heavy proteinuria, and end-stage renal disease and doubled levels of serum creatinine were as much as 30 times more common, the researchers reported in the Feb. 3 issue of the Journal of the American Medical Association.
"Prognosis associated with a given level of eGFR varies substantially based on the presence and severity of proteinuria," Hemmelgarn and colleagues concluded.
"In fact, patients with heavy proteinuria but without overtly abnormal eGFR appeared to have worse clinical outcomes than those with moderately reduced eGFR but without proteinuria."
They added that the findings were important because current recommendations for managing chronic kidney disease rely on eGFR for staging purposes without consideration of proteinuria.
"Future revisions of the classification system for chronic kidney disease should incorporate information from proteinuria," the researchers urged.
The results emerged from a laboratory registry covering some 921,000 adults in the province of Alberta who had had measurements of eGFR, serum creatinine, and urinary protein from 2002 to 2007.
Proteinuria was measured with a urine dipstick or the albumin-creatinine ratio. Dipstick readings of at least 2 points were considered heavy proteinuria. Readings showing at least trace protein but less than 2 points were classed as mild; negative readings were considered normal.
The stratifications of albumun-creatinine ratio were greater than 300 mg/g, 30 to 300 mg/g, and less than 30 mg/g for heavy, mild, and normal, respectively.
Other registry data for the province provided outcomes in these individuals, with median follow-up of 35 months.
Among individuals with eGFR rates of at least 60 mL/min/1.73 m2, death rates were 7.2 per 1,000 for those with dipstick-measured heavy proteinuria (95% CI 6.6 to 7.8) and 5.8 per 1,000 for mild proteinuria (95% CI 5.5 to 6.0) compared with 2.7 per 1,000 for those with normal urine protein (95% CI 2.6 to 2.8).
At the other end of the eGFR spectrum -- those with levels of 15 to 29.9 mL/min/1.73 m2 -- proteinuria remained an independent predictor of death: Mortality rates were 10.4 per 1,000 with heavy proteinuria (95% CI 9.3 to 11.6) and 9.1 per 1,000 with mild proteinuria (95% CI 8.2 to 10.0) versus 6.7 per 1,000 with normal urine protein (95% CI 6.2 to 7.3).
These death rates reflected adjustments for a host of potential confounding factors and comorbidities, including age, sex, diabetes, hypertension, liver disease, and cardiovascular conditions.
Proteinuria also predicted myocardial infarction in patients stratified by eGFR, but not as strongly. In the group with eGFR above 60 mL/min/1.73 m2, rates of MI were 1.6 per 1,000 (95% CI 1.3 to 2.0) and 0.9 (95% CI 0.9 to 1.0) for heavy and normal urinary protein, respectively, as measured by dipstick.
MI rates were also increased with proteinuria in participants with eGFR below 30 mL/min/1.73 m2, the researchers reported.
End-stage renal disease was enormously more common with dipstick-measured heavy proteinuria, independent of baseline eGFR.
Individuals with eGFR above 60 mL/min/1.73 m2 were diagnosed with the condition at a rate of 1.0 per 1,000 (95% CI 0.7 to 1.4) if they had heavy proteinuria, compared with 0.03 per 1,000 (95% CI 0.02 to 0.09) among those with normal urine protein.
A five-fold difference in rates of end-stage renal disease was still apparent among those with eGFR below 30 mL/min/1.73 m2: 65.9 (95% CI 52.3 to 82.9) versus 12.7 per 1,000 (95% CI 9.3 to 17.3) for heavy versus normal protein, respectively.
These results were confirmed when cross-checked against the more accurate albumin-creatinine ratio, Hemmelgarn and colleagues indicated.
Each 10-fold increase in albumin-creatinine ratio was associated with the following relative rates of the major study outcomes, after adjusting for eGFR:
* Death: 1.22 (95% CI 1.21 to 1.24)
* MI: 1.18 (95% CI 1.14 to 1.21)
* Doubling of serum creatinine: 1.76 (95% CI 1.70 to 1.82)
* End-stage renal disease: 1.92 (95% CI 1.81 to 2.04)
Hemmelgarn and colleagues noted several limitations to the study including the fact that the sample was restricted to outpatients undergoing laboratory evaluations for kidney function and urinary protein, and the data were based on single measurements. Missing were data on alcohol, tobacco, and antihypertensive drug use, which might have affected the findings.
The researchers also indicated that the follow-up period may have been too short to fully evaluate risks of progression to kidney failure.
Primary source: Journal of the American Medical Association
Source reference:
Hemmelgarn B, et al "Relation between kidney function, proteinuria, and adverse outcomes" JAMA 2010; 303: 423-29.
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