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What to Measure—Albuminuria or Total Proteinuria?
Editorial What to Measure—Albuminuria or Total Proteinuria? Related Article, p. 21
T
he publication of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative guidelines on the classification of chronic kidney disease (CKD) in 20021 has drawn much attention to optimization of risk prediction in individuals with CKD. Since staging of CKD is based on glomerular filtration rate (GFR) and albuminuria, these 2 diagnostic tests have been discussed intensively in the last decade. Most reports dealt with the optimization of estimated GFR in large population databases. Fewer studies have addressed optimization of methods for assessing urinary albumin or the question of whether albumin is the optimal urinary protein to be measured. In this issue of the American Journal of Kidney Diseases, Methven et al shed some light on the latter issue, asking whether it is urinary albumin or total urinary protein that is more tightly linked to outcomes.2 This question should be considered in historical perspective. In the period from the 1960s until the 1980s, nephrologists were interested in the urinary loss of large amounts of protein (typically more than 2-3 grams of protein per day) in patients with glomerular disorders. Laboratory methods for detection of total protein were available and sensitive enough for this purpose. In addition, nephrologists studied whether the loss of proteins was related only to loss of albumin (about 60,000 daltons) or also to loss of largermolecular-weight proteins, such as immunoglobulins (about 160-180,000 daltons). It was shown in various studies that the presence of large-molecular-weight proteins is associated with poor kidney survival.3,4 In the 1980s and 1990s, diabetologists became interested in the predictive value of small amounts of proteins in the urine. As the quantity of urinary total protein could not reliably be measured in these lower ranges, most studies used the more sensitive measurement of albumin, and referred to small amounts of albumin in the urine as “microalbuminuria.”5,6 Microalbuminuria, however, is not only related to diabetes, but is also associated with most traditional cardiovascular risk factors, including hypertension, obesity, and smoking.7 It has been argued that the loss of large amounts of albumin is a manifestation of kidney disease, while low amounts of albumin in the urine (microalbuminuria) is considered a manifestation of generalized vascular damage.8 Irrespective of the amount, albuminuria results from damage to the glomerular vascular endothelium. However, since the tubules reabsorb Am J Kidney Dis. 2011;57(1):1-2
90%-95% of all albumin filtered by the glomerulus,9 it has been questioned whether the presence of microalbuminuria might rather reflect a tubular disorder or a combination of a glomerular and tubular disorder.10 In the case of overt proteinuria or macroalbuminuria, usually around 20% of proteins are of nonalbumin nature, frequently including proteins with a higher molecular weight than albumin.11 In contrast, in microalbuminuria, and particularly in the normoalbuminuria ranges, up to 80% of the proteins can be of nonalbumin nature. It is most likely that these 80% of nonalbumin proteins are low-molecular-weight proteins (tubular) rather than high-molecular-weight proteins. Methven et al studied a cohort of 5,586 individuals that had been referred to a renal unit to evaluate the predictive value of albuminuria and proteinuria on 3 outcomes: (1) all-cause mortality, (2) start of renal replacement therapy, and (3) doubling of serum creatinine. The predictive utility of urinary total protein was comparable to that of urinary albumin for all 3 outcomes, regardless of whether it was expressed on a continuous scale or a categorical scale. Individuals with a wide range of albuminuria were included in the study; about one-third had normoalbuminuria (albumin-creatinine ratio [ACR] ⬍30 mg/g), one-third had microalbuminuria (ACR 30-300 mg/g), and one-third had macroalbuminuria (ACR ⬎300 mg/g). Urinary total protein and urinary albumin predicted outcomes to a similar extent not only in those with macroalbuminuria but also in those with microalbuminuria. At first glance, this is surprising. First, since the measurement of albumin is more specific, more sensitive, and better standardized than that of total protein,12,13 one would expect this to result in better risk assessment.14 Second, when total protein is assessed, one is not informed of the nature of the proteins present in the sample. The finding that urinary total protein in the microalbuminuria range (most likely consisting of tubular proteins) and urinary albumin are equally associated with renal outcomes supports the hypothesis that albuminuria reflects a generalized tubular disorder. The relatively large contribution of tubular proteins to total urinary protein compared to Address correspondence to Paul E. de Jong, Division of Nephrology, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: [email protected] © 2010 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2010.11.005 1
de Jong et al
albumin also makes one wonder whether the level of total protein would independently add to the level of albumin in the outcome prediction. It would have been interesting if the authors had performed such an evaluation in addition to the evaluations presented in their article. Although it is understandable that total protein may predict renal outcomes as well as albumin, it is more difficult to understand why both are comparable in their relationship to total mortality, which most likely relates to associations with cardiovascular outcomes. How could generalized vascular damage to the kidney result in tubular dysfunction? It has been argued that generalized atherosclerosis leads to medullary hypoperfusion and hypoxia, thus inducing renal tubular dysfunction, which causes impaired reabsorption of albumin and other tubular proteins.15 Importantly, Methven et al assessed both urinary albumin and urinary protein in fresh samples. This makes their data fairly unique, because other studies investigating the predictive value of proteinuria or albuminuria used stored, frozen samples. In a number of studies, we showed previously that frozen storage leads to increased variability in and decreased predictive value of albuminuria, in particular when urine samples are stored at ⫺20°C without appropriate alkalinization prior to assessment.14,16,17 Should these findings influence our practice regarding risk prediction in CKD? The data emphasize that in patients referred for CKD who appear to have ⬍300 mg of protein per day, we should perform more sensitive protein or albumin measurements to better predict future risk. Methven et al argue that the costs for a total protein assay are lower than for an albumin assay, but this argument may not withstand economic developments around these assays in the near future. The better argument would be one that is based on scientific grounds. First, these data should of course be confirmed before changing clinical practice. Second, as long as we do not know what kind of specific proteins we measure and thus do not know what exactly underlies the predictive power of the total protein assay, the present findings clearly warrant further research studies. Such investigations could lead to better prediction of cardiovascular and renal events, but will also increase our understanding of the pathophysiology of CKD and its link with atherosclerotic cardiovascular disease. Paul E. de Jong, MD, PhD Stephan J.L. Bakker, MD, PhD Ron T. Gansevoort, MD, PhD University Medical Centre Groningen
2
University of Groningen Groningen, the Netherlands
ACKNOWLEDGEMENTS Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. National Kidney Foundation. K/DOQI Clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266. 2. Methven S, MacGregor MS, Traynor JP, Hair M, O’Reilly DSJ, Deighan CJ. Comparison of urinary albumin and urinary total protein as predictors of patient outcomes in CKD. Am J Kidney Dis. 2011;57(1):21-28. 3. Tencer J, Bakoush O, Torffvit O. Diagnostic and prognostic significance of proteinuria selectivity index in glomerular diseases. Clin Chim Acta. 2000;297(1-2):73-83. 4. Bazzi C, Petrini C, Rizza V, Arrigo G, D’Amico G. A modern approach to selectivity of proteinuria and tubulaointerstitial damage in nephritic syndrome. Kidney Int. 2000;58(4):1732-1741. 5. Parving HH, Oxenboll B, Svendsen PA, et al. Early detection of patients at risk of developing diabetic nephropathy. Acta Endocrinol. 1982;100(4):550-555. 6. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med. 1984; 311(2):89-93. 7. de Jong PE, Brenner BM. From secondary to primary prevention of progressive renal disease: the case for screening for albuminuria. Kidney Int. 2004;66(6):2109-2118. 8. Glassock RJ, Winearls C. An epidemic of chronic kidney disease: fact or fiction? Nephrol Dial Transplant. 2008;23(4):11171123. 9. Maack T, Johnson V, Kau ST, Figueiredo J, Sigulem D. Renal filtration, transport, and metabolism of low-molecular weight proteins: a review. Kidney Int. 1979;16(3):251-270. 10. Gansevoort RT, Nauta FL, Bakker SJL. Albuminuria: all you need to predict outcomes in chronic kidney disease. Curr Opin Nephrol Hypertens. 2010;19(6):513-518. 11. Bakoush O, Grubb A, Rippe B, Tencer J. Urine excretion of protein HC in proteinuric glomerular disease correlates to urine IgG but not albuminuria. Kidney Int. 2001;60(5):1904-1909. 12. Stevens P, MacKenzie F, Lamb E. How should proteinuria be detected and measured? Ann Clin Biochem. 2009;46(Pt 3):205217. 13. Miller WG, Bruns DE, Hortin GL, et al. Current issues in measurement and reporting of urinary albumin excretion. Clin Chem. 2009;55(1):24-38. 14. Brinkman JW, de Zeeuw D, Gansevoort RT, et al. Prolonged frozen storage of urine reduces the value of albuminuria for mortality prediction. Clin Chem. 2007;53(1):153-154. 15. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006;17(1):17-25. 16. Brinkman JW, de Zeeuw D, Lambers Heerspink HJ, et al. Apparent loss of urinary albumin during long-term frozen storage: HPLC vs immunonephelometry. Clin Chem. 2007;53(8):15201526. 17. Lambers Heerspink HJ, Nauta FL, van der Zee CP, et al. Alkalinization of urine samples preserves albumin concentrations during prolonged frozen storage in patients with diabetes mellitus. Diabet Med. 2009;26(5):556-559.
Am J Kidney Dis. 2011;57(1):1-2
T
he publication of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative guidelines on the classification of chronic kidney disease (CKD) in 20021 has drawn much attention to optimization of risk prediction in individuals with CKD. Since staging of CKD is based on glomerular filtration rate (GFR) and albuminuria, these 2 diagnostic tests have been discussed intensively in the last decade. Most reports dealt with the optimization of estimated GFR in large population databases. Fewer studies have addressed optimization of methods for assessing urinary albumin or the question of whether albumin is the optimal urinary protein to be measured. In this issue of the American Journal of Kidney Diseases, Methven et al shed some light on the latter issue, asking whether it is urinary albumin or total urinary protein that is more tightly linked to outcomes.2 This question should be considered in historical perspective. In the period from the 1960s until the 1980s, nephrologists were interested in the urinary loss of large amounts of protein (typically more than 2-3 grams of protein per day) in patients with glomerular disorders. Laboratory methods for detection of total protein were available and sensitive enough for this purpose. In addition, nephrologists studied whether the loss of proteins was related only to loss of albumin (about 60,000 daltons) or also to loss of largermolecular-weight proteins, such as immunoglobulins (about 160-180,000 daltons). It was shown in various studies that the presence of large-molecular-weight proteins is associated with poor kidney survival.3,4 In the 1980s and 1990s, diabetologists became interested in the predictive value of small amounts of proteins in the urine. As the quantity of urinary total protein could not reliably be measured in these lower ranges, most studies used the more sensitive measurement of albumin, and referred to small amounts of albumin in the urine as “microalbuminuria.”5,6 Microalbuminuria, however, is not only related to diabetes, but is also associated with most traditional cardiovascular risk factors, including hypertension, obesity, and smoking.7 It has been argued that the loss of large amounts of albumin is a manifestation of kidney disease, while low amounts of albumin in the urine (microalbuminuria) is considered a manifestation of generalized vascular damage.8 Irrespective of the amount, albuminuria results from damage to the glomerular vascular endothelium. However, since the tubules reabsorb Am J Kidney Dis. 2011;57(1):1-2
90%-95% of all albumin filtered by the glomerulus,9 it has been questioned whether the presence of microalbuminuria might rather reflect a tubular disorder or a combination of a glomerular and tubular disorder.10 In the case of overt proteinuria or macroalbuminuria, usually around 20% of proteins are of nonalbumin nature, frequently including proteins with a higher molecular weight than albumin.11 In contrast, in microalbuminuria, and particularly in the normoalbuminuria ranges, up to 80% of the proteins can be of nonalbumin nature. It is most likely that these 80% of nonalbumin proteins are low-molecular-weight proteins (tubular) rather than high-molecular-weight proteins. Methven et al studied a cohort of 5,586 individuals that had been referred to a renal unit to evaluate the predictive value of albuminuria and proteinuria on 3 outcomes: (1) all-cause mortality, (2) start of renal replacement therapy, and (3) doubling of serum creatinine. The predictive utility of urinary total protein was comparable to that of urinary albumin for all 3 outcomes, regardless of whether it was expressed on a continuous scale or a categorical scale. Individuals with a wide range of albuminuria were included in the study; about one-third had normoalbuminuria (albumin-creatinine ratio [ACR] ⬍30 mg/g), one-third had microalbuminuria (ACR 30-300 mg/g), and one-third had macroalbuminuria (ACR ⬎300 mg/g). Urinary total protein and urinary albumin predicted outcomes to a similar extent not only in those with macroalbuminuria but also in those with microalbuminuria. At first glance, this is surprising. First, since the measurement of albumin is more specific, more sensitive, and better standardized than that of total protein,12,13 one would expect this to result in better risk assessment.14 Second, when total protein is assessed, one is not informed of the nature of the proteins present in the sample. The finding that urinary total protein in the microalbuminuria range (most likely consisting of tubular proteins) and urinary albumin are equally associated with renal outcomes supports the hypothesis that albuminuria reflects a generalized tubular disorder. The relatively large contribution of tubular proteins to total urinary protein compared to Address correspondence to Paul E. de Jong, Division of Nephrology, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: [email protected] © 2010 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2010.11.005 1
de Jong et al
albumin also makes one wonder whether the level of total protein would independently add to the level of albumin in the outcome prediction. It would have been interesting if the authors had performed such an evaluation in addition to the evaluations presented in their article. Although it is understandable that total protein may predict renal outcomes as well as albumin, it is more difficult to understand why both are comparable in their relationship to total mortality, which most likely relates to associations with cardiovascular outcomes. How could generalized vascular damage to the kidney result in tubular dysfunction? It has been argued that generalized atherosclerosis leads to medullary hypoperfusion and hypoxia, thus inducing renal tubular dysfunction, which causes impaired reabsorption of albumin and other tubular proteins.15 Importantly, Methven et al assessed both urinary albumin and urinary protein in fresh samples. This makes their data fairly unique, because other studies investigating the predictive value of proteinuria or albuminuria used stored, frozen samples. In a number of studies, we showed previously that frozen storage leads to increased variability in and decreased predictive value of albuminuria, in particular when urine samples are stored at ⫺20°C without appropriate alkalinization prior to assessment.14,16,17 Should these findings influence our practice regarding risk prediction in CKD? The data emphasize that in patients referred for CKD who appear to have ⬍300 mg of protein per day, we should perform more sensitive protein or albumin measurements to better predict future risk. Methven et al argue that the costs for a total protein assay are lower than for an albumin assay, but this argument may not withstand economic developments around these assays in the near future. The better argument would be one that is based on scientific grounds. First, these data should of course be confirmed before changing clinical practice. Second, as long as we do not know what kind of specific proteins we measure and thus do not know what exactly underlies the predictive power of the total protein assay, the present findings clearly warrant further research studies. Such investigations could lead to better prediction of cardiovascular and renal events, but will also increase our understanding of the pathophysiology of CKD and its link with atherosclerotic cardiovascular disease. Paul E. de Jong, MD, PhD Stephan J.L. Bakker, MD, PhD Ron T. Gansevoort, MD, PhD University Medical Centre Groningen
2
University of Groningen Groningen, the Netherlands
ACKNOWLEDGEMENTS Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. National Kidney Foundation. K/DOQI Clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266. 2. Methven S, MacGregor MS, Traynor JP, Hair M, O’Reilly DSJ, Deighan CJ. Comparison of urinary albumin and urinary total protein as predictors of patient outcomes in CKD. Am J Kidney Dis. 2011;57(1):21-28. 3. Tencer J, Bakoush O, Torffvit O. Diagnostic and prognostic significance of proteinuria selectivity index in glomerular diseases. Clin Chim Acta. 2000;297(1-2):73-83. 4. Bazzi C, Petrini C, Rizza V, Arrigo G, D’Amico G. A modern approach to selectivity of proteinuria and tubulaointerstitial damage in nephritic syndrome. Kidney Int. 2000;58(4):1732-1741. 5. Parving HH, Oxenboll B, Svendsen PA, et al. Early detection of patients at risk of developing diabetic nephropathy. Acta Endocrinol. 1982;100(4):550-555. 6. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med. 1984; 311(2):89-93. 7. de Jong PE, Brenner BM. From secondary to primary prevention of progressive renal disease: the case for screening for albuminuria. Kidney Int. 2004;66(6):2109-2118. 8. Glassock RJ, Winearls C. An epidemic of chronic kidney disease: fact or fiction? Nephrol Dial Transplant. 2008;23(4):11171123. 9. Maack T, Johnson V, Kau ST, Figueiredo J, Sigulem D. Renal filtration, transport, and metabolism of low-molecular weight proteins: a review. Kidney Int. 1979;16(3):251-270. 10. Gansevoort RT, Nauta FL, Bakker SJL. Albuminuria: all you need to predict outcomes in chronic kidney disease. Curr Opin Nephrol Hypertens. 2010;19(6):513-518. 11. Bakoush O, Grubb A, Rippe B, Tencer J. Urine excretion of protein HC in proteinuric glomerular disease correlates to urine IgG but not albuminuria. Kidney Int. 2001;60(5):1904-1909. 12. Stevens P, MacKenzie F, Lamb E. How should proteinuria be detected and measured? Ann Clin Biochem. 2009;46(Pt 3):205217. 13. Miller WG, Bruns DE, Hortin GL, et al. Current issues in measurement and reporting of urinary albumin excretion. Clin Chem. 2009;55(1):24-38. 14. Brinkman JW, de Zeeuw D, Gansevoort RT, et al. Prolonged frozen storage of urine reduces the value of albuminuria for mortality prediction. Clin Chem. 2007;53(1):153-154. 15. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006;17(1):17-25. 16. Brinkman JW, de Zeeuw D, Lambers Heerspink HJ, et al. Apparent loss of urinary albumin during long-term frozen storage: HPLC vs immunonephelometry. Clin Chem. 2007;53(8):15201526. 17. Lambers Heerspink HJ, Nauta FL, van der Zee CP, et al. Alkalinization of urine samples preserves albumin concentrations during prolonged frozen storage in patients with diabetes mellitus. Diabet Med. 2009;26(5):556-559.
Am J Kidney Dis. 2011;57(1):1-2