Preventing Microalbuminuria in Type 2 Diabetes
http://www.100md.com
《新英格兰医药杂志》
To the Editor: We applaud the effort by Ruggenenti et al. (Nov. 4 issue)1 to address the issue of primary prevention of microalbuminuria (as a surrogate for early stages of kidney involvement) in patients with hypertension, type 2 diabetes, and normoalbuminuria. Regrettably, they do not provide baseline values for the glomerular filtration rate. From the average baseline data reported, we calculated values for the glomerular filtration rate (using Cockcroft–Gault and modified Modification of Diet in Renal Disease [MDRD] equations2,3) of 63 to 84 ml per minute per 1.73 m2 of body-surface area — values that are low, possibly because of hypertension, diabetes, or aging. Indeed, histologic evidence of kidney involvement in patients with diabetes and normoalbuminuria has been reported.4 Taken together, these issues raise the possibility that some of the observed benefits of therapy reported by Ruggenenti et al. may in fact have been due to a slowing of progression of already established kidney disease, rather than primary prevention. It would be helpful for the authors to provide the results of baseline measurements of the glomerular filtration rate and kidney-biopsy information, when available.
Kambiz Zandi-Nejad, M.D.
Barry M. Brenner, M.D.
Brigham and Women's Hospital
Boston, MA 02115
bbrenner@partners.org
References
Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-1951.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461-470.
Moriya T, Tanaka K, Moriya R. Glomerular structural changes and structural-functional relationships at early stage of diabetic nephropathy in Japanese type 2 diabetic patients. Med Electron Microsc 2000;33:115-122.
To the Editor: Ruggenenti et al. suggest that treatment with trandolapril delays the emergence of microalbuminuria in patients with normoalbuminuria, hypertension, and type 2 diabetes. The primary end point of the study was microalbuminuria, determined on the basis of multiple measurements of the albumin excretion rate over a two-month period. Given the implication that angiotensin-converting–enzyme inhibitors should be administered to patients with hypertension and type 2 diabetes, several questions should be answered. How many patients in each group had microalbuminuria, including transient microalbuminuria,1 at the end of the study? What were the actual albumin excretion rates at the end of the study? In a surprising number of patients in the placebo and verapamil groups, microalbuminuria developed during the first three to six months of the study, despite excellent metabolic control. Patients were randomly assigned six weeks after discontinuation of medications that blocked the renin–angiotensin system. However, some may have had residual suppression of their albumin excretion rate by such drugs.2 How many of the patients in whom microalbuminuria developed at three months were receiving renin–angiotensin system blockers as compared with other antihypertensive medications?
Michael Mauer, M.D.
University of Minnesota
Minneapolis, MN 55455
mauer002@umn.edu
Paola Fioretto, M.D., Ph.D.
University of Padua
35126 Padua, Italy
References
Perkins BA, Ficociello CH, Silva KH, Finkelstein DM, Warram JH, Krowleski AS. Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348:2285-2293.
Mathiesen ER, Hommel E, Giese J, Parving H-H. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ 1991;303:81-87.
The authors reply: Zandi-Nejad and Brenner calculated the baseline glomerular filtration rate of patients in our study, the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT), with use of the Cockcroft–Gault and modified MDRD equations. However, in persons with normal renal function, these formulas underestimate the glomerular filtration rate by 29 percent.1 We measured the glomerular filtration rate by plasma iohexol clearance2 in a representative subgroup of 56 of the patients in BENEDICT with baseline characteristics (age, sex distribution, smoking status, blood pressure, body-mass index, glycosylated hemoglobin level, serum creatinine level, and albuminuria) similar to those of the whole study group. The mean (±SD) glomerular filtration rate in these patients was 111.0±19.0 ml per minute per 1.73 m2; the rate was greater than 120 ml per minute per 1.73 m2 in 13 patients and was 80 to 120 ml per minute per 1.73 m2 in 43. Interestingly, not a single patient had a glomerular filtration rate of less than 80 ml per minute per 1.73 m2. In the same group of patients, the MDRD equation3 yielded a value of 85.3±12.7 ml per minute per 1.73 m2, which underestimated the measured glomerular filtration rate by 23 percent. The same equation applied to the BENEDICT study group as a whole gave a result of 81.0±14.9 ml per minute per 1.73 m2, which would translate into a glomerular filtration rate of 105 ml per minute per 1.73 m2. Thus, we are confident that the observed benefit of therapy in the patients in BENEDICT reflects primary prevention rather than a slowing of progression of already established disease. Given that the patients had normal renal function and normal urinary albumin excretion, we did not consider renal biopsy justified.
In reply to the questions by Mauer and Fioretto: first, either transient or persistent microalbuminuria developed in 35 patients receiving verapamil plus trandolapril, as compared with 40 receiving trandolapril, 58 receiving verapamil, and 52 receiving placebo. Second, the actual mean albumin excretion rate at the end of the study was 8.1±11.1 μg per minute among those receiving verapamil plus trandolapril, 7.4±7.0 μg per minute among those receiving trandolapril, 12.0±24.0 μg per minute among those receiving verapamil, and 11.0±23.7 μg per minute among those receiving placebo. Finally, microalbuminuria had developed at three months in 21 patients receiving verapamil or placebo: 10 had previously received renin–angiotensin system blockers, and 11 had received other antihypertensive medications.
It is notable that the incidence of microalbuminuria throughout the study period was significantly lower with verapamil plus trandolapril and with trandolapril than it was with placebo (P=0.03 and P<0.05, respectively), even when patients in whom microalbuminuria had developed at three months were not considered. Thus, we conclude that the effect of verapamil plus trandolapril and of trandolapril in protecting against the development of microalbuminuria was not influenced by previous treatment with renin–angiotensin system blockers.
Piero Ruggenenti, M.D.
Annalisa Perna, Stat.Sci.D.
Giuseppe Remuzzi, M.D.
Mario Negri Institute for Pharmacological Research
24125 Bergamo, Italy
manuelap@marionegri.it
References
Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med 2004;141:929-937.
Gaspari F, Perico N, Ruggenenti P, et al. Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate. J Am Soc Nephrol 1995;6:257-263.
Levey AS, Greene T, Kusek JK, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:155A-155A. abstract.
Kambiz Zandi-Nejad, M.D.
Barry M. Brenner, M.D.
Brigham and Women's Hospital
Boston, MA 02115
bbrenner@partners.org
References
Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-1951.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461-470.
Moriya T, Tanaka K, Moriya R. Glomerular structural changes and structural-functional relationships at early stage of diabetic nephropathy in Japanese type 2 diabetic patients. Med Electron Microsc 2000;33:115-122.
To the Editor: Ruggenenti et al. suggest that treatment with trandolapril delays the emergence of microalbuminuria in patients with normoalbuminuria, hypertension, and type 2 diabetes. The primary end point of the study was microalbuminuria, determined on the basis of multiple measurements of the albumin excretion rate over a two-month period. Given the implication that angiotensin-converting–enzyme inhibitors should be administered to patients with hypertension and type 2 diabetes, several questions should be answered. How many patients in each group had microalbuminuria, including transient microalbuminuria,1 at the end of the study? What were the actual albumin excretion rates at the end of the study? In a surprising number of patients in the placebo and verapamil groups, microalbuminuria developed during the first three to six months of the study, despite excellent metabolic control. Patients were randomly assigned six weeks after discontinuation of medications that blocked the renin–angiotensin system. However, some may have had residual suppression of their albumin excretion rate by such drugs.2 How many of the patients in whom microalbuminuria developed at three months were receiving renin–angiotensin system blockers as compared with other antihypertensive medications?
Michael Mauer, M.D.
University of Minnesota
Minneapolis, MN 55455
mauer002@umn.edu
Paola Fioretto, M.D., Ph.D.
University of Padua
35126 Padua, Italy
References
Perkins BA, Ficociello CH, Silva KH, Finkelstein DM, Warram JH, Krowleski AS. Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348:2285-2293.
Mathiesen ER, Hommel E, Giese J, Parving H-H. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ 1991;303:81-87.
The authors reply: Zandi-Nejad and Brenner calculated the baseline glomerular filtration rate of patients in our study, the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT), with use of the Cockcroft–Gault and modified MDRD equations. However, in persons with normal renal function, these formulas underestimate the glomerular filtration rate by 29 percent.1 We measured the glomerular filtration rate by plasma iohexol clearance2 in a representative subgroup of 56 of the patients in BENEDICT with baseline characteristics (age, sex distribution, smoking status, blood pressure, body-mass index, glycosylated hemoglobin level, serum creatinine level, and albuminuria) similar to those of the whole study group. The mean (±SD) glomerular filtration rate in these patients was 111.0±19.0 ml per minute per 1.73 m2; the rate was greater than 120 ml per minute per 1.73 m2 in 13 patients and was 80 to 120 ml per minute per 1.73 m2 in 43. Interestingly, not a single patient had a glomerular filtration rate of less than 80 ml per minute per 1.73 m2. In the same group of patients, the MDRD equation3 yielded a value of 85.3±12.7 ml per minute per 1.73 m2, which underestimated the measured glomerular filtration rate by 23 percent. The same equation applied to the BENEDICT study group as a whole gave a result of 81.0±14.9 ml per minute per 1.73 m2, which would translate into a glomerular filtration rate of 105 ml per minute per 1.73 m2. Thus, we are confident that the observed benefit of therapy in the patients in BENEDICT reflects primary prevention rather than a slowing of progression of already established disease. Given that the patients had normal renal function and normal urinary albumin excretion, we did not consider renal biopsy justified.
In reply to the questions by Mauer and Fioretto: first, either transient or persistent microalbuminuria developed in 35 patients receiving verapamil plus trandolapril, as compared with 40 receiving trandolapril, 58 receiving verapamil, and 52 receiving placebo. Second, the actual mean albumin excretion rate at the end of the study was 8.1±11.1 μg per minute among those receiving verapamil plus trandolapril, 7.4±7.0 μg per minute among those receiving trandolapril, 12.0±24.0 μg per minute among those receiving verapamil, and 11.0±23.7 μg per minute among those receiving placebo. Finally, microalbuminuria had developed at three months in 21 patients receiving verapamil or placebo: 10 had previously received renin–angiotensin system blockers, and 11 had received other antihypertensive medications.
It is notable that the incidence of microalbuminuria throughout the study period was significantly lower with verapamil plus trandolapril and with trandolapril than it was with placebo (P=0.03 and P<0.05, respectively), even when patients in whom microalbuminuria had developed at three months were not considered. Thus, we conclude that the effect of verapamil plus trandolapril and of trandolapril in protecting against the development of microalbuminuria was not influenced by previous treatment with renin–angiotensin system blockers.
Piero Ruggenenti, M.D.
Annalisa Perna, Stat.Sci.D.
Giuseppe Remuzzi, M.D.
Mario Negri Institute for Pharmacological Research
24125 Bergamo, Italy
manuelap@marionegri.it
References
Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med 2004;141:929-937.
Gaspari F, Perico N, Ruggenenti P, et al. Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate. J Am Soc Nephrol 1995;6:257-263.
Levey AS, Greene T, Kusek JK, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:155A-155A. abstract.