Correspondence Combination effect of hypertension and diabetes mellitus on urinary protein excretion Tomoyuki Kawada
O
hara et al. [1] examined the effect of hypertension on urinary protein excretions in combination with type 2 diabetes mellitus. The authors set four groups according to the existence of diabetes mellitus and hypertension as follows: age-matched control (n ¼ 72), diabetes mellitus (n ¼ 52), hypertension (n ¼ 32) and diabetes mellitus and hypertension (n ¼ 45). All the individuals presented normoalbuminuria with urinary albumin-to-creatinine ratio under 15 mg/g, and urinary excretion of immunoglobulin G (IgG), ceruloplasmin (CRL), transferrin (Tf), albumin, a2-macroglobulin (A2) and N-acetylglucosaminidase (NAG) were used as effect markers. As a result, urinary IgG, CRL, Tf, albumin and NAG and estimated glomerular filtration rate were significantly elevated in the groups of diabetes mellitus and diabetes mellitus and hypertension compared with controls. Furthermore, urinary IgG, CRL and Tf were significantly higher in the diabetes mellitus and hypertension group than those in the diabetes mellitus group. In contrast, no significant difference in urinary albumin or NAG was found between the groups of diabetes mellitus and hypertension and diabetes mellitus. From the summary of the results, diabetes mellitus has more adverse effect on glomerulus and proximal tubules than hypertension, and there is no additive effect on NAG excretion. I have some concerns on their report. First, urinary albumin excretion is an indicator of disturbed glomerular permeability. In contrast, NAG cannot pass through the glomerulus, and urinary NAG is presented by the damage of renal proximal tubules. Statistical difference of albumin and NAG among four groups can be recognized from the different mechanism by diabetes mellitus and hypertension. As there was a wide range of clinical severity on diabetes mellitus, and the limitation of samples caused the difficulty of subanalysis regarding several confounders on diabetes mellitus. As the second concern, the level of urinary excretion of three specific plasma proteins showed that there is a significant renal effect by hypertension. Namely, urinary Tf in patients with hypertension significantly increased, and urinary IgG and CRL in patients with diabetes mellitus and hypertension were significantly higher than those in patients with diabetes mellitus. Their cross-sectional study cannot present the causality of the association between urinary protein excretion and diabetes mellitus and hypertension, and the authors mentioned it as the study
Journal of Hypertension
limitation. In advanced cases of diabetes mellitus including 30% patients with increased albuminuria, Yang et al. [2] reported that the duration of diabetes mellitus rather than the duration of hypertension was significantly associated with albuminuria and renal insufficiency. The role of renin– angiotensin system inhibition in preventing diabetes, hypertension and cardiovascular disease has also been considered [3,4], and I appreciate the study by Ohara et al. presenting urinary protein excretions as early markers of kidney damage. I recommend a follow-up study to determine the urinary protein excretion by diabetes mellitus and hypertension, with special reference to the severity of diabetes mellitus. Finally, the authors used multiple regression analysis with adjustment for age, sex and diabetes mellitus duration. As their analyses were conducted within each four group by diabetes mellitus and hypertension, I recommend their regression analysis by using all data for predicting urinary proteins such as urinary IgG, Tf, CRL, albumin, A2 and NAG, with diabetes mellitus and hypertension as independent variables.
ACKNOWLEDGEMENTS Disclosure statement: The author has indicated no financial support. Conflicts of interest There is no conflict of interest in this study.
REFERENCES 1. Ohara N, Hanyu O, Hirayama S, Nakagawa O, Aizawa Y, Ito S, et al. Hypertension increases urinary excretion of immunoglobulin G, ceruloplasmin and transferrin in normoalbuminuric patients with type 2 diabetes mellitus. J Hypertens 2014; 32:432–438. 2. Yang CW, Park JT, Kim YS, Kim YL, Lee YS, Oh YS, et al. Prevalence of diabetic nephropathy in primary care type 2 diabetic patients with hypertension: data from the Korean Epidemiology Study on Hypertension III (KEY III study). Nephrol Dial Transplant 2011; 26:3249– 3255. 3. Fonseca VA. Insulin resistance, diabetes, hypertension, and renin– angiotensin system inhibition: reducing risk for cardiovascular disease. J Clin Hypertens (Greenwich) 2006; 8:713–720. 4. Hsueh WA, Wyne K. Renin–angiotensin–aldosterone system in diabetes and hypertension. J Clin Hypertens (Greenwich) 2011; 13: 224–237.
Journal of Hypertension 2014, 32:2277–2281 Department of Hygiene and Public Health, Nippon Medical School, Bunkyo-Ku, Tokyo, Japan Correspondence to Tomoyuki Kawada, MD, Department of Hygiene and Public Health, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo 113-8602, Japan. Tel: +81 3 3822 2131; fax: +81 3 5685 3065; e-mail: [email protected] J Hypertens 32:2277–2281 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000352
www.jhypertension.com
2277
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence
Reply
N-acetylglucosaminidase, were associated with HbA1c; both HbA1c and office mean BP levels were associated with high levels of glomerular markers. These results support the combination effect of hypertension and diabetes mellitus on the kidney, perhaps mainly the glomerulus, in patients with normoalbuminuria.
Nobumasa Ohara, Osamu Hanyu, and Hirohito Sone
W
e thank Dr Kawada [1] for his interest in our study [2]. Dr Kawada noted a wide range of clinical severities of diabetes mellitus and pointed out the difficulty with subanalysis regarding confounders for diabetes mellitus caused by the limited sample size. We
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
TABLE 1. Variables predictive of urinary protein levels according to a multiple logistic regression analysis of 201 individuals who participated in the cross-sectional study
Predictive variable
U-IgG/Cr (mg/g Cr)
U-CRL/Cr (mg/g Cr)
U-Tf/Cr (mg/g Cr)
U-Alb/Cr (mg/g Cr)
U-A2/Cr (mg/g Cr)
U-NAG/Cr (U/g Cr)
High/normal (n ¼ 26/275)
High/normal (n ¼ 28/283)
High/normal (n ¼ 7/194)
High/normal (n ¼ 4/197)
High/normal (n ¼ 0/201)
High/normal (n ¼ 26/175)
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
HbA1c (%) 2.03 (1.44–2.86)
O
hara et al. [1] examined the effect of hypertension on urinary protein excretions in combination with type 2 diabetes mellitus. The authors set four groups according to the existence of diabetes mellitus and hypertension as follows: age-matched control (n ¼ 72), diabetes mellitus (n ¼ 52), hypertension (n ¼ 32) and diabetes mellitus and hypertension (n ¼ 45). All the individuals presented normoalbuminuria with urinary albumin-to-creatinine ratio under 15 mg/g, and urinary excretion of immunoglobulin G (IgG), ceruloplasmin (CRL), transferrin (Tf), albumin, a2-macroglobulin (A2) and N-acetylglucosaminidase (NAG) were used as effect markers. As a result, urinary IgG, CRL, Tf, albumin and NAG and estimated glomerular filtration rate were significantly elevated in the groups of diabetes mellitus and diabetes mellitus and hypertension compared with controls. Furthermore, urinary IgG, CRL and Tf were significantly higher in the diabetes mellitus and hypertension group than those in the diabetes mellitus group. In contrast, no significant difference in urinary albumin or NAG was found between the groups of diabetes mellitus and hypertension and diabetes mellitus. From the summary of the results, diabetes mellitus has more adverse effect on glomerulus and proximal tubules than hypertension, and there is no additive effect on NAG excretion. I have some concerns on their report. First, urinary albumin excretion is an indicator of disturbed glomerular permeability. In contrast, NAG cannot pass through the glomerulus, and urinary NAG is presented by the damage of renal proximal tubules. Statistical difference of albumin and NAG among four groups can be recognized from the different mechanism by diabetes mellitus and hypertension. As there was a wide range of clinical severity on diabetes mellitus, and the limitation of samples caused the difficulty of subanalysis regarding several confounders on diabetes mellitus. As the second concern, the level of urinary excretion of three specific plasma proteins showed that there is a significant renal effect by hypertension. Namely, urinary Tf in patients with hypertension significantly increased, and urinary IgG and CRL in patients with diabetes mellitus and hypertension were significantly higher than those in patients with diabetes mellitus. Their cross-sectional study cannot present the causality of the association between urinary protein excretion and diabetes mellitus and hypertension, and the authors mentioned it as the study
Journal of Hypertension
limitation. In advanced cases of diabetes mellitus including 30% patients with increased albuminuria, Yang et al. [2] reported that the duration of diabetes mellitus rather than the duration of hypertension was significantly associated with albuminuria and renal insufficiency. The role of renin– angiotensin system inhibition in preventing diabetes, hypertension and cardiovascular disease has also been considered [3,4], and I appreciate the study by Ohara et al. presenting urinary protein excretions as early markers of kidney damage. I recommend a follow-up study to determine the urinary protein excretion by diabetes mellitus and hypertension, with special reference to the severity of diabetes mellitus. Finally, the authors used multiple regression analysis with adjustment for age, sex and diabetes mellitus duration. As their analyses were conducted within each four group by diabetes mellitus and hypertension, I recommend their regression analysis by using all data for predicting urinary proteins such as urinary IgG, Tf, CRL, albumin, A2 and NAG, with diabetes mellitus and hypertension as independent variables.
ACKNOWLEDGEMENTS Disclosure statement: The author has indicated no financial support. Conflicts of interest There is no conflict of interest in this study.
REFERENCES 1. Ohara N, Hanyu O, Hirayama S, Nakagawa O, Aizawa Y, Ito S, et al. Hypertension increases urinary excretion of immunoglobulin G, ceruloplasmin and transferrin in normoalbuminuric patients with type 2 diabetes mellitus. J Hypertens 2014; 32:432–438. 2. Yang CW, Park JT, Kim YS, Kim YL, Lee YS, Oh YS, et al. Prevalence of diabetic nephropathy in primary care type 2 diabetic patients with hypertension: data from the Korean Epidemiology Study on Hypertension III (KEY III study). Nephrol Dial Transplant 2011; 26:3249– 3255. 3. Fonseca VA. Insulin resistance, diabetes, hypertension, and renin– angiotensin system inhibition: reducing risk for cardiovascular disease. J Clin Hypertens (Greenwich) 2006; 8:713–720. 4. Hsueh WA, Wyne K. Renin–angiotensin–aldosterone system in diabetes and hypertension. J Clin Hypertens (Greenwich) 2011; 13: 224–237.
Journal of Hypertension 2014, 32:2277–2281 Department of Hygiene and Public Health, Nippon Medical School, Bunkyo-Ku, Tokyo, Japan Correspondence to Tomoyuki Kawada, MD, Department of Hygiene and Public Health, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo 113-8602, Japan. Tel: +81 3 3822 2131; fax: +81 3 5685 3065; e-mail: [email protected] J Hypertens 32:2277–2281 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000352
www.jhypertension.com
2277
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence
Reply
N-acetylglucosaminidase, were associated with HbA1c; both HbA1c and office mean BP levels were associated with high levels of glomerular markers. These results support the combination effect of hypertension and diabetes mellitus on the kidney, perhaps mainly the glomerulus, in patients with normoalbuminuria.
Nobumasa Ohara, Osamu Hanyu, and Hirohito Sone
W
e thank Dr Kawada [1] for his interest in our study [2]. Dr Kawada noted a wide range of clinical severities of diabetes mellitus and pointed out the difficulty with subanalysis regarding confounders for diabetes mellitus caused by the limited sample size. We
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
TABLE 1. Variables predictive of urinary protein levels according to a multiple logistic regression analysis of 201 individuals who participated in the cross-sectional study
Predictive variable
U-IgG/Cr (mg/g Cr)
U-CRL/Cr (mg/g Cr)
U-Tf/Cr (mg/g Cr)
U-Alb/Cr (mg/g Cr)
U-A2/Cr (mg/g Cr)
U-NAG/Cr (U/g Cr)
High/normal (n ¼ 26/275)
High/normal (n ¼ 28/283)
High/normal (n ¼ 7/194)
High/normal (n ¼ 4/197)
High/normal (n ¼ 0/201)
High/normal (n ¼ 26/175)
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
HbA1c (%) 2.03 (1.44–2.86)
