Abstract
Aim: The aim of this study was to clarify the rates of remission and progression for microalbuminuria in patients with type 2 diabetes (T2DM); and factors associated with remission and progression of diabetic nephropathy (DN). Patients and Methods: T2DM patients with a urinary albumin excretion (UAE) rate of 30-300 mg/gCr who were attending the medical clinic in the Tsugaru region in Japan were enrolled into this prospective, observational study for 36 months (N=317). We investigated the rate of remission (UAE <30 mg/g creatinine (Cr); normal albuminuria) and the rate of progression (UAE ≥300 mg/gCr; overt proteinuria) 36 months after study registration. Results: The number of patients whose UAE levels were <30 mg/gCr (DN remission) at 36 months after registration was 64 (27.4%), and the number of patients whose UAE levels were ≥300 mg/gCr (DN progression) at 36 months after registration was 32 (13.7%). From multiple logistic regression analysis, the sole factor that contributed to remission at 36 months after registration was the UAE levels at registration (OR: 0.99; 95% CI: 0.98-1.00, p=0.003), and the factors that contributed to progression at 36 months after registration were the levels of UAE (OR: 1.01; 95% CI: 1.01-1.02, p=0.000) and systolic blood pressure (OR: 0.96; 95% CI: 0.93-1.00, p=0.033) at registration. Conclusion: Results suggest that patients with less severe microalbuminuria among microalbuminuric patients might more commonly experience DN remission and that earlier intervention is very important for promoting microalbuminuria remission in DN.
Diabetic nephropathy (DN) is the leading cause of end-stage renal failure in patients with type 2 diabetes mellitus, and its prevalence is increasing annually worldwide. Compared to 20 years ago, the incidence of diabetic complications without DN has decreased; however, DN is still the main complication in diabetes (1). On the other hand, high incidences of DN in type 2 diabetic patients have been reported, at 40-60% (2, 3). Further DN is a strong risk factor for atherosclerosis and cardiovascular disease compared to chronic kidney disease without diabetes (4). Additionally, at present, patients with end-stage DN in Japan comprise over 40% of the patients starting dialysis therapy in one year (5).
Therefore, if we could prevent DN progression, we could be able to consequently prevent the need for dialysis in these patients. Unfortunately, an effective treatment strategy has not yet been developed for DN. According to recent studies, the early detection and treatment of DN, including measuring urinary albumin excretion (UAE), the strict control of blood sugar, blood pressure and treatment for other risks (multifactorial intervention), are considered very important (6-9). However, it is unclear whether such procedure/treatment is actually routinely performed.
Thus, the aim of the present study was to clarify whether multifactorial intervention was actually performed. Because we were investigating the change of albuminuria in patients with DN, we assessed the remission and progression rates of microalbuminuria using a 36-month follow-up survey.
Patients and Methods
Study design and procedure. Type 2 diabetes patients with a UAE of 30-300 mg/g creatinine (Cr) who were attending the medical clinic in the Tsugaru region of Aomori district Japan were enrolled in this study after giving their written informed consent. Each medical clinic sent the study registration data [verification of age, gender, diabetes duration, medication, UAE, systolic and diastolic Bp, pulse rate, blood urea nitrogen (BUN), creatinine (Cr), sodium (Na), potassium (K), chloride (Cl), uric acid (UA), BS, and HbA1C] to the study office by facsimile. Complete registration was confirmed at the office. Similarly, follow-up data (UAE, systolic and diastolic Bp, pulse rate, BUN, Cr, Na, K, Cl, UA, BS, and HbA1C) were obtained 36 months after registration.
Because we were expecting increased awareness about DN in the clinic in this region during the study, we added comments regarding the current standard management of DN at registration (Treatment Guide for Diabetes 2010-2011) (10).
We investigated the rate of remission (UAE <30 mg/gCr; normal albuminuria) and the rate of progression (UAE ≥300 mg/gCr; overt proteinuria) at 36 months after registration. In addition, we investigated the factors contributing to remission or progression in this study.
The present study was approved by the Ethical Review Board of Hirosaki University Graduate School of Medicine. The study was carried out on receiving their written informed consent after providing with the information about the study. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (no. UMIN000022124).
Statistical analysis. The data are expressed as the mean±SD. The data obtained at registration and at 36 months after registration were compared by a paired t-test. Comparison of the data among three groups (normal albuminuria, microalbuminuria, and overt proteinuria) at 36 months after registration was analysed with Bonferroni's adjustment after one-way ANOVA. To investigate the factors contributing to remission or progression, a relative odds ratio was calculated using multiple logistic regression analysis. p<0.05 was considered statistically significant.
Results
Three hundred and seventeen patients were enrolled in this study, and 234 (74.5%) patients were followed-up for 36 months after registration. The data obtained at registration are shown in Table I.
The changes in Bp and blood analysis between registration and 36 months after registration are shown in Table II. The levels of UAE, BUN, Cr, K and UA had increased significantly 36 months after registration. The systolic and diastolic Bp had decreased significantly 36 months after registration.
The number of patients whose levels of UAE were <30 mg/gCr (DN remission) at 36 months after registration was 64 (27.4%) and the number of patients whose levels of UAE were ≥300 mg/gCr (DN progression) at 36 months after registration was 32 (13.7%).
Comparison of data at registration and 36 months after registration among the three groups (remission [normal albuminuria], microalbuminuria and progression [overt proteinuria]) are shown in Table III. At registration, the levels of UAE in the progression group were significantly higher than those in the remission and microalbuminuria groups. At registration, the levels of K in the remission group were significantly lower than those in the microalbuminuria group. At registration, the levels of HbA1C in the remission group were significantly lower than those in the microalbuminuria and progression groups.
On the other hand, at 36 months after registration, the levels of Na in the remission group were significantly higher than those in the progression group. Furthermore, the levels of HbA1C in the remission group were also significantly lower than those in the progression group.
In addition, the differences in the data obtained at registration and 36 months after registration among the three groups are shown in Table IV. The BS levels in the remission group were significantly lower than those in the progression group. The frequency of use of dipeptidyl peptidase (DPP)-4 inhibitors in the remission and microalbuminuria groups had significantly increased at 36 months after registration compared with that at registration. There was no increase in the frequency of DPP-4 inhibitor use in the progression group over the 36 months.
The relative odds ratios (OR) of the factors associated with the remission and progression of microalbuminuria as assessed using multiple logistic regression analysis are shown in Table V. From this analysis, the sole factor that contributed to remission at 36 months after registration was the levels of UAE at registration (OR: 0.99; 95% CI: 0.98-1.00, p=0.003), and the factors that contributed to progression at 36 months after registration were the levels of UAE (OR: 1.01; 95% CI: 1.01-1.02, p=0.000) and systolic Bp (OR: 0.96; 95% CI: 0.93-1.00, p=0.033) at registration.
Discussion
We showed that the levels of UAE significantly increased over 36 months in an observational study of 234 patients with stage 2 DN. This may be why there was a large increase in the UAE levels in some individuals between registration and 36 months post-registration, as the progression rate was 13.7%, which did not seem to be that high. Additionally, this may be another reason why the levels of UAE had increased in many of the patients in the microalbuminuria group. The levels of BUN, Cr, K and UA had significantly increased 36 months after registration; this might be because of the gradual progression of DN over the 36 months and the increased use of renin-angiotensin system (RAS) inhibitors. The systolic and diastolic Bp significantly decreased over the 36 months; this might be because of the increased use of RAS inhibitors and increased antihypertensive therapy.
Demographic and clinical data.
We investigated the changes in the use of RAS inhibitors, statins, and DPP-4 inhibitors during this study. Between registration and 36 months after registration, the use of RAS inhibitors increased from 67.5% to 73.5%, the use of statins increased from 32.1% to 38.0%, and the use of DPP-4 inhibitors increased form 34.2% to 53.0%. The increased use of these drugs could be attributed to the additional comments about the current standard management of DN at registration from the study office. Although this study was not an interventional study, these results suggest that the clinicians in the region gradually gained more knowledge on the diagnosis and management of DN throughout the duration of this study.
Compared to the results from several studies which that showed the rate of microalbuminuria remission in DN (8, 11-16), the rate found in the present study, 27.4%, was not very high. Most of the contributors in this study were general physicians, not diabetes specialists, many previous papers on DN were reported from diabetic specialist faculties, such as, university hospitals or diabetic centers (8, 11-16). Consequently, our results in this study might accurately reflect the situation of actual clinical practice.
Comparison between the data obtained at registration and 36 months after registration.
As shown in Table III, the levels of UAE, K and HbA1C at registration were significantly different among the remission, microalbuminuria and progression groups. When the levels of UAE at registration are low, remission may be more likely after 36 months, and early onset of low UAE could be interrupted as a higher likelihood of microalbuminuria remission. Similarly, good control of BS at registration might be interrupted as a higher likelihood of remission. The levels of Na, BS and HbA1C 36 months after registration were significantly different among the remission, microalbuminuria and progression groups. The control of BS 36 months after registration in the remission group was significantly better than that in the progression group. These results suggest that strict control of BS might contribute to microalbuminuria remission 36 months after registration. These results were similar to those of precious reports (8, 14, 16).
As shown in Table V, the sole factor that contributed to remission at 36 months after registration was the levels of UAE at registration. The results suggest that the strict control of the UAE levels is very important. Recently, it was reported that DPP-4 inhibitors and sodium glucose co-transporter (SGLT)-2 inhibitors decreases albuminuria in patients with DN (17, 18). Consequently, the early intervention, example, the use of RAS inhibitors, DPP-4 inhibitors and/or SGLT-2 inhibitors might be effective for promoting microalbuminuria remission.
Comparison of data among the three groups (normal, microalbuminuria and overt proteinuria).
In conclusion, we showed that 27.4% and 13.7% of diabetic patients with microalbuminuria experienced remission and progression, respectively, over the course of 36 months. The sole factor that contributed to remission was the UAE levels at registration, and the factors that contributed to progression were the UAE levels and systolic Bp at registration. These results suggest that patients with less severe microalbuminuria among microalbuminuric patients might be more likely to experience DN remission and that early intervention is very important for promoting microalbuminuria remission in DN.
Comparison of data obtained at study registration and 36 months after registration.
The relative odds ratios of the factors associated with remission and progression of microalbuminuria as assessed using multiple logistic regression analysis.
Acknowledgements
The Authors would like to thank the members of Diabetic Nephropathy Treatment Study Group. They were as follows: Dr. Takako Moriyama, Dr. Miyuki Yanagimachi, Dr. Jun Matsui and Dr. Makoto Daimon (Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine), Dr. Shinsaku Fukuda (Community Medicine, Hirosaki University Graduate School of Medicine), Dr. Takashi Itsukaichi (Itsukaichi Naika Clinic), Dr. Ken-ichi Imamura (Imamura Clinic), Dr. Yoshifumi Umemura (Umemura Iin), Dr. Katsuhiro Okamoto (Okamoto Naika Iin), Dr. Naoko Kusumi and Dr. Eriko Ogura (Tokiwa-kai Hospital), Dr. Yoshihiko Kakisaka (Kakisaka Iin), Dr. Hideo Kakuta (Kakuta Geka Clinic), Dr. Yutaka Kanehira (Kanehira Clinic), Dr. Takashi Kudo (Kudo Naika Syonika Iin), Dr. Takeshi Kudo (Okidate Heart Clinic), Dr. Yoshihiko Sawada (Sawada Naika Iin), Dr. Masayuki Shimizu (Shimizu Clinic), Dr. Ken-ichi Shirato and Dr. Tasuku Shiroto (Hirosaki Chuo Hospital), Dr. Masahiko Tanaka (Tanaka Geka Naika Iin), Dr. Yuichi Tamada (Tamada Naika Iin), Dr. Hironobu Chiba (Chiba Ichoka Naika Iin), Dr. Koji Fujimoto (Tsugaru General Hospital) and Dr. Seiichi Miyamoto (Kensei Hospital).
The authors would like to thank Enago (www.enago.jp) for the English language review and Kaze no An (www.medstat-support.com) for the support of statistical analysis.
Footnotes
This article is freely accessible online.
Conflicts of Interest
The Authors declare that there is no conflict of interest associated with the manuscript.
- Received February 21, 2017.
- Revision received March 19, 2017.
- Accepted March 21, 2017.
- Copyright © 2017 The Author(s). Published by the International Institute of Anticancer Research.
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