Diabetic nephropathy is one of the greatest primary diseases necessitating hemodialysis in patients with end-stage renal disease. It is very important to control the development of symptoms and progress of nephropathy in the medical treatment of diabetes. However, the detailed mechanisms of the development and progression of diabetic nephropathy are still unknown.
There are many reports indicating that the increase of intrarenal angiotensinogen (AGT) and the activation of the renin-angiotensin system (RAS) are involved in diabetic nephropathy [
On the other hand, it is reported that medicines associated with incretin, such as dipeptidyl peptidase- (DPP-) 4 inhibitors and glucagon like peptide-1, have a renoprotective effect in addition to improving glycemic control [
This experimental protocol was approved by the institutional review board of Social Insurance Miyazaki Konan Hospital (Miyazaki, Japan). Patients with type 2 diabetes (T2D) were recruited from Miyazaki University affiliated hospitals from August 2011 to June 2012, and written informed consents were obtained. T2D was defined as fasting blood glucose ≥126 mg/dL, glycated hemoglobin (HbA1c) ≥6.5%, according to the guidelines of the American Diabetes Association, or receiving treatments with oral hypoglycemic agents. Patients whose HbA1c levels were ≥6.1% for at least 3 months, in spite of nondrug treatments (i.e., exercise, diet, and lifestyle modification) or medications with a stable dose of oral hypoglycemic agents (except DPP-4 inhibitors), were included. Patients (1) with administration of insulin; (2) with hepatic or renal impairment (aspartate aminotransferase or alanine aminotransferase ≥2.5 × upper limit of normal or serum creatinine (Cr) ≥2 mg/dL); (3) with cardiovascular disease within 6 months (i.e., myocardial infarction or stroke); (4) taking a moderate or high dose of glimepiride (i.e., >3 mg/day); (5) and taking sulfonylureas other than glimepiride were excluded. Other antihyperglycemic and antihypertensive medications were not changed during this study.
The patients took 25 mg alogliptin once daily for 12 weeks, and serum HbA1c, serum Cr, urinary albumin (Alb), urinary AGT, and urinary Cr were measured, at baseline and after 12 weeks.
HbA1c concentration, determined using a latex agglutination immunoassay, was estimated as a National Glycohemoglobin Standardization Program (NGSP) equivalent value calculated with the following formula: HbAlc (NGSP, %) = HbAlc (Japan Diabetes Society, %) + 0.4. To estimate renal function, the estimated glomerular filtration rate (eGFR) derived using the following equation was used: eGFR (mL/min/1.73 m2) = 194 × age (years)−0.287 × serum Cr (mg/dL)−1.094 (if women × 0.739) [
All statistical analyses were performed with JMP software version 10 (SAS Institute Inc., Tokyo, Japan). Age, body mass index (BMI), and treatment duration of T2D were expressed as means ± standard error (SE). UAlbCR, UAGTCR, HbA1c, eGFR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) before and after treatment by alogliptin were expressed as means ± SE and were compared using a paired
Based on this cutoff value of UAGTCR before the treatment, we divided all patients into 2 groups. We compared % change in UAlbCR and ΔUAlbCR between the 2 groups using an unpaired
43 patients (18 women and 25 men,
Patient profiles.
|
43 |
Men/women | 25/18 |
Age (years) | 66.1 ± 1.71 |
BMI (kg/m2) | 24.8 ± 0.5 |
Treatment duration of T2D (years) | 7.1 ± 1.18 |
Medications | |
ARB | 23 (53.5%) |
|
8 (18.6%) |
TZD | 5 (11.6%) |
ARB: angiotensin II receptor blockers,
Laboratory data of before and after treatment by alogliptin.
Before | After |
|
|
---|---|---|---|
UAlbCR (mg/g Cr) | 114.6 ± 36.0 | 99.6 ± 26.8 |
|
UAGTCR ( |
27.2 ± 4.2 | 29.9 ± 8.0 |
|
HbA1c (NGSP) (%) | 7.2 ± 0.1 | 7.0 ± 0.1 |
|
eGFR (mL/min/1.73 m2) | 74.3 ± 3.1 | 72.2 ± 3.0 |
|
Systolic blood pressure (mmHg) | 140.5 ± 2.9 | 138.3 ± 2.9 |
|
Diastolic blood pressure (mmHg) | 77.8 ± 1.7 | 78.7 ± 1.6 |
|
The alogliptin treatment tended to decrease UAlbCR (
(a) Urinary concentrations of Alb normalized by urinary concentrations of creatinine (UAlbCR) before and 12-week after treatment with alogliptin. Alogliptin treatment tended to decrease UAlbCR (
Patients were divided into two groups: those for whom UAlbCR decreased less than 25% and those for whom it decreased more than 25%. A logistic analysis of UAGTCR before treatment showed AUC as 0.644. When we set the cutoff value of UAGTCR as 20.8
Logistic analysis of urinary concentrations of angiotensinogen normalized by urinary concentrations of creatinine (UAGTCR) before treatment. Good responders to the alogliptin treatment were defined in terms of % change in urinary concentrations of Alb normalized by urinary concentrations of creatinine less than −25% after the 12-week treatment, and a logistic analysis of UAGTCR before treatment showed the area under the curve as 0.644. When we set the cutoff value of UAGTCR as 20.8
Based on this cutoff value of UAGTCR (i.e., ≥20.8
Patient profiles partitioned by the cutoff value of UAGTCR before treatments.
Group | High | Low |
|
---|---|---|---|
|
20 | 23 | |
Men/women | 11/9 | 14/9 |
|
Age (years) | 67.0 ± 2.5 | 65.4 ± 2.4 |
|
BMI (kg/m2) | 24.1 ± 0.7 | 25.4 ± 0.7 |
|
Treatment duration of T2D (years) | 6.9 ± 1.8 | 7.4 ± 1.6 |
|
Medications | |||
ARB | 12 (60.0%) | 11 (47.8%) |
|
|
4 (20.0%) | 4 (17.4%) |
|
TZD | 1 (5.00%) | 4 (17.4%) |
|
ARB: angiotensin II receptor blockers,
Laboratory data at the entry partitioned by the cutoff value of UAGTCR before treatments.
Group | High | Low |
|
---|---|---|---|
HbA1c (NGSP) (%) | 7.26 ± 0.15 | 7.23 ± 0.14 |
|
eGFR (mL/min/1.73 m2) | 76.6 ± 4.6 | 72.3 ± 4.3 |
|
Systolic blood pressure (mmHg) | 143.6 ± 4.3 | 137.9 ± 4.0 |
|
Diastolic blood pressure (mmHg) | 77.0 ± 2.5 | 78.4 ± 2.4 |
|
ΔUrinary concentrations of Alb normalized by urinary concentrations of creatinine (UAlbCR) defined by the cutoff value of urinary concentrations of angiotensinogen normalized by urinary concentrations of creatinine (UAGTCR) before treatment. When all patients were redivided into two groups, those with higher UAGTCR levels before treatment (Group H,
In addition, % change in UAlbCR was significantly lower in Group H than in Group L (
% change in urinary concentrations of Alb normalized by urinary concentrations of creatinine (UAlbCR) defined by the cutoff value of urinary concentrations of angiotensinogen normalized by urinary concentrations of creatinine (UAGTCR) before treatment. When all patients were redivided into two groups, those with higher UAGTCR levels before treatment (Group H,
Recently, there has been increased emphasis on the role of the local/tissue RAS in specific tissues in organ injury. The importance of the tissue RAS was demonstrated in the brain, heart, adrenal glands, vasculature, and kidneys [
The intrarenal RAS is involved in the development and progression of renal damage [
The underlying mechanisms of the development and progression of diabetic nephropathy are still under investigation. Diabetic nephropathy is associated with the increased reactive oxygen species (ROS) and involves various mechanisms, including hyperglycemia, activation of the intrarenal RAS, and high blood pressure. Hyperglycemia induces acyl glycerol and activates protein kinase C. Glomerular injury is caused by the generation of ROS or the peroxidation of lipids [
In terms of activation of the intrarenal RAS, it has been demonstrated that ROS and intrarenal AGT levels increase in diabetic rats [
This study focused on the effects of a DPP-4 inhibitor on urinary AGT in patients with diabetes. Even though ARB may affect AGT synthesis [
It is assumed that the increase in intrarenal AGT and ROS formation underlying T2D [
In the RENAAL study [
We chose UAGTCR as biomarker not UAlbCR. Urinary AGT shows a positive correlation with urinary Alb in this study as well as in other studies. However, an increase in urinary AGT appears earlier than an increase in urinary Alb in diabetes. Others [
In this study, not only the amount of change but also the rate of change in urinary Alb displayed a larger drop in the higher urinary AGT group. An amount of change will tend to be larger when one starts with higher levels. However, a rate of change will tend to be larger when one starts with lower levels. Because both the amount of change and the rate of change in urinary Alb significantly decreased in the higher urinary AGT group, these results in this study were very important.
In this study, UAlbCR tended to fall after treatment with DPP-4 inhibitor and possibly exerted a renoprotective effect. However, the difference was not statistically significant, possibly due to the small sample size. In this study, there is also a restriction of the amount of samples. Therefore, the data addressing the underlying mechanism cannot be measured in this study. Further studies will be required to address this issue. We are now planning a multicenter randomized prospective study on urinary AGT as a prognostic marker of renoprotective effects of DPP-4 inhibitors in patients with T2D.
In conclusion, treatments of alogliptin in patients with T2D may protect kidney function in some patients. Urinary AGT could be a prognostic marker of renoprotective effects of alogliptin in patients with T2D.
The authors have declared that no competing interests exist.
The authors acknowledge Ms. Aya Masuda and Ms. Miho Seki (Kagawa University School of Medicine) for their technical assistance.