Recent Progress in the Treatment of Diabetic Nephropathy: Importance of Strict Glycemic Control on the Regression of Diabetic Nephropathy
Ryuzo Kawamori Keiji Kamado Takenobu Kamada
INTRODUCTION it is not yet clear whether strict glycemic control can prevent the onset or progression of diabetic microvascular complications, and where the glycemic threshold is to arrest the progression of microangiopathies, we have conducted studies, retrospectively and prospectively, to clarify the relationship between the degree of glycemic control and progression of diabetic microangiopathies. Since
First Department of Medicine, Osaka University Medical School, Osaka, Japan
METHODS Studies on Diabetic Nephropathy: Estimation of Renal Glomerular Changes From Clinico-laboratory Data-With the Aid of Markov Process:
Reprint requests to be sent to: Dr. flyuzo Kawamori, First Department of Medicine, Osaka University Medical School, l-l-50, Fukushima, Fukushima-ku, Osaka, Japan 553.
0 1991 Elsevler Science Publishing 0891-6632/91/$3.50
88
Co., Inc
For the patho-histological diagnosis of nephropathy, it is necessary to perform biopsies frequently. But it is difficult to perform them especially in diabetic patients. To analyze the incidence and precipitating factors of diabetic nephropathy and the mutual relationships among the precipitating factors in terms of clinico-laboratory variables, canonical correlation analysis was applied to the clinico-laboratory and patho-histological variables in 40 cases whose patho-histological changes were already known from biopsy or autopsy. Testing of the accuracy of estimation was carried out in the 40 cases and resulted in a 90% coincidence between the estimated patho-histological changes of renal glomeruli based on the clinico-laboratory data and the patho-histological changes. In an attempt to reevaluate the present treatment of diabetic nephropathy, the influence of correcting the five clinically controllable variables of 11 variables adopted for patho-histological changes of the renal glomeruli, was studied using the Markov process with 220 diabetic outpatients. The Markov process is the method for long-term prognosis suitable for chronic diseases. In this model, first the stochastic matrix is determined from short-term observations, then, by multiplying and weighing the matrix, long-term prognosis can be conjectured. By the Markov process, the prognosis of an estimated stage of renal glomerular lesions was attempted. It was demonstrated that control of blood glucose, blood pressure, and the obesity index showed some relation to the development and/or progress of the glomerular changes. As shown in Figure 1, it was revealed that the poorer the glycemic regulation, the faster and the higher the percentage of appearance of stages 3 and 4 where there were nodular lesions, and stage 5 meaning death by nephropathy.’ In summary, with the aid of the Markov process, it became possible to prognose the onset or progress in diabetic nephropathy. It is suggested that correction of factors, especially those that can be readily controlled by daily clinical practice, could prevent and arrest the development of diabetic nephropathy. A forecast was done approximately ten years ago. Since then, we have tried using as strict glycemic controls as possible. Results of eight years were superimposed on Figure 1. It was clearly demonstrated that real changes in scores matched exactly with the forecasted prognosis.
89
GLYCEMIC CONTROL AS TREATMENT OF NEPHROPATHY
No=
No= 89 Ns = 222 N= 29
80
80 R
A: (-139mg
dl )
6:
( lb@-199mp
dl)
F/G. 1 Sequential changes of percent distribution from state 1 to the other states determined by Markov process (thin lines) and those obtained by follow-up data (thick lines} on fasting blood glucose (FBG) levels. A: FBG control was good, B: FBG control was poor. No is case number and Ns is summation count for stochastic matrix. N is case number of follow-up study.
Glycemic Threshold for the Regression or Prevention of Diabetic Microvascular Complications: Randomized Prospective Study for up to Four Years: There are a few reports concerning the normalization of the metabolic and endocrinologic indices by strict glycemic control using multiple insulin injections therapy or continuous subcutaneous insulin infusion (CSII) therapy. However, it is not yet clear whether intensive glycemic control can prevent the onset or progression of diabetic microvascular complications or where the glycemic threshold is to arrest the progression of microangiopathies. In the study, a randomized prospective study was undertaken to determine the glycemic threshold in 50 insulin-treated patients. The study was carried out in patients showing early diabetic microvascular complications treated once or twice daily with intermediate-acting insulin injection for at least one year and for the average period of 6.4 years. In all 50 cases, urinary C-peptide excretion per day was lower than 20 pg. These were divided randomly into two groups. Twenty-two patients, kept on intermediate-acting insulin once-a-day injection therapy, were used as a control group. The other 28 patients were given multiple insulin injection therapy. In the latter group, all patients were hospitalized for up to three months and changed to multiple insulin injections therapy combining short-, intermediate-, and longacting insulins. During the experimental period, in both groups, insulin doses were frequently adjusted to accomplish glycemic control as strictly as possible. At the time of randomization, there was no statistical difference in age, known duration of diabetes, duration of insulin therapy, or insulin dose between the two groups. There was no statistical difference in M value or mean blood glucose concentration (MBG). However, the mean amplitude of glycemic excursions (MAGE) and gly-
cosylated hemoglobin (HbA,) were lower in the control group. In the control group, there was no significant improvement in any indices for glycemic regulation for 48 months (Figure 2). In the multiple insulin injections group, the M value improved significantly from 51 to 25 at three months and remained at the low level thereafter, even on an outpatient basis. The MBG also showed significant improvement, from 243 2 13 to 166 ? 15 mgfl00 mL at three months, and remained at the improved value for 48 months. The MAGE also improved significantly from 182 ? 19 to 105 IT 8 mg/lOO mL at three months, and remained so for 48 months. HbA, markedly improved from 12.5 ? 0.4 to 8.2 ? 0.3 percent at three months, and thereafter it was maintained at levels around 8.5%. The insulin dose in the control group did not significantly change throughout the period; from 20.0 +- 1 .O to 22.3 + 1.3 U/day at 48 months. In the multiple insulin injections group, it increased significantly; from 23.2 ? 1.8 to 39.8 t 2.6 U/day at 48 months. In the control group, there was no significant change in urinary excretion of total protein. In the multiple insulin injections group, the insulin dose decreased markedly from the control value of 587 * 112 to 130 it 39, 128 ? 46, and 65 ? 25 mgl day at 3, 12, and 48 months (Figure 2). Because systolic and diastolic blood pressures did not change during the period in either group, these improvements seemed to be an effect of glycemic control. On the other hand, the urinary excretion of f&.-microglobulin did not significantly change in either group. The motor nerve conduction velocity between the elbow and the wrist showed no significant change at any point and kept a low value in the control group. In the multiple insulin injections group, it showed significant improvement at every point; from 47.1 -c 1.2 to 52,O 2 0.9, 52.2 5 0.4, 53.7 2 0.9, 53.6 ? 1.0, and 53.9 t 1.1
KAWAMORI ET AL
2oor
^
MIT
(22)
-
CIT
(21)
Zi
4L,
0
’ 3
’ 6
I 12
I 24
I 36
I 48 (M)
800 r 600 -
x
400 200 -
h
E *
I *
I\*
3
6
12
24
OLI 0 3I
6
12
24
*
I
O- 0
5:
* P
I
*p
Ryuzo Kawamori Keiji Kamado Takenobu Kamada
INTRODUCTION it is not yet clear whether strict glycemic control can prevent the onset or progression of diabetic microvascular complications, and where the glycemic threshold is to arrest the progression of microangiopathies, we have conducted studies, retrospectively and prospectively, to clarify the relationship between the degree of glycemic control and progression of diabetic microangiopathies. Since
First Department of Medicine, Osaka University Medical School, Osaka, Japan
METHODS Studies on Diabetic Nephropathy: Estimation of Renal Glomerular Changes From Clinico-laboratory Data-With the Aid of Markov Process:
Reprint requests to be sent to: Dr. flyuzo Kawamori, First Department of Medicine, Osaka University Medical School, l-l-50, Fukushima, Fukushima-ku, Osaka, Japan 553.
0 1991 Elsevler Science Publishing 0891-6632/91/$3.50
88
Co., Inc
For the patho-histological diagnosis of nephropathy, it is necessary to perform biopsies frequently. But it is difficult to perform them especially in diabetic patients. To analyze the incidence and precipitating factors of diabetic nephropathy and the mutual relationships among the precipitating factors in terms of clinico-laboratory variables, canonical correlation analysis was applied to the clinico-laboratory and patho-histological variables in 40 cases whose patho-histological changes were already known from biopsy or autopsy. Testing of the accuracy of estimation was carried out in the 40 cases and resulted in a 90% coincidence between the estimated patho-histological changes of renal glomeruli based on the clinico-laboratory data and the patho-histological changes. In an attempt to reevaluate the present treatment of diabetic nephropathy, the influence of correcting the five clinically controllable variables of 11 variables adopted for patho-histological changes of the renal glomeruli, was studied using the Markov process with 220 diabetic outpatients. The Markov process is the method for long-term prognosis suitable for chronic diseases. In this model, first the stochastic matrix is determined from short-term observations, then, by multiplying and weighing the matrix, long-term prognosis can be conjectured. By the Markov process, the prognosis of an estimated stage of renal glomerular lesions was attempted. It was demonstrated that control of blood glucose, blood pressure, and the obesity index showed some relation to the development and/or progress of the glomerular changes. As shown in Figure 1, it was revealed that the poorer the glycemic regulation, the faster and the higher the percentage of appearance of stages 3 and 4 where there were nodular lesions, and stage 5 meaning death by nephropathy.’ In summary, with the aid of the Markov process, it became possible to prognose the onset or progress in diabetic nephropathy. It is suggested that correction of factors, especially those that can be readily controlled by daily clinical practice, could prevent and arrest the development of diabetic nephropathy. A forecast was done approximately ten years ago. Since then, we have tried using as strict glycemic controls as possible. Results of eight years were superimposed on Figure 1. It was clearly demonstrated that real changes in scores matched exactly with the forecasted prognosis.
89
GLYCEMIC CONTROL AS TREATMENT OF NEPHROPATHY
No=
No= 89 Ns = 222 N= 29
80
80 R
A: (-139mg
dl )
6:
( lb@-199mp
dl)
F/G. 1 Sequential changes of percent distribution from state 1 to the other states determined by Markov process (thin lines) and those obtained by follow-up data (thick lines} on fasting blood glucose (FBG) levels. A: FBG control was good, B: FBG control was poor. No is case number and Ns is summation count for stochastic matrix. N is case number of follow-up study.
Glycemic Threshold for the Regression or Prevention of Diabetic Microvascular Complications: Randomized Prospective Study for up to Four Years: There are a few reports concerning the normalization of the metabolic and endocrinologic indices by strict glycemic control using multiple insulin injections therapy or continuous subcutaneous insulin infusion (CSII) therapy. However, it is not yet clear whether intensive glycemic control can prevent the onset or progression of diabetic microvascular complications or where the glycemic threshold is to arrest the progression of microangiopathies. In the study, a randomized prospective study was undertaken to determine the glycemic threshold in 50 insulin-treated patients. The study was carried out in patients showing early diabetic microvascular complications treated once or twice daily with intermediate-acting insulin injection for at least one year and for the average period of 6.4 years. In all 50 cases, urinary C-peptide excretion per day was lower than 20 pg. These were divided randomly into two groups. Twenty-two patients, kept on intermediate-acting insulin once-a-day injection therapy, were used as a control group. The other 28 patients were given multiple insulin injection therapy. In the latter group, all patients were hospitalized for up to three months and changed to multiple insulin injections therapy combining short-, intermediate-, and longacting insulins. During the experimental period, in both groups, insulin doses were frequently adjusted to accomplish glycemic control as strictly as possible. At the time of randomization, there was no statistical difference in age, known duration of diabetes, duration of insulin therapy, or insulin dose between the two groups. There was no statistical difference in M value or mean blood glucose concentration (MBG). However, the mean amplitude of glycemic excursions (MAGE) and gly-
cosylated hemoglobin (HbA,) were lower in the control group. In the control group, there was no significant improvement in any indices for glycemic regulation for 48 months (Figure 2). In the multiple insulin injections group, the M value improved significantly from 51 to 25 at three months and remained at the low level thereafter, even on an outpatient basis. The MBG also showed significant improvement, from 243 2 13 to 166 ? 15 mgfl00 mL at three months, and remained at the improved value for 48 months. The MAGE also improved significantly from 182 ? 19 to 105 IT 8 mg/lOO mL at three months, and remained so for 48 months. HbA, markedly improved from 12.5 ? 0.4 to 8.2 ? 0.3 percent at three months, and thereafter it was maintained at levels around 8.5%. The insulin dose in the control group did not significantly change throughout the period; from 20.0 +- 1 .O to 22.3 + 1.3 U/day at 48 months. In the multiple insulin injections group, it increased significantly; from 23.2 ? 1.8 to 39.8 t 2.6 U/day at 48 months. In the control group, there was no significant change in urinary excretion of total protein. In the multiple insulin injections group, the insulin dose decreased markedly from the control value of 587 * 112 to 130 it 39, 128 ? 46, and 65 ? 25 mgl day at 3, 12, and 48 months (Figure 2). Because systolic and diastolic blood pressures did not change during the period in either group, these improvements seemed to be an effect of glycemic control. On the other hand, the urinary excretion of f&.-microglobulin did not significantly change in either group. The motor nerve conduction velocity between the elbow and the wrist showed no significant change at any point and kept a low value in the control group. In the multiple insulin injections group, it showed significant improvement at every point; from 47.1 -c 1.2 to 52,O 2 0.9, 52.2 5 0.4, 53.7 2 0.9, 53.6 ? 1.0, and 53.9 t 1.1
KAWAMORI ET AL
2oor
^
MIT
(22)
-
CIT
(21)
Zi
4L,
0
’ 3
’ 6
I 12
I 24
I 36
I 48 (M)
800 r 600 -
x
400 200 -
h
E *
I *
I\*
3
6
12
24
OLI 0 3I
6
12
24
*
I
O- 0
5:
* P
I
*p
