Impact of dialysis therapy on insulin resistance in end-stage renal disease: comparison of haemodialysis and continuous ambulatory peritoneal dialysis

Shuzo Kobayashi1, Syunichi Maejima1, Toshio Ikeda2 and Mitsumasa Nagase3

1 Department of Nephrology, Shonan Kamakura General Hospital, Yamazaki Kamakura, 2 Division of Nephrology, Department of Medicine, NTT Kanto Teishin Hospital, Gotanda, Shinagawa and 3 First Department of Medicine, Teikyo University School of Medicine, Itabashiku, Tokyo, Japan

Correspondence and offprint requests to: Shuzo Kobayashi, MD, PhD., Department of Medicine, Shonan Kamakura General Hospital, 1202–1 Yamazaki Kamakura 247-8533, Japan.



   Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Insulin resistance contributes to the pathogenesis of atherosclerotic cardiovascular disease and, thus, has an important impact on the mortality of uraemic patients. Haemodialysis (HD) is known to improve insulin resistance observed in uraemia. However, it is not known whether continuous ambulatory peritoneal dialysis (CAPD) alleviates insulin resistance in adult uraemic patients. The objective of this study was to compare the effect of two different dialysis modalities, HD and CAPD, on insulin resistance in adult uraemic patients and to identify the possible predictive factors for changes in insulin resistance.

Methods. Insulin resistance was examined in 19 non-diabetic patients with end-stage renal disease (ESRD) before and after dialysis therapy (HD, n=10; CAPD, n=9), as well as in 10 healthy controls using the hyperinsulinaemic euglycaemic glucose clamp technique. The glucose disposal rate (GDR mg/kg/min) was used as an index of insulin sensitivity during the clamp technique. We also determined which of various biochemical parameters might be associated with change in insulin resistance by carrying out multiple logistic regression analysis.

Results. GDR was significantly lower (6.44±1.76) in ESRD subjects than in normal subjects (9.90±2.01). HD and CAPD therapies significantly normalized GDR from 6.53±1.84 to 9.74±2.88 and from 6.35±1.65 to 8.18±1.76 respectively. Multiple logistic regression analysis showed that changes in BUN, haematocrit and plasma bicarbonate were significant predictive factors for the change in insulin resistance.

Conclusion. CAPD therapy, in spite of its possible adverse effects in patients with atherosclerotic disease, has been shown to improve insulin resistance in adult uraemic patients, similarly to HD therapy.

Keywords: atherosclerosis; continuous ambulatory peritoneal dialysis; glucose metabolism; haemodialysis; insulin resistance; uraemia



   Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Increasing numbers of patients are being treated with dialysis therapy and atherosclerotic cardiovascular disorders have been found to have a great impact on mortality in these patients [1]. It has been shown that insulin resistance may contribute to the pathogenesis of atherosclerotic cardiovascular disease [2], and if the prognosis of chronic dialysis patients is to be improved, we should devote more attention to insulin resistance in uraemic patients. Furthermore, hyperinsulinaemia per se has also been implicated as a direct causative factor in the pathogenesis of atherosclerosis [3]. It is widely known that hypertension and hyperlipidaemia play important roles in the progression of renal disease [4] and that insulin resistance may be involved in the pathogenesis of hypertension [5]. Furthermore, nutritional, metabolic, and cardiovascular complications of renal disease may be consequences of abnormal insulin action [6]. Therefore, long-standing renal insufficiency may cause atherosclerosis prior to the initiation of dialysis therapy. It has been known for the last 80 years that patients with end-stage renal disease (ESRD) exhibit glucose intolerance [7], which is due to insulin resistance, as evident from their reduced peripheral sensitivity to the hypoglycaemic action of insulin [810].

DeFronzo et al. [8,9,11,12] investigated glucose intolerance in uraemic patients using a glucose clamp technique and showed that thrice weekly haemodialysis (HD) for 10 weeks improved insulin resistance in ESRD [11]. Mak et al. [13,14] and others [15,16] demonstrated that the correction of anaemia or treatment with 1,25 dihydroxycholecalciferol reversed insulin resistance, although their results were not confirmed by others [17,18]. Despite numerous clinical studies regarding insulin sensitivity of patients undergoing HD therapy, there is little data available concerning the effect of continuous ambulatory peritonal dialysis (CAPD) therapy, particularly in adult uraemic patients. This is a critical issue concerning the choice of dialysis therapy for patients at risk for atherosclerotic disorders.

Using the euglycaemic hyperinsulinaemic glucose clamp technique, we compared the effects of HD and CAPD on insulin resistance in adult uraemic patients. In addition, we determined which of various biochemical parameters are most closely associated with a change in insulin resistance by carrying out multiple logistic regression analysis.



   Methods
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 Methods
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Subjects
Nineteen patients (aged 30–79 years, mean 54±13) with ESRD were studied. The aetiology of ESRD included idiopathic chronic glomerulonephritis, but not diabetic nephropathy. The relevant clinical and biochemical data are presented in Table 1Go. None of the patients suffered from cardiac failure. All patients were admitted to our hospital for HD (n=10; male 5, female 5 aged 30–79 years, mean 55±15) or CAPD (n=9; male 6, female 3, aged 34–68, mean 53±11) therapy. The patients were assigned to their respective modalities of dialysis based on individual preferences. There was no statistically significant difference between the patient groups with respect to age and sex. Dialysis was initiated based on a creatinine clearance below 10 ml/min or the presence of uraemic symptoms such as nausea or cramp in spite of conservative therapy. Other severe symptoms were not present and the patients had been or were currently being treated with antihypertensives (except ß-blockers), 1,25(OH)2 D3, calcium carbonate, and sodium bicarbonate. None of the patients were currently on or had been on corticosteroids during the 2 years prior to the study. Their daily diet was prescribed initially as follows: 6 g sodium; 0.6 g/kg body weight (BW) protein at a total of 32 kcal/kg BW. Once dialysis was initiated, the diet included 9 g sodium and 1.2 g/kg BW protein at a calorie intake of 35 kcal/kg BW. Controls consisted of 10 healthy subjects (aged 28–63) who were not on any type of medication. Residual renal function had been assessed in the two groups of dialysis patients by 24-h creatinine clearance and was not different (HD 3.8±0.5 ml/min, CAPD 4.1±0.6 ml/min). The daily CAPD regimen comprised two exchanges of 2 l of 1.36% glucose solution and two exchanges of 2 l of 3.86% glucose solution. HD was performed 12 h/weeks with a biocompatible membrane. None of the controls had a history of any significant illness or any family history of diabetes mellitus. The mean body mass index in controls was 22.5±2.3. The purpose and potential risks of the study were explained to all subjects, and voluntary consent was obtained prior to their participation. The study protocol was approved by the hospitals Human Investigations Committee.


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Table 1. Anthropometric measurements, biochemical parameters and echocardiographic study
 
Hyperinsulinaemic euglycaemic glucose clamp technique
The initial clamp procedure was performed 7 days after admission, but prior to beginning HD or CAPD therapy and was started at about 9 A.M. after an overnight fast of 14 h. All medication was stopped on the morning of the procedure. Subjects rested in the supine position after voiding urine and determination of body weight and were not allowed anything to eat or drink apart from water during the studies. Insulin sensitivity was examined by the euglycaemic hyperinsulinaemic clamp technique, according to DeFronzo et al. [19], using an artificial endocrine pancreas (model STG-22, Nikkiso, Japan). Two intravenous lines were inserted in contralateral arms. One intravenous line was inserted in an antecubital vein for infusion of insulin and glucose. For blood sampling, an indwelling catheter was placed in a vein on the dorsum of the opposite hand and kept patent by a slow intravenous infusion of normal saline. The puncture site on the arm was wrapped with a heating mat instead of using a heating chamber practically to arterialize the blood [20].

After fasting serum samples for glucose and insulin were obtained, a continuous infusion of insulin (Humarin R, Shionogi, Japan) was administered initially at 3.56 mU/kg/min for 1 min and gradually decreased every 1 min to a constant rate of 1.12 mU/kg/min to achieve a steady-state hyperinsulinaemia. At 5 min intervals, serum glucose concentration was measured in blood samples that were continuously withdrawn at 2 ml/h through the catheter. The glucose clamp level was 100 mg/dl during the 2-h clamp study and was maintained by infusion of 20% glucose. These procedures were performed using automation according to insulin and glucose algorithms controlled by a computer system installed in the artificial endocrine pancreas based on the instructions of the manufacture. Under steady-state conditions of euglycaemia and hyperinsulinaemia, the rate of glucose infusion during euglycaemic clamp studies provides an index of insulin-stimulated glucose metabolism and is used as an index of insulin sensitivity (GDR, mg/kg/min). For the last 30 min, GDR values (six measurements from 90 to 120 min) were averaged to obtain the insulin sensitivity of the subject. The glucose clamp technique was again performed at the time of discharge (4.9±0.8 weeks and 5.4±1.3 weeks after initiation of HD and CAPD therapy respectively; P=0.32), as mentioned above. The patients undergoing HD therapy were subjected to the clamp procedure between two HD sessions scheduled three times a week and patients on CAPD therapy were subjected to the study without dialysate to avoid glucose load. HD patients were examined after an overnight fast and CAPD patients were examined 3 h after the dialysate was drained from the abdomen.

Biochemical measurements
The serum glucose concentration was measured using the glucose oxidase method. The insulin level was measured by means of a competitive enzyme immunoassay with a double antibody procedure using EIA Test Insulin II kit (BMY, Boehringer). Cholesterol and triglyceride levels were measured by means of an enzymatic technique using an automatic analyser. High-density lipoprotein cholesterol (HDL) was measured after precipitation of low-density lipoprotein, very-low-density lipoprotein, and chylomicrons with dextran sulfate, magnesium chloride, and polyethylene glycol, respectively. The atherogenic index (AI) was defined as (total cholesterol–HDL)/HDL. Other variables were measured by standard methods on a multichannel autoanalyser. As parameters of a change in body fluid, the cardiothoracic rate (CTR) was examined by thoracic radiography and the left ventricular mass index (LVMI) was estimated by echocardiography. The LVMI [21] was determined by means of Penn conversion using the following formula: LVM (left ventricular mass)=1.04[(IVS+LVID+PWT)3–LVID3]–13.6, where IVS is the width of the interventricular septum at the end of the mitral leaflet in diastole, PWT is the posterior wall thickness of the left ventricule in diastole and LVID is the diameter of the ventricle at the end of diastole. The LVMI was expressed as the LVM divided by the height of the subject (g/m).

Statistical analyses
All values were expressed as means±SD. Statistical differences were analysed by the paired Student's t-test or ANOVA followed by Student-Newman–Keuls test. Multiple logistic regression analysis was performed using a stepwise forward–backward procedure to determine the respective relationships between various factors and altered insulin resistance after HD/CAPD therapy of uraemic patients. The F value for a candidate's inclusion in or exclusion from the discriminant function test was set at 4.0. A P value of <0.05 was considered significant.



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 Abstract
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 Methods
 Results
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All subjects were well and without any severe symptoms prior to HD or CAPD therapy. Both therapies were without complications. The anthropometric measurements and serum albumin concentrations were not different between the two groups (HD versus CAPD) as shown in Table 1Go, suggesting no difference in nutritional status.

The steady-state plasma glucose concentration during the last 30 min of the glucose clamp study was 98.9±1.8 mg/dl for patients before dialysis therapy and 98.3±1.6 for the control, a difference which was not statistically significant. The coefficient of variation of the plasma glucose level during the study was <3%. The mean values of plasma insulin determined at 120 min during the glucose clamp study were 64.8±10.8 µU/ml in normal subjects, 75.5±9.8µU/ml and 66.8±9.1µU/ml in pre- and post-HD patients, and 77.9±8.6 µU/ml and 70.6±10.2 µU/ml in pre- and post-CAPD patients respectively. There was no statistically significant difference between these groups. As shown in Figure 1Go, insulin sensitivity (GDR mg/kg/min) as measured by the glucose infusion rate during the last 30 min of the glucose clamp, was 9.93±1.33 in healthy control subjects. In contrast, the GDR of uraemic individuals was 6.44±1.76 significantly lower than that of control subjects, which suggested insulin resistance in ESRD patients (Figure 1Go). After HD therapy (n=10), insulin sensitivity increased by 49.0% (P<0.01) from 6.53±1.84 to 9.74±2.88 so that the value was no longer different from control values (Figure 1Go). The GDR of patients on CAPD (n=9) was also significantly improved after dialysis (from 6.35±1.65 to 8.18±1.76, P<0.05) (Figure 1Go). Thus, both HD and CAPD therapy improved insulin resistance found in the patients with ESRD. The changes in GDR, plasma levels of metabolites and hormones, CTR and LVMI from before the start of therapy and at the end of follow-up are shown in Table 1Go. Body weight did not change significantly with therapy, nor was there a change in CTR and LVMI, suggesting that there was no change in levels of body fluid. In contrast, blood urea nitrogen, Ht, HCO3 and phosphate were all normalized significantly by both HD and CAPD therapy. Serum creatinine decreased significantly in patients with HD, whereas no significant reduction was found in patients with CAPD. There was no change in the serum potassium or calcium concentration. Plasma insulin and glucose levels were unchanged by both dialysis therapies. Serum total protein, albumin, and lipid profile were not significantly changed. However, in the patients with CAPD, there was a trend for total cholesterol and triglyceride to be increased, but it did not reach statistically significant levels.



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Fig. 1. Glucose disposal rate (GDR) is shown in healthy controls and ESRD patients before and after HD or CAPD therapy. The GDR is significantly lower in ESRD patients, compared to healthy controls and both HD (4.9±0.8 weeks) and CAPD (5.4±1.3 weeks) patients. These therapies normalized this value, suggesting that insulin resistance found in ESRD was improved. *P<0.05 vs controls.

 
Table 2Go shows the results of the stepwise multiple linear regression analysis of the potential factors contributing to an increase in insulin sensitivity after dialysis therapy with the change in the mean GDR after dialysis therapy taken as a dependent variable. The variables selected for the stepwise multiple regression function were age, Ht, Cr, BUN, HCO3, PO4, TC, TG, HDL, LDL and atherogenic index, all of which, as a single factor, showed significant or close-to-significant changes after dialysis therapy. Multiple linear regression analysis, however, showed that changes in BUN, Ht and HCO3 were found to be significant predictive factors for a change in insulin sensitivity after dialysis therapy. The unstandarized coefficient (R) calculated from the regression function with these combined three factors was 0.800 and R2 was 0.639 (P<0.01). Among three factors, Ht alone however, failed to show a significant association with insulin sensitivity (r=0.312, P=0.211) (data not shown).


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Table 2 The results in the stepwise multiple linear regression analysis for change of insulin sensitivity (GDR mg/kg/min) after dialysis therapy as dependent variables
 


   Discussion
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 Abstract
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 Methods
 Results
 Discussion
 References
 
Impaired glucose tolerance in uraemic patients has been recognized for many years [7]. Previous studies using the glucose clamp technique by DeFronzo et al. have demonstrated that peripheral tissue insensitivity to insulin is the primary cause of glucose intolerance in patients with ESRD [9,11]. Furthermore, insulin resistance in chronic renal failure is thought to be caused primarily by a post binding defect in insulin action, [12,22] although impaired insulin binding to erythrocytes in uraemia has been reported [23].

The present study clearly confirmed that before the initiation of dialysis therapy, insulin-mediated glucose disposal rate (insulin sensitivity as measured by the clamp technique) was markedly reduced in ESRD patients compared with control subjects. The mean duration of 4.9 weeks of HD therapy completely normalized insulin sensitivity. This result is compatible with the finding by DeFronzo and Mak et al. who demonstrated that 10 weeks of HD therapy resulted in a marked improvement in glucose metabolism, but did not completely normalize glucose utilization [11].

There is little data available regarding the effect of CAPD therapy on insulin sensitivity. This is important because of the possibility that glucose loading may worsen insulin sensitivity. In the present study we showed that CAPD therapy for 5.4 weeks normalized insulin resistance similar to HD therapy. Recently, Mak reported similar favourable results regarding the effect of peritoneal dialysis therapy on insulin resistance in uraemia. He compared the effect of continuous cycling peritoneal dialysis (CCPD) to that of HD on insulin resistance in younger adolescent uraemic patients, and showed that the percentage increase, as well as the final insulin sensitivity, was significantly higher in the CCPD group than the HD group [24]. In the present study, this trend is reversed. Although we do not have an explanation, the difference may be due to the different modalities of peritoneal dialysis, namely CAPD and CCPD. There is another report showing that CAPD tended to improve insulin resistance [25]. In contrast, there is a report, albeit with a less sophisticated technique, that CAPD patients display an insulin-resistance [26].

Numerous factors have been implicated in the pathogenesis of carbohydrate intolerance of uraemia [8,10,27]. It seems unlikely that excess body fluid is involved in insulin resistance in peripheral tissues since body weight, CTR and LVMI measured by echocardiography were unchanged after dialysis therapy. It has been recently reported that the correction of anaemia by erythropoietin reversed insulin resistance in uraemic patients [13,15,16]. However, the subjects studied by those investigators were already being maintained on regular HD so that values of other biochemical parameters such as BUN were not changed after correction of the anaemia. Therefore, the role of factors other than anaemia could not be ascertained even if insulin resistance is caused, at least in part, by the anaemia. All patients were receiving epoetin so that Ht increased up to 30%. We carried out a statistical investigation of various biochemical parameters using multiple logistic regression analysis although the value of this statistical analysis may be limited because of a large number of factors in small groups of patients. The results indicated that BUN, HCO3 and Ht were independent predictive factors for a change in insulin resistance. However, when only the Ht value was altered, there was no correlation between Ht and insulin resistance (data not shown). In contrast, a close correlation was found between changes in BUN or HCO3, and insulin resistance. This suggests that a change in Ht, which contributes to insulin resistance, must accompany a change in BUN or HCO3. On the other hand, it has been reported that urea is probably not the crucial toxin [28] and the duration of azotaemia may be important [29]. We believe that, in addition to BUN, unknown uraemic toxin(s) can contribute to insulin resistance. These may be guanidino substances, hippurate or pseudouridine or other toxins including advanced glycation end products [3032]. Indeed, there is a report that specific uraemic toxins such as creatinine, creatine and glycocyamine may play an important role in the mechanisms of altered insulin binding to erythrocyte receptors during HD [23]. Taking another approach, Mak et al. [33] studied the effect of protein restriction on the insulin sensitivity of uraemic patients. Six months after the initiation of protein restriction with amino acid and keto acid supplementation, significant reductions in blood urea concentrations were observed and these were accompanied by normalization of insulin resistance.

Metabolic acidosis has also been known to contribute to insulin resistance [34]. In our study, blood HCO3 levels correlated well with GDR values. Malnutrition [35], an excess of PTH [36] or a deficiency in 1,25(OH)2D3 [14] has been implicated in the pathogenesis of insulin abnormalities in uraemia. However, since in the present study, serum albumin and PTH levels were unchanged after dialysis, it is unlikely that either nutrition or PTH level is an important factor. We unfortunately did not measure 1,25(OH)2D3 which may be an important contributing factor [14]. Among other important factors, dyslipidaemia might have a contributory role in insulin resistance [3739]. Serum LDL level was significantly lowered in patients who received HD therapy, while there was no change in LDL level in patients with CAPD. Moreover, no change in the level of any lipid could be significantly correlated with a change in GDR, nor did multiple regression analysis result in selection of these variables. Therefore, a role for dyslipidaemia in insulin resistance is less likely. It is also unlikely that the change in physical activity [40] contribute to the altered insulin sensitivity since patients were still in hospital.

In conclusion, we showed that the patients with ESRD before the initiation of dialysis therapy had insulin resistance, which was completely reversed by either HD or CAPD therapy. Stepwise forward multiple regression analysis revealed that changes in BUN, Ht and HCO3 were significant predictive factors for an improvement in insulin resistance. Since there is evidence suggesting that insulin resistance may be involved in the pathogenesis of hypertension and atherosclerosis often seen in uraemia and since cardiovascular complications are the most significant causes of mortality and morbidity in patients with ESRD, delayed initiation of dialysis therapy or insufficient dialysis may worsen atherosclerosis through long-standing insulin resistance. Of particular importance in the present study is the finding that CAPD therapy also improved insulin resistance found in ESRD patients.



   References
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 Abstract
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 Methods
 Results
 Discussion
 References
 

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Received for publication: 22. 3.99
Accepted in revised form: 13. 9.99





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