Background
Mortality and morbidity due to cardiovascular diseases are frequent in patients with diabetes mellitus and high prevalence of diabetes and cardiovascular disease, also, are observed in patients with end-stage renal disease treated by renal replacement therapy, either renal transplantation (RT) and dialysis 1. Although uremia is typically associated with impaired glucose metabolism via multiple mechanisms 234, hemodialysis improves, although not completely, the uremic induced glucose impairment 567. Impaired glucose metabolism is also a common and an important problem after RT. By improvement of immunosuppression after RT, the incidence of post transplant diabetes (PTDM) has been decreased from 41% to 2.5% 89. Although we routinely screen and treat only full-blown diabetes at the post transplant periods, an overlooked aspect is the impaired glucose tolerance, which may be a risk factor to induce atherosclerosis. Impaired glucose tolerance de novo, may be a risk factor of post-transplantation mortality and morbidity 10. Although increased levels of glycosylated hemoglobin (HbA1C) and lipid concentrations have been shown in hemodialysis patients 11 and renal transplant recipients 12 with diabetes, their impairment is not clear in the both groups with impaired glucose tolerance without apparent diabetes mellitus. In this study we investigated glucose tolerance and lipid profiles in non-diabetic hemodialysis and renal transplant patients.
Methods
We selected fifty five RT recipients with more than one year of good renal allograft function (serum Cr < 1.5 mg/dl), under conventional triple therapy composed of cyclosporine A (CsA), azathiopurine and prednisolone. Their allograft sources were living donors. Fifty five stable HD patients and another fifty five healthy controls (C), were also enrolled in this study. The mean age (39 ± 7 years), sex (F/M ratio was 33/22), body mass index (BMI) 24.7 ± 1.28 kg/m2) were similar in the three groups (see table 1). Patients with diabetes mellitus and propranolol consumers were excluded.
<p>Table 1</p>
Demographical, biochemical, hematological and therapeutical factors in hemodialysis patients and renal transplant recipients.
HD
RT
Control
Age (years)
48 ± 3
46 ± 4
47 ± 4
Male/female ratio
33/22
33/22
33/22
BMI (Kg/m2)
24.6 ± 1.4
23.8 ± 1.2
23.6 ± 1.3
Cholesterol (mg/dl)
199.2 ± 36.6
269.7 ± 54
190.5 ± 34
Triglycerides (mg/dl)
217.2 ± 55
214.3 ± 13
100.2 ± 18
HgA1C (g/dl)
6.42 ± 0.7
6.2 ± 0.9
5.7 ± 0.7
Hb level
10.9 ± 0.8
12.4 ± 1.1
13.3 ± 0.8
Therapy with vitamin D3 0.5 μg/day (number)
25
--
--
Impaired glucose tolerance (number)
12*
4**
--
*Significant correlation with BMI, serum triglycerides and HgA1C
** Significant correlation with serum cholesterol, CysA concentration and HgA1C
The levels of serum triglyceride, cholesterol (measured by enzymatic spectrophotometry)13, CsA (measured by ELISA in whole blood, only in renal transplant recipients) and glycosylated haemoglobin concentration (Hb A1c) (measured by column chromatography) were measured after 10 hours fasting (in the hemodialysis group, in the early morning before hemodialysis). Fasting blood sugar and the standard 2 hours glucose tolerance test (after ingestion of 75 g of glucose) were detected in the three groups by spectrophotometry. Statistical analysis was performed by Kuruskal wallis, U-Mann Whitney, multiple comparison and regression correlation coefficient tests, using SPSS 10.05.
Results
On the basis of WHO classification 14, four of our (7.5%) renal transplant recipients and twelve (22%) of the hemodialysis patients had impaired glucose tolerance, i.e. the 2 hour of glucose tolerance test was between 140 and 200 mg/dl. It was more obvious at the end of the second hour of GTT. Although BMI was roughly similar in the three groups (Table 1), a significant linear correlation was observed between BMI and impaired glucose tolerance only in HD patients (r = 0.4, p = 0.05) (fig 1), but not in the RT recipients. The glucose tolerance (especially at the first hour) in the HD patients had a significant linear correlation with the level of serum triglycerides (r = 0.87, p = 0.001) (Fig 2). Serum triglyceride concentration was 217.2 ± 55 mg/dl in HD vs. 214.3 ± 13 mg/dl in RT and 100.2 ± 18 mg/dl in C groups, (p = 0.001). On the other hand the four RT recipients with IGTT (i.e. 100% of RT recipients with IGTT) had the higher serum cholesterol levels (308.4 ± 24.4 mg/dl)) compared with the remaining RT recipients with normal GTT (248.7 ± 55.6 mg/dl) with p = 0.031 (table 2). The mean of serum cholesterol was 269.7 ± 54 mg/dl in RT vs. 199.2 ± 36.6 mg/dl in HD and190.5 ± 34 mg/dl in C groups (p = 0.0001). A linear correlation was observed between impaired GTT and both of the serum Cyclosporine level (r = 0.9, p = 0.001) and HbA1c in RT recipients (Fig 3). The mean of HbA1c was 6.2 ± 0.6 gr/dl in the RT recipients with normal GTT vs. 4.34 ± 0.26 g/dl in the RT recipients with IGGT (p < 0.001, table 2). The later correlation was also observed in HD patients, in whom the mean of HbA1C level was 6.4 ± 0.7 gr/dl in the group (r = 67, p = 0.001). In contrast of a close relationship of IGTT and higher HbA1c, the gender, age, times after transplantation and BMI did not impact on IGTT in RT recipients. Although in logistic regression analysis higher serum level of cyclosporine was correlated with increased GTT impairment, we could not evaluate the implication of corticosteroids on this test, because all of the 55 RT recipients were received prednisolone at a doses of 5 to 10 mg/day.
<p>Figure 1</p>
GTT has a linear relationship with BMI in hemodialysis patients
GTT has a linear relationship with BMI in hemodialysis patients. Impairment of GTT is more significant in the hemodialysis patients with higher BMI. Gtt2 = glucose tolerance test at the second hours of 75 gr oral glucose. bmih = body mass index in hemodialysis patients
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<p>Figure 2</p>
The glucose tolerance in the HD patients had a significant linear correlation with the level of serum triglycerides
The glucose tolerance in the HD patients had a significant linear correlation with the level of serum triglycerides. gttd1= glucose tolerance test in dialysis patients, tgh= serum concentration of triglyceride in hemodialysis patients.
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<p>Figure 3</p>
Cyclosporine level and HbA1c have correlations with the IGTT in RT recipients
Cyclosporine level and HbA1c have correlations with the IGTT in RT recipients ▲ = Serum Cyclosporine level ○ = HbA1c concentration
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<p>Table 2</p>
Impaired glucose tests in HD and RT recipients have higher values of serum triglyceride, serum cholesterol and cyclosporine concentration than patients with normal glucose tolerance tests.
no. of cases
Serum Triglyceride(mg/dl)
Serum Cholesterol(mg/dl)
HbA1c (gr/l)
Cyclosporine (mg/dl)
RT recipients with IGTT
4
231.4 ± 150
308.4 ± 24.4
7.34 ± 0.26
320.4 ± 36.6
RT Recipients With normal GTT
51
201 ± 75
248.7 ± 55.6
6.2 ± 0.6
295.1 ± 29
P = 0.59
P = 0.02
P = 0.001
P = 0.2
HD patients with IGTT
12
272.1 ± 41.3
201.1 ± 39
7 ± 1
HD patients with normal GTT
43
195.9 ± 45
198.5 ± 36.8
5.9 ± 0.7
P = 0.001
P = 0.87
P = 0.007
Controls
55
100.2 ± 18
190.5 ± 34
5.7 ± 0.7
Discussion
Impaired glucose tolerance occurs in about 50% of patients with chronic renal failure (CRF) patients. It is due to multiple factors, which the two most important of them being insulin resistance at target organs and impaired insulin secretion from the pancreas 15. Insulin sensitivity would be reduced by up to 60% in non-diabetic patients with CRF before dialysis 16. Marked improvement in insulin sensitivity and consequently glucose tolerance has been reported in non-diabetic patients after 10 weeks of HD, although they are not completely returned to normal 15. Thereby, impaired glucose tolerance during HD is secondary to non-effective removable toxins by HD compared with peritoneal dialysis. In the latter more effective removal of middle molecule toxins causes better glucose tolerance, although glucose rich dialyzet solution is used 16. The other causes of impaired glucose tolerance in HD patients may be secondary to metabolic disturbances, such as anemia 17, malnutrition 18 and vitamin D3 deficiency 19. Although all of our HD patients had normochromic-normocytic anemia, the severity was not proportionate with impaired glucose tolerance (The data has not been shown). The patients were well nourished and were under treatment with daily oral vitamin D3 (Rocaltrol), 0.5 micrograms per day. So malnutrition and vitamin D3 deficiency could not to contribute to impaired glucose tolerance in our HD patients. Impaired glucose tolerance was also observed in 7.5% of our RT recipients. All of the presumed risk factors for post transplant diabetes mellitus such as old age 18, family history of any known diabetes mellitus in their first relatives21, cadaveric allografts 22 and obesity did not exist in the patients. Previously Boudreaux et al. 23 reported that those patients who weighed more than 70 kg had a higher incidence of post transplant diabetes mellitus (PTDM). A relative risk of 1.4 for developing PTDM for every 10 kg increase in body weight more than 60 kg has been shown 12. Although in our study obese patients (BMI > 30 kg/m2) were not included in the both groups, a correlation was observed between impaired glucose tolerance and higher BMI in our HD patients. In RT recipients, the major risk factor for impaired glucose tolerance was immunosuppressive therapy. Through using higher doses of CsA and corticosteroids, PTDM was previously more common, but the complication has been decreased to 2–5% in FK506-based immunosuppressive protocols 2425. Although this relatively uncommon complication is a major cause of post-transplant mortality and morbidity, even minor glucose intolerance is associated with an increased long-term risk for cardiovascular disease 26. The importance of impaired glucose tolerance should not be underestimated in these patients with high risk of atherosclerosis. Hyperlipidemia, another risk factor for atherosclerosis, on one hand accompanies the impaired glucose tolerance observed in the HD and RT patients and on the other hand increases the risk of atherosclerosis induced by impaired glucose tolerance. As reported previously, a tendency to higher pre-transplantation serum triglyceride concentration was associated with post-transplantation impaired glucose tolerance 27.
Hypertriglyceridemia is common complication in dialysis patients. In non-transplant populations it is regarded (along with low HDL cholesterol levels) as a prominent feature of insulin resistance syndrome, and also is a cardiovascular risk factor in organ transplant recipients 28. Our study confirmed the relationship between impaired glucose tolerance and triglyceride levels in HD patients, and between impaired glucose tolerance and cholesterol levels in RT recipients. The latter was also accompanied by a higher level of HgA1C. Commonly used tests of HgA1C may be unreliable in patients with end-stage renal disease because of the presence of anemia, shortened red blood cell survival, and assay interferences from uremia. But HgA1C in the range of 6% to 7%, as was found in our study, estimates glycemic control within the range of patients without severe renal impairment 1. So in the range of mild to moderate increased HgA1C in HD and uremic patients, it would be a reliable marker of impaired glucose tolerance.
Conclusions
There was increased HgA1C and impaired glucose tolerance in HD and RT patients. This was accompanied by hyperlipidemia in HD patients (with hypertriglyceridemia) and RT recipients (with hypercholesterolemia). The impact upon the progression of atherosclerosis needs more study in haemodialysis and renal transplant populations at a long term follow up.
Competing interests
None declared.
Authors' contributions
HA reviewed the literatures and wrote the manuscript and also helped to do statistical analysis, AN performed GTT and the other biochemical markers, MN participated as coordinator between laboratory and clinic, HTK selected the patients and collected data