| Abstract|| |
This study was undertaken to study the changes in neuropathy in type 1 diabetic patients with end-stage renal disease (ESRD) after renal transplantation. From April 2007 to June 2010, 30 renal transplanted patients with type 1 diabetes mellitus (RT) and 30 type 1 diabetic patients with ESRD were enrolled in this study. Electroneurodiagnostic tests of peroneal, sural, ulnar, and median nerves were performed. Nerve conduction velocity (NCV), compound motor action potentials (CMAPs), and sensory nerve action potentials (SNAPs) were analyzed at 6, 12, and 18 months after renal transplantation. The NCV improved in the RT group in 18 months of the follow-up period (P <0.01 versus baseline). This parameter worsened significantly in the control group throughout the study period (P = 0.03), but in the cross-sectional analysis between the groups, we could not find any remarkable differences (P = 0.07). Both SNAP and CMAP amplitudes improved in the RT (SNAP Sural = 0.04, SNAP Median = 0.01 and CAMP Peroneal = 0.03, CAMP Ulnar = 0.02) but worsened in the control group (SNAP Sural < 0.001, SAP Median < 0.01 and CAMP Peroneal < 0.01, CAMP Ulnar < 0.01). Comparison of both groups did not show any significant statistical changes. Electroneurodiagnostic values improved after renal transplantation in type 1 diabetic patients with ESRD, but cross-sectional analysis did not reveal statistically significant differences between the studied groups.
|How to cite this article:|
Noshad H. Neuropathy in type 1 diabetic renal transplanted patients. Saudi J Kidney Dis Transpl 2012;23:719-23
| Introduction|| |
Diabetic neuropathy (DN) is one of the most important complications of type 1 diabetes mellitus.  DN is a major contributor to the etiology of diabetic foot in these patients. Electrodiagnostic studies have been used for diagnosing DN.  Up to now, little has been known about the effect of kidney transplantation on DN. The number of kidney transplanted patients with type I diabetes mellitus is increasing.  However, it is still unclear whether renal transplantation alone can improve the long-term complications of diabetes. Renal function may be affected by immunosuppressive therapies.  There are several reports about successful kidney transplantation in type 1 diabetic patients with beneficial effect on angiopathy, cardiovascular dysfunction,  and also retinal complications.  Improvement or stabilization of neuropathy apparently has not been investigated after kidney transplantation.  The purpose of this study was to evaluate whether renal transplantation improves neuropathy in type 1 diabetic patients with end-stage renal disease (ESRD).
| Materials and Methods|| |
From April 2007 to June 2010, 30 patients (age 32.4 ± 3.2 years and male to female ratio: 16/14) with HbA1C level of 5-6% with successful renal transplantation (RT group) were enrolled in our study. Another group of 30 patients with ESRD and type 1 diabetes were recruited as the control group (age 34.3 ± 3.1 years and male to female ratio 20/15). Their neuropathy was assessed electrodiagnostically.  Insulin therapy was continued after transplantation for tight control of serum glucose level in RT as well as in the control group. HbA 1 C level was maintained optimally in the range of 5-6% [Table 1]. 
Nerve conduction studies were performed by a physician who was blinded to the patient's group. This was taken on the standard laboratory and technical condition at initiation and 6, 12, and 18 months after transplantation. For sensory evaluation, sural and median nerves and for motor evaluation, ulnar and peroneal nerves were examined. Amplitude of sensory and motor responses, mean sensory nerve action potentials (SNAP), and compound muscle action potentials (CMAP) together with each nerve conduction velocity were recorded for final analysis. We calculated a nerve conduction velocity (NCV) index for each patient. 
Four nerve NCV Z scores were were obtained. Patient's NCV values were extracted from difference of patients NCV and mean NCV value in the control group and then dividing the result by standard deviation (SD) of the NCV value of the same nerve in the control group. NCV indexes were the mean of each nerve NCV Z score. Age-related normal values were considered for calculation. Deviation of individual NCV values from the mean value of the general population in terms of SD was estimated by the NCV index. This limited the intraindividual variability for each nerve trunk and allowed us for a longer term follow-up. More negative NCV values revealed more severe neuropathies. NCV indexes at the different follow-up periods (6, 12, and 18 months) were compared with the initial values by means of the paired "t" test for paired samples and with the RT and control subgroups. Changes from baseline of NCV indices at the different follow-up periods (6, 12, and 18 months) were compared between the RT and the control groups by means of the Student "t" test. We also performed repeated measures of ANOVA for clarifying the time effect in both groups (RT and control). This could explore the renal transplantation and time effect on the same subject and reveal the time and treatment effect on the NCV of patients.
| Results|| |
No significant intergroup differences were found for age (RT: 32.4 ± 3.2 vs. control: 34.3 ± 3.1 years, P = 0.63), baseline body weight (RT 61.3 ± 9.6 vs. control 62.0 ± 2.2 kg, P = 0.59), diabetes duration (RT 26.3 ± 10.4 vs. control 22.2 ± 9.6 years, P = 0.11) and dialysis duration (RT 11.2 ± 4.2 vs. control 10.4 ± 3.1 years, P = 0.08). Measurement of HbA 1 C (%) level revealed no significant difference between the groups during the study and, therefore, was the blood glucose control, which was almost similar between the investigated groups [Table 1].
Differences of pre-transplant NCV scores between the RT and control groups was not statistically significant (P = 0.18). Before transplantation, the SNAP Sural, SNAP Median, CAMP Peroneal, and CMAP Ulnar values did not have a statistically significant difference between the RT and control groups [Table 1].
Both RT and control groups had neuropathy at baseline according to the electrodiagnostic findings. NCV index improved in the RT group, reaching statistical significance in comparison with pre-transplant values at 18 months of follow-up (P <0.01). On the other hand, NCV worsened in the control group (P = 0.03). At the latest follow-up (18 months), the improvement of NCV score in comparison with baseline values was maintained in the RT group, whereas it worsened further in the control group [Table 2]. When we compared the NCV changes from baseline between the groups, there was no statistically significant difference at the 18 months follow-up period (P = 0.07).
Improvement of SNAP amplitudes for sural and median nerves was seen all through the different time points up to the 18 months of follow-up, which was recognized in the RT group and was statistically significant when compared with the baseline values (P = 0.04 and P = 0.01, respectively). In the control group, both median and sural SNAP progressively worsened into a neuropathic range (P <0.01 and P <0.001, respectively). However, median and sural SNAP did not show a statistically significant improvement in the RT group compared with the control group (P = 0.09 and P = 0.13, respectively) [Table 2]. In the RT group, CMAP amplitudes showed improvement of either peroneal or ulnar nerves at the 18-month follow-up compared with the baseline values (P = 0.03 and P = 0.02, respectively). On the contrary, CMAP amplitudes of both nerves progressively declined in the control group after 18 months. Again, CMAP amplitudes of the peroneal or ulnar nerves did not show statistically significant improvement in the RT group compared with the control group at the 18-month follow-up period (P = 0.11 and P = 0.21, respectively) [Table 2].
Repeated measures of ANOVA revealed that renal transplantation improved the NCV index (P <0.01), Sural SNAP (P = 0.04), Median SNAP (P = 0.01), peroneal CMAP (P = 0.03), and ulnar CAMP (P = 0.02) in the RT group longitudinally. It was shown that the above-mentioned parameters worsened in the control group [Table 2].
| Discussion|| |
Kidney transplantation may induce long-lasting stabilization of diabetic neuropathy. Electroneurography is the most sensitive method for assessing DN.  In fact, the NCV index improved in the RT group from the first control (six months), and was maintained all through the follow-up period. On the other hand, in the control group, the NCV progressively worsened during the 18 months of study period. Because the pre-transplant variables such as age, sex, laboratory values, and electrodiagnostic findings were not significantly different between the two groups at baseline, we conclude that this result is not affected by selection of the groups but is due to the deteriorating kidney function.
It has been previously reported that kidney transplantation may eliminate an important neuropathic factor seen in ESRD.  Intensive insulin treatment has shown to improve peripheral nerve function significantly. In type 1 diabetic patients, this improvement has been observed in both autonomic and sensori-motor nerves. In those who had neuropathy at baseline (similar to that seen in our studied groups), intensive therapy reduced the appearance of clinical neuropathy at five years by 57%.  Various biochemical consequences of intracellular metabolism of hyperglycemia are considered to be responsible for its injurious effect on vessels and nerves, including advanced glycation end products. 
Previous works have already reported the beneficial effects of kidney transplantation on neuropathy, , but our studied patients were those with diabetes mellitus who had ESRD due to diabetic nephropathy. Hence, neuropathy was supposed to be even more severe, and the positive role of kidney transplantation was a highlight of our study. Peripheral nerve function was evaluated only by means of NCVs by Lee et al  for the follow-up period of two years. Varkonyi et al  evaluated DN only with a perceptive test of sensory threshold in a follow-up period as long as 9.5 years on average. This is probably the first study based on nerve conduction studies to demonstrate that kidney transplantation may induce long-lasting improvement of neuropathy in type 1 DN.
Study of other electroneurographic findings such as the amplitude of both SNAPs and CMAPs  revealed that they improved steadily throughout the follow-up period in the RT group. On the contrary, the amplitude of both peroneal and ulnar nerve CMAPs worsened progressively through the follow-up period in the control group [Table 1], denoting that axonal damage was steadily progressing in the control group. The amplitude of both sural and median nerve SNAPs increased through the different time points in the RT group, whereas the same parameter showed a decreasing pattern in the control group. This suggests that kidney transplantation positively affects even sensory nerve fibers.
In fact, NCV changes in diabetic patients are related to glycemic control and kidney transplantation (21), because glycemic control was similar in both groups as both had comparable HbA 1 C levels (5-6%, P = 0.6). Therefore, one can say that improvements in the NCV index, which indicate an overall improvement of patient's nerve function, are due to the beneficial effect of kidney transplantation. NCV mainly reflects the pathological processes of large-diameter axons  and, for this reason, the longitudinal analysis of either SNAP or CMAP amplitudes, considered as a means of assessing the contribution of smaller slow-conduction nerve fibers, was also performed. 
It was reported that kidney transplantation combined with islet cell pancreatic transplantation improves diabetic polyneuropathy in type 1 diabetic patients.  According to our results, kidney transplantation alone could improve the quality of life in diabetic patients with auto-nomic neuropathy and/or painful forms of neuropathy.
In our small group of patients, electroneuro-physiologic parameters improved after kidney transplantation in the RT group, but we could not find any significant difference between the RT and the control group. It may be due to the small number of the studied groups or short time of follow-up period; therefore, we suggest studies with a greater number of patients in a longer follow-up period.
| References|| |
|1.||Ziegler D. Treatment of diabetic neuropathy and neuropathic pain: how far have we come? Diabetes Care 2008;31 Suppl 2:S255-61. |
|2.||Noshad H, Argani H, Nezami N, et al. Arterial atherosclerosis in patients with chronic kidney disease and its relationship with serum and tissue endothelin-1. Iran J Kidney Dis 2009;3: 203-9. |
|3.||Apfel SC. Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med 1999;107: 34S-42S. |
|4.||Urrea A. Immunosuppression for kidney transplant recipients: Current strategies. Rev Invest Clin 2005;57:213-24 |
|5.||Cohen D, Galbraith C. General health management and long-term care of the renal transplant recipient. Am J Kidney Dis 2001;38(6 Suppl 6):S10-24. |
|6.||Magee CC, Pascual M. Update in renal transplantation. Arch Intern Med 2004;164:1 373-88. |
|7.||American Diabetes Association. Clinical Practice Recommendations 2001 Diabetes Care 2001;24 Suppl 1:S1-133. |
|8.||Lozeron P, Nahum L, Lacroix C, Ropert A, Guglielmi JM, Said G. Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients. J Neurol 2002;249:569-75. |
|9.||Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 2006;29:1294-9. |
|10.||Diabetes control and complications trial research group. The effect of intensive treatment of diabetes on the development and progresssion of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86. |
|11.||Martinenghi S, Comi G, Galardi G, Di Carlo V, Pozza G, Secchi A. Amelioration of nerve conduction velocity following simultaneous kidney/pancreas transplantation is due to the glycaemic control provided by the pancreas. Diabetologia 1997;40:1110-2. |
|12.||Zochodne DW. Diabetic polyneuropathy: An update. Curr Opin Neurol 2008;21:527-33. |
|13.||Marre M. Nephropathy in type 1 diabetes. Semin Vasc Med 2002;2:97-107. |
|14.||Waldman SD. Diabetic neuropathy: Diagnosis and treatment for the pain management specialist. Curr Rev Pain 2000;4:383-7. |
|15.||Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJ. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 1998;21:1071-5. |
|16.||Van der Vlient JA, Navarro X, Kennedy WR, Goetz FC, Sutherland DE, Najarian JS. Diabetic polyneuropathy and renal transplantation, Transplant Proc 1987;19:3597-9. |
|17.||Mamoli B, Kopsa H, Gerstenbrand F, Kotzaurek R, Pateisky K. Uraemic polyneuropathy after renal transplantation. Neural 1974;208:63-9 |
|18.||Lee TC, Barshes NR, O'Mahony CA, et al. The effect of pancreatic islet transplantation on progression of diabetic retinopathy and neuropathy. Transplant Proc 2005;37:2263-5. |
|19.||Várkonyi TT, Farkas G, Fülöp Z, et al. Beneficial effect of fetal islet grafting on development of late diabetic complications. Transplant Proc 1998;30:330-1. |
|20.||Meijer JW, van Sonderen E, Blaauwwiekel EE, et al. Diabetic neuropathy examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care 2000;23:750-3. |
|21.||Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract 2000;47:123-8. |
|22.||Martin CL, Albers J, Herman WH, et al. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care 2006;29:340-4. |
|23.||Del Carro U, Fiorina P, Amadio S, et al. Evaluation of polyneuropathy markers in type 1 diabetic kidney transplant patients and effects of islet transplantation: neurophysiological and skin biopsy longitudinal analysis. Diabetes Care 2007;30:3063-9. |
Internal Medicine Group, Sina Hospital, Tabriz University of Medical Sciences, Tabriz
[Table 1], [Table 2]