Effect of pancreatic and/or renal transplantation on diabetic autonomic neuropathy

Diabetologia, Aug 1991

Summary Thirty-nine Type 1 (insulin-dependent) diabetic patients were studied prospectively after simultaneous pancreas and kidney (n=26) and kidney grafting alone (n=13) by measuring heart rate variation during various manoeuvers and answering a standardized questionnaire every 6 to 12 months post-transplant. While age, duration of diabetes, and serum creatinine (168.1±35.4 vs 132.7±17.7 μmol/l) were comparable, haemoglobin A1 levels were significantly lower (6.6±0.2 vs 8.5±0.3%; p<0.01) and the mean observation time longer (35±2 vs 25±3 months; p<0.05) in the pancreas recipients when compared with kidney transplanted patients. Heart rate variation during deep breathing, lying/standing and Valsalva manoeuver were very similar in both groups initially and did not improve during follow-up. However, there was a significant reduction in heart rate in the pancreas recipient group. Autonomic symptoms of the gastrointestinal and thermoregulatory system improved more in the pancreas grafted subjects, while hypoglycaemia unawareness deteriorated in the kidney recipients. This study suggests that long-term normoglycaemia by successful pancreatic grafting is able to halt the progression of autonomic dysfunction.

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Effect of pancreatic and/or renal transplantation on diabetic autonomic neuropathy

S l Effect of pancreatic and/or renal transplantation on diabetic autonomic neuropathy J. Nusser 0 R. Scheuer 0 D. Abendroth W.-D. Iliner W. Land R. Landgraf 0 0 Department of Internal Medicine, Klinikum Innenstadt and 2 Division of Transplant Surgery, Klinikum Grosshadern, University of Munich , F R G S u m m a r y . Thirty-nine Type 1 (insulin-dependent) diabetic patients were studied prospectively after simultaneous pancreas and kidney (n=26) and kidney grafting alone (n=13) by measuring heart rate variation during various manoeuvers and answering a standardized questionnaire every 6 to 12 months post-transplant. While age, duration of diabetes, and serum creatinine (168.1+35.4 vs 132.7+17.7 btmol/1) were comparable, haemoglobin A 1 levels were significantly lower (6.6+0.2 vs 8.5+0.3%; p<0.01) and the mean observation time longer (35+2 vs 25+3 months; p<0.05) in the pancreas recipients when compared with kidney transplanted patients. Heart rate variation during deep breathing, lying/standing and Valsalva manoeuver were very similar in both groups initially and did not improve during follow-up. However, there was a significant reduction in heart rate in the pancreas recipient group. Autonomic symptoms of the gastrointestinal and thermoregulatory system improved more in the pancreas grafted subjects, while hypoglycaemia unawareness deteriorated in the kidney recipients. This study suggests that long-term normoglycaemia by successful pancreatic grafting is able to halt the progression of autonomic dysfunction. Autonomic neuropathy - Diabetes mellitus; Type 1 - Pancreas transplantation 9 Springer-Verlag 1991 I n t r o d u c t i o n Polyneuropathy affecting the somatic and autonomic nervous system is a common complication of diabetes mellitus. Autonomic neuropathy can affect nearly all organs with a wide spectrum of symptoms and complaints. Once it has developed the patient has a poor prognosis (Ewing and Clarke 1986; Watldns 1990) . Various forms of treatment such as continuous subcutaneous insulin infusion (Fedele et al. 1984) or aldose-reductase inhibitors (Jaspan et al. 1983) showed some improvement of autonomic neuropathy, but these interventions were short. With the increasing success of pancreas transplantation the fate of neuropathy can be studied prospectively for much longer. Studies performed until now focus mainly on cardiorespiratory reflex tests using one or two parameters of standardized reflex tests (Solders et al. 1987; Kennedy et al. 1990) without analyzing autonomic signs and symptoms. Therefore, the effect of functioning pancreatic grafts on autonomic neuropathy was studied prospectively. Patients and m e t h o d s Patients. The study group consisted of 26 Type 1 (insulin-dependent) diabetic patients, 12 men and 14 women (mean age 32+1.6 years, duration of diabetes 23+1 years) who received combined panereas-/kidney-transplantation. Thirteen Type 1 diabetic patients (4 men, 9 women, mean age 33+2 years, duration of diabetes 21+3 years) who underwent simultaneous pancreas- and kidney-transplantation but lost the pancreatic function within three months of transplantation (kidney-alone group) served as controls. For further details see Table 1. The first autonomic test in both groups was performed within eight weeks of transplantation. In the pancreas/kidney group 32 patients were restudied 1 year, 25 after 2 years, and 21 after 3 years. In the kidney-alone group nine patients had a follow-up after 1 year and six patients after 2 and 3 years. Mean observation period was 35+2 months in the pancreas/kidney and 25+3 months in the kidney-alone recipients (p<0.05). All patients were on the same triple drug immunosuppressive therapy consisting of cielosporin, azathioprine and corticosteroids adapted to the individual requirements. All patients with a functioning pancreas graft required no insulin and had normal HbA 1 values throughout the study. At the last follow-up serum creatinine levels of both groups were comparable (168.1+35.4 vs 137.7+17.7 ~tmol/1), the HbA 1 levels were quite different (6.5+0.1 vs 8.3+0.3 %, p<0.01). Methods. For the assessment of autonomic neuropathy the following standardized methods were used: cardiac autonomic neuropathy was tested by deep breathing (6 breathshnin) with calculation of mean RR distances, E/I ratio and score (Wheeler and Watkins 1973) . Furthermore lying-standing (Dyrberg et al. 1981) and the Valsalva manoeuver (Levin 1966) were performed and the 30/15 (Dyrberg et al. 1981) and the Valsalva ratio (Levin 1966) were calculated. In addition, a standardized graded questionnaire was used asking for typical signs and symptoms of autonomic neuropathy (Table 2). Changes were evaluated comparing each patient's first and last examination after transplantation. Statistical analysis. For statistical analysis the Wilcoxon-signedrank testwas used. p-values of lessthan 0.01 were considered to indicate significantdifferences.Concerning symptoms evaluated by the graded questionnairechanges of two or more points (in a scaleof five possible points) were considered significant. If not stated otherwise values are shown as mean  SEM. T a b l e I . Patient characteristics. Pancreas and kidney kidney-alone n Male/Female Age (years) Duration of diabetes (years) Serum creatinine (pmol/l) 168.1+35.4 HbA 1 (normal 6-8%) Immunosuppressive therapy triple drug values = mean + SEM, a p<0.01 R e s u l t s 26 12114 32+1.6 23+1 6.5+0.1 13 4/9 33+2 21+2 132.7+17.7 8.3+0.3 a triple drug Tachycardia diminished clearly in the pancreas-kidneygroup shown by a significant increase of mean R-R~:g :l , _ ~ I 2 Y e a r s a n e r t r a n s p l a n t a t i o n 3 distances 1 and 2 years after transplantation (p<0.01). RR-distances slightly increased also in the kidney-alone group, the difference however was not significant (Fig. 1). An improvement of cardiac autonomic neuropathy was seen in the kidney recipients concerning the E/I ratio which showed an increase (p<0.05) 1 year after transplantation (Fig. 2). All other parameters of the various cardiorespiratory reflex tests showed no significant increase or decrease in both groups during the observation period. Concerning symptoms of autonomic neuropathy related to the cardiocirculatory system there were improvements and deteriorations in both groups without clear differences. Symptoms of gastroparesis worsened clearly in four patients of the pancreas-kidney group and improved in one patient of the kidney-alone recipients. Constipation slightly improved in the pancreas-kidney group, thermoregulatory symptoms clearly improved in the combined transplanted patients and remained unchanged in the kidney. alone group. Reduction of urinary stream or sensation of incomplete bladder emptying occurred more often in the pancreas-kidneygroup. Penile erection or retrograde ejaculation problems showed no change. About one third of the kidney recipients complained of decreased hypoglycaemic symptoms and/or hypoglycaemic symptoms at blood glucose levels below 2.2 mmol/1 within 3 years after transplantation. This study demonstrates that heart rate variation as a parameter of cardiac autonomic function is unchanged 2 to 3 years after successful pancreas and kidney transplantation and in diabetic patients after kidney grafting only. In a former study similar results were reported concerning cardiac autonomic parameters (Solders et al. 1987) . However, recently Kennedy et al. (1990) were able to demonstrate a beneficial effect of pancreatic grafting on heart rate variability while cardiac autonomic dysfunction deteriorated in kidney recipients. These obvious discrepancies can be explained at least partially by differences in blood glucose control in the patient groups under study. Our kidney recipients had intensified insulin therapy achieving near normoglycaemia, while the same patient group in the study of Kennedy et al. (1990) showed a much poorer glucose control (HbAlc>10%). Although under debate (Wheeler and Watkins 1973) Fedele et al. (1984) reported improvements of autonomic neuropathy after intensified insulin therapy. It is therefore important in this kind of study that the study and control groups are comparable with respect not only to the degree of neuropathy but also to kidney function and metabolic control. Strict glucose control can strengthen severity and prolongation of hypoglycaemia (Dyrberg et al. 1981) . When analyzing the questionnaire in this study the most striking finding was that one third of the kidney recipients complained of deteriorating awareness of hypoglycaemia, which can be explained both by the intensified insulin therapy and a progression of autonomic neuropathy. Dishydrosis improved clearly, while symptoms of delayed gastric emptying were higher in the pancreas/kidney group. This can be interpreted also as an improvement of afferent autonomic dysfunction as far as these patients now are able to detect their delayed gastric emptying (Levin 1966) . Since symptoms of autonomic neuropathy improved mainly in the pancreas/kidney recipients, it is suggested that long-term normalization of glucose metabolism can halt the progression of autonomic dysfunction. However, the improvements are only marginal within the observation period of 36 months indicating that severe lesions of the autonomic nervous system present in all our patients are rather "resistant" to amelioration despite long-term normoglycaemia. It is therefore concluded that much longer observation times or patients with earlier stages of diabetic neuropathy are needed to demonstrate marked improvements in diabetic neuropathy. However, even in diabetic subjects with advanced autonomic dysfunction, pancreatic grafting is beneficial since the risk of severe and life-threatening hypoglycaemic attacks due to unawareness of low blood glucose is eliminated. Acknowledgements. We would like to thank the nursing and laboratory staff of our hospitals for excellent patient care and technical assistance. We would also like to thank Ms. R. Solym~r for help with the preparation of the manuscript. Amiel SA , Tambedane WV , Simonson DC , Sherwin RS ( 1987 ) Defective glucose counterregulatiou after strict glycemie control of insulin-dependent diabetes mellims . N Eng J Med 316 : 1376 - 83 Dyrberg T , Benn J , Christiansen JS , Hilsted 1, Nerup J ( 1981 ) Prevalence of diabetic autonomic neuropathy measured by simple bedside test . Diabetologia 20 : 190 - 194 Ewing DJ , Clarke BF ( 1986 ) Diabetic Autonomic Neuropathy: Present insights and Future Prospects . Diabetes Care 9 : 648 - 665 Fedele D , Negrin P , Cardone C et al. ( 1984 ) Influence of continuous subcutaneous insulin infusion (CSII) treatment on diabetic somatic and autonomic neuropathy . J Endocrinol Invest 7 : 623 - 628 Jaspan I , Maselli R , Herold K , Bartkus C ( 1983 ) Treatment o f severely painful diabetic neuropathy with an aldose reductase inhibitor: relief of pain and improved somatic and autonomic nerve function . Lancet 2 : 758 - 762 Kennedy WR , Navarro X , Goetz FC , Sutherland DER , Najafian IS ( 1990 ) Effects of pancreatic transplantation on diabetic neuropathy . N Engl J Med 322 : 1031 - 1036 Levin AB ( 1966 ) A simple test of cardiac function based upon the heart rate changes induced by the Valsalva maneuver . Am I Cardiol 18 : 91 - 97 Rathmann W , Enck P , Frieburg T , Gries FA ( 1990 ) Visceral afferent neuropathy in diabetic gastroparesis . Diabetologia 33 , A34 Solders G , Wilczek H , Gunnarsson R , Tydrn G , Perssou A , Groth C-G ( 1987 ) Effects of combined pancreatic and renal transplantation on diabetic neuropathy: a two-year follow-up study . Lancet 2 : 1232 - 1235 The St. Thomas Diabetic Study Group ( 1986 ) Failure of improved glyeaemie control to reverse diabetic autonomic neuropathy . Diabetic Med 3 : 330 - 334 Watkins PJ ( 1990 ) Diabetic autonomic neuropathy . N Engl I Met 322 : 1078 . 1079 Wheeler T , Watkins PJ ( 1973 ) Cardiac denervation in diabetes . Br Med J 267 : 584 - 586 Ziemssenstrasse 1 8000 Munich 2


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J. Nusser, R. Scheuer, D. Abendroth, W. -D. Illner, W. Land, R. Landgraf. Effect of pancreatic and/or renal transplantation on diabetic autonomic neuropathy, Diabetologia, 1991, S118-S120, DOI: 10.1007/BF00587635