Nephrology Consultant Am J Nephrol 1992:12:363-368
Participants: Christoph Wannerb Joachim Bdhlerh Walter H. Horlc a Professor of Medicine, University of Southern California School of Medicine. Los Angeles. Calif., USA; b Assistant Professor of Medicine, University of Freiburg; c Professor of Medicine and Director, Division of Nephrology. University of Homburg/Saar. FRG
Endocrine and Metabolic Disorders following Kidney Transplantation
K e y w o rd s
Kidney transplantation Ciclosporin Azathioprine Cholesterol Triglyceride Diabetes mellitus Insulin
Dr. Feinstein Today’s case presentation concerns 2 patients with met abolic disturbances following cadaveric renal transplanta tion. Dr. Wanner, will you present the 1st case? Dr. Wanner A 48-year-old woman with end-stage renal disease secondary to interstitial nephritis received a cadaveric renal transplant on Janu ary 6. 1989. Twenty-Five years before, unilateral nephrectomy had been performed due to kidney tuberculosis. There was no history of metabolic or endocrine disorders before or during the hemodialysis period. A hysterectomy was performed in 1983 due to suspected car cinoma. After transplantation the patient developed moderate hy perglycemia (blood glucose < 200 mg/dl) during rejection therapy. A cytomegalovirus infection was diagnosed serologically without clini cal symptoms. Despite a reduction of steroids during the follow-up course, elevated blood glucose values had to be controlled by diet and oral antidiabetic therapy. Otherwise transplantation follow-up was uncomplicated, and serum creatinine fell to 0.9 mg/dl. Five months later spontaneous seizures occurred which were treated with carbamazepine. Ten months after transplantation, a routine laboratory' evaluation revealed serum triglycerides of 1.991 mg/dl and a serum cholesterol level of 328 mg/dl. A therapy with a fibric acid derivative (bedobrate I00mg/day) was started. Five months later, while on bcclobrate. serum triglycerides rose to 11,077 mg/dl and cholesterol to 1,033 mg/dl. The patient was admitted to the hospital. A cholester ol-restricted diet (cholesterol content < 200 mg/day) decreased se rum cholesterol to 520 mg/dl and triglyceride to 1.740 mg/dl over a
Edited transcript of Renal Rounds held at the University of Freiburg. FRG, October 1991.
Received: February 7 . 1992 Accepted: May 22,1992
period of 14 days. Laboratory analysis at the time of admission revealed sodium 131 mmol/1 and potassium 3.5mmol/l. Chloride was 94 mmol/I. and serum lipase was 12 U/l: a-amylase was 44 U/l. Several parameters of serum chemistry could not be measured due to lipemie serum. Medication at hospital admission consisted of ciclosporinA (CS-A), prednisolone (5 mg/day). allopurinol (300 mg/day), carbamazepine (400 mg/day), xipamide (10 mg/day), isoniazid (100 mg/day), conjugated estrogens (1.25 mg/day) and medrogesterone (5 mg/day), beclobrate (100 mg/day). and digitoxin.
Dr. Feinstein Thank you, Dr. Wanner. Dr. Horl will now discuss the differential diagnosis o f hyperlipoproteinemia after kidney transplantation. Could you please focus on the special situ ation o f this patient? Dr. Horl
Since Ghosh et al. [1] first noted a high prevalence of hyperlipidemia among transplant recipients, hypertriglyc eridemia and hypercholesterolemia [2-21] have often been observed in patients after successful renal transplan tation. Ibels et al. [ 12] studied lipoprotein electrophoreses in 175 adult, 19 pediatric, and 11 diabetic transplant recipients and found type IV hyperlipoproteinemia in 26%. type lib in 23, and type lia in 11 % of the patients.
E.l. Feinstein. MD University of Southern California School of Medicine Los Angeles. Calif. (USA)
€> 1992 S. Kargcr AG. Basel 0250-8095/92/0125-0363 $2.75/0
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Moderator: Eben I. Feinsteina
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Dr. Feinstein Thank you. Dr. Hört. Dr. Wanner please could you describe the patient ’s follow-up after discharge from the hospital? Dr. Wanner After discharge from the hospital the patient’s triglyceride values were controlled by a calorie-restricted antidiabetic diet and oral antidiabetic medication. A weight reduction from 60 to 54 kg was achieved. However. 3 months later serum triglyceride levels began to rise and varied in the 2.000 to 4.000-mg/dl range. A therapy with nicotinic acid (2 g/day) was prescribed elsewhere. During the follow ing 3 months blood glucose began to rise, and HbAlc was 10.9% (normal 4.5%). Triglycerides were found to be 6.470 mg/dl. with an alkaline phosphatase level of 701 U/i (normal 60-200 U/l). Hcpatosplenomegaly and hypodensic areas in the liver were evident. There was a complaint of intermittent retrosternal pain. Nicotinic acid was stopped and insulin treatment instituted. Two weeks later serum cholesterol was 261 mg/dl. and triglycerides were 375 mg/dl and alkaline phosphatase normalized. However, during the following 4 months compliance problems, frequently observed in the posttrans plant follow-up of this patient, did not prevent adequate control of blood glucose and lipids. Unfortunately, the patient had a myocar dial infarction in April 1990. at which time her triglyceride level was in the 2,000-mg/dl range.
Dr. Feinstein Thank you. Dr. Wanner. Dr. Hörl will you comment on that and discuss the therapeutical approach.
Dr. Hörl A controlled hypocaloric fat-deficient diet controlled acute hypertriglyceridemia. Plasma exchange, a therapy of choice, was not selected in the present case in order to avoid imbalance of immunosuppression. Further treat ment was based on the concept to exclude or to remove all potential factors responsible for depressed lipolysis. First, a conversion of immunosuppressive therapy from CS-A to azathioprine was carried out. Reasons for conversion were: (1) Imprecise CS-A blood level measurements which showed enormous variations, probably due to the lipcmic serum. According to recent observations of Verrill et al. [31] and Nemunaitis et al. [32] CS-A can easily be bound to triglyceride-containing chylomycrons and very low density lipoprotein and consequently would not be bio logically available to either lymphocytes or kidney tissue. On the other hand, Versluis et al. [33, 34] studied nondia betic recipients of cadaveric renal transplants before and 3 months after conversion from CS-A to azathioprine. In all patients fasting serum triglyceride and cholesterol lev
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Corticosteroids have long been implicated as the cause of the hyperlipidemia after renal transplantation. Ponticelli et al. [ 15] and Chan et al. [22] have demonstrated a significant positive correlation between total steroid doses and serum triglyceride concentrations. Other au thors failed to find any difference in the maintenance dose of steroids between normo- and hyperlipidémie pa tients. Alternate-day steroid administration has also been discussed by several groups, with inconsistent results [5. 16, 23], The effects of antihypertensive drugs as well as proteinuria must always be considered when studying the etiology of posttransplant hyperlipidemia [22. 24-26]. CS-A has been demonstrated to independently cause elevations in serum cholesterol in a double-blind placebocontrolled randomized study in 36 patients with amyo trophic lateral sclerosis [27], Hodel et al. [28] studied serum lipids in a group of nondiabetic transplant recipi ents of conventional immunosuppression with azathio prine and prednisone in comparison with a transplanted group on CS-A monotherapy. Frequency and degree of hyperlipidemia in the two groups showed no significant difference. Harris et al. [29] studied 13 nondiabctic ca daveric renal transplant recipients 3 months after trans plantation when CS-A was given for immunosuppression and again 4 months after successful conversion to aza thioprine. Fasting serum cholesterol and triglyceride con centrations fell significantly after conversion, implying that discontinuation of CS-A might also reverse hyperlip idemia. In azathioprine-treated renal transplant recipi ents, the lipoprotein lipase activity was normal [7], but was found to be decreased in patients immunosuppressed with CS-A [30]. According to the lipoprotein analysis, the patient re sembled hyperlipidemia type V. The differential diagno sis of this disorder includes primary genetically deter mined dyslipidemias, familial lipoprotein lipase defi ciency or inhibitor, as well as familial type V hyperlipo proteinemia. The lipid pattern before transplantation (cholesterol 244 mg/dl, high-density lipoprotein choles terol 28, triglycerides 226 mg/dl) and a negative familial history gave no direct evidence for a genetic origin of the disease. Isoelectric focusing revealed an apoE 3/3 pheno type. There was no evidence for hypothyroidism, dysgammaglobulinemia, or systemic disease, and the grafted kid ney exhibited a normal creatinine value. However, the patient’s history revealed consumption of alcohol (about 30g/day) as well as the presence of diabetes mellitus. It has been shown that lipoprotein lipase is insufficiently activated in insulin deficiency.
Dr. Feinstein Thank you. Dr. Hört. Dr. Böhler will now present the 2nd case. Dr. Böhler A 44-year-old man with end-siage renal disease secondary to rap idly progressive glomerulonephritis received a cadaveric renal trans plant in January 1974. The grafted kidney functioned well until 1984 when recurrent glomerulonephritis with focal-segmental prolifera tions. marked interstitial fibrosis, and some vascular rejection devel oped. The immunosuppressive regimen over the years consisted of azathioprine (2.7 mg/kg b.w. daily) and prednisone (0.16 mg/kg b.w. every other day). The renal function continued to deteriorate, and chronic hemodialysis had to be restarted in June 1987. In March.
1989 the patient received a second cadaveric renal transplant. A rejection episode on the 5th postoperative day was successfully treated with prednisone three times 500 mg intravenously on every other day. and serum creatinine stabilized at 1.6 mg/dl. During the first 25 days, early-morning whole-blood trough levels of CS-A of up to 330ng/ml were measured (specific radioimmunoassay). Steady state CS-A blood levels between 120 and 200 ng/ml were achieved on day 25. Azathioprine was tapered from 200 mg to 75 mg daily during the first 6 weeks and was maintained for 12 months. Prednisone was tapered to 20 mg at the end of the 3rd month. Two months after receiving his second kidney transplant, the patient developed hyper glycemia with fasting blood glucose levels of 140-190 mg/dl. Dia betes mellitus treated with diet alone has persisted since then. Glucosuria varied with values of up to 9 g/day. Proteinuria of more than 500 mg/day started after 5 months, gradually increasing to 2.4 g/day 18 months after transplantation. Microscopic hematuria with eryth rocytes of typical renal morphology could repeatedly be detected. The glomerular filtration rate remained stable at 80 ml/min. The patient refused biopsy of the transplant.
Dr. Feinstein Thank you, Dr. Böhler. Dr. Hört will now discuss the etiology o f new onset o f diabetes mellitus after kidney transplantation. Dr. HörI
The carbohydrate metabolism after transplantation is frequently altered, and several possible causes can be implicated, since all these patients are simultaneously treated with several drugs. Steroids have long been recog nized as a cause for posttransplant hyperglycemia [35— 37], They increase the glycogen contents of tissues even in the fasting individual, and glycogen is synthesized at high and even at low blood glucose levels [38]. In our patient, combination therapy of prednisone with azathioprine over more than a decade after the first renal transplanta tion did not induce diabetes mellitus, although consider able weight gain was apparent (1974/67 kg, 1976/90 kg, 1987/89 kg; height 176 cm). Immediately after the second transplantation high doses of prednisone for several days also did not induce hyperglycemia. After 2 months of combined prednisone, azathioprine. and CS-A therapy, however, the first laboratory evidence of diabetes mellitus developed, and hyperglycemia and glucosuria increased progressively. Despite a negative family history for dia betes, it is possible that this patient might have developed the disease at some point in his life regardless of drug side effects. The close correlation between start of CS-A ther apy for his second transplant and development of dia betes mellitus, however, should be reason to review the current knowledge about CS-A effects on carbohydrate metabolism.
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els decreased. However, these authors diagnosed acute rejection episodes in 7 out of 30 patients within 6 months. It was concluded that the effects of conversion on lipid profile and glucose tolerance, with their putative pre ventive effects on atherosclerosis, may be trivial in view of the demonstrated increased risk for rejection and graft loss [33]. However, this therapeutical approach was not successful in this patient. (2) The suppressing potential of CS-A on lipoprotein lipase activity. Derfler et al. [30] have demonstrated that CS-A treated kidney recipients had lower levels of lipo protein lipase than a group of azathioprine-treated pa tients. Furthermore, the patient was repeatedly advised to cease the intake of alcohol. A maximal control of diabetes by weight reduction and blood glucose control was insti tuted. Estrogens and thiazide diuretics were avoided. Later during the course of the disease, the patient was unfortunately placed on nicotinic acid despite the knowl edge of glucose intolerance under this regimen. Conse quently, blood glucose values could not be controlled ade quately, as demonstrated by a HbAlc value of 10.1 %. In addition, nictoninic acid associated hepatopathy with ele vation of alkaline phosphatase (max. 760 U/l) emerged, but returned to normal 4 weeks after cessation of the drug. In summary, based on the knowledge of the Apo E phe notype. family history, and pretransplant lipid profile, an underlying familial combined hyperlipidemia which ex acerbated in the presence of a combination of multipledrug regimen, diabetes mellitus, and moderate alcohol consumption would be most likely the cause of the lifethreatening lipoprotein profile in this patient. As demon strated intermittently, adherence to an appropriate di etary protocol and adequate control of diabetes mellitus could lower serum triglycerides to near normal values.
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inhibition of insulin secretion by CS-A has repeatedly been documented [51-53], Yale et al. [54] and Hahn et al. [55] demonstrated that therapeutic doses of CS-A induce glucose intolerance. An increase of the CS-A dose worsens glucose intolerance due to inhibition of insulin secretion and/or synthesis. A study by Yale et al. [56] suggests that glucose intoler ance after CS-A administration is due to simultaneous peripheral insulin resistance and inhibition of insulin secretion by (3-cells. Isolated hepatocytes obtained from CS-A-treated rats show significantly lower basal rates of glycogen synthesis. While addition of insulin stimulated glycogen synthesis in control animals. CS-A-exposed cells failed to respond to the hormone. In diabetics CS-A decreases the number of insulin receptors [57] on erythro cytes. However. Betschart et al. [58] found no alteration in the number of cellular insulin receptors or in the bind ing affinity of hepatocytes of nondiabetic animals. The role of insulin receptors for the peripheral insulin resis tance after CS-A therapy is currently not clear. Riegel et al. [59] investigated direct effects of CS-A on the carbohydrate metabolism in peripheral tissues. The activity of phosphoenol pyruvate carboxykinase, a key enzyme of gluconeogenesis, was significantly enhanced in the liver of rats receiving CS-A. The activity of the liver glycogen synthetase significantly decreased after CS-A, and consequently the glycogen content in the liver was reduced, in agreement with the hypoinsulinemia of the CS-A treated rats. According to these data, hyperglycemia is mainly due to inhibition of liver glycogen synthesis [60] which is partly due to hypoinsulinemia. CS-A not only inhibits the induction of glycogen syn thesis by insulin in isolated rat hepatocytes, but also the glycogenolysis induced by glucagon which may explain the similar glycogen contents in liver cells of control and CS-A-treated animals [58]. In another study [61], how ever. kidney glycogen and glucose content were higher in rats treated with 50 mg CS-A/kg body weight, probably due to enhanced ketone body utilization of the kidney. CS-A also inhibits renal mitochondrial electron transport and respiration [62. 63], thus the last steps in glucose metabolism. In summary, there is little doubt that CS-A has the capacity to significantly disturb the carbohydrate metabo lism. The multiplicity of possible causes for diabetes mel litus in transplanted patients makes it difficult, however, to clearly define the magnitude of the risk for an individ ual patient. Yoshimura et al. [42] found a 30% higher incidence of diabetes mellitus after CS-A (17.1 %) than in azathioprine (12.8%) treated renal transplant recipients.
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Strong clinical evidence has accumulated since 1983, implicating CS-A as a factor in disturbed carbohydrate metabolism after transplantation. Gunnarsson et al. [39] first reported deteriorating glucose metabolism after ad ministration of CS-A in pancreatic transplant recipients. These findings were corroborated by several other studies in patients treated with CS-A after renal transplantation [40] or heart transplantation [41], Comparing renal trans plant recipients, Yoshimura et al. [42] found a higher inci dence of diabetes mellitus requiring insulin therapy in patients treated with CS-A (17.1 %) than with the use of azathioprine (12.8%), despite significantly lower methylprednisolone doses in the CS-A-treated group. The onset of diabetes mellitus correlated with high CS-A through levels. Insulin treatment was no longer needed in 6 of 8 patients 3 months after conversion of immunosuppres sion from CS-A to azathioprine. In another series, oral glucose tolerance testing induced less hyperglycemia 3 months after conversion from CS-A to azathioprine [29, 34], although fasting glucose or insulin concentrations did not change. In contrast, glucose tolerance deteriorated, and the insulinogenic index, an indicator of insulin release, decreased when CS-A was introduced for immu nosuppression in renal tansplant patients [43], Ôst et al. [44] found normal K values during intravenous glucose tolerance testing in 13 out of 14 renal transplant patients treated with azathioprine and prednisolone. However, only 9 out of 19 patients treated with CS-A and predniso lone had normal K values. Smith et al. [45] also observed an increasing fasting glucose level and an impaired insulin response with the use of CS-A as compared with azathio prine regimens. Suppression of insulin levels correlated with CS-A trough levels [46], In diabetic patients detrimental effects on carbohy drate metabolism have to be balanced against CS-A’s use fulness as an immunosuppressant after pancreatic trans plantation as well as in early type I diabetes to minimize autoimmune destruction of islet cells [47], Animal and in vitro studies were conducted to eluci date the mechanisms by which CS-A might interfere with carbohydrate metabolism. CS-A was found to decrease insulin production and release from pancreatic (3-cells. A reduced number or responsiveness of insulin receptors in peripheral tissues may contribute to peripheral insulin resistance. CS-A affects endocrine more than exocrine pancreatic function [48], It induces an increased permeability of pan creatic (3-cells [49]. In the mouse at 50 mg CS-A/kg body weight/day hypoinsulinemia, degranulation, and hy dropic degeneration of islet (3-cells [50] develops. The
A recent study of 901 transplanted patients [64] described an overall much lower rate of diabetes mellitus of only 4% and did not see a higher incidence in CS-A-treated patients. At the current state of knowledge, the beneficial effects of CS-A for renal transplant survival outweigh markedly the possible risks of induction of diabetes melli tus. The carbohydrate metabolism should regularly be monitored, particularly in patients at increased risk to
develop diabetes mellitus, e.g., patients with a family his tory of diabetes and possibly those with HLA B8. If dia betes mellitus develops in a transplanted patient, conver sion of immunosuppression from CS-A to azathioprine might be considered, but careful monitoring of those patients is recommended in order to avoid rejection epi sodes.
R eferences 14 Ponticelli C, Gianluigi B, Cantaluppi A. Donati C, Annoni G. Brancaccio D: Lipid abnor malities in maintenance dialysis patients and renal transplant recipients. Kidney Int 1978; 13:72-78. 15 Ponticelli C, Barbi GL. Cantaluppi A, De Vecchi A, Annoni G, Donati C, Cecchettin M: Lipid disorders in renal transplant recipients. Nephron 1978;20:189-195. 16 Saldanha LF, Hurst KS. Amend WJC, Lazarus JM, Lowrie EG, Ingelfinger J, Grupe W. Levey R: Hyperlipidemia after renal transplantation in children. Am J Dis Child 1976; 130:951 — 953. 17 Savdie E, Gibson J, Stewart J. Simons L: Highdensity lipoprotein in chronic failure and after renal transplantation. Br Med J I979:i:928930. 18 Jung K. Scheifler A, Blank W, Scholz D, Schuzle B-D, Hansen C: Changed composition of high-density lipoprotein subclasses HDL2 and HDL3 after renal transplantation. Transplan tation 1988:46:407-409. 19 Cassader M. Ruiu G. Gambino R. Alemanno N, Triolo G. Pagano G: Lipoprotein-apolipoprotein changes in renal transplant recipients: A 2-year follow-up. Metabolism 1991:40:922925. 20 Kasiske BL, Tortorice KL, heim-Duthoy KL, Walid MA. Rao KV: The adverse impact of cyclosporine on serum lipids in renal trans plant recipients. Am J Kidney Dis 1991:17: 700-707. 21 Hricik DE. Mayes JT. Schulak JA: Indepen dent effects o f cyclosporine and prednisone on posttransplant hypercholesterolemia. Am J Kidney Dis 1991;18:353-358. 22 Chan MK. Varghese Z. Persaud JW. Fernando ON. Moorhead JF: The role of multiple phar macotherapy in the pathogenesis of hyperlipid emia after renal transplantation. Clin Nephrol 1981;15:309-313. 23 Curtis JJ, Galla HJ, Woodford SY. Lucas BA, Luke RG: Effect of alternate-day prednisone on plasma lipids in renal transplant recipients. Kidney Int 1982;22:42-47. 24 Hört WH. Hörl M. Heidland A: Fettstoffwechselslörungen bei Nicrenkrankheiten: Pathoge netische Mechanismen. Klin Wochenschr 1982;60:327-336.
25 Jackson JM. Lee HA: The role o f propranolol therapy and proteinuria in the etiology of post renal transplantation hyperlipidemia. Clin Nephrol 1982;18:95-100. 26 Lowry RP. Soltys G, Mangel R. Kwiterovitch P. Snidermann AD: Type 11 hyperlipidemia, hyperapobetalipoproteinemia. and hyperalphal poprotcinemia following renal transplan tation: Prevalence and precipitating factors. Transplant Proc 1987:19:2229-2332. 27 Ballantyne CM. Podet EJ. Patsch WP, Harati Y, Appel V, Gotto AM, Young JB: Effects of cyclosporine therapy on plasma lipoprotein levels. JAMA 1989:262:53-56. 28 Hodel K. Mordasini RC. Brunner FP. Thiel G: Cyclosporin A und Hyperlipidamie nach Nierentransplantation. Schweiz Med Wochenschr 1986;116:885-888. 29 Harris KPG. Russell GI, Parvin SD. Veitch PS, Walls J: Alterations in lipid and carbohydrate metabolism attributable to cyclosporin A in renal transplant recipients. Br Med J 1986:292:
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30 Derfler K. Hayde M. Heinz G. Hirschi MM. Steger G. Hauser A-C. Balcke P. Widhalm D: Decreased postheparin lipolytic activity in re nal transplant recipients with cyclosporin A. Kidney Int 1991;40:720-727. 31 Verrill HL, Girgis RE, Easterling RE. Malhi BS, Mueller WF: Distribution of cyclosporin in blood of a renal-transplant recipient with type V hyperlipoproteinemia. Clin Chem 1957:33. 32 Nemunaitis J, Deeg HJ, Yee GC: High cyclo sporin levels after bone marrow transplanta tion associated with hypertriglyceridaemia. Lancet 1986;ii: 744-745. 33 Versluis DJ. Wenting GJ. Weimar W: Altera tions in lipid and carbohydrate metabolism attributable to cyclosporin A in renal trans plant recipients. Br Med J 1987:292:272. 34 Versluis DJ. Wenting GJ. Derkx FHM. Schalekamp MADH, Jeekel J. Weimar W: Who should be converted from cyclosporine to con ventional immunosuppression in kidney trans plantation, and whv. Transplantation 1987:44: 387-389. 35 Amer P, Gunnarsson R, Blomdahl S. Groth CG: Some characteristics of steroid diabetes: A study in renal-transplant recipients receiving high-dose corticosteroid therapy. Diabetes Care 1983;6:23-25.
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1 Ghosh P. Evans DB. Tomlinson SA, Caine RY: Plasma lipids following renal transplantation. Transplantation 1973;15:521-523. 2 Bagdade J, Casaretto A, Albers J: Effects of chronic uremia, hemodialysis, and transplanta tion on plasma lipids and lipoproteins in man. J Lab Clin Med 1976;87:37-48. 3 Bagdade JD. Albers JJ: Plasma high-density lipoprotein concentrations in chronic-hemodi alysis and renal-transplant patients. N Engl J Med 1977;296:1436-1440. 4 Casaretto A. Marchioro TL. Goldsmith R, Bag dade JD; Hyperlipidaemia after successful re nal transplantation. Lancet 1974;i:481 —484. 5 Cattran DC, Steiner G, Wilson DR. Fenton SSA: Hyperlipidemia after renal transplanta tion: Natural history and pathophysiology. Ann Intern Med 1979;91:554-559. 6 Chatterjee SN, Chin HP. Azen SP. Blankenhorn DH, Boothe S, Massry SG: Abnormal serum lipid pattern in primary renal allograft recipients. Surgery 1977:82:655-659. 7 Crawford GA. Savdie E, Stewart JH: Heparinreleased plasma lipases in chronic renal failure and after renal transplantation. Clin Sei 1979; 57:155-165. 8 Frey FJ. Mordasini RC. Schlumpf E, Marone C. Montandon A. Flury W, Riva G: Serumli pide bei eingeschränkter Nierenfunktion und nach Nierentransplantation. Schweiz Med Wochenschr 1977:107:1248-1253. 9 Ibels LS. Alfrey AC. Subryan V. Weil R: Hyper lipidemia following renal transplantation. Trans Am SocArtif Intern Organs 1975:22:4653. 10 Ibels LS. Simons LA, King JO, Williams PF, Neale FC, Stewart JH: Studies on the nature and causes of hyperlipemia of uremia, mainte nance dialysis and renal transplantation. Q J Med 1975:44:601-614. 11 Ibels LS. Reardon MF, Nestel PJ: Plasma post heparin lipolytic activity and triglyceride clear ance in uremia and hemodialysis patients and renal allograft recipients. J Lab Clin Med 1976; 87:648-658. 12 Ibels LS. Alfrey AC, Weil R: Hyperlipidemia in adult, pediatric and diabetic renal transplant recipients. Am J Med 1978:64:634-642. 13 Mordasini R. Frey F. Flury W. Klose G. Greten H: Selective deficiency of hepatic triglyceride lipase in uremic patients. N Engl J Med 1977; 297:1362-1366.
36 Friedman EA. Shyh T. Beyer MM, Manis T. Bull KMH: Postlransplant diabetes in kidney transplant recipients. Am J Nephrol 1985;5: 196-202. 37 McGeown MG. Douglas JF. Brown WA, Don aldson RA, Kennedy JA, Loughride WG, Metha S. Nelson SD. Doherty CC. Johnstone R. Todd G. Hill CM: Advantages o f low dose ste roid from the day after renal transplantation. Transplantation 1987:29:287-289. 38 Hers HG: Effects of glucocorticoids on carbo hydrate metabolism. Agents Actions 1985; 17: 248-254. 39 Gunnarsson R, Klintmalm R. Lundgren G. Wilczek H, Ostman J, Groth CG: Deteriora tion in glucose metabolism in pancreatic trans plant recipients given cyclosporin. Lancet 1983:ii:571—572. 40 Yagisawa T. Takahashi K. Teraoka S. Toma H, Agishi T, Ota K: Deterioration in glucose me tabolism in cyclosporin-treated kidney trans plant recipients and rats. Transplant Proc 1986;18:1548-1551. 41 Ladowski JS. Kormos RL. Uretsky BF. Lee A. Curran M. Clark R. Armitage JM. Griffith BP. Hardesty RL: Posttransplantation diabetes mellitus in heart transplant recipients. J Heart T ransplant 1989;8:181-183. 42 Yoshimura N, Nakai 1, Ohmori Y, Aikawa 1, Fukuda M. Yasumura T. Matsui S, Hamashima T. Oka T: Effect of cyclosporine on the endocrine and exocrine pancreas in kidney transplant recipients. Am J Kidney Dis 1981: 1: 11-17. 43 Yamazaki Y. Takahashi K. Yagisawa T. Oba S, Teraoka S, Toma H, Agishi T. Ota K: Altera tions in glucose tolerance and insulin release in renal transplant recipients receiving cyclospo rine and corticosteroid. Transplant Proc 1988; 20:158-159. 44 Ôst L, Tyden G. Fehrman I: Impaired glucose tolerance in cyclosporine-prednisolone-treatcd renal graft recipients. Transplantation 1988: 46:370-372.
45 Smith WGJ. Thomas S. Griffin PJA. Salaman JR: Comparative effects of immunosuppres sive therapy on glucose metabolism (abstract). Nephrol Dial Transplant 1988:3:581. 46 van Schilfgaardc R. van der Burg M. van Suylichem PTR. Frölich M. Gooszen HG. Moolenaar AJ: Interference by cyclosporine with the endocrine function of the canine pancreas. Transplantation 1987;44:13-16. 47 Dupre J, Stiller CR. Gent M, Donner A. von Graffenried B. Heinrichs D, Jenner M. Keown P, Mahon J, Martcll R, Momah CL, Murphy G. Rodger NW. Wolfe BM: Clinical trials of cyclosporin in IDDM. Diabetes Care 1988:11 (suppl 1):37—44. 48 Müller MK. Bergmann K. Degenhardt H. Klöppel G. Löhr M. Coone HJ. Goebell H: Dif ferential sensitivity of rat exocrine and endo crine pancreas to cyclosporine. Transplanta tion 1988;45:698-700. 49 Jansson L. Sandler S: The influence of cyclo sporin A on the vascular permeability of the pancreatic islets and on diabetes induced by multiple low doses of streptozotocin in the mouse. Virchows Arch 1988:412:225-230. 50 Heimchen U. Schmidt WE. Siegel EG. Creutz feldt W: Morphological and functional changes of pancreatic B-cells in cyclosporinc-A-treatcd rats. Diabetologia 1984:27:416-418. 5 1 Andcrsson A. Borg H. Hallberg A, Hellerstrom C. Sandler S. Schnell A: Long-term effects of cyclosporine A on cultured mouse pancreatic islets. Diabetologia 1984:27:66-69. 52 Nielsen JH. Mandrup-Poulsen T. Nerup J: Di rect effects of cyclosporin A on human pan creatic ß-cells. Diabetes 1986:35:1049—1052. 53 Robertson RP: Cyclosporin-induced inhibition of insulin secretion in isolated rat islets and HIT cells. Diabetes 1986;35:1016-1019. 54 Yale JF. Roy RD. Grose M. Seemaycr TA. Murphy GF. Marliss EB: Effects of cyclospo rine on glucose tolerance in the rat. Diabetes 1985:34:1309-1313.
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61 Bertani T. Perico N, Abbate M, Battaglia C. Rcmuzzi G: Renal injury induced by long-term administration of cyclosporin A to rats. Am J Pathol 1987;127:569-579. 62 Jung K, Pergande M: Influence of cyclosporin A on the respiration of isolated rat kidney mitochondria. FEBS Lett 1985:183:167-169. 63 Jung K. Reinholdt C. Scholz D: Inhibited effi ciency of kidney mitochondria isolated from rats treated with cyclosporin A. Nephron 1987: 45:43-45. 64 von Kiparski A. Frei D. Uhlschmid G, Largiader F. Binswanger U: Post-transplant dia betes mellitus in renal allograft recipients: A matched-pair control study. Nephrol Dial Transplant 1990:5:220-225.'
Participants: Christoph Wannerb Joachim Bdhlerh Walter H. Horlc a Professor of Medicine, University of Southern California School of Medicine. Los Angeles. Calif., USA; b Assistant Professor of Medicine, University of Freiburg; c Professor of Medicine and Director, Division of Nephrology. University of Homburg/Saar. FRG
Endocrine and Metabolic Disorders following Kidney Transplantation
K e y w o rd s
Kidney transplantation Ciclosporin Azathioprine Cholesterol Triglyceride Diabetes mellitus Insulin
Dr. Feinstein Today’s case presentation concerns 2 patients with met abolic disturbances following cadaveric renal transplanta tion. Dr. Wanner, will you present the 1st case? Dr. Wanner A 48-year-old woman with end-stage renal disease secondary to interstitial nephritis received a cadaveric renal transplant on Janu ary 6. 1989. Twenty-Five years before, unilateral nephrectomy had been performed due to kidney tuberculosis. There was no history of metabolic or endocrine disorders before or during the hemodialysis period. A hysterectomy was performed in 1983 due to suspected car cinoma. After transplantation the patient developed moderate hy perglycemia (blood glucose < 200 mg/dl) during rejection therapy. A cytomegalovirus infection was diagnosed serologically without clini cal symptoms. Despite a reduction of steroids during the follow-up course, elevated blood glucose values had to be controlled by diet and oral antidiabetic therapy. Otherwise transplantation follow-up was uncomplicated, and serum creatinine fell to 0.9 mg/dl. Five months later spontaneous seizures occurred which were treated with carbamazepine. Ten months after transplantation, a routine laboratory' evaluation revealed serum triglycerides of 1.991 mg/dl and a serum cholesterol level of 328 mg/dl. A therapy with a fibric acid derivative (bedobrate I00mg/day) was started. Five months later, while on bcclobrate. serum triglycerides rose to 11,077 mg/dl and cholesterol to 1,033 mg/dl. The patient was admitted to the hospital. A cholester ol-restricted diet (cholesterol content < 200 mg/day) decreased se rum cholesterol to 520 mg/dl and triglyceride to 1.740 mg/dl over a
Edited transcript of Renal Rounds held at the University of Freiburg. FRG, October 1991.
Received: February 7 . 1992 Accepted: May 22,1992
period of 14 days. Laboratory analysis at the time of admission revealed sodium 131 mmol/1 and potassium 3.5mmol/l. Chloride was 94 mmol/I. and serum lipase was 12 U/l: a-amylase was 44 U/l. Several parameters of serum chemistry could not be measured due to lipemie serum. Medication at hospital admission consisted of ciclosporinA (CS-A), prednisolone (5 mg/day). allopurinol (300 mg/day), carbamazepine (400 mg/day), xipamide (10 mg/day), isoniazid (100 mg/day), conjugated estrogens (1.25 mg/day) and medrogesterone (5 mg/day), beclobrate (100 mg/day). and digitoxin.
Dr. Feinstein Thank you, Dr. Wanner. Dr. Horl will now discuss the differential diagnosis o f hyperlipoproteinemia after kidney transplantation. Could you please focus on the special situ ation o f this patient? Dr. Horl
Since Ghosh et al. [1] first noted a high prevalence of hyperlipidemia among transplant recipients, hypertriglyc eridemia and hypercholesterolemia [2-21] have often been observed in patients after successful renal transplan tation. Ibels et al. [ 12] studied lipoprotein electrophoreses in 175 adult, 19 pediatric, and 11 diabetic transplant recipients and found type IV hyperlipoproteinemia in 26%. type lib in 23, and type lia in 11 % of the patients.
E.l. Feinstein. MD University of Southern California School of Medicine Los Angeles. Calif. (USA)
€> 1992 S. Kargcr AG. Basel 0250-8095/92/0125-0363 $2.75/0
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Moderator: Eben I. Feinsteina
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Dr. Feinstein Thank you. Dr. Hört. Dr. Wanner please could you describe the patient ’s follow-up after discharge from the hospital? Dr. Wanner After discharge from the hospital the patient’s triglyceride values were controlled by a calorie-restricted antidiabetic diet and oral antidiabetic medication. A weight reduction from 60 to 54 kg was achieved. However. 3 months later serum triglyceride levels began to rise and varied in the 2.000 to 4.000-mg/dl range. A therapy with nicotinic acid (2 g/day) was prescribed elsewhere. During the follow ing 3 months blood glucose began to rise, and HbAlc was 10.9% (normal 4.5%). Triglycerides were found to be 6.470 mg/dl. with an alkaline phosphatase level of 701 U/i (normal 60-200 U/l). Hcpatosplenomegaly and hypodensic areas in the liver were evident. There was a complaint of intermittent retrosternal pain. Nicotinic acid was stopped and insulin treatment instituted. Two weeks later serum cholesterol was 261 mg/dl. and triglycerides were 375 mg/dl and alkaline phosphatase normalized. However, during the following 4 months compliance problems, frequently observed in the posttrans plant follow-up of this patient, did not prevent adequate control of blood glucose and lipids. Unfortunately, the patient had a myocar dial infarction in April 1990. at which time her triglyceride level was in the 2,000-mg/dl range.
Dr. Feinstein Thank you. Dr. Wanner. Dr. Hörl will you comment on that and discuss the therapeutical approach.
Dr. Hörl A controlled hypocaloric fat-deficient diet controlled acute hypertriglyceridemia. Plasma exchange, a therapy of choice, was not selected in the present case in order to avoid imbalance of immunosuppression. Further treat ment was based on the concept to exclude or to remove all potential factors responsible for depressed lipolysis. First, a conversion of immunosuppressive therapy from CS-A to azathioprine was carried out. Reasons for conversion were: (1) Imprecise CS-A blood level measurements which showed enormous variations, probably due to the lipcmic serum. According to recent observations of Verrill et al. [31] and Nemunaitis et al. [32] CS-A can easily be bound to triglyceride-containing chylomycrons and very low density lipoprotein and consequently would not be bio logically available to either lymphocytes or kidney tissue. On the other hand, Versluis et al. [33, 34] studied nondia betic recipients of cadaveric renal transplants before and 3 months after conversion from CS-A to azathioprine. In all patients fasting serum triglyceride and cholesterol lev
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Endocrine and Metabolic Disorders following Kidney Transplantation
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Corticosteroids have long been implicated as the cause of the hyperlipidemia after renal transplantation. Ponticelli et al. [ 15] and Chan et al. [22] have demonstrated a significant positive correlation between total steroid doses and serum triglyceride concentrations. Other au thors failed to find any difference in the maintenance dose of steroids between normo- and hyperlipidémie pa tients. Alternate-day steroid administration has also been discussed by several groups, with inconsistent results [5. 16, 23], The effects of antihypertensive drugs as well as proteinuria must always be considered when studying the etiology of posttransplant hyperlipidemia [22. 24-26]. CS-A has been demonstrated to independently cause elevations in serum cholesterol in a double-blind placebocontrolled randomized study in 36 patients with amyo trophic lateral sclerosis [27], Hodel et al. [28] studied serum lipids in a group of nondiabetic transplant recipi ents of conventional immunosuppression with azathio prine and prednisone in comparison with a transplanted group on CS-A monotherapy. Frequency and degree of hyperlipidemia in the two groups showed no significant difference. Harris et al. [29] studied 13 nondiabctic ca daveric renal transplant recipients 3 months after trans plantation when CS-A was given for immunosuppression and again 4 months after successful conversion to aza thioprine. Fasting serum cholesterol and triglyceride con centrations fell significantly after conversion, implying that discontinuation of CS-A might also reverse hyperlip idemia. In azathioprine-treated renal transplant recipi ents, the lipoprotein lipase activity was normal [7], but was found to be decreased in patients immunosuppressed with CS-A [30]. According to the lipoprotein analysis, the patient re sembled hyperlipidemia type V. The differential diagno sis of this disorder includes primary genetically deter mined dyslipidemias, familial lipoprotein lipase defi ciency or inhibitor, as well as familial type V hyperlipo proteinemia. The lipid pattern before transplantation (cholesterol 244 mg/dl, high-density lipoprotein choles terol 28, triglycerides 226 mg/dl) and a negative familial history gave no direct evidence for a genetic origin of the disease. Isoelectric focusing revealed an apoE 3/3 pheno type. There was no evidence for hypothyroidism, dysgammaglobulinemia, or systemic disease, and the grafted kid ney exhibited a normal creatinine value. However, the patient’s history revealed consumption of alcohol (about 30g/day) as well as the presence of diabetes mellitus. It has been shown that lipoprotein lipase is insufficiently activated in insulin deficiency.
Dr. Feinstein Thank you. Dr. Hört. Dr. Böhler will now present the 2nd case. Dr. Böhler A 44-year-old man with end-siage renal disease secondary to rap idly progressive glomerulonephritis received a cadaveric renal trans plant in January 1974. The grafted kidney functioned well until 1984 when recurrent glomerulonephritis with focal-segmental prolifera tions. marked interstitial fibrosis, and some vascular rejection devel oped. The immunosuppressive regimen over the years consisted of azathioprine (2.7 mg/kg b.w. daily) and prednisone (0.16 mg/kg b.w. every other day). The renal function continued to deteriorate, and chronic hemodialysis had to be restarted in June 1987. In March.
1989 the patient received a second cadaveric renal transplant. A rejection episode on the 5th postoperative day was successfully treated with prednisone three times 500 mg intravenously on every other day. and serum creatinine stabilized at 1.6 mg/dl. During the first 25 days, early-morning whole-blood trough levels of CS-A of up to 330ng/ml were measured (specific radioimmunoassay). Steady state CS-A blood levels between 120 and 200 ng/ml were achieved on day 25. Azathioprine was tapered from 200 mg to 75 mg daily during the first 6 weeks and was maintained for 12 months. Prednisone was tapered to 20 mg at the end of the 3rd month. Two months after receiving his second kidney transplant, the patient developed hyper glycemia with fasting blood glucose levels of 140-190 mg/dl. Dia betes mellitus treated with diet alone has persisted since then. Glucosuria varied with values of up to 9 g/day. Proteinuria of more than 500 mg/day started after 5 months, gradually increasing to 2.4 g/day 18 months after transplantation. Microscopic hematuria with eryth rocytes of typical renal morphology could repeatedly be detected. The glomerular filtration rate remained stable at 80 ml/min. The patient refused biopsy of the transplant.
Dr. Feinstein Thank you, Dr. Böhler. Dr. Hört will now discuss the etiology o f new onset o f diabetes mellitus after kidney transplantation. Dr. HörI
The carbohydrate metabolism after transplantation is frequently altered, and several possible causes can be implicated, since all these patients are simultaneously treated with several drugs. Steroids have long been recog nized as a cause for posttransplant hyperglycemia [35— 37], They increase the glycogen contents of tissues even in the fasting individual, and glycogen is synthesized at high and even at low blood glucose levels [38]. In our patient, combination therapy of prednisone with azathioprine over more than a decade after the first renal transplanta tion did not induce diabetes mellitus, although consider able weight gain was apparent (1974/67 kg, 1976/90 kg, 1987/89 kg; height 176 cm). Immediately after the second transplantation high doses of prednisone for several days also did not induce hyperglycemia. After 2 months of combined prednisone, azathioprine. and CS-A therapy, however, the first laboratory evidence of diabetes mellitus developed, and hyperglycemia and glucosuria increased progressively. Despite a negative family history for dia betes, it is possible that this patient might have developed the disease at some point in his life regardless of drug side effects. The close correlation between start of CS-A ther apy for his second transplant and development of dia betes mellitus, however, should be reason to review the current knowledge about CS-A effects on carbohydrate metabolism.
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els decreased. However, these authors diagnosed acute rejection episodes in 7 out of 30 patients within 6 months. It was concluded that the effects of conversion on lipid profile and glucose tolerance, with their putative pre ventive effects on atherosclerosis, may be trivial in view of the demonstrated increased risk for rejection and graft loss [33]. However, this therapeutical approach was not successful in this patient. (2) The suppressing potential of CS-A on lipoprotein lipase activity. Derfler et al. [30] have demonstrated that CS-A treated kidney recipients had lower levels of lipo protein lipase than a group of azathioprine-treated pa tients. Furthermore, the patient was repeatedly advised to cease the intake of alcohol. A maximal control of diabetes by weight reduction and blood glucose control was insti tuted. Estrogens and thiazide diuretics were avoided. Later during the course of the disease, the patient was unfortunately placed on nicotinic acid despite the knowl edge of glucose intolerance under this regimen. Conse quently, blood glucose values could not be controlled ade quately, as demonstrated by a HbAlc value of 10.1 %. In addition, nictoninic acid associated hepatopathy with ele vation of alkaline phosphatase (max. 760 U/l) emerged, but returned to normal 4 weeks after cessation of the drug. In summary, based on the knowledge of the Apo E phe notype. family history, and pretransplant lipid profile, an underlying familial combined hyperlipidemia which ex acerbated in the presence of a combination of multipledrug regimen, diabetes mellitus, and moderate alcohol consumption would be most likely the cause of the lifethreatening lipoprotein profile in this patient. As demon strated intermittently, adherence to an appropriate di etary protocol and adequate control of diabetes mellitus could lower serum triglycerides to near normal values.
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inhibition of insulin secretion by CS-A has repeatedly been documented [51-53], Yale et al. [54] and Hahn et al. [55] demonstrated that therapeutic doses of CS-A induce glucose intolerance. An increase of the CS-A dose worsens glucose intolerance due to inhibition of insulin secretion and/or synthesis. A study by Yale et al. [56] suggests that glucose intoler ance after CS-A administration is due to simultaneous peripheral insulin resistance and inhibition of insulin secretion by (3-cells. Isolated hepatocytes obtained from CS-A-treated rats show significantly lower basal rates of glycogen synthesis. While addition of insulin stimulated glycogen synthesis in control animals. CS-A-exposed cells failed to respond to the hormone. In diabetics CS-A decreases the number of insulin receptors [57] on erythro cytes. However. Betschart et al. [58] found no alteration in the number of cellular insulin receptors or in the bind ing affinity of hepatocytes of nondiabetic animals. The role of insulin receptors for the peripheral insulin resis tance after CS-A therapy is currently not clear. Riegel et al. [59] investigated direct effects of CS-A on the carbohydrate metabolism in peripheral tissues. The activity of phosphoenol pyruvate carboxykinase, a key enzyme of gluconeogenesis, was significantly enhanced in the liver of rats receiving CS-A. The activity of the liver glycogen synthetase significantly decreased after CS-A, and consequently the glycogen content in the liver was reduced, in agreement with the hypoinsulinemia of the CS-A treated rats. According to these data, hyperglycemia is mainly due to inhibition of liver glycogen synthesis [60] which is partly due to hypoinsulinemia. CS-A not only inhibits the induction of glycogen syn thesis by insulin in isolated rat hepatocytes, but also the glycogenolysis induced by glucagon which may explain the similar glycogen contents in liver cells of control and CS-A-treated animals [58]. In another study [61], how ever. kidney glycogen and glucose content were higher in rats treated with 50 mg CS-A/kg body weight, probably due to enhanced ketone body utilization of the kidney. CS-A also inhibits renal mitochondrial electron transport and respiration [62. 63], thus the last steps in glucose metabolism. In summary, there is little doubt that CS-A has the capacity to significantly disturb the carbohydrate metabo lism. The multiplicity of possible causes for diabetes mel litus in transplanted patients makes it difficult, however, to clearly define the magnitude of the risk for an individ ual patient. Yoshimura et al. [42] found a 30% higher incidence of diabetes mellitus after CS-A (17.1 %) than in azathioprine (12.8%) treated renal transplant recipients.
Feinstein/Wanncr/Böhler/Hörl
Endocrine and Metabolic Disorders following Kidney Transplantation
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Strong clinical evidence has accumulated since 1983, implicating CS-A as a factor in disturbed carbohydrate metabolism after transplantation. Gunnarsson et al. [39] first reported deteriorating glucose metabolism after ad ministration of CS-A in pancreatic transplant recipients. These findings were corroborated by several other studies in patients treated with CS-A after renal transplantation [40] or heart transplantation [41], Comparing renal trans plant recipients, Yoshimura et al. [42] found a higher inci dence of diabetes mellitus requiring insulin therapy in patients treated with CS-A (17.1 %) than with the use of azathioprine (12.8%), despite significantly lower methylprednisolone doses in the CS-A-treated group. The onset of diabetes mellitus correlated with high CS-A through levels. Insulin treatment was no longer needed in 6 of 8 patients 3 months after conversion of immunosuppres sion from CS-A to azathioprine. In another series, oral glucose tolerance testing induced less hyperglycemia 3 months after conversion from CS-A to azathioprine [29, 34], although fasting glucose or insulin concentrations did not change. In contrast, glucose tolerance deteriorated, and the insulinogenic index, an indicator of insulin release, decreased when CS-A was introduced for immu nosuppression in renal tansplant patients [43], Ôst et al. [44] found normal K values during intravenous glucose tolerance testing in 13 out of 14 renal transplant patients treated with azathioprine and prednisolone. However, only 9 out of 19 patients treated with CS-A and predniso lone had normal K values. Smith et al. [45] also observed an increasing fasting glucose level and an impaired insulin response with the use of CS-A as compared with azathio prine regimens. Suppression of insulin levels correlated with CS-A trough levels [46], In diabetic patients detrimental effects on carbohy drate metabolism have to be balanced against CS-A’s use fulness as an immunosuppressant after pancreatic trans plantation as well as in early type I diabetes to minimize autoimmune destruction of islet cells [47], Animal and in vitro studies were conducted to eluci date the mechanisms by which CS-A might interfere with carbohydrate metabolism. CS-A was found to decrease insulin production and release from pancreatic (3-cells. A reduced number or responsiveness of insulin receptors in peripheral tissues may contribute to peripheral insulin resistance. CS-A affects endocrine more than exocrine pancreatic function [48], It induces an increased permeability of pan creatic (3-cells [49]. In the mouse at 50 mg CS-A/kg body weight/day hypoinsulinemia, degranulation, and hy dropic degeneration of islet (3-cells [50] develops. The
A recent study of 901 transplanted patients [64] described an overall much lower rate of diabetes mellitus of only 4% and did not see a higher incidence in CS-A-treated patients. At the current state of knowledge, the beneficial effects of CS-A for renal transplant survival outweigh markedly the possible risks of induction of diabetes melli tus. The carbohydrate metabolism should regularly be monitored, particularly in patients at increased risk to
develop diabetes mellitus, e.g., patients with a family his tory of diabetes and possibly those with HLA B8. If dia betes mellitus develops in a transplanted patient, conver sion of immunosuppression from CS-A to azathioprine might be considered, but careful monitoring of those patients is recommended in order to avoid rejection epi sodes.
R eferences 14 Ponticelli C, Gianluigi B, Cantaluppi A. Donati C, Annoni G. Brancaccio D: Lipid abnor malities in maintenance dialysis patients and renal transplant recipients. Kidney Int 1978; 13:72-78. 15 Ponticelli C, Barbi GL. Cantaluppi A, De Vecchi A, Annoni G, Donati C, Cecchettin M: Lipid disorders in renal transplant recipients. Nephron 1978;20:189-195. 16 Saldanha LF, Hurst KS. Amend WJC, Lazarus JM, Lowrie EG, Ingelfinger J, Grupe W. Levey R: Hyperlipidemia after renal transplantation in children. Am J Dis Child 1976; 130:951 — 953. 17 Savdie E, Gibson J, Stewart J. Simons L: Highdensity lipoprotein in chronic failure and after renal transplantation. Br Med J I979:i:928930. 18 Jung K. Scheifler A, Blank W, Scholz D, Schuzle B-D, Hansen C: Changed composition of high-density lipoprotein subclasses HDL2 and HDL3 after renal transplantation. Transplan tation 1988:46:407-409. 19 Cassader M. Ruiu G. Gambino R. Alemanno N, Triolo G. Pagano G: Lipoprotein-apolipoprotein changes in renal transplant recipients: A 2-year follow-up. Metabolism 1991:40:922925. 20 Kasiske BL, Tortorice KL, heim-Duthoy KL, Walid MA. Rao KV: The adverse impact of cyclosporine on serum lipids in renal trans plant recipients. Am J Kidney Dis 1991:17: 700-707. 21 Hricik DE. Mayes JT. Schulak JA: Indepen dent effects o f cyclosporine and prednisone on posttransplant hypercholesterolemia. Am J Kidney Dis 1991;18:353-358. 22 Chan MK. Varghese Z. Persaud JW. Fernando ON. Moorhead JF: The role of multiple phar macotherapy in the pathogenesis of hyperlipid emia after renal transplantation. Clin Nephrol 1981;15:309-313. 23 Curtis JJ, Galla HJ, Woodford SY. Lucas BA, Luke RG: Effect of alternate-day prednisone on plasma lipids in renal transplant recipients. Kidney Int 1982;22:42-47. 24 Hört WH. Hörl M. Heidland A: Fettstoffwechselslörungen bei Nicrenkrankheiten: Pathoge netische Mechanismen. Klin Wochenschr 1982;60:327-336.
25 Jackson JM. Lee HA: The role o f propranolol therapy and proteinuria in the etiology of post renal transplantation hyperlipidemia. Clin Nephrol 1982;18:95-100. 26 Lowry RP. Soltys G, Mangel R. Kwiterovitch P. Snidermann AD: Type 11 hyperlipidemia, hyperapobetalipoproteinemia. and hyperalphal poprotcinemia following renal transplan tation: Prevalence and precipitating factors. Transplant Proc 1987:19:2229-2332. 27 Ballantyne CM. Podet EJ. Patsch WP, Harati Y, Appel V, Gotto AM, Young JB: Effects of cyclosporine therapy on plasma lipoprotein levels. JAMA 1989:262:53-56. 28 Hodel K. Mordasini RC. Brunner FP. Thiel G: Cyclosporin A und Hyperlipidamie nach Nierentransplantation. Schweiz Med Wochenschr 1986;116:885-888. 29 Harris KPG. Russell GI, Parvin SD. Veitch PS, Walls J: Alterations in lipid and carbohydrate metabolism attributable to cyclosporin A in renal transplant recipients. Br Med J 1986:292:
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30 Derfler K. Hayde M. Heinz G. Hirschi MM. Steger G. Hauser A-C. Balcke P. Widhalm D: Decreased postheparin lipolytic activity in re nal transplant recipients with cyclosporin A. Kidney Int 1991;40:720-727. 31 Verrill HL, Girgis RE, Easterling RE. Malhi BS, Mueller WF: Distribution of cyclosporin in blood of a renal-transplant recipient with type V hyperlipoproteinemia. Clin Chem 1957:33. 32 Nemunaitis J, Deeg HJ, Yee GC: High cyclo sporin levels after bone marrow transplanta tion associated with hypertriglyceridaemia. Lancet 1986;ii: 744-745. 33 Versluis DJ. Wenting GJ. Weimar W: Altera tions in lipid and carbohydrate metabolism attributable to cyclosporin A in renal trans plant recipients. Br Med J 1987:292:272. 34 Versluis DJ. Wenting GJ. Derkx FHM. Schalekamp MADH, Jeekel J. Weimar W: Who should be converted from cyclosporine to con ventional immunosuppression in kidney trans plantation, and whv. Transplantation 1987:44: 387-389. 35 Amer P, Gunnarsson R, Blomdahl S. Groth CG: Some characteristics of steroid diabetes: A study in renal-transplant recipients receiving high-dose corticosteroid therapy. Diabetes Care 1983;6:23-25.
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1 Ghosh P. Evans DB. Tomlinson SA, Caine RY: Plasma lipids following renal transplantation. Transplantation 1973;15:521-523. 2 Bagdade J, Casaretto A, Albers J: Effects of chronic uremia, hemodialysis, and transplanta tion on plasma lipids and lipoproteins in man. J Lab Clin Med 1976;87:37-48. 3 Bagdade JD. Albers JJ: Plasma high-density lipoprotein concentrations in chronic-hemodi alysis and renal-transplant patients. N Engl J Med 1977;296:1436-1440. 4 Casaretto A. Marchioro TL. Goldsmith R, Bag dade JD; Hyperlipidaemia after successful re nal transplantation. Lancet 1974;i:481 —484. 5 Cattran DC, Steiner G, Wilson DR. Fenton SSA: Hyperlipidemia after renal transplanta tion: Natural history and pathophysiology. Ann Intern Med 1979;91:554-559. 6 Chatterjee SN, Chin HP. Azen SP. Blankenhorn DH, Boothe S, Massry SG: Abnormal serum lipid pattern in primary renal allograft recipients. Surgery 1977:82:655-659. 7 Crawford GA. Savdie E, Stewart JH: Heparinreleased plasma lipases in chronic renal failure and after renal transplantation. Clin Sei 1979; 57:155-165. 8 Frey FJ. Mordasini RC. Schlumpf E, Marone C. Montandon A. Flury W, Riva G: Serumli pide bei eingeschränkter Nierenfunktion und nach Nierentransplantation. Schweiz Med Wochenschr 1977:107:1248-1253. 9 Ibels LS. Alfrey AC. Subryan V. Weil R: Hyper lipidemia following renal transplantation. Trans Am SocArtif Intern Organs 1975:22:4653. 10 Ibels LS. Simons LA, King JO, Williams PF, Neale FC, Stewart JH: Studies on the nature and causes of hyperlipemia of uremia, mainte nance dialysis and renal transplantation. Q J Med 1975:44:601-614. 11 Ibels LS. Reardon MF, Nestel PJ: Plasma post heparin lipolytic activity and triglyceride clear ance in uremia and hemodialysis patients and renal allograft recipients. J Lab Clin Med 1976; 87:648-658. 12 Ibels LS. Alfrey AC, Weil R: Hyperlipidemia in adult, pediatric and diabetic renal transplant recipients. Am J Med 1978:64:634-642. 13 Mordasini R. Frey F. Flury W. Klose G. Greten H: Selective deficiency of hepatic triglyceride lipase in uremic patients. N Engl J Med 1977; 297:1362-1366.
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