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Renal transplantation
RENAL
TRANSPLANTATION*
Complications in Patients with Juvenile Diabetes KIUMARS
BAKSHANDEH,
REGINALDO ELIAS
PICACHE,
BASTOUNIS,
MEHMET
M.D.
A. HABERAL,
B. S. HUSBERG,
M.D.
M.D. M.D.,
M.D. PH.D.
From the Department of Surgery, University Medical Center, and Veterans Administration Denver, Colorado
of Colorado Hospital,
ABSTRACT - Four cases of patients with juvenile diabetes who received kidney transplants are repwted. Problems with selection and management are discussed, and the high mortality and morbidity rates in this group of patients is emphasized.
For almost two decades patients with juvenile diabetes have been excluded from dialysis and transplantation programs. Drukker et al. in 1970,’ Blagg, Eschbach, and Sawyer in 197L2 and Comty and Shapiro in 19713consider these patients high risks with soaring morbidity and mortality rates during chronic hemodialysis. The introduction of combined pancreas-kidney transplantation,4 and the subsequent popularity of kidney transplantation, began a new chapter in the treatment of juvenile diabetic patients with end stage uremia. 5 Medical literature on this subject indicates high mortality and morbidity rates. Our purpose is not to present a statistical analysis but to emphasize the importante of patient selection and to underline the major complications in juvenile diabetic patients undergoing kidney transplantation. Principles
of Treatment
Case histories of 4 patients diabetes who received kidney
with juvenile transplants are
*Supported by research grants from Veterans Administration, AI-AM-08898 and AM-07772, and RR-00051 and RK00069, General Clinical Research Centers Program, Division of Research Resources, National Institutes of Health.
UROLOCY
/ JANUARY 1975
/
VOLUMEV,
NUMBER 1
reported. They were first admitted to the University of Colorado Medical Center between September, 1973, and December, 1973, and represent two thirds of the patients with juvenile diabetes who had transplants during this time. Each patient received 200 mg. of azathioprine (Imuran) at an average dose of 2 to 3 mg. per kilogram on the day of surgery, with subsequent doses adjusted according to the daily white blood cel1 count. Steroid therapy was begun with 200 mg. of prednisone on the day of the surgery and was decreased by 10 mg. daily until a dose of 50 mg. per day was reached. The dosage was then decreased by 5 mg. every fifth day until the daily dose of 35 mg. was reached. The subsequent decrease in steroid dosage was individualized. ALG (antilymphocyte globulin) was given intramuscularly (6 to 8 mg. antibody protein per kilogram) from the day of surgical intervention every day for two weeks, then every other day for another two weeks. The related cases received three days of prednisone, azathioprine, and ALG therapy prior to transplantation.6 At the time of surgery and immediately thereafter, patients were given regular insulin, 15 to 20 units in 1,000 ml. of 5 per cent dextrose in
21
water, and blood glucose determinations were made at least every eight hours. This schedule of diabetes control was continued until the patients were able to eat, after which long-acting insulin therapy was begun. Al1 patients were kept in the hospita1 for three weeks and were then followed up as outpatients every other day for one month. Rejection episodes were handled by increasing the oral prednisone dose to 200 mg. daily and then decreasing it 20 mg. daily. Intermittent intravenous infusions of 1 Gm. methylprednisolone (Solu-Medrol) were also administered. If the kidneys were swollen and tender, local radiation therapy of 150 rads was given every other day until450 rads were reached. Case Reports
Case 1 A thirty-three-year-old man had juvenile diabetes at the age of seven. He was begun on chronic dialysis in 1972. His past medical history included mild hypertension, congestive heart failure, hepatitis, and intermittent claudication. He received an E-match cadaveric kidney on September 26, 1973. Extensive arteriosclerosis was found at the time of surgery. Postoperatively, the blood urea nitrogen and creatinine decreased to 72 mg. and 2.7 mg. per 100 ml., respectively, within eight days. Ten days postoperatively a ureteroureteral anastomosis was performed to correct a urinary leak, and bilateral autogenic nephrectomy and splenectomy were carried out at the same time. On October 24, 1973, the patient was discharged with a blood urea nitrogen of 57 mg. and creatinine of 1.7 mg. per 100 ml. His diabetes was wel1 under control. He was readmitted one month later because of a rejection episode, which was reversed with increased doses of steroids. On December 13, 1973, he was readmitted for the third time with a mild cellulitis in the area of the right ankle. His diabetes at that time was under satisfactory control. The responsible organism for the cellulitis was Serratia marcescens which was sensitive to gentamicin. The patient responded wel1 to antibiotic therapy (gentamicin, 2 mg. per kilogram daily) as judged clinically, and was discharged on January 1, 1974, with stable kidney íìmction and well-controlled diabetes. On January 11, 1974, he was again admitted with an exacerbation of the cellulitis. The wound was surgically revised and S. marcescens sensitive to gentamicin was
22
again cultured from the wound. The immunosuppressive medications were decreased to azathioprine 50 mg. and prednisone 25 mg. daily. This was done without detectable deterioration of graft iünction. After sensitivity testing and gentamicin serum leve1 determinations, chloramphenicol (Chloromycetin) 100 mg. per kilogram was added and the gentamicin dose was increased to 4 mg. per kilogram. In the absente of both leukocytosis and elevated temperature, and with the normal appearance of the skin surrounding the infected areas, the infection was thought to be under control. However, on January 24, a new wound revision was done under genera1 anesthesia, and the infection was found to have spread into the muscle compartments of the leg. Once again the steroid dose was decreased and an amputation above the knee at least 14 cm. proximal to the margin of infected tissue was performed. A wound culture of the stump surface taken at the time of surgery grew Serratia. The patient died three days later because of cardiac arrest. Results of autopsy showed the cause of death to be myocardial infarction. There were small, sterile pus collections at the splenectomy site and around the transplanted kidney; a smal1 gastric ulcer was als0 present. Case 2 A twenty-four-year-old man in whom juvenile diabetes developed at the age of seven was seen at another hospital at the age of seventeen for diabetic retinopathy and at the age of twenty-two for diabetic nephropathy. His renal failure had never progressed to the point where dialysis was required. He had a moderate hypertension and borderline congestive heart failure. He had no history of peptic ulcer. On October 15, 1973, he received a D-match kidney from his mother (MLC* index of 1.1 per cent) and underwent simultaneous bilateral nephrectomy and splenectomy. His blood urea nitrogen decreased to 33 mg. and serum creatinine to 1 mg. per 100 ml. on the fifth day postoperatively. On the tenth postoperative day a mild rejection episode developed which was reversed by steroids. During this period he showed a steady decrease in hematocrit, with occult blood in the stools. He admitted that he did not take his antacid medication regularly because of the unpleasant taste. He was placed on a strict *Mixed lymphocyte culture.
UROLOGY
/ JANUARY 1975 / VOLUMEV,
NUMBER 1
ulcer regimen, and this episode of gastrointestinal bleeding subsided. Eighteen days postoperatively, massive upper gastrointestinal bleeding again developed which required surgical intervention. Six superficial gastric ulcers were found, and a Billroth 1 resection was performed. Because of a temporary decrease in the steroid doses, his kidney fimction deteriorated but improved shortly thereafter. On November 21, 1973, he was discharged with stable graft function and well-controlled diabetes. He was followed up for one month as an outpatient and then retumed to his home in another state. Twenty days later another episode of upper gastrointestinal bleeding suddenly developed which required emergency surgical treatment in his hometown hospital. The gastric remnant was resected and modified to a Billroth 11. Postoperatively the duodenal stump disrupted, leading to peritonitis and death three days later. Case 3 A thirty-five-year-old man had juvenile diabetes since the age of twelve. Diabetic nephropathy developed, and he was placed on chronic hemodialysis in January, 1970. He had several shunts and fistulas, the last one being a Thomas’ shunt to the right femoral artery and vein. He also had hypertension, neuropathy, and retinopathy. He was accepted as a transplant candidate because of dialysis access problems, and he received a cadaveric kidney transplant (E-match, MLC index 2.1 per cent) in the left iliac fossa on November 24, 1973. The graft did not function satisfactorily, although renal scan and blood flow studies showed good perfusion. Dialysis was continued. On December 2, 1973, he was given a second cadaveric kidney transplant (E-match) in the right iliac fossa. Urine output postoperatively was good, but the serum blood urea nitrogen and creatinine did not decrease satisfactorily. He received high doses of corticosteroids. Meanwhile, a wound infection developed with Pseudomonas aeruginosa involving the site of the first transplant and the Thomas shunt area. He was given gentamicin which controlled the infection, as judged clinically. His kidney function improved slowly until January, 1974, when it deteriorated again. A repeat course of increased doses of steroids was given without any change in the function of the graft. On January 17, 1974, dialysis treatment was reinstated and immunosuppression drastically re-
UROLOGY
/ JANUARY 1975 / VOLUMEV,
NUMBERl
duced. At this time the shunt site was again infected with Ps. aeruginosa. On January 21, he underwent bilateral graft nephrectomy. Postoperatively he was febrile with positive blood cultures (Ps. aeruginosa) and suffered frequent seizures. Results of lumbar puncture, as wel1 as brain scan, were negative, and an electroencephalogram was nondiagnostic. He was given appropriate antibiotic drugs, diphenylhydantoin (Dilantin), and phenobarbital. The patient deteriorated steadily and died from sepsis and bilateral bronchopneumonia. Case 4 A forty-two-year-old white man had suffered from juvenile diabetes for twenty-four years. He had been on hemodialysis since 1972. He had moderate hypertension and peripheral vascular insufliciency in the legs. He received a cadaveric kidney transplant (E-match) in the left groin on December 13,1973, without any significant postoperative complications. On December 19, 1973, his blood urea nitrogen was 46 mg. and serum creatinine 1.5 mg. per 100 ml. He experienced only one mild rejection episode and was discharged twenty-one days later in good condition. In January, 1974, an infiltrate was seen on chest x-ray film. An endobronchial needle biopsy was obtained and pentamidine isothionate treatment was begun, suspecting the diagnosis of Pneumocystis carinii. However, the biopsy specimens failed to demonstrate P. carinii, but a sputum culture grew Aspergillus fumigatus. Amphotericin B (Fungizone) treatment was instituted at this time. The infiltrate resolved slowly, confirmed by serial chest x-ray films. In March, 1974, he was treated with heparin because of a peripheral thrombophlebitis in his right leg. He was also treated with increased doses of steroids and twice received local irradiation (total dose 600 rads) because of decreased graft function. However, it soon became apparent that the transplant was undergoing chronic rejection. In April, 1974, he received a second renal transplant in the right iliac fossa and was discharged twenty days postoperatively, with good kidney function (blood urea nitrogen 53 mg. and creatinine 1.3 mg. per 100 ml.). In May, 1974, he was readmitted because of thrombosis of the left iliofemoral vein (confirmed by venography) and was treated with heparin. A few days after admission the right kidney became tender and swollen, and renal function deteriorated.
23
On May 19, 1974, he underwent surgery, and a collection of serosanguineous fluid was found around the second transplant. The kidney was grossly rejected. The first kidney transplant was necrotic and infected. Both kidneys were removed and, although in a poor condition, he was placed on hemodialysis. Infiltrates developed as seen on chest x-ray film, and several sputum cultures grew S. marcescens. He was treated with gentamicin and chloramphenicol. He died June 24, 1974, from cardiac arrest. Autopsy was not obtained. Comments There is no doubt that kidney transplantation in diabetic patients has a greater risk than in other persons. However, the outcome of transplantation is better than that of hemodialysis in juvenile diabetic patients.5,8,s,‘0 The 4 cases reported demonstrate the frequent complications in patients with juvenile diabetes undergoing kidney transplantation. It is important to realize that although these complications might have a good prognosis and outcome in nondiabetic transplant patients, they can be of a serious nature in diabetic patients. In the first patient urinary leak developed because of ureteral necrosis ten days postoperatively. This complication is more frequently found in diabetic transplant patients and is probably caused by vascular insufficiency of the ureter, secondary to underlying smal1 vessel disease.*-l0 The patient was later infected with S. marcescens, which usually does not have a fulminating course. The infection was not considered serious and, after apparent response to antibiotic therapy, he was managed as an outpatient. After the second admission, in spite of persistent infection, the leve1 of immunosuppression was not effectively decreased at once. The gravity of the infection was not appreciated until the leg was amputated far from the infected site, and the responsible organism could stil1 be grown from the cut surface. Infection is the leading cause of early post-transplant deaths in diabetic patients, and in the face of immunosuppression even minor infections should be considered potentially dangerous and must be treated earlys8 The patient died of myocardial infarction, another frequent cause of death peculiar to juvenile diabetes. * Gastrointestinal bleeding and perforation are major complications that can befall transplant patients, with relatively high morbidity and
24
mortality rates. The adverse effects of steroids on connective tissue, decrease in the resistance of gastrointestinal epithelium to its secretion, and poor circulation to the anastomotic line due to underlying vascular disease in diabetic patients may al1 contribute to impaired healing of the anastomotic site.” Immunosuppressive therapy, particularly corticosteroids, masks the signs and symptoms of intraperitoneal sepsis by preventing and abdominal findings. l2 fever, leukocytosis, These factors may have played a major role in the development of intra-abdominal sepsis in Case 2. To improve the results, prompt diagnosis, early surgical intervention with a reduction in immunoand close postoperative clinical suppression, observation are mandatory. Case 3 illustrates two problems: (1) patient selection, and (2) side effects of high-dosage steroid therapy. The patient had undergone multiple procedures for shunt and fistulas in the past. and at the time of transplantation he had aThornas shunt. When the first kidney was rejected, large amounts of steroids were administered. When he received his second kidney transplant, again high doses of steroids were given which eventually led to infection in the shunt. In retrospect. this patient should not have been transplanted at this late stage, since he already had a history of shunt and fistula problems. The Thomas shunt poses an increased risk of infection if it cannot be removed shortly after transplantation. Also, if infection occurs, al1 foreign material cannot be easily removed. l3 In Case 4 severe vascular disease developed. In reviewing the chest x-ray films, the infiltrates were probably caused by a pulmonary embolus. A necrotic kidney on the left and an iliofemoral venous thrombosis later developed. It is uncertain whether the first kidney transplant, which was not removed at the time of the second transplantation, caused the thrombosis or if the thrombosis caused the renal necrosis. However, the fact remains that vascular problems are inherent in patients with juvenile diabetes undergoing kidney transplantation.’ To achieve better results with kidney transplantation in diabetic patients, the following points are of great importante: (1) Strict discretion should be used in the selection of juvenile diabetic patients as candidates for kidney transplantation. Transplantation should be performed early so that hypertension, advanced uremia, retinopathy, and lack of dialysis access sites do not constitute added risks. (2) Steroids cause more
UROLOGY
/ JANUARY JYï5
/ VOLUMEV,
NUMBER
1
dangerous side effects in diabetic patients, and less vigorous attempts should be made to save kidneys undergoing rejection. (3) The seriousness of any kind of complication, especially infection, should be appreciated early and treated promptly. Department of Urology of Miami School of Medicine Department of Urology P.O. Box 520875 Biscayne Annex Miami, Florida 33152 (DR. BAKSHANDEH)
University
References DRUKKER, W., HAAGSMA-SCHOUTER, W. A. G., ALBERTS, C. H. R., and BAARDA, R.: Report of regular dialysis treatment in Europe, Proc. Eur. Dialysis Transplant Assoc. 7: 3 (1970). BLAGG, C. R., ESCHBACH, J. W., SAWYER, T. K., and CASARETTO, A. A.: Dialysis for end-stage diabetic nephropathy, Proc. Clin. Dialysis Transplant. Forum 1: 133 (1971). COMTY, C. M., and SHAPRIO, F. L.: Abstracts, Management and prognosis of diabetic patients treated by chronic hemodialysis, Am. Sec. Nephrol. 5: 15 (1971).
UROLOGY / JANUARY1975 / VOLUME V, NUMBER 1
4. LILLEHEI, R. C., et al.: Pancreatico-duodenal allotransplantation: experimental and clinical experience, Ann. Surg. 172: 405 (1970). 5. KJELLSTRAND, C. M., et al. : Mortality and morbidity in diabetic patients accepted for renal transplantation, Proc. Eur. Dialysis Transplant Assoc. 9: 345 (1972). 6. STAFUL, T. E., et al. : Renal homotransplantation, part 1, Curr. Probl. Surg. April, 1974, p. 6. 7. THOMAS, G. 1.: A large-vessel applique A-V shunt for hemodialysis, Trans. Am. Sec. Artif. Intern. Organs 15: 288 (1969). 8. KJELLSTRAND, C. M., et aE. : Renal transplantation in patients with insulin-dependent diabetes, Lancet 2: 4 (1973). 9. NAJARIAN, J. S., et al. : Renal transplantation for diabetic glomerulosclerosis, Ann. Surg. 178: 477 (1973). 10. NAJARIAN,J. S., et al. : Transplantation for diabetic glomerulosclerosis, Transplant. Proc. 1: 799 (1973). 11. HADJIYANNAKIS,E. J., EVANS, D. B., SOMELLIE, W. A., and CALNE, R. Y.: Gastrointestinal complications after renal transplantation, Lancet 2: 781 (1971). 12. PENN, I., et al. : Surgically correctable intra-abdominal complications before and after renal homotransplantation, Ann. Surg. 168: 865 (1968). 13. THOMAS, G. 1.: Large vessel applique arteriovenous shunt for hemodialysis (a new concept), Am. J. Surg. 120: 244 (1970).
25
TRANSPLANTATION*
Complications in Patients with Juvenile Diabetes KIUMARS
BAKSHANDEH,
REGINALDO ELIAS
PICACHE,
BASTOUNIS,
MEHMET
M.D.
A. HABERAL,
B. S. HUSBERG,
M.D.
M.D. M.D.,
M.D. PH.D.
From the Department of Surgery, University Medical Center, and Veterans Administration Denver, Colorado
of Colorado Hospital,
ABSTRACT - Four cases of patients with juvenile diabetes who received kidney transplants are repwted. Problems with selection and management are discussed, and the high mortality and morbidity rates in this group of patients is emphasized.
For almost two decades patients with juvenile diabetes have been excluded from dialysis and transplantation programs. Drukker et al. in 1970,’ Blagg, Eschbach, and Sawyer in 197L2 and Comty and Shapiro in 19713consider these patients high risks with soaring morbidity and mortality rates during chronic hemodialysis. The introduction of combined pancreas-kidney transplantation,4 and the subsequent popularity of kidney transplantation, began a new chapter in the treatment of juvenile diabetic patients with end stage uremia. 5 Medical literature on this subject indicates high mortality and morbidity rates. Our purpose is not to present a statistical analysis but to emphasize the importante of patient selection and to underline the major complications in juvenile diabetic patients undergoing kidney transplantation. Principles
of Treatment
Case histories of 4 patients diabetes who received kidney
with juvenile transplants are
*Supported by research grants from Veterans Administration, AI-AM-08898 and AM-07772, and RR-00051 and RK00069, General Clinical Research Centers Program, Division of Research Resources, National Institutes of Health.
UROLOCY
/ JANUARY 1975
/
VOLUMEV,
NUMBER 1
reported. They were first admitted to the University of Colorado Medical Center between September, 1973, and December, 1973, and represent two thirds of the patients with juvenile diabetes who had transplants during this time. Each patient received 200 mg. of azathioprine (Imuran) at an average dose of 2 to 3 mg. per kilogram on the day of surgery, with subsequent doses adjusted according to the daily white blood cel1 count. Steroid therapy was begun with 200 mg. of prednisone on the day of the surgery and was decreased by 10 mg. daily until a dose of 50 mg. per day was reached. The dosage was then decreased by 5 mg. every fifth day until the daily dose of 35 mg. was reached. The subsequent decrease in steroid dosage was individualized. ALG (antilymphocyte globulin) was given intramuscularly (6 to 8 mg. antibody protein per kilogram) from the day of surgical intervention every day for two weeks, then every other day for another two weeks. The related cases received three days of prednisone, azathioprine, and ALG therapy prior to transplantation.6 At the time of surgery and immediately thereafter, patients were given regular insulin, 15 to 20 units in 1,000 ml. of 5 per cent dextrose in
21
water, and blood glucose determinations were made at least every eight hours. This schedule of diabetes control was continued until the patients were able to eat, after which long-acting insulin therapy was begun. Al1 patients were kept in the hospita1 for three weeks and were then followed up as outpatients every other day for one month. Rejection episodes were handled by increasing the oral prednisone dose to 200 mg. daily and then decreasing it 20 mg. daily. Intermittent intravenous infusions of 1 Gm. methylprednisolone (Solu-Medrol) were also administered. If the kidneys were swollen and tender, local radiation therapy of 150 rads was given every other day until450 rads were reached. Case Reports
Case 1 A thirty-three-year-old man had juvenile diabetes at the age of seven. He was begun on chronic dialysis in 1972. His past medical history included mild hypertension, congestive heart failure, hepatitis, and intermittent claudication. He received an E-match cadaveric kidney on September 26, 1973. Extensive arteriosclerosis was found at the time of surgery. Postoperatively, the blood urea nitrogen and creatinine decreased to 72 mg. and 2.7 mg. per 100 ml., respectively, within eight days. Ten days postoperatively a ureteroureteral anastomosis was performed to correct a urinary leak, and bilateral autogenic nephrectomy and splenectomy were carried out at the same time. On October 24, 1973, the patient was discharged with a blood urea nitrogen of 57 mg. and creatinine of 1.7 mg. per 100 ml. His diabetes was wel1 under control. He was readmitted one month later because of a rejection episode, which was reversed with increased doses of steroids. On December 13, 1973, he was readmitted for the third time with a mild cellulitis in the area of the right ankle. His diabetes at that time was under satisfactory control. The responsible organism for the cellulitis was Serratia marcescens which was sensitive to gentamicin. The patient responded wel1 to antibiotic therapy (gentamicin, 2 mg. per kilogram daily) as judged clinically, and was discharged on January 1, 1974, with stable kidney íìmction and well-controlled diabetes. On January 11, 1974, he was again admitted with an exacerbation of the cellulitis. The wound was surgically revised and S. marcescens sensitive to gentamicin was
22
again cultured from the wound. The immunosuppressive medications were decreased to azathioprine 50 mg. and prednisone 25 mg. daily. This was done without detectable deterioration of graft iünction. After sensitivity testing and gentamicin serum leve1 determinations, chloramphenicol (Chloromycetin) 100 mg. per kilogram was added and the gentamicin dose was increased to 4 mg. per kilogram. In the absente of both leukocytosis and elevated temperature, and with the normal appearance of the skin surrounding the infected areas, the infection was thought to be under control. However, on January 24, a new wound revision was done under genera1 anesthesia, and the infection was found to have spread into the muscle compartments of the leg. Once again the steroid dose was decreased and an amputation above the knee at least 14 cm. proximal to the margin of infected tissue was performed. A wound culture of the stump surface taken at the time of surgery grew Serratia. The patient died three days later because of cardiac arrest. Results of autopsy showed the cause of death to be myocardial infarction. There were small, sterile pus collections at the splenectomy site and around the transplanted kidney; a smal1 gastric ulcer was als0 present. Case 2 A twenty-four-year-old man in whom juvenile diabetes developed at the age of seven was seen at another hospital at the age of seventeen for diabetic retinopathy and at the age of twenty-two for diabetic nephropathy. His renal failure had never progressed to the point where dialysis was required. He had a moderate hypertension and borderline congestive heart failure. He had no history of peptic ulcer. On October 15, 1973, he received a D-match kidney from his mother (MLC* index of 1.1 per cent) and underwent simultaneous bilateral nephrectomy and splenectomy. His blood urea nitrogen decreased to 33 mg. and serum creatinine to 1 mg. per 100 ml. on the fifth day postoperatively. On the tenth postoperative day a mild rejection episode developed which was reversed by steroids. During this period he showed a steady decrease in hematocrit, with occult blood in the stools. He admitted that he did not take his antacid medication regularly because of the unpleasant taste. He was placed on a strict *Mixed lymphocyte culture.
UROLOGY
/ JANUARY 1975 / VOLUMEV,
NUMBER 1
ulcer regimen, and this episode of gastrointestinal bleeding subsided. Eighteen days postoperatively, massive upper gastrointestinal bleeding again developed which required surgical intervention. Six superficial gastric ulcers were found, and a Billroth 1 resection was performed. Because of a temporary decrease in the steroid doses, his kidney fimction deteriorated but improved shortly thereafter. On November 21, 1973, he was discharged with stable graft function and well-controlled diabetes. He was followed up for one month as an outpatient and then retumed to his home in another state. Twenty days later another episode of upper gastrointestinal bleeding suddenly developed which required emergency surgical treatment in his hometown hospital. The gastric remnant was resected and modified to a Billroth 11. Postoperatively the duodenal stump disrupted, leading to peritonitis and death three days later. Case 3 A thirty-five-year-old man had juvenile diabetes since the age of twelve. Diabetic nephropathy developed, and he was placed on chronic hemodialysis in January, 1970. He had several shunts and fistulas, the last one being a Thomas’ shunt to the right femoral artery and vein. He also had hypertension, neuropathy, and retinopathy. He was accepted as a transplant candidate because of dialysis access problems, and he received a cadaveric kidney transplant (E-match, MLC index 2.1 per cent) in the left iliac fossa on November 24, 1973. The graft did not function satisfactorily, although renal scan and blood flow studies showed good perfusion. Dialysis was continued. On December 2, 1973, he was given a second cadaveric kidney transplant (E-match) in the right iliac fossa. Urine output postoperatively was good, but the serum blood urea nitrogen and creatinine did not decrease satisfactorily. He received high doses of corticosteroids. Meanwhile, a wound infection developed with Pseudomonas aeruginosa involving the site of the first transplant and the Thomas shunt area. He was given gentamicin which controlled the infection, as judged clinically. His kidney function improved slowly until January, 1974, when it deteriorated again. A repeat course of increased doses of steroids was given without any change in the function of the graft. On January 17, 1974, dialysis treatment was reinstated and immunosuppression drastically re-
UROLOGY
/ JANUARY 1975 / VOLUMEV,
NUMBERl
duced. At this time the shunt site was again infected with Ps. aeruginosa. On January 21, he underwent bilateral graft nephrectomy. Postoperatively he was febrile with positive blood cultures (Ps. aeruginosa) and suffered frequent seizures. Results of lumbar puncture, as wel1 as brain scan, were negative, and an electroencephalogram was nondiagnostic. He was given appropriate antibiotic drugs, diphenylhydantoin (Dilantin), and phenobarbital. The patient deteriorated steadily and died from sepsis and bilateral bronchopneumonia. Case 4 A forty-two-year-old white man had suffered from juvenile diabetes for twenty-four years. He had been on hemodialysis since 1972. He had moderate hypertension and peripheral vascular insufliciency in the legs. He received a cadaveric kidney transplant (E-match) in the left groin on December 13,1973, without any significant postoperative complications. On December 19, 1973, his blood urea nitrogen was 46 mg. and serum creatinine 1.5 mg. per 100 ml. He experienced only one mild rejection episode and was discharged twenty-one days later in good condition. In January, 1974, an infiltrate was seen on chest x-ray film. An endobronchial needle biopsy was obtained and pentamidine isothionate treatment was begun, suspecting the diagnosis of Pneumocystis carinii. However, the biopsy specimens failed to demonstrate P. carinii, but a sputum culture grew Aspergillus fumigatus. Amphotericin B (Fungizone) treatment was instituted at this time. The infiltrate resolved slowly, confirmed by serial chest x-ray films. In March, 1974, he was treated with heparin because of a peripheral thrombophlebitis in his right leg. He was also treated with increased doses of steroids and twice received local irradiation (total dose 600 rads) because of decreased graft function. However, it soon became apparent that the transplant was undergoing chronic rejection. In April, 1974, he received a second renal transplant in the right iliac fossa and was discharged twenty days postoperatively, with good kidney function (blood urea nitrogen 53 mg. and creatinine 1.3 mg. per 100 ml.). In May, 1974, he was readmitted because of thrombosis of the left iliofemoral vein (confirmed by venography) and was treated with heparin. A few days after admission the right kidney became tender and swollen, and renal function deteriorated.
23
On May 19, 1974, he underwent surgery, and a collection of serosanguineous fluid was found around the second transplant. The kidney was grossly rejected. The first kidney transplant was necrotic and infected. Both kidneys were removed and, although in a poor condition, he was placed on hemodialysis. Infiltrates developed as seen on chest x-ray film, and several sputum cultures grew S. marcescens. He was treated with gentamicin and chloramphenicol. He died June 24, 1974, from cardiac arrest. Autopsy was not obtained. Comments There is no doubt that kidney transplantation in diabetic patients has a greater risk than in other persons. However, the outcome of transplantation is better than that of hemodialysis in juvenile diabetic patients.5,8,s,‘0 The 4 cases reported demonstrate the frequent complications in patients with juvenile diabetes undergoing kidney transplantation. It is important to realize that although these complications might have a good prognosis and outcome in nondiabetic transplant patients, they can be of a serious nature in diabetic patients. In the first patient urinary leak developed because of ureteral necrosis ten days postoperatively. This complication is more frequently found in diabetic transplant patients and is probably caused by vascular insufficiency of the ureter, secondary to underlying smal1 vessel disease.*-l0 The patient was later infected with S. marcescens, which usually does not have a fulminating course. The infection was not considered serious and, after apparent response to antibiotic therapy, he was managed as an outpatient. After the second admission, in spite of persistent infection, the leve1 of immunosuppression was not effectively decreased at once. The gravity of the infection was not appreciated until the leg was amputated far from the infected site, and the responsible organism could stil1 be grown from the cut surface. Infection is the leading cause of early post-transplant deaths in diabetic patients, and in the face of immunosuppression even minor infections should be considered potentially dangerous and must be treated earlys8 The patient died of myocardial infarction, another frequent cause of death peculiar to juvenile diabetes. * Gastrointestinal bleeding and perforation are major complications that can befall transplant patients, with relatively high morbidity and
24
mortality rates. The adverse effects of steroids on connective tissue, decrease in the resistance of gastrointestinal epithelium to its secretion, and poor circulation to the anastomotic line due to underlying vascular disease in diabetic patients may al1 contribute to impaired healing of the anastomotic site.” Immunosuppressive therapy, particularly corticosteroids, masks the signs and symptoms of intraperitoneal sepsis by preventing and abdominal findings. l2 fever, leukocytosis, These factors may have played a major role in the development of intra-abdominal sepsis in Case 2. To improve the results, prompt diagnosis, early surgical intervention with a reduction in immunoand close postoperative clinical suppression, observation are mandatory. Case 3 illustrates two problems: (1) patient selection, and (2) side effects of high-dosage steroid therapy. The patient had undergone multiple procedures for shunt and fistulas in the past. and at the time of transplantation he had aThornas shunt. When the first kidney was rejected, large amounts of steroids were administered. When he received his second kidney transplant, again high doses of steroids were given which eventually led to infection in the shunt. In retrospect. this patient should not have been transplanted at this late stage, since he already had a history of shunt and fistula problems. The Thomas shunt poses an increased risk of infection if it cannot be removed shortly after transplantation. Also, if infection occurs, al1 foreign material cannot be easily removed. l3 In Case 4 severe vascular disease developed. In reviewing the chest x-ray films, the infiltrates were probably caused by a pulmonary embolus. A necrotic kidney on the left and an iliofemoral venous thrombosis later developed. It is uncertain whether the first kidney transplant, which was not removed at the time of the second transplantation, caused the thrombosis or if the thrombosis caused the renal necrosis. However, the fact remains that vascular problems are inherent in patients with juvenile diabetes undergoing kidney transplantation.’ To achieve better results with kidney transplantation in diabetic patients, the following points are of great importante: (1) Strict discretion should be used in the selection of juvenile diabetic patients as candidates for kidney transplantation. Transplantation should be performed early so that hypertension, advanced uremia, retinopathy, and lack of dialysis access sites do not constitute added risks. (2) Steroids cause more
UROLOGY
/ JANUARY JYï5
/ VOLUMEV,
NUMBER
1
dangerous side effects in diabetic patients, and less vigorous attempts should be made to save kidneys undergoing rejection. (3) The seriousness of any kind of complication, especially infection, should be appreciated early and treated promptly. Department of Urology of Miami School of Medicine Department of Urology P.O. Box 520875 Biscayne Annex Miami, Florida 33152 (DR. BAKSHANDEH)
University
References DRUKKER, W., HAAGSMA-SCHOUTER, W. A. G., ALBERTS, C. H. R., and BAARDA, R.: Report of regular dialysis treatment in Europe, Proc. Eur. Dialysis Transplant Assoc. 7: 3 (1970). BLAGG, C. R., ESCHBACH, J. W., SAWYER, T. K., and CASARETTO, A. A.: Dialysis for end-stage diabetic nephropathy, Proc. Clin. Dialysis Transplant. Forum 1: 133 (1971). COMTY, C. M., and SHAPRIO, F. L.: Abstracts, Management and prognosis of diabetic patients treated by chronic hemodialysis, Am. Sec. Nephrol. 5: 15 (1971).
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4. LILLEHEI, R. C., et al.: Pancreatico-duodenal allotransplantation: experimental and clinical experience, Ann. Surg. 172: 405 (1970). 5. KJELLSTRAND, C. M., et al. : Mortality and morbidity in diabetic patients accepted for renal transplantation, Proc. Eur. Dialysis Transplant Assoc. 9: 345 (1972). 6. STAFUL, T. E., et al. : Renal homotransplantation, part 1, Curr. Probl. Surg. April, 1974, p. 6. 7. THOMAS, G. 1.: A large-vessel applique A-V shunt for hemodialysis, Trans. Am. Sec. Artif. Intern. Organs 15: 288 (1969). 8. KJELLSTRAND, C. M., et aE. : Renal transplantation in patients with insulin-dependent diabetes, Lancet 2: 4 (1973). 9. NAJARIAN, J. S., et al. : Renal transplantation for diabetic glomerulosclerosis, Ann. Surg. 178: 477 (1973). 10. NAJARIAN,J. S., et al. : Transplantation for diabetic glomerulosclerosis, Transplant. Proc. 1: 799 (1973). 11. HADJIYANNAKIS,E. J., EVANS, D. B., SOMELLIE, W. A., and CALNE, R. Y.: Gastrointestinal complications after renal transplantation, Lancet 2: 781 (1971). 12. PENN, I., et al. : Surgically correctable intra-abdominal complications before and after renal homotransplantation, Ann. Surg. 168: 865 (1968). 13. THOMAS, G. 1.: Large vessel applique arteriovenous shunt for hemodialysis (a new concept), Am. J. Surg. 120: 244 (1970).
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