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Renal Disease

Medical and Surgical Complications of Renal Transplantation: Diagnosis and Management

Nodo Yoshimura, MD, PhD,* and Takahiro aka, MD, PhDt

Although the survival of patients on chronic dialysis has improved in recent decades, the quality of life and status of rehabilitation still remain poor. The artificial kidney serves as a part-time excretory organ, but it cannot replace the endocrine function of the kidney. Therefore, the problems of anemia, osteodysfunction, neuropathy, and infertility continue to worsen in these patients. On the other hand, developments in surgical techniques, immunosuppressive drugs, and increasing experiences in immune modulation have had a strong impact on both the safety and efficacy of kidney transplantation; hence, kidney transplantation has now emerged as the treatment of first choice for end-stage renal failure. Successful transplantation depends upon careful preparation of the donor and recipients, experience in surgical techniques, and suitable manipulation of the immune responses to prevent graft rejection. It also depends upon the precise diagnosis and rapid treatment of any type of complications after transplantation. In this article, we address the diagnosis and treatment of the following medical and surgical complications (excluding rejections) of kidney transplantation: operative complications, infectious complications, gastrointestinal complications, hypertension, orthopedic complications, hematologic complications, and oncologic complications.

OPERATIVE COMPLICATIONS Complications directly related to the transplant operation may lead to deterioration of renal function. The surgical complications of renal transFrom the Second Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan *Assistant Professor of Surgery tProfessor and Chairman of Surgery

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plantation are conveniently separated into two groups: vascular complications and urologic complications. Vascular Complications

Arterial Complications. Renal artery thrombosis is a relatively rare complication, occurring in slightly more than 1% of renal-transplant recipients. 1O Thrombosis may be due to an unidentified flap that has not been tacked down. There may be a predisposition to stenosis and thrombosis with an end-to-end anastomosis to the internal iliac artery if there is a large disparity in size between the recipient and donor arteries. Other factors that can contribute to the development of renal artery thrombosis are multiple anastomosis with multiple renal arteries, internal damage due to preservation or trauma from rough handling, and stenosis.]9 A sudden cessation of urine output in a functioning kidney should lead to suspicion of renal artery thrombosis. The Foley catheter should be irrigated to rule out plugging by a clot. If the central venous pressure is low, a fluid challenge should be given. If there is no resulting increase in urine output, an arteriogram is performed to rule out thrombosis or renal artery stenosis. Renal artery stenosis occurs in 0.6 to 13.5% of total renal transplant patients" and can be seen early or late in the post-transplant course. New onset of hypertension that is difficult to control, an unexplained decline in renal function, or the presence of a bruit over the iliac artery should arouse suspicion of renal artery stenosis. Arteriograms are necessary to confirm diagnosis and to assist in classification of the type and degree of stenosis present. Vascular occlusion is associated with absence of any Doppler signal. Thus, duplex sonography techniques have the potential of differentiating rejection from occlusive arterial problems. Aneurysm may be anastomotic (pseudoaneurysm) or infected (mycotic). The causes of anastomotic aneurysms include suture breakage or the use of biodegradable suture. Diagnosis can be confirmed by arteriogram, and repair, including resection and reanastomosis, is recommended. A rapidly expanding, warm, tender pulsatile mass in the iliac fossa should be a suspect for mycotic aneurysm. Usually fever and leukocytosis are also present. Diagnosis can be confirmed by arteriogram. Treatment includes antibiotics and surgical removal of all infected tissue. Venous Complications. Renal vein thrombosis occurs in 1 to 4% of transplantations. 28 It is thought to occur as a result of intimal injury during organ retrieval; because of kinking of the anastomosis of the iliac vein; as an extension of thrombosis from the iliac-venous system; because of pressure on the iliac vein due to a lymphocele, urinoma, hematoma, or silent left iliac vein compression syndrome; or occasionally because of severe rejection. The occurrence of renal vein thrombosis should be suspected if there is oliguria or anuria that is accompanied by graft swelling, massive proteinuria, or hematuria. Venography is the confirmatory test for renal vein thrombosis. Duplex sonography also can be used to evaluate patency of the transplant renal vein. When thrombosis is incomplete, heparin treatment or thrombectomy or both is recommended. Nephrectomy will be necessary if thrombosis is complete. A deep-vein thrombosis may be associated with ipsilateral leg swelling.

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Urologic Complications Although there has been significant improvement in graft and patient survival in the last decade, urologic complications continue to be a major cause of morbidity and mortality after renal transplantation. These complications include ureteral obstruction, urinary fistula, and bladder leak. The most common cause of sudden cessation of urinary output in the immediate postoperative period is a clot in the bladder outlet or in the urethral catheter. This may be corrected by irrigation. The ureteroneocystostomy may be occluded by hematoma at the site of the mucosal tunnel in the bladder or by a technically unsatisfactory anastomosis. Diagnosis of these complications is usually determined by intravenous pyelogram, cystogram, retrograde pyelogram, or surgical exploration. Recent advances in diagnostic testing also include ultrasonography,16 renal isotope scanning, 20 computed tomography (CT) scanning,14 magnetic resonance imaging (MRI) scanning,13 and endourologic percutaneous techniques. 21 Ureteral Obstruction. This complication has been reported to occur in 1 to 9.7% of transplant recipients. 15 Diagnosis can be confirmed by ultrasonography, which demonstrates hydronephrosis with ureterectasis. An intravenous pyelogram will give information as to the degree and site of the ureteral obstruction. Computed tomography or MRI scan should be used only when ultrasound studies are nondiagnostic or when further detail is necessary to investigate a suspect extrinsic periureteral process. Retrograde pyelography will give accurate information when the procedure is feasible. After diagnosis of ureteral obstruction has been established, the strategy is to re-establish patency of the ureter. This has traditionally been done by reimplantation of the ureter, ureteroureterostomy, or a ureteropyelostomy with the use of the native ureter. U reteroureterostomy or pyelostomy has been associated with significant graft loss and mortality (9 to 19%)Y A more conservative approach used in recent years has been the placement of a percutaneous nephrostomy tube to allow for stabilization of the patient. 8 After renal function has improved, appropriate surgical procedure may be undertaken. Urinary Fistula. Devascularization of the ureter or ureteral ischemia may lead to the development of ureteral fistulas in the first few days or weeks after transplantation. 12 Signs and symptoms include pain, swelling over the graft area, fever, progressive increase in serum creatinine, oliguria, cutaneous urinary drainage, and sepsis. Ultrasonography, renal scan, cystogram, CT or :\lRI scan, retrograde pyelogram, or antegrade pyelogram may be used to confirm diagnosis. Early operative treatment is indicated owing to high mortality and morbidity. Bladder Leak. This type of fistula develops at the site of anterior cvstostomv closure or at the ureteral hiatus. Vesical fistulas after renal t;aI1splant~tion have been reported in 0.6 to 4.4% of the recipients in the first 2 weeks after transplantation 23 and result in decreased urinary output, elevated serum creatinine, a palpable mass over the pubis, and fever or pain or both in the suprapubic area or around the graft. Ultrasonography will demonstrate perivesical fluid collection. Radioisotope scan may be used to show urinary extravasation but is not useful for determining the source.

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Vesical fistulas are treated by continuing catheter drainage of the bladder or immediate repair.

INFECTIOUS COMPLICATIONS Infections are by far the most common problems that affect transplant recipients. Although the incidence of infections has decreased in recent years, the risk prevails throughout the post-transplant period, and infection is still the leading cause of death in transplant patients. Clinical experiences suggest that the risk of infection is higher in older individuals and in diabetic patients and after antirejection therapy.41 As outlined in Table 1, infections in the recipients do not occur at random but according to an expected "timetable" that is determined by the type, intensity, and duration of immunosuppression administered, technical complications, and environmental exposures. The antimicrobial regimen for individual infections is also outlined in Table 1. Bacterial Infections Bacterial infections are the most common infection in the early posttransplant period. The most frequent infecting organisms are staphylococci, Table 1. Infection in Renal Transplant Patients OCCllRRE:'-JCE PATHOGEN

Bacterial Staphylococci Streptococci Gram-negative Pneumococcus Viral Herpes simplex Varicella/zoster Cytomegalovirus Epstein-Barr virus

(WKl

0-4 0-4 0-4 0-4 or > 12

0-12

>7 4-16 >7

Adenovirus Hepatitis virus

ANTIMICROBIAL SITE OF I)'o;FECTION

THERAPY

Wound Urinary tract Line-related Lung

Vancomycin Ampicillin Gentamicin Erythromycin, penicillin, ampicillin

Skin, genital Lung, nervous system Lung B Iymphocytes, pharyngeal, epithelial Urinary tract, lung Liver

Acyclovir Acyclovir Ganciclovir Acyclovir

Nystatin, amphotericin B Amphotericin B Ketoconazole, amphotericin B

Fungal Candida

0-24

Oral, lung

Aopergillus C ryptocOCCllS

>4 >16

Lung Lung, nervous system

Protozoa Pneumocystis carinii

>8

Lung

No drug Interferon

Trimethopriml sulfamethoxazole, pentamidine

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streptococci, and gram-negative rods. These infections usually occur following surgical procedures or antirejection therapy. It is important to emphasize that infection with such opportunistic pathogens as Aspergillus, Legionella, Pseudomonas, or Nocardia species does not usually occur in this time period. After appropriate materials have been obtained for culture, antibiotic therapy should be initiated early rather than late in the course of infection. In patients with severe infection, it may become necessary to reduce the dose of or discontinue the immunosuppressive drugs. High caloric intake by either the intravenous or oral route is essential to minimize tissue catabolism and hasten recovery. Granulocyte transfusions should be considered in patients who are leukopenic. Infusion of broad-spectrum gamma globulin may be beneficial in an occasional patient. Viral Infections Viral, fungal, and protozoan infections are similar in solid-organ transplant recipients such as heart, liver, and kidney transplant recipients. Infections with these organisms are indicative of attenuated cell-mediated immunity, which is the result of therapy with immunosuppressive medication used to prevent or treat allograft rejection or as a side effect of cytotoxic chemotherapy. Cytomegalovirus (CMV) is one of the most frequent infectious agents affecting recipients, but it also has a profoundly detrimental effect on both patient and allograft survival rates. 37 Cytomegalovirus can cause a variety of infectious disease syndromes that may range from mild and subclinical to life-threatening events associated with marked end-organ involvement, profound immunodepression, and increased risks for bacterial, fungal, or protozoan superinfections. 34 Cytomegalovirus has also been reported to cause renal allograft dysfunction, either as a trigger for acute renal allograft rejection 24 or by causing a glomerulopathy, as others have suggested. 3(; The diagnosis of CMV infection is made by a minimum fourfold rise in antibody titers, seroconversion in previously CMV-negative patients, or culture proof of viral shedding. These diagnostic criteria are often unreliable, however. A more reliable test is the characteristic cytopathic effect in viral culture, which is confirmed by immunofluorescence staining with a CM V-specific monoclonal antibody. Lautenschlager et aPS have described a rapid culture method with indirect immunofluorescence, using a monoclonal antibody to CMV early nuclear protein, together with IgM serology, as a useful tool to diagnose CMV infection. Molecular biology technique, such as complementary DNA (cDNA) probe for CMV, could be useful. We tested 15 patients serially after kidney transplantation by using urine samples and found good correlation between the clinical features of CMV infection and the expression of CMV-DNA in cytologic specimens in patient's urineY The polymerase chain reaction brings a new and more sensitive technology to the diagnosis of CMV infection. This technique, in particular, permits the detection of latent viruses at concentrations below that detectable by culture. 7, 26 This technology may be very useful in predicting risk for reactivation after induction of immunosuppression. Once the diagnosis of CMV disease is established, antiviral therapy should begin with intravenous acyclovir, ganciclovir, or selective use of

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high-titer gammaglobulin. The duration of therapy is determined by clinical response, surveillance viral culture, and repeat evaluation of tissue specimens when indicated. Management of CMV disease also includes a variable reduction in immunosuppression, aggressive nutritional and metabolic support, prophylaxis, or treatment of superinfection. In addition to CMV, other latent viruses, including Epstein-Barr, herpes simplex, and varicella zoster may develop or reactivate during immunosuppressive therapy. Mucocutaneous infection with herpesvirus (either simplex or zoster) is not uncommon. Fungal Infection Both superficial and deep fungal infections occur in renal transplant recipients. Of the superficial infections, oropharyngeal moniliasis is the most prevalent in the early post-transplant period. Candida vaginitis or cystitis is another common presentation. Disseminated candidiasis involving multiple organs is rare. In patients who have visceral involvement, such as endocarditis, meningitis, or endophthalmitis, intravenous amphotericin B in low doses is recommended. As a preventive measure, nystatin swish and swallow is routinely prescribed to the graft recipients for 3 to 4 months after transplantation. Among the deep fungal infections, cryptococcosis, aspergillosis, histoplasmosis, coccidioidomycosis, and mucormycosis have been reported in renal allograft recipients. Diagnosis is made by serologic tests, special stains, or culture of the blood or bone marrow. Sputum cultures are often negative. Invasive studies such as transbronchial or openlung biopsy may be needed to establish the correct diagnosis. In particular, pulmonary infection with Aspergillus or Candida is easily detected using the bronchoalveolar lavage technique. Fungal disease requires treatment with amphotericin, occasionally with the addition of 5-flucytosine. Nocardia is best treated with a sulfonamide or trimethoprim/sulfamethaxazole (Bactrim), and treatment needs to be prolonged for several weeks after clinical resolution to prevent relapse. Protozoan Infection

Pneurnocystis carinii (PC) is a protozoan organism that has a cyst phase and a free-living trophozoite phase in its life-cycle; it has been the single most important organism producing fatal pneumonia in the transplant population. Pneurnocystis carinii pneumonia occurs relatively late in the postoperative course (usually after 2 to 3 months or more of transplantation) compared to other infections. Fever and breathlessness often precede radiologic changes, which are typically diffuse and bilateral. The absence of physical signs in the chest is characteristic. The yields of sputum staining and culture are quite low; therefore, these tests are not reliable. There is no other definitive test, short of transbronchial biopsy of the lung tissue, which on histologic examination demonstrates Pneurnocystis carinii. Pneumocystis carinii pneumonia is treated with trimethoprim intravenously or orally in a dosage of 20 mg and 100 mg of sulfamethoxazole per kg per day divided into two to four doses. If severe renal failure is present, the dosages will be adjusted by measuring free sulfa levels, aiming for values between

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100 and 1.50 mg/L. In moderate renal impairment (creatinine clearance between 1.5 and ,30 mllmin), a standard dosage can generally bc used for 3 days, followed by a .50% decrease, but again plasma levels should be tested. Response to treatment is good when the diagnosis is made early. If the clinical response to trimethoprim is inadequate or hypersensitivity to trimethoprim develops, treatment with pentamidine (4 mg/kg/day by intramuscular or intravenous infusion for 1 hr) should be initiatcd.

GASTROINTESTINAL COMPLICATIONS Peptic Ulcer Disease Peptic ulcer disease complicates the course in approximately .5% of allograft recipients. Bleeding or perforation resulting from peptic ulcer disease carries a mortality of approximately 50%. Antacids are recommended for all patients, but especially for those with history of ulcer disease documented by radiologic studies or gastroscopy. Prophylactic use of the H" receptor antagonist cimetidine (Tagamet) or ranitidine (Zantac) has shown benefit. No increased incidence of rejection episodes was found in those receiving the drugs, and ulcer incidence was low in both experimental and control groups.;3 The prophylactic use of antacids has only minor side effects, and their regular use is urged for at least 1 year following transplantation, with intensification of the dosage regimen during treatment with steroid boosts for rejection. 27 Colonic Complication Colonic perforation is also a potentially lethal complication following renal transplantation. Although this is a relatively rare complication (11 of 1000 transplants at Cleveland Clinic, and 1 of 3.50 transplants at our institution), the mortality rate was as high as 88% prior to 197,5. At present, mortality is still higher than 30%, even though prompt recognition and operative intervention have led to improved results. Predisposing factors include renal failure itself, frequent constipation, and a high incidence of diverticular disease in young uremic patients. It is not surprising that renal transplant patients are subject to "spontaneous" colon perforations. Impaired capacity for healing and tissue weakness in such patients are contributing factors. The early use of abdominal radiographs and CT scans with rectally administered contrast agents may be beneficial in defining the problem. Prompt surgical treatment is most important. Appropriate antibiotics coverage is essential. Pancreatitis Pancreatitis is a potentially serious complication following transplantation that occurs in 2 to 7% of renal allograft recipients. 9 This complication, which is considered an outcome of the use of corticosteroids, may be precipitated by steroid-bolus therapy for rejection and has been related also to azathioprine. 30 Elevated serum amylase levels in the presence of abdominal and back pain are diagnostic. Severe sequelae, including hemorrhagic pancreatitis, abscess, or pseudocyst formation, are relatively com-

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mon in immunosuppressed patients. Ultrasonography and CT scanning should be used to detect such potentially fatal problems. Because of the high mortality rate associated with this complication (as high as 53%),33 aggressive treatment should be instituted early. This includes total parenteral nutrition, nasogastric suction, antacid therapy, and careful metabolic monitoring with appropriate corrections, including transfusions. Surgical intervention is indicated in case of pancreatic abscess or pseudocyst. Acute pancreatitis also might be associated with cyslosporine (CsA). In our studies, 4 of 105 recipients treated with CsA and prednisolone developed acute pancreatitis and displayed high CsA-trough level, and two of them died. 42 Essentials of treatment include prompt reduction or discontinuation of CsA. HYPERTENSION

Hypertension is one of the most common complications of renal transplantation. The incidence of post-transplant hypertension can be as high as 50%.1 Several factors in the etiology of post-transplant hypertension must be considered: (1) the status of the native kidneys, (2) the status of allograft function, (3) methods of immunosuppression, and (4) the presence of renal artery stenosis. Some hypertensive patients will respond favorably to native nephrectomy. 22 The association between post-transplant hypertension and decreased long-term graft survival has been noted. 6 It is not clear whether hypertension per se leads to allograft dysfunction or whether renal dysfunction, usually secondary to chronic rejection or repeated episodes of acute rejection, results in hypertension. The role of steroids in the development of hypertension continues to remain uncertain; reduction in steroid dosage rarely leads to significant improvement in hypertension. The appearance of a new bruit over the transplant, or alteration of a preexisting bruit, especially when there is a new onset of hypertension, must also alert the clinician to the possibility of renal artery stenosis (RAS). The incidence of RAS in renal allograft recipients ranges from 3 to 25%, depending upon the vigor with which the diagnosis is sought. 40 Percutaneous angiography is diagnostic, and several patterns of RAS have been described. Technical problems such as inverted adventitia, twisting of the anastomosis, and partial suture closure of the lumen are obvious causes of RAS. Kinks in the renal artery due to poor positioning or uncomfortable "lie" of the allograft may also lead to RAS. Surgical correction and percutaneous transluminal dilatation (PTO) are the two alternative methods of treatment of RAS that is not immunologically mediated. Percutaneous transluminal dilatation is relatively safe and has approximately a 76% success rate at 1 month. 35 Surgical exploration and repair should be performed in technically unsuccessful PTO or in recipients with recurrence of RAS. A technical success rate of 74% from operative correction can be expected,28 but the mortality rates are higher than those for PTO, and graft loss has recently been reported to be 10 to 20%, even in the most experienced hands. 28 Cyclosporine has been used as a major immunosuppressive agent after transplantation for 10 years. However, its use has been associated with an increased prevalence of hypertension in

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recipients of bone marrow transplants, cardiac transplants, and kidney transplants. The mechanism of cyclosporine-related hypertension is unclear; animal studies have suggested that cyclosporine may stimulate the reninangiotensin system,38 whereas in humans the renin-angiotensin system appears to be suppressed by cyclosporine. 2 Curtis 6 has recently demonstrated that conversion of immunosuppression from cyclosporine to conventional azathioprine and prednisone resulted in increased graft renal plasma flow and lowered blood pressure, without change in serum creatinine, implying that the mechanism of cyclosporine-induced hypertension may be related to increased allograft vascular resistance and that it is distinct from nephrotoxic effects.

ORTHOPEDIC COMPLICATIONS Osteoporosis and aseptic necrosis may occur with or without hypcrparathyroidism. A number of variables have been examined and may help to predict which patients will develop aseptic necrosis. These include underlying renal disease, the length of time on dialysis, the severity of bone disease prior to transplantation, calcium and phosphate levels, and the total dose of steroids received. Thus far, none of these factors have proved to be significant discriminating variables. 29 The most frequent presenting symptom of aseptic necrosis is bone pain, particularly during weight bearing. The plain radiograph may not be revealing. Yearly bone scans may show increased focal activity even before clinical symptoms are apparent. Kubo et al,J7 however, showed that MRI technique is more effective than scintigraphy in the early diagnosis of aseptic necrosis (Fig. 1). With an early diagnosis, surgical intervention, such as the Hungerford decompression procedure, may abort frank necrosis and obviate the need

Figure 1. Evaluation of aseptic necrosis offemoral head. A, Plain radiograph, no abnormal findings; B, Scintigraphy, no abnormal uptake in the femoral head; and C, MRI, abnormal low signal area with ring-like pattern in Tl weighted image. The patient received a kidney transplantation 3 months before testing.

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for a more extensive surgical procedure. Although the hip is the most common site of involvement, virtually any other bone may suffer the same degenerative process. Total hip replacement is frequently necessary in ischemic necrosis of the femoral head. In patients receiving CsA and small doses of steroids, the incidence of avascular osseous necrosis has been decreased.

HEMATOLOGIC COMPLICATIONS Anemia, leukopenia, and thrombocytopenia are well-known complications of cytotoxic drug therapy. The white blood cell count is generally the first to decrease, and if recognized early enough, it responds to simple dose reduction of azathioprine. Persistent marrow depression, which is a rare occurrence, necessitates discontinuance of the drug for an extended period. Long-term use of azathioprine is associated with two significant hematologic effects: macrocytic anemia and myelodysplasia. 40 Recently, we had a patient with pure red cell aplasia; he was treated with azathioprine and steroids for 7 years. Azathioprine was incriminated for aplastic anemia and confirmed by prompt increase in hematocrit by substituting azathioprine with cyclosporine.

ONCOLOGIC COMPLICATIONS After transplantation, there is no increase in incidence of the neoplasms commonly seen in the general population, including carcinomas of the lung, prostate, colon, and rectum, and female breast and invasive carcinoma of the uterine cervix. On the other hand, there is a remarkably high incidence of certain tumors, such as carcinoma of skin and lips (4- to 21-fold increase), non-Hodgkin's lymphomas (28- to 49-fold increase), Kaposi sarcoma (400to 500-fold increase), and carcinomas of the vulva and anus (WO-fold increase).31 The average time of appearance of all tumors after conventional immunosuppressive therapy is 59 months, compared with 14 months in patients treated with CsA. :32 Because the incidence of cancer increases with the length of follow-up, all transplant recipients must be followed indefinitely. Skin lesions in transplant patients frequently mimic cancer, so any suspicious skin areas should be biopsied. Follow-up of female patients should include routine pelvic examinations and cervical smear for early detection of lesions. New neurologic signs should prompt a study for a central nervous system tumor or invasive or metastatic tumors. Reduction in immunosuppressive drug when possible and conservative treatment are the usual approaches for the treatment of cancer in transplant recipients. In patients requiring cytotoxic therapy for widespread cancers, we must consider that most agents depress the bone marrow function. It is advisable to stop or reduce azathioprine dosage during such therapy to prevent severe bone marrow suppression. Because most cytotoxic agents have immunosuppressive side effects, satisfactory allograft function may persist for a pro-

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longed period of time. Treatment with prednisone may be continued because it is an important constituent of many cytotoxic regimens.

SUMMARY Renal transplantation is a common modality of therapy in end-stage renal failure, but it has the potential of developing many complications, both surgical and medical in nature. In transplantation surgery, more than in any other type of surgery, prevention of these complications is essential. This includes attention to many details, including optimum organ salvage, preservation, implantation, and postoperative care. Although infection has decreased in frequency and severity with the advent of antiviral and antibacterial agents, prevention, early diagnosis, and suitable treatment with appropriate antibiotic(s) will be necessary to obtain desirable results and to reduce morbidity and mortality. It should be stressed that although careful attention to the patients and adjustment of the immunosuppressive regimen may mitigate much of the gastrointestinal, hematologic, and osteogenic complications, high incidence of cancer of the skin and mucous membrane continues.

REFERENCES 1. Bachy C, Alecandre GP], Van Ypersele C, et al: Hypertension after renal transplantation. Br Med J 2:1287, 1976 2. Bantle JP, ~ath KA, Sutherland DER, et al: Effects of cyclosporine on the reninangiotensin-aldosterone system and potassium excretion in renal transplant recipients. Arch Intern Med 145:505. 1985 3. Bulseson RC, Kronhaus RI, Marberger PO, et al: Cimetidine, posttransplant peptic ulcer: Complications and renal allograft survival, a clinical and investigational perspective. Arch Surg 117:933, 1989 4. Church IM, Faxio VW, Braun WE, et al: Perforation of the colon in renal homograft recipients. Am J Surg 203:67, 1986 5. Clunie G: Renal transplantation. Selection preparation of donors, immunosuppression and surgical complications. In Chatterjee S (ed): Organ Transplantation. Littleton, MA, John Wright, 1982, p 151 6. Curtis JJ: Hypertension and kidney transplantation. Am J Kidney Dis 7:181, 1986 7. Demmler GJ, Buffone GJ, Schmbor CM, et al: Detection of cytomegalovirus in urine from newborn by using polymerase chain reaction DNA amplification. J Infect Dis 158:1177, 1989 8. Eklund B, Edgren J, Laasonen L, et al: Percutaneous nephrostomy: A therapeutic procedure for the management of urinary leakage and obstruction in renal transplantation. Transplant Proc 16: 1304, 1984 9. Fernandez JA, Rosenberg JC: Post transplantation pancreatitis. Surg Gynecol Ob stet 143:795, 1976 10. Goldman MH, Tilney NL, Vineyard GC, et al: A twenty-year survey of arterial complications of renal transplantations. Surg Gynecol Ob stet 141:758, 1975 11. Helling TS, Thomas CY, Moore JD, et al: The surgical approach to obstructive problems of the transplant ureter. Transplant Proc 14:751, 1982 12. Hriko GM, Birtch AG, Bennett AH, et al: Factors responsible for urinary fistula in the renal transplant recipients. Ann Surg 178:609, 1973 13. Jordan ML, Novick AC, Gersinger M, et al: Imaging of the transplanted kidney with nuclear magnetic response. Transplant Proc 17:32, 1985

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14. Kauthusr AH, Letehvre YJ, SquifHet JP, et al: Anterior extravesical ureteroneocvstostomy: The procedure of choice in kidney transplantation. Transplant Proc 17: 176, 1985. 15. Kinnaert P, Hall M, Janssen F, et a1: Ureteral stenosis after kidney transplantation: True incidence and long-term follow up after surgical correction. J Urol 133:17, 1988 16. Koehler PH, Kanemoto HH, ~!axwell JC: Ultrasonic "B" scanning in the diagnosis of complications in renal transplant patients. Radiology 119:661, 1976 17. Kubo T, Sakakida K, Kusakabe T, et al: Magnetic resonance imaging of aseptic necrosis offemoral head [abstract]. 17th SICOT. ~1unich, 1987 18. Lautenschlager I, Suni J, Abhonen J, et al: Hapid diagnosis of cytomegalovirus infection in renal transplant recipients. Transplant Proc 20:408, 1988 19. Lee HM, Mendez-Picon G: Complications of renal transplantation. In Greenfield LJC (ed): Complications in Surgery and Trauma. Philadelphia, JB Lippincott, 1984, p 773 20. Liberman HP, Glass NR, Crummy AB, et al: Non-operative percutaneous management of urinary fistulas and strictures in renal transplantation. Surg Gynecol Ob stet 155:667, 1982 21. Lieberman RP, Crummy AB, Glass NR, et a1: Fine needle antegrade pyelography in the renal transplant. J Urol 126:155, 1981 22. Litschitz MD, Rios M, Radwin HM, et al: Renal failure with post-transplant reninangiotensin mediated hypertension. Arch Intern Med 138:14, 1978 23. Loughlin KR, Tilney :\IL, Richie JP: Urologic complications in 718 renal transplant patients. Surgery 5:297, 1984 24. Mourad G, Chong G, Pouliquen MY, et al: Withdrawal of azathioprine and antilymphocyte globulins in kidney transplant recipients with cytomegalovirus. Transplant Proc 16:1313, 1984 25. Iv!urrey JF, Felton CP, Garey SM, et al: Pulmonary complications of the acquired immunodeficiency syndrome. Report of a :\Iational Heart, Lung and Blood Institute workshop. N Engl J Med 310, 1682, 1984 26. Myerson D, Gleaves CA, Smess A, et a1: CMV detection in lung tissue by polymerase chain reaction. Mod Pathol 2:364, 1989 27. Owens MC, Passano E, Wilson SE, et al: Treatment of peptic ulcer disease in the renal transplant patients. Ann Surg 186:19, 1979 28. Palleschi J, Novick AC, Baraum WE, et al: Vascular complications of renal transplantations. Urology 16:61, 1980 29. Parbrey PS, Farge D, Parbrey l\:A, et al: The decreased incidence of aseptic necrosis in renal transplant recipient: A case control study. Transplantation 41:182, 1986 30. Peitzman S, Agarwel BN: Hemorrhagic pancreatitis with duoclenopancreatic fistula in a renal homograft patient. Am J Gastroenterol 63:420, 197.5 :31. Penn 1: Cancer is a complication of several immunosuppression. Surg Gynecol Obstet 162:603, 1986 32. Penn I, First MR: Development ancl incidence of cancer following cyclosporine therapy. Transplant Proc 18:210, 1986 33. Renning JA, Warclen GD, Stevens LE, et al: Pancreatitis after renal transplantation. Am J Surg 123:293, 1972 .14. Hancl KH, Pollard RB, Merigan TC, et a1: Incrcased pulmonary superinfections in cardiac transplant patients unclergoing primary cytomegalovirus infection. N Engl J Med 298:9,51, 1978 :3.5. Ravnaucl A, Bedrosian J, Remy P: Percutaneous transluminal angioplastv of renal transplant stenosis. Am J Hadiol 146:8.53, 1986 :36. Hichardson WP, Clovin RB, Cheeseman SH, et al: Glomerulopathy associated with cytomegalovirus viremia in renal allografts. N Engl J Med 305:.57, 1980 .17. Hubin HM, Tolkoff-Rubin l\:E, Oliver D, et al: Multicenter seroepiclemiologic study of the impact of cytomegalovirus infection on renal transplantation. Transplantation 40:243, 198.5 38. Siegel ~!, Ryffe B: Effect of cyclosporin on renin-angiotensin-aldosterone system. Lancet I1:1274, 1982 39. Sjogren V, Thysell ~1, Lindholm T: Bone marrow morphology in patients in long-term treatment with azathioprine. Scand J Hematol 26:82, 1981 40. Tilney NL, Rocha A, Strom TB, et al: Renal artery stenosis in transplant patient. Ann Surg 199:4.5, 1984 41. Yoshimura N, Oka T, Ohmori Y, et a1: Molecular biology method for rapid and reliable

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diagnosis of cytomegalovirus (CMV) infection in renal allograft recipient. Transplant Proc 21:2077, 1989 42. Yoshimura N, "Iakai I, Ohmori Y, et al: Effect of cyclosporine on the endocrine and exocrine pancreas in kidney transplant recipients. Am J Kidney Dis 12:11, 1988

Address reprint requests to Norio Yoshimura, MD, PhD Kyoto Prefectural University of Medicine 465 Hirokouji, Kawaramachi, Kamikyo-ku Kyoto City, Kyoto 602 Japan