Status of Renal Transplantation: A Clinical Perspective

Symposium on Renal Disease

Status of Renal Transplantation A Clinical Perspective

K. Venkateswara Rao, M.D. *

Although the survival of patients on chronic dialysis has improved in recent years, the quality of life and status of rehabilitation remains poor. For example, a recent multicenter survey carried out in the United States revealed that only 60 per cent of nondiabetic patients and 33 per cent of diabetic patients receiving chronic dialysis were engaged in physical activities beyond self care. 55 Because of renal failure and the problems surrounding it, dialysis patients are considered disabled by the Social Security Administration and receive disability benefits. The artificial kidney machine serve's as a part-time excretory organ but cannot replace the endocrine functions of the human kidney. Therefore, the problems of anemia, osteodystrophy, neuropathy, pruritus, and infertility continue and may gradually worsen in patients receiving long-term dialysis. This form of chronic therapy also adds a significant amount of emotional strain, physical inconvenience, and time commitment for both the patient and the family members. Further, it is estimated that by 1984 more than 55,000 people in the United States will be receiving dialysis treatments and the cost for medical services alone will be more than $3 billion, to which must be added the cost, incurred because of loss of productivity. 36 The two modalities of therapy (chronic dialysis and renal transplantation) have to complement each other and should be utilized in an integrated fashion in the management of patients with end-stage renal failure. Physicians should not be biased and commit their patients to one or the other form of long-term treatment.

PATIENT SELECTION FOR TRANSPLANTATION With the large number of patients currently receiving dialysis therapy, the obvious question is, how would one go about selecting a patient *Assistant Professor of Medicine, University of Minnesota Medical School; Director, Renal Transplantation, Regional Kidney Disease Program, Hennepin County Medical Center, Minneapolis, Minnesota

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for transplantation? Each transplant center follows its own criteria in selecting candidates. We consider all patients under the age of 70 years if they have an estimated life span of two or more years and have the potential for a better quality of life after transplantation. Serious medical problems involving multiple organ systems, uncorrectable lower urinary tract dysfunction, and psychiatric illness that impairs patient cooperation are considered contraindications.

EVALUATION OF RECIPIENT Once the patient decides to pursue renal transplantation (after the pros and cons have been discussed with the transplant nephrologist or the surgeon), further evaluation is carried out per the protocols set up by the individual transplant centers. This evaluation includes a detailed history, thorough physical examination, and assessment of diseases pertaining to individual organ systems. With the aid of clinical and laboratory data, the physician searches for evidence of cardiovascular, lung, liver, or gastrointestinal diseases; neurological disorders; and psychiatric problems; notes the status of anemia, osteodystrophy, and peripheral neuropathy; looks for any abnormalities of the genitourinary tract; and revIews previous infections, malignancies, and surgical procedures. An attempt to establish the etiology of renal failure is made using the available clinical, radiologic, and histologic data. The status of rehabilitation both before and after the initiation of dialysis treatments is assessed.

PREPARATION FOR TRANSPLANTATION Depending on the results obtained from the medical evaluation, prospective transplant recipients may need to undergo prophylactic surgical procedur~s such as vagotomy and pyloroplasty for peptic ulcer disease, segmental colon resection for diverticular disease, cholecystectomy for gallbladder disease, bilateral nephrectomy for uncontrolled hypertension, large' polycystic kidneys, vesicoureteral reflux or repeated urinary tract infections, and parathyroidectomy if there is evidence of uncontrolled secondary hyperparathyroidism. The issue of pretransplant splenectomy is somewhat controversial. 50, 101, 123 Most centers perform routine splenectomies and provide polyvalent pneumococcal vaccine to potential transplant recipients. Controlled studies have shown 13 to 16 per cent improvement in graft survival in the splenectomized patients. 50 During the earlier years of clinical transplantation, blood transfusions were discouraged because of concern that recipients might become sensitized to their prospective donors. However, following the elegant observations of Opelz and Terasaki in the mid-1970s,99 blood transfusions became a prerequisite for renal transplantation. Currently, patients are deliberately given a minimum of five units of packed red cells (not washed or frozen). Usually, one to two units of blood are given during a single dialysis treatment.

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Two to three weeks after completion of the transfusions, blood specimens are drawn from the recipients to determine the "responsiveness" against a random panel of donor lymphocytes. If the recipient's serum contains antibodies against the lymphocyte antigens of all the donors used in the panel (generally 24 to 36 donors with different HLA antigens on their lymphocytes), the per cent reactivity is called 100. If the recipient's serum reacts to only half of the panel lymphocytes, the cytotoxicity of the serum is 50 per cent. Despite multiple transfusions; only 15 to 20 per cent of patients form significant amounts of cytotoxic antibodies. 100 The role of these antibodies in determining the ultimate success or failure of the transplanted kidney is still a controversial issue. 43 , 97 Our own experience suggests that the graft survival rate in patients with cytotoxic antibodies is similar to that in patients without such antibodies, although the average waiting time to receive a suitable kidney is longer.

DONOR EVALUATION Live Donors Live related donor transplants comprise about 40 per cent of all transplants performed in the United States, whereas their proportion is much less (10 to 15 per cent) in Europe and Australia. Even in the United States, depending on the center's philosophy, this proportion varies from one program to another. For example, in 1982, of the 159 transplants performed at University of Minnesota Hospitals, 97 (61 per cent) were of kidneys obtained from live donors, whereas at Hennepin County Medical Center, of the 55 transplants performed in 1982, only one involved a live related donor. The ethical aspects of accepting kidneys from family members are somewhat controversial even among the pioneers of renal transplantation, 49 in part because the long-term effects of the deprivation of one kidney on the donors are not fully known, although recent studies have shown no significant deleterious effects, even 10 to ,15 years after kidney donation.5, 141 The prerequisites for live donor transplantation at our institution are the following: (1) the donor should come forward voluntarily and not·be compelled by anyone other than himself or herself, (2) there should be no mismatches in the HLA antigens and the blood group between the donor and the recipient, (3) the mixed-Iymphocyte culture (MLC) reaction between the donor and recipient should be low, (4) the initial and final crossmatch tests should be negative, (5) the donor should be in perfect physical and mental health and should have two normal kidneys, (6) there should be no abnormalities in the lower urinary tract, and (7) at least one of the donor's kidneys should have a single renal artery and vein. The donor has the option of withdrawing until the day of transplantation. To protect the donors from family pressures, we would give them a medical excuse at any time. Cadaver Donors With the increasing awareness in the community of the need for cadaver kidneys for transplantation, the availability of donors has increased

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in recent years. In addition, the nationwide computer system has facilitated the use of nearly all cadaver kidneys for suitable recipients within the country and abroad. With the adoption of the brain death law in most states, the kidneys are now harvested while the heart is beating; the shorter warm ischemia time that results from this practice significantly reduces the incidence of post-transplant acute tubular necrosis (ATN)58 and facilitates immediate graft function. (Warm ischemia time is defined as the time that elapsed between the death of the donor and cooling of the kidney to 4° C plus the time required for anastomosing the renal artery with the recipient's iliac artery.) Under the following circumstances, a cadaver donor is considered unsuitable: (1) age greater than 55 years, (2) hypertension or significant vascular disease, (3) evidence of septicemia or infection in the kidneys, (4) a history of malignancy with primary or metastatic involvement of the kidneys, (5) serum creatinine concentration 2::: 3.0 mg per dl at the time of death, and (6) unacceptable warm ischemia time (30 min or longer). Despite careful scrutiny by the harvesting team, bacterial and viral infections as well as malignancies are occasionally transmitted from donors to recipients via renal allografts.l8, 102, 106 To reduce the incidence of post-transplant ATN, the following resuscitative measures are necessary before donor nephrectomy: (1) maintenance of normal blood pressure by means of intravenous fluids or vasopressors, (2) establishment of adequate diuresis (i.e., urine output 2::: 100 ml per hr), and (3) use of alpha-adrenergic blockers (phentolamine) and membrane stabilizers (high-dose intravenous corticosteroids). These latter measures dissipate the intrarenal vasospasm and improve the perfusion of the donor kidney.89, 93 After the kidneys are harvested, they are preserved and transported using either the surface cooling method31 or the hypothermic pulsatile perfusion machine. 13, 94 Machine preservation has the advantage of permitting assessment of the viability of kidneys before transplantation. If perfusion is poor (indicated by decreased perfusate flow or increased renal vascular resistance), the kidneys are generally discarded. The use of such preservation methods has allowed the transplant team to find the best possible recipient for the available kidneys on the basis of the HLA typing and the final crossmatch tests. Engraftment has been successful even after 72 hours of cold perfusion.

SURGICAL ASPECTS The donor kidney is transplanted into the recipient by placing it extraperitoneally in one of the iliac fossae. The renal artery is anastomosed to the external iliac artery of the recipient, and the renal vein is anastomosed to the external iliac vein. The donor ureter with its blood supply intact is anastomosed to the recipient's bladder by creating a submucosal tunnel and a new orifice (neocystoureterostomy). Paying special attention to the ureteric blood supply has decreased the incidence of ureteral necro-

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sis and urine leak into the peritoneal cavity in recent years,l° Similarly, the end-to-side anastomosis of the renal artery to the external iliac artery, as opposed to the previous practice of end-to-end anastomosis to the internal iliac artery, has reduced the incidence of post-transplant renal artery stenosis. Immunosuppressive therapy is initiated on the day of transplantation and continued throughout the post-transplant period. POST -TRANSPLANT CARE Follow-up Schedule After the initial period of hospitalization (average time 2 to 3 weeks) the follow-up care is provided in the transplant clinic. The schedule of clinic visits may vary from center to center. At our hospital,ll2 the number of visits gradually decreases from three times a week at one month after transplantation to once a month at one year after transplantation. All our transplant recipients undergo a thorough evaluation. At this annual visit, significant problems that occurred during the preceding 12 months are assessed, and appropriate plans are made for their management. The clinical and laboratory data are obtained once a month on all long-term patients and entered in their respective flow charts. These data are reviewed frequently, and appropriate measures are taken if significant abnormalities are discovered. Immunosuppressive Therapy There are two types of protocols. One protocol deals with prophylactic immunosuppression, which is given to all patients in a standard fashion. The other protocol is antirejection therapy, which is given to patients who develop rejection episodes. These immunosuppressive protocols differ from center to center. At our institution, azathioprine and prednisone are used as basic immunosuppressive drugs. Initially, intravenoJIs steroids (Solu-Medrol) are used starting at 1 gm per day. The dose is decreased by half at two-day intervals and discontinued after six days. On the seventh post-transplant day, oral prednisone is begun at 60 mg per day. The dose is gradually reduced to 20 mg per day at three months and 15 mg per day at six months. A year after transplantation, the dose of prednisone is changed from 15 mg daily to 15 mg every other day if renal function is stable. The conversion from daily to alternate-day therapy is done slowly, over a fourmonth period, as described previously.1l2 If there are no acute rejection episodes, the minimal dose of every-other-day prednisone is continued indefinitely. Azathioprine is given at a dose of 5 mg per kg of body weight on the day of transplantation but reduced to 2.5 mg per kg the following day. Further reduction to 2.0 mg per kg is done about three weeks posttransplant and maintained at that level indefinitely unless there is evidence of severe infection, leukopenia, or liver dysfunction. We use antilymphoblast globulin prepared at the University of Minnesota124 as an adjunctive immunosuppressive agent. The dose is 15 mg per kg daily for 14 days starting on the day of transplantation. The drug is

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diluted in 250 ml of saline and infused over a four-hour period through a large vein such as the subclavian vein or given via an arteriovenous fistula. Approximately 5 per cent of patients have allergic reactions to this heterologous antiserum; in these patients, antiserum prepared in a different species, such as goats or rabbits, is used instead of the horse antiserum. The allergic manifestations include severe hypertension, hyperpyrexia, and arthralgias. Pruritus, maculopapular skin rash, bradycardia, and hypotension are rarely encountered. Many transplant centers around the country are using the antithymocyte globulin (ATG) manufactured by the Upjohn Company, whereas others still manufacture their own ATG. There has been no consistency in the use of ATG, so the preparation, route of administration, dose schedule, and duration of therapy have varied considerably from place to place. Although cyclophosphamide was once used for prophylactic immunosuppression,128 particularly in patients with azathioprineinduced liver disease, there is a general belief among transplant physicians that it is more toxic to the bone marrow and enhances the risk of infections. In recent years, there has been a trend to lower the dose of prednisone used for prophylactic immunosuppression. Some centers in Europe have adopted this low-dose prednisone protocol from the day of transplantation and reported satisfactory graft survival results and lower morbidity.91.95 During the past two years, there have been encouraging clinical reports regarding cyclosporine (formerly called cyclosporin A), which is used in organ transplantation24, 44, 129 in conjunction with low-dose prednisone. Frequent monitoring of the serum levels is necessary to avoid nephrotoxicity. Preliminary observations suggest that prophylactic immunosuppression with cyclosporine reduces the incidence of clinical rejections without increasing the risk of infections. The principal problems encountered are nephrotoxicity, hepatotoxicity, and an increased incidence of malignant lymphomas. The immunosuppressive protocols used for controlling acute rejection episodes will be discussed later in this article. Management of Early Post-Transplant Complications Generally speaking, those problems that occur within the first six months after transplantation are called early complications and those occurring later are considered late complications. However, there could be an overlap in these complications and their relation to the different time frames. Acute Renal Failure. Acute tubular necrosis is responsible for approximately 90 per cent of episodes of acute renal failure within the first few weeks after transplantation. This phenomenon is observed in 34 per cent 'Of recipients of cadaver kidneys and 9 per cent of those with livedonor kidneys.l13 This is thought to result from ischemic injury during harvesting, preservation, and transport of renal allografts. Post-transplant ATN must be distinguished from other causes of acute renal failure such as renal artery thrombosis, hyperacute rejection, and obstruction of the urinary tract. The following tests are useful in the differential diagnosis:

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Hippuran renogram, allograft ultrasound, renal angiography, retrograde pyelography, and allograft biopsy. Of these, the biopsy is probably the most accurate for establishing the diagnosis of post-transplant ATN and is required if diagnostic dilemmas exist after the second week. The principles of management of post-transplant ATN are similar to those in other ATN states. Special attention should be paid to fluid and electrolyte balance, nutritional status, and avoidance of nephrotoxic agents. Every-other-day dialysis is indicated until the creatinine clearance improves to 20 ml per min, and the dose of azathioprine has to be reduced to prevent bone-marrow toxicity. Whether there are any detrimental effects on long-term graft function or patient survival is a subject of controversy .17, 76 Allograft Rejection. This is an immunologic reaction mediated by the host's cellular and humoral defense mechanisms targeted against the transplanted kidney, leading to reduced renal function and ultimately to graft failure. Three types of rejection occur in the early post-transplant period that can be distinguished on clinical and histologic grounds and by their response to antirejection therapy. Hyperacute rejection occurs in patients who have preformed circulating antibodies against the tissue antigens of the donor and results in diffuse intrarenal thrombosis and permanent loss of graft function.l 42 It occurs within a few minutes to a few hours after establishment of the vascular anastomosis. The diagnosis is made on the basis of anuria, absence of renal blood flow (established by radioisotopic studies or angiography), and histologic evidence of renal infarction. The treatment is graft nephrectomy; otherwise, life-threatening events such as disseminated intravascular coagulation and microangiopathic hemolytic anemia may ensue. The incidence of hyperacute rejections can be decreased by avoiding ABO bloodgroup incompatability and by paying special attention to the cross match studies. Patients who have warm T-cell antibodies are more prone to hyperacute rejections than are those with cold-reactive T-cell antibodies or B-cell antibodies. , Accelerated acute rejection usually occurs between three days and three months after transplantation. It too is mediated by antibodies directed against donor antigens, but in this case the antibodies are not preformed but rather are developed after the patient is exposed to graft antigens. 16, 73 It may be an anamnestic response, that is, the recipient may previously have had antibodies directed against antigens similar to those in the donor kidney but not in a concentration high enough to be detected in the final crossmatch test. The incidence may be decreased by collecting multiple samples of sera at monthly intervals and testing them (especially the sample containing the highest number of cytotoxic antibodies against a random panel) with the donor lymphocytes prior to transplantation. In accelerated acute rejection, the allograft may function well for a few days to a few weeks before the occurrence of irreversible acute renal failure. The diagnosis is established by the presence of oliguria, sudden deterioration in graft function, diminished cortical blood flow shown by radioisotopic studies, and histologic evidence of vascular occlusion, fibrin thrombi, interstitial hemorrhage, and tubular necrosis. There is no satisfactory therapy, although intense plasma exchange is being tried at some 13IJ

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transplant centers with variable success rates. Graft nephrectomy is the ultimate choice. Acute cellular rejection occurs during the second week after transplantation except in patients receiving prophylactic ALG, in whom the first rejection episode is generally postponed until the fifth post-transplant week. 23 This rejection is mediated by cellular defense mechanisms. The clinical manifestations include fever, hypertension, oliguria, graft tenderness, and impaired renal function occasionally requiring temporary dialysis. These classical features may not be present in all cases, however, because the rejection phenomenon is modified by factors such as the interval between transplantation and the onset of rejection, pretransplant preparation (transfusions and splenectomy), post-transplant immunosuppressive therapy, and the immunologic tolerance of the host to the graft antigen. Acute rejection episodes occurring in the late post-transplant period are often asymptomatic. 22 Several laboratory studies have been proposed to aid in the diagnosis of acute rejection. Some of these are urine cytology,104 urine and serum -beta 2-microglobulin levels,119 circulating T lymphocytes and their subsets (helper- and suppressor-cell ratio), 33, 78 radioisotope renogram, 38 renal transplant ultrasound,68 and allograft biopsy.47 Although most of these studies have the advantage of being noninvasive, they are not specific for the diagnosis of rejection. Renal histology provides the most useful information in diagnosing acute cellular rejection. The histologic features consist of perivascular mononuclear-cell infiltration, marked interstitial edema, and atrophy of the tubular epithelium with minimal or no alterations in the glomeruli and vessels. The infiltrating cells are predominantly lymphocytes, but one often sees an admixture of plasma cells, eosinophils, and polymorphonuclear cells in the interstitium of rejected kidneys. Histology is valuable not only in making the diagnosis but also in directing subsequent therapy. For instance, in febrile patients who have normal renal histology, ATN, or cytomegalovirus glomerulopathy,118 additional immunosuppressive drugs are not warranted and may even be harmful. There may be other lesions, such as recurrence of the original disease, chronic allograft rejection, or acute humoral rejection in the biopsy specimen. The choice of antirejection therapy depends on the extent and severity of these other lesions. At our institution, percutaneous allograft biopsies are often performed in patients with an unexplained decrease in renal function. Transplant ultrasound is done first, however, to rule out technical problems such as hydronephrosis or perirenal fluid collections. The mainstay of therapy for acute cellular rejection is the administration of high-dose corticosteroids. The exact protocol for antirejection therapy varies from center to center. In our program,112 acute cellular rejections are treated with intravenous methyl-prednisolone sodium succinate (Solu-Medrol) as single infusions starting at 1 gm per day. The dose is reduced by half at two-day intervals and discontinued after six days. On day seven, oral prednisone is begun at 60 mg per day. The dose is reduced at weekly intervals, 10 mg at a time, until the prerejection dose is reached. Some transplant centers use higher doses of oral prednisone instead, start-

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ing at 2 or 3 mg per kg per day and tapering the dose to the prerejection level in approximately two to three weeks. When high-dose corticosteroids are contraindicated, such as when there is concomitant sepsis or gastrointestinal bleeding, external graft irradiation has been tried as a means of combating rejection. 45 Controlled studies, however, showed that graft irradiation was not beneficial. 53 We use external irradiation only in selected instances, giving 150 rads on each of three days. The total dose should not exceed 1500 rads because of the risk of radiation nephritis. To reduce the toxicity related to high-dose steroids, some investigators have used antilymphocyte serum, 10 to 20 mg per kg per day for 10 to 21 days, with satisfactory results. 46. 64 The prerejection dose of prednisone was continued in these patients. Occasionally, we use ALG for the treatment of acute cellular rejections, the typical patient being one who has had three previous rejections at short intervals that were controlled with high-dose intravenous steroids. In these sporadic cases, we observed that ALG was beneficial in stabilizing graft function and reducing the frequency of subsequent rejections. The use of monoclonal antibodies for the treatment of acute rejection has generated interest in recent years.l2l Controlled clinical trials are under way, but the results are still too preliminary to make any comment. Intense plasmapheresis has been used in an attempt to control the rejection episodes, but its efficacy is doubtful. 54 Intravenous heparin and other forms of anticoagulation have not been useful when added to conventional antirejection therapy. Technical or Surgical Complications. The following complications are listed under the heading "technical" because they result either directly or indirectly from the surgical technique. Most of them are devastating and result in graft failure. 42 Examples are renal artery thrombosis, renal vein thrombosis, necrosis of the renal pelvis or ureter, stenosis of the ureter, perirenallymphoceles, and renal artery stenosis. The high-dose corticosteroids and superimposed infections compound these surgical problems, leading to much of the morbidity and mortality in the early post-transplant period. With the experience acquired over the years, surgeons are taking prophylactic measures at the time of transplantation as opposed to dealing with these problems after they occur. Preservation of ureteral blood supply, appropriate use of antibiotics, intraperitoneal drainage of lymphoceles, reduction in the dose of corticosteroids, and early surgical intervention are some of the measures that have lowered the frequency and severity of the surgical complications in recent years. 10. 135, 138 Infectious Complications. Infections are by far the most common problem to affect transplant recipients. Although the incidence of infections decreases in later years, the risk prevails throughout the post-transplant period, and infection is still the leading cause of death in transplant patients. 140 Because of their lack of immunologic defense, any factor that disrupts the skin and mucosal barriers enhances the risk of infection in these patients. Examples of such factors are long-standing intravenous catheters, indwelling bladder catheters, surgical wounds, draining chest tubes, and openly draining lymphoceles. Infections can also be transmitted

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with the donor kidney .18. 102 Clinical experience suggests that the risk of infection is higher in older individuals and in diabetic patients and after antirejection therapy. The sites involved are the lungs, urinary tract, blood, central nervous system, skin, and joints, in decreasing order of frequency. Bacterial infections are most prevalent throughout the post-transplant period, followed by fungal, viral, and parasitic infections. Among the viral infections, cytomegalovirus (CMV) is responsible for much of the morbidity and mortality. In recent years, the judicious use of antirejection drugs, attention to nutritional status, early surgical intervention and appropriate use of antibiotics have reduced the severity of infections and lowered the death rate in recipients of kidney transplants.I 35. 138 Bacterial infections. Infections with staphylococci, streptococci, and gram-negative rods usually occur following surgical procedures or antirejection therapy.3 They are ultimately responsible for the death of patients who are hospitalized long term with complications such as liver disease or bone-marrow suppression. Pneumococcal pneumonia and bacteremia occur with increased frequency in the spleneCtomized patients. 74 Salmonella infections often involve the blood vessels, leading to mycotic aneurysms; rupture of these may be fatal. 90 Salmonella osteomyelitis involving long bones is not uncommon in diabetic patients. Mycobacterial infections, both tuberculous and nontuberculous, affect transplant recipients. I. 80 Tuberculosis developing after transplantation is usually the result of reactivation of a latent infection. Tuberculous monoarthritis, meningitis, and pneumonia can occur. Atypical mycobacteria are often difficult to eradicate and thus require long-term therapy. Nocardiosis usually presents as a cavitating lung nodule or cerebral abscess. Disseminated nocardiosis involving multiple sites, including the skin, muscles, lymph nodes, and liver, has been described. l03 Diagnostic tests for nocardiosis include computerized tomography, aspiration of joint fluid, and surgical drainage of abscess cavities with Gram's stain or culture of the fluid, which reveals the characteristic gram-positive filamentous rods. We have successfully treated a patient with nocardial arthritis involving the knee with trimethoprim sulfamethoxazole (Septra).l14 Listeria monocytogenes is a gram-negative bacillus, easily grown in blood cultures, 72 that is often mistaken for diphtheroids. The primary site of infection is the central nervous system. Bacteremia and encephalitis have been described. 98 Legionnaire's disease has been reported as a virulent epidemic in some transplantation units. 57 The clinical presentation is that of rapidly changing nodular or lobar consolidation seen on chest radiographs. Diagnosis is made by culture, by direct fluorescent-antibody staining of the tissue sections, or by demonstrating rising antibody titers in the serum. A number of other bacteria have been isolated from immunosuppressed patients, including Legionella-like bacteria, the Pittsburgh pneumonia agent, and Chlamydia. After appropriate materials have been obtained for culture, antibiotic therapy should be initiated early rather than late in the course of infection. The immunosuppressive drugs should be decreased or discontinued in pa-

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tients with severe infection. High caloric intake by either the intravenous or oral route is essential to minimize tissue catabolism and improve the chances of recovery. It is unlikely that a patient with severe infection and malnutrition would reject the allograft until he recovers from these problems, but in the rare event of concomitant uremia, frequent dialysis and low-dose heparin are indicated. Granulocyte transfusions should be considered in patients who are leukopenic. Infusion of broad-spectrum gammaglobulin may be beneficial in an occasional patient. Prophylactic measures such as the polyvalent pneumococcal vaccine for splenectomized patients, isoniazid for patients with previous mycobacterial infection, mycostatin suspension for oral moniliasis, and trimethoprim sulfamethoxazole for urinary tract infection should be considered in the early post-transplant period. These prophylactic drugs can be discontinued when the maintenance dose of prednisone is lowered to 30 mg per day. For children who have had a splenectomy, oral penicillin, 250 mg per day, is recommended for an indefinite period. Fungal infections. Both superficial and deep fungal infections occur in renal transplant patients. 51, 67 Most of them run a slow indolent course, presenting with general malaise or as incidental findings at autopsy. The lungs are a common portal of entry. Discrete, slowly changing pulmonary nodules are often seen on chest radiographs. 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 three to four months after transplantation. Among the deep fungal infections, cryptococcosis, aspergillosis, histoplasmosis, coccidioidomycosis, and mucormycosis have been reported in renal allograft recipients. Diagnosis is mad~ by serologic tests, special stains, or culture of the blood or bone marrow. Sputum cultures are often negative. Invasive studies such as transbronchial or open-lung biopsy may be needed to establish the correct diagnosis. India ink preparation or staining of the spinal fluid for the polysaccharide antigen is frequently positive in patients with cryptococcosis. The mainstay of therapy for systemic fungal infections is intravenous amphotericin B.30 Initially, the drug is given in smaller doses such as 5 to 10 mg per day. If the patient tolerates this, the dose is gradually increased, the maximum being 50 to 70 mg per day. It is necessary to continue the treatment for several weeks until a cumulative dose of 1.0 to 1.5 has been given. In patients with impaired renal function, the daily dose should be lowered or the drug should be administered every other day or on a twicea-week schedule. Many patients have fever, chills, muscle pains, and hypertension while receiving the drug. These reactions can be controlled by administering diphenhydramine (Benadryl), meperidine (Demerol), or hydrocortisone intravenously before infusion of amphotericin. The other

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problems from this drug include renal tubular acidosis, hypokalemia, and renal failure. High-dose intravenous potassium bicarbonate may be required to correct the hypokalemia and acidosis. Earlier reports indicated that mannitol would decrease the nephrotoxicity of amphotericin, but controlled studies have not shown it to be effective. 5-Fluorocytosine often enhances the therapeutic effects of amphotericin B, but if it is administered alone, resistance develops rapidly. The dose is 10 to 20 mg per kg four times daily, adjusted on the basis of the serum level, the patient's renal function, and bone-marrow tolerance. Surgery may be required in patients who have uncontrolled hemoptysis or fungus balls. Viral infections. Of the viral infections, the herpes group is most often responsible for morbidity and mortality in the early post-transplant period. 62 Viruses in this group include cytomegalovirus (CMV), herpes simplex, herpes zoster-varicella, and the Epstein-Barr virus. Cytomegalovirus is the most common infection in renal allograft recipients. Laboratory evidence of viral infection, such as urinary excretion or a four-fold or greater rise in serum antibody titers, can be demonstrated in :lS many as 90 per cent of post-transplant patients. 4 The infection may be subclinical or present with fever alone or fever associated with pneumonia or hepatitis. The common clinical expression is that of diffuse interstitial pneumonia, arterial hypoxemia, and leukopenia in a febrile patient. Young people with no previous exposure often die with this disseminated form of infection. Involvement of the gastrointestinal tract resulting in cecal ulceration, bleeding, and bowel perforation has been reported. llo , 143 Retinitis, encephalitis, peripheral neuritis, autonomic dysfunction, arthralgias, and skin rash are other manifestations of this disease, The hepatic involvement may be mild, with elevation of serum enzyme levels, or severe, with diffuse parenchymal damage, encephalopathy, and death, Impairment of renal function occurs either as a result of direct glomerular involvement or secondary to fever and dehydration, Although the virus itself may depress the immune response, allograft rejection can occur cOncomitantly or immediately after the infection. 125 When dilemmas exist, allograft biopsy should be performed to arrive at the correct diagnosis. The disease occurs either as a primary infection or reinfection; different strains of the virus may account for the latter. It is a common observation that the second or third episode of infection is mild and often diagnosed retrospectively on the basis of an increased serum antibody titer. 27 The virus may be transmitted with the graft63 or via blood transfusions. In most instances, the diagnosis is made retrospectively by demonstrating a four-fold or greater rise in antibody titer between the acute and convalescent sera. Cytomegalovirus inclusions may occasionally be seen in the buffy-coat of white blood cells from febrile patients ll8 and can also be found in biopsy specimens obtained from the liver, kidney, bowel, or lungs. There is no effective therapy for cytomegalovirus infections, In patients who are severely ill, immunosuppression should be decreased or discontinued. Adequate caloric intake should be ensured to decrease tissue catabolism and increase the body's defense. Most patients recover within three to six weeks. Not all patients require hospitalization; this decision

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can be made depending on the severity of the clinical illness. Other modes of therapy still in the experimental stage include transfer factor, leukocyte interferon, and passive immunization with concentrated antisera obtained from patients who have recovered from the infection. The recently introduced antiviral drug acyclovir is not beneficial. l22 Herpes simplex virus infection often presents as mucocutaneous ulcerations of the mouth and external genitalia. These lesions generally respond to local application of iodoxyuridine or acyclovir. The most serious complications are hepatitis96 and encephalitis. 83 Involvement of the brain may result in paralysis of the face or the extremities. The diagnosis is based on serologic tests or brain biopsy. Acyclovir appears promising. 122 Herpes zoster virus infection presents as a painful vesicular skin rash along the distribution of the spinal nerve roots or the trigeminal nerve over the face. The lesions generally subside within one to two weeks, although occasionally the disease spreads and causes pneumonia. Therapeutic measures include the administration of analgesics, decreasing the immunosuppressive drugs, and local application of iodoxyuridine or acyclovir. In patients with disseminated herpes zoster, intravenous adenine arabinoside (vidarabine),ll or acyclovir may be required. Postherpetic neuralgia is a residual problem and often incapacitating. Phenytoin (Dilantin) and carbamazepine (Tegretol) have been tried for the relief of neuralgia with variable success. Nerve block with alcohol or phenol may be necessary in patients with intractable pain. Varicella (chicken pox), can affect immunosuppressed patients if they have not been exposed to this in childhood. The disease presents as fever, vesicular skin rash, and small nodular infiltrates on the chest radiographs. There is no effective treatment, and the usual principles of management apply. Hepatitis B virus infection occurs frequently both in patients waiting for transplants and those who have received them, and is usually transmitted via blood transfusions given to patients when they are on dialysis or during surgery. If the liver enzyme concentrations are normal or minimally elevated, hepatitis B infection is not ,a contraindication for renal transplantation. 28 The viral antigen persists in the serum for long periods without clinical evidence of liver disease. The long-term ill effects are not fully known, but some patients, particularly those with chronic active hepatitis, die with liver failure in the late post-transplant period. 75 The clinical experience with hepatitis A and with non-A, non-B hepatitis is limited at this point. Infection with influenza virus has been described in graft recipients. When epidemics threaten, immunization i,s called for.25 Live-virus vaccines should not be used. Sometimes, these viral infections may trigger a rejection episode. 21 Papovavirus infections, particularly warts, are common after transplantation; the treatment is surgical excision or cauterization with liquid nitrogen. In patients who have recurrent problems, the dose of azathioprine may have to be lowered. A progressive multifocal leukoencephalopathy caused by papovavirus was described in a transplant recipient. 85 There is no known therapy. Parasitic infections. Pneumocystis carinii is the most common parasitic infection in transplant recipients. 40 , 70 The infection is generally limited to

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the lungs and frequently associated with other viral or fungal infections. The clinical manifestations include fever, nonproductive cough, tachypnea, cyanosis, and severe hypoxia. Physical findings are often sparse. Serial chest radiographs reveal diffuse hazy infiltrates in the perihilar area spreading gradually into the peripheral lung fields. The diagnosis is made by demonstrating the organisms with silver-methenamine stain in secretions obtained by bronchial lavage or brushings. To increase the yield, it is often necessary to perform an open-lung biopsy and stain the tissue imprints. The organism appears as a folded cyst with a double outer membrane. The infection responds to trimethoprim sulfamethoxazole,7° and because of the common practice in most transplant centers of using this drug as a prophylactic agent against urinary tract infections, the incidence of Pneumocystis pneumonia has decreased in recent years. Pentamidine is no longer used because of its many toxic effects. Toxoplasmosis also occurs in transplanted patients. 52. 137 Clinical manifestations include meningitis, encephalitis, and endophthalmitis. The diagnosis is made by lymph node biopsy or the Sabin-Feldman dye test. Treatment consists of sulfadiazine and pyrimethamine combination. Strongyloidosis may present as a cavitating pneumonia and sepsis35 and is diagnosed by finding the larvae in the sputum or bronchial washings or by demonstrating the larvae within the alveoli from lung biopsy specimens. m Other protozoan and parasitic infections include malaria, sparganosis, and protatacosis. Appropriate chemotherapeutic agents are available for these infections. Thromboembolic Disease and Pulmonary Embolism. These problems occur with high frequency during the first six months after transplantation. In an earlier study, we analyzed the clinical data and autopsy material in 100 consecutive patients who received kidney transplants at the Cincinnati General Hospital. Forty-one thromboembolic events occurred in 25 patients, and thromboembolic disease accounted for 20 per cent of total deaths. u5 Fourteen patients had pulmonary embolism; antemortem diagnosis was made only in two instances. A source for pulmonary embolism (such as iliofemoral venous thrombosis) was found in nine cases. The other sites of emboli included the renal artery, renal vein, popliteal artery, inferior vena cava, coronary arteries, and cerebral vessels. The incidence increased with age and correlated inversely with the length of the posttransplant period. Steroids, which are given in higher doses during the early months, may predispose patients to thromboembolism. Aggressive treatment of hypertension and hyperlipidemia and reduction in the dose of corticosteroids or alternate-day steroid administration may reduce the risk of thromboembolic disease. In those with hypertension and transplant malfunction, it is probably best to remove the allograft and return the patients to dialysis. Prophylactic antiplatelet drugs may be beneficial. Our patients routinely take 10 grains (650 mg) of aspirin daily throughout the post-transplant period unless there is a specific contraindication. This, in addition to low-dose prednisone, has significantly reduced the incidence of thromboembolism in our post-transplant patients. Hypertension. The incidence of post-transplant hypertension ranges from 50 to 60 per cent in adult allograft recipients. 132 The etiologic factors include post-transplant ATN, volume overload, acute and chronic rejec-

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tion, high-dose corticosteroids, renal artery stenosis, recurrence of the original disease (such as membranoproliferative glomerulonephritis or scleroderma renal disease), "Page kidney" secondary to a thick fibrotic capsule, hydronephrosis, and hyperaldosteronism. 59 It is important to evaluate this problem thoroughly to find any curable cause. Every effort should be made to regulate the hypertension so as to preserve graft function. Diuretics should be used with discretion as they may impair renal function. Beta blockers and vasodilators are prescribed commonly and appear to be a good combination. Conversion to alternateday prednisone therapy has ameliorated hypertension in several of our patients. Captopril should not be used if there is evidence of renal artery stenosis because of the danger of renal failure. 69 In patients with significant renal artery stenosis, balloon angioplasty, endarterectomy, or a bypass procedure is recommended. Because of the risk of tearing the renal artery of a solitary functioning kidney, balloon angioplasty should not be attempted by inexperienced radiologists. 84 Rupture of the Allograft. Rupture of the renal allograft usually occurs in association with rejection. 65 The clinical picture is that of sudden onset of pain over the allograft and shock resulting from profuse hemorrhage. Nephrectomy is necessary in almost all cases, although in a few instances surgical repair has been successful. Hyperlipidemia. Lipid abnormalities occurring after transplantation may be a continuation of the problem from the hemodialysis period. 7 Corticosteroids may enhance the risk by increasing the synthesis of triglycerides. 8 The combination of hyperlipidemia and sustained hypertension may contribute to the occlusive vascular disease 131 and associated complications that are seen in transplant recipients. Therapeutic measures include dietary manipulation and administration of lipid-lowering drugs. Reduction in the daily dose of steroids or conversion to alternate-day administration appears to be beneficial. 26 In hypothyroid subjects, thyroid hormone supplementation lowers the serum lipid levels. Gastrointestinal Problems. Peptic ulcetation with its associated complications, such as hemorrhage and perforation of bowel,56 and pancreatitis 136 have been described in transplant recipients. Both these problems cause serious morbidity and mortality in the immunosuppressed patient. Therefore, for patients with prior complications of peptic ulcer disease or who present with an active ulcer, prophylactic vagotomy and a drainage procedure is recommended before transplantation .126 As noted earlier, ulceration of the cecum leading to hemorrhage and bowel perforation has been associated with cytomegalovirus infections.l43 Unless there are additional complications, peptic ulcers occurring after transplantation can be managed medically using a combination of a histamine (H 2) antagonist and antacids. The dose of prednisone should be reduced, and drugs such as salicylates and other nonsteroidal anti-inflammatory drugs must be avoided. The routine administration of antacids between meals for several weeks after transplantation may lessen the risk of peptic ulcer disease. Management of Late Complications The following complications have been observed in patients who have had functioning kidney transplants for six months and beyond: (1) hema-

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turia, proteinuria, and nephrotic syndrome; (2) recurrence of the original renal disease; (3) chronic rejection; (4) atherosclerotic cardiovascular disease; (5) chronic liver disease; (6) malignancies; (7) aseptic bone necrosis; (8) cataracts; (9) post-transplant diabetes mellitus; and (10) suicide. Hematuria, Proteinuria, and Nephrotic Syndrome. Approximately 2 to 3 per cent of patients have microscopic or gross hematuria in the late post-transplant period. In most cases, the cause is unknown, but in other instances hematuria is associated with bladder tumors, ureteral ischemia, acute rejection, and infections affecting the kidney or the lower urinary tract. Hematuria and proteinuria occur together in patients with recurrent glomerular disease. The evaluation should include intravenous pyelography or ultrasound of the transplanted kidney, cystoscopy, renal angiography, and allograft biopsy. The treatment is directed at the cause. In idiopathic cases with chronic blood loss, supplemental iron therapy is beneficial. Proteinuria occurs in association with acute and chronic rejections,19, 29 congestive heart failure, de novo or recurrent glomerular disease,34, 130 and renal vein thrombosis. 6 The proteinuria associated with acute cellular rejection is usually of lower magnitude and composed of low-molecularweight proteins. Nonselective proteinuria of higher magnitude occurs with chronic rejections, de novo or recurrent glomerular disorders, and renal vein thrombosis. Treatment is directed at the cause. Higher doses of steroids or addition of other cytotoxic agents does not appear to alter the course of nephrotic syndrome but may predispose these individuals to fatal infections. Dietary measures such as a low-sodium, high-protein, and highcaloric diet, diuretics, or parenteral administration of salt-poor albumin should be utilized in some cases. De Novo and Recurrent Glomerulonephritis. Nil-lesion (steroid resistant) nephrotic syndrome92 as well as membranous glomerulonephritis 130 have occurred in renal allografts of patients who had other types of disease in their native kidneys. Focal glomerulosclerosis,79 membranous nephropathy,81 membranoproliferative glomerulonephritis (especially the densedeposit type),37 IgA nephropathy,14 anti-glomerular basement membrane nephritis,12 progressive systemic sclerosis,l44 diabetes,88 systemic lupus erythematosus, 146 amyloidosis, 82 hemolytic-uremic syndrome,48 and Henoch-Schonlein purpura9 have been reported to recur with variable frequency in transplant recipients. Despite the morphologic appearance of the original disease, the graft continues to function for long periods in most cases. Therefore, patients with the above original diseases should not be categorically deprived of the opportunity to receive kidney transplants. Chronic Allograft Rejection. Chronic rejection is the most frequent cause of renal dysfunction in the late post-transplant period and often leads to end-stage renal failure. 100 However, acute cellular rejections can occur in the late post-transplant period, resulting in graft functional impairment. At times, they may be superimposed on chronic rejection. Diagnosis of these acute rejections is of paramount importance, since they are controllable with antirejection therapy, whereas chronic allograft rejection is not amenable to any form of treatment. If empirical antirejection treatment is used, the patients will be predisposed to serious infections and other

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steroid-related complications. The clinical triad described in patients with chronic rejection is hypertension, proteinuria or nephrotic syndrome, and decreased renal function. 61 Recurrence of the original disease should be considered in the differential diagnosis. In patients with established chronic rejection, if renal function deteriorates rapidly, other common causes such as drug allergy, nephrotoxicity from antibiotics, intravascular volume depletion, and obstructive uropathy should be considered. Reversible acute renal failure after use of captopril has recently been described in graft recipients with renal artery stenosis. 69 Allograft biopsy provides valuable information in the differential diagnosis and management of patients with diminished renal function in the late post-transplant period and should be utilized more frequently. The histologic features of chronic rejection are diffuse interstitial fibrosis with minimal cellular infiltration, ischemic glomeruli with wrinkling of the capillary basement membrane, segmental or global glomerulosclerosis, and concentric medial hypertrophy and internal proliferation of vessel walls. The tubules may show patchy atrophy and dilatation. Chronic rejection leads to progressive deterioration in graft function, the course of which may last from a few months to several years. The dose of azathioprine may have to be reduced in patients with decreased renal function. Hypertension should be controlled with appropriate medications. When the creatinine clearance decreases to 15 ml per min or less, regular dialysis should be considered. Patients who wish to receive another transplant should be placed on the waiting list for a cadaver kidney unless there is a suitable donor available in the family. Atherosclerotic Cardiovascular Disease. Enhanced atherosclerosis affecting coronary arteries, cerebral vessels, and the peripheral vasculature has been described in renal allograft recipients. 20, 71 The clinical manifestations include angina pectoris, myocardial infarction, transient ischemic episodes, hemiplegias, intermittent claudication, and ischemic ulcers over the extremities. Occlusive vascular disease is a more serious complication in diabetic patients, and approximately 15 percent of diabetic patients with functioning renal transplants require amputations because of ischemic ulcers and superimposed sepsis involving the extremities. !OB Corticosteroids are often blamed for accentuating the underlying atherosclerotic vascular disease. The management consists of reducing the dose of corticosteroids to the lowest possible level and attending to the clinical problems as they occur. The routine use of antiplatelet drugs may be beneficial, but controlled clinical trials are lacking. Chronic Liver Disease. Liver failure is emerging as a leading cause of death in recipients of renal allografts. 75. 77 Although viral hepatitis96, 139 (hepatitis B, cytomegalovirus, herpes simplex, non-A, non-B) is still the principal cause of liver dysfunction, drug-induced hepatitis,l34 iron overload,116 and alcoholism, and malignancy are important contributing causes. Of these, hemosiderosis is the only condition that can be treated effectively, with intermittent phlebotomies. Therefore, it is imperative not to miss this condition during the post-transplant period. Appropriate precautionary measures during blood transfusions and the use of hepatitis B vaccine may reduce the incidence of liver disease in transplant patients. Vac-

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cination against cytomegalovirus infection may be available in the near future. In those with drug-induced liver disease, the offending drug should be withdrawn. In patients with significant liver disease, the dose of azathioprine may have to be reduced to prevent bone-marrow toxicity. Malignancies. It is estimated that the risk of cancer is 35 times higher in patients receiving chronic immunosuppressive therapy than normal controls. 66 Recent studies suggest that uremic patients receiving chronic dialysis are also at higher risk. 86 It is not clear what the risk of cancer recurrence is among patients who had various types of malignancies before transplantation. Two patients who had renal cell carcinoma in their native kidneys have subsequently received renal transplants at our institution. One of them, a 59-year-old woman, died with metastatic carcinoma of the lungs and pleura 28 months after transplantation. The other one, a 56-year-old man, has metastatic lesions in the bones and lungs and is receiving chemotherapy 69 months after the transplantation. Skin tumors account for approximately 40 per cent of the neoplasms, followed by lymphomas (20 per cent). Other solid-tissue tumors, in decreasing order of frequency, affect the female reproductive organs, gastrointestinal tract (including liver and pancreas), lungs, breast, head and neck, renal allograft, and brain.l°7 Epstein-Barr virus was recently linked to the development of a malignant post-transplant B-cell lymphoma which responded to acyclovir. 60 Most physicians prefer to reduce or discontinue azathioprine in patients suffering from cancer, as a combination of this drug with other chemotherapeutic agents may profoundly depress the bone marrow. Surgical intervention, radiation therapy, and chemotherapy are indicated, depending on the individual circumstances. Aseptic Bone Necrosis. Approximately 10 to 15 per cent of patients with successful renal transplants develop this complication, III and the total cumulative dose of corticosteroids is not always high. The hip joints are most frequently involved. However, aseptic necrosis can occur in the knees, ankles, shoulders, and wrists. The most common symptom is pain on locomotion. Radiographs will confirm the diagnosis; however, in the early stages it may be necessary to obtain technetium scans of the bone. 41 Treatment consists of analgesics, non-weight-bearing exercises such as swimming, and taking the weight off the hip with a cane while walking. In advanced stages, prosthetic replacement or arthrodesis is required to relieve the pain. Cataracts. Posterior subcapsular cataracts occur in 10 to 15 per cent of patients in the late post-transplant period. In one series, although 34 per cent of patients had a detectable cataract, only half had less than normal vision. IS Visual difficulty with bright sunlight or car headlights is often the first symptom. When vision is seriouly impaired, surgical extraction of the lens is done and patients wear contact lenses or glasses. Post-Transplant Diabetes. Five to six per cent of patients develop diabetes mellitus after renal transplantation. 12o Although in most instances the hyperglycemia improves after reduction in the dose of corticosteroids, a fair number of patients require insulin therapy for indefinite periods. Occasionally, patients present in a nonketotic hyperosmolar coma.l 4S Hy-

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perglycemia may artificially raise the serum creatinine levels and should not be confused with graft rejection. 87 Suicide. Suicides are not uncommon in patients with functioning renal transplants. 140 It is obviously stressful for these patients to live with uncertainties and on borrowed time. Awareness of this problem and appropriate psychiatric consultation are necessary. CLINICAL RESULTS

The most commonly used measures of the success or failure of a transplant center are the patient and graft survival rates and the degree of rehabilitation. Innovative discoveries such as tissue typing133 and crossmatch studies and preservation and transport of cadaver kidneys, 13, 31, 94 have contributed significantly to the success rate of renal transplants during the past two decades. Along with clinical experience, factors such as splenectomy,SO ALG administration,124 reduction in the dose of corticosteroids,138 and the use of cyclosporine, 44, 129 have contributed to the improvement in graft survival results in recent years. The transplant registries in the United States,2 Europe,22 and Australia39 have provided useful reference material, compiling the data on a large number of patients. Unfortunately, in the United States the data collection by the registry was terminated in 1977. The standards committee of the American Society of Transplant Surgeons127 has fulfilled only a small portion of the registry responsibilities. The current results obtained with transplantation are summarized in Table 1. The most gratifYing aspect of renal transplantation is the marked improvement in patient rehabilitation. For example, the European Dialysis and Transplant Registry reported that 95 per cent of live-donor transplant recipients and 92 per cent of cadaver-donor recipients were able to work at one year after transplantation. 32 At our own institution, 89 per cent of those with fuctioning allografts were fully r~habilitated six months after transplantation. Patients were considered fully rehabilitated if their physical and emotional status was stable and they had resumed activities identical to or perceived as equivalent to those in which they were engaged before the onset of renal failure. Case 1 A 23-year-old man developed renal failure secondary to "focal glomerulosclerosis." He received a 2-antigen-match cadaver allograft late in 1982. Approximately two months after the transplant, after treatment of a clinical rejection episode, he had a fulminant cytomegalovirus infection which affected his lungs, liver, and kidney. The allograft ruptured as a result of the inflammation and intraparenchymal edema but was surgically repaired. The patient required ventilator support in an intensive care unit along with intermittent dialysis treatments. The immunosuppressive drugs were withheld. Over the next six weeks, his pulmonary status improved, and the kidney allograft recovered from the viral glomerulopathy and associated renal failure. The maintenance immunosuppressive drugs were

446 Table 1.

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Summary of Current Results Obtained with Renal Transplantation TOTAL CASES*

Live Donor Transplants 1. Am Soc Transplant Surgeons Standards Committee (1981)127 305 2. European Dialysis and Transplant Assoc Combined Report (1980)32 833 3. Australian Dialysis and Transplant Registry, Combined Report (1981)3. 44 4. Harvard University-Peter Bent Brigbam Hospital (1978)135 33 5. University of California at San Francisco (1980)138 49 Cadaver Donor Transplants 1. Am Soc Transplant Surgeons Standards Committee (1981)127 574 2. European Dialysis and Transplant Assoc Combined Report (1980)32 5782 3. Australian Dialysis and Transplant Registry, Combined Report (1981)39 1120 4. Harvard University-Peter Bent Brigham Hospital (1978)135 53 5. University of California at San Francisco (1980)138 432 6. Hennepin County Medical Center, Minneapolis (1983)112 lOOt

ONE-YEAR PATIENT SURVIVAL

ONE-YEAR GRAFT SURVIVAL

95

79

92

75

91

79

98

85

99

93

89

55

83

56

79

51

95

52

91

53

87

81

*First transplants only. t Absolute patient and graft survival rate for 100 consecutive patients transplanted between 1977 and 1980. Only 5 of these patients received live donor transplants. Fifteen patients with multiple transplants, 21 patients with diabetes mellitus, and 28 patients older than 50 years were included in this analysis.

reinstituted. Now, 17 months post-transplant, his creatinine clearance is 60 ml per min, and he is a fulltime student. He also won the top prize at a national bowling tournament.

Case 2 A 68-yem:-old woman, a retired music teacher, received a cadaver transplant in 1978. The renal failure was caused by long-standing hypertension. Three months after the transplant, she developed cytomegalovirus infection after the treatment of a clinical rejection episode. Six months post-transplant she developed de novo membranous glomerulonephritis in the allograft with nephrotic syndrome. Despite proteinuria and minimal impairment of renal function (creatinine clearance, 60 ml per min), she is leading a normal life with no limitations on her physical activities. She regularly participates as a judge in opera competitions.

Case 3 A 44-year-old man received a cadaver renal transplant in 1980. He has longstanding insulin-dependent diabetes mellitus, which led to renal failure and blindness in both eyes. Despite these medical problems, this gentleman is regularly involved in karate exercises and holds a black belt. He is employed full-time as a computer programmer and is supporting his family.

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A transplant recipient surviving with a functioning kidney is much more productive to himself or herself, the family, and society. On the other hand, chronic dialysis patients have to be supported with enormous financial expenditure and community resources plus all the inconveniences borne by the patient and the family. These two methods of therapy, namely dialysis and transplantation, should therefore be integrated. The primary aim should be that of supporting all eligible patients who have end-stage renal failure with renal transplantation while utilizing dialysis until a suitable kidney is found or when the graft fails after transplantation. Obviously, those who are not considered candidates for transplantation (even with the liberal criteria followed at present) should be supported with chronic dialysis. CAUSES OF DEATH IN TRANSPLANT RECIPIENTS Sepsis is still the leading cause of death in recipients of renal transplants, accounting for 40 per cent of total deaths. 32, 140 It is followed by cardiovascular disease, which comprises 20 per cent of deaths. Included in this category are myocardial infarction, pulmonary embolism, and cerebrovascular accidents. Gastrointestinal problems are responsible for 10 to 15 per cent of deaths; bleeding, bowel perforation, pancreatitis, and liver failure are included in this group. Malignant neoplasms account for 5 to 10 per cent of deaths. The rest of the deaths are from a variety of miscellaneous disorders. It is pertinent that a significant number of patients have committed suicide. Approximately one half of the deaths in transplant recipients occur within the first year after transplantation. Physicians providing long-term care should be aware of the pattern of death in transplant patients and take necessary steps to minimize the risk factors.

CONCLUSION; At present, patient survival and rehabilitation are quite satisfactory in both cadaver- and live-donor transplant recipients. Although the graft survival results in live-donor kidney recipients have improved, the cadavergraft survival rate remains low (see Table 1). Along with reduction in immunosuppressive drugs, the comprehensive patient care approach that we adopted at our institution may be utilized by other transplant centers. The recently introduced drug cyclosporine and the use of monoclonal antibodies may prove to be useful. Other techniques, such as induction of graft tolerance, are promising experiments for the future.

REFERENCES 1. Abbott, M. R., and Smith, D. D.: Mycobacterial infection in immunosuppressed patients. Med. J. Aust., 1 :351, 1981. 2. Advisory Committee to the Renal Transplant Registry: The 13th Report of the Human Renal Transplant Registry. Transplant. Proc., 9:9, 1977.

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3. Ahern, M. J., Comite, H., and Androile, V. T.: Infectious complications associated with renal transplantation: An analysis of risk factors. Yale J. BioI. Med., 51:513, 1978. 4. Andersen, H. K., and Spencer, E. S.: Cytomegalovirus infection among renal allograft recipients. Acta Med. Scand., 186:7, 1969. 5. Anderson, C. F., Frohnert, P. P., Torres, U., et al.: Follow up L.R. kidney donors 8 to 18 years after unilateral nephrectomy. (abstract). Chicago, Illinois, American Society of Transplant Physicians, Second Annual Meeting, 1983, p. P-1. 6. Arruda, J. A. L., Jonasson, 0., Guttierrez, L. F., et al.: Renal-vein thrombosis in kidney allografts. Lancet, 2:585, 1973. 7. Bagdade, J., Casaretto, A., and Albers, J.: Effect of chronic uremia, hemodialysis and renal transplantation on plasma lipids and lipoproteins in man. J. Lab. Clin. Med., 87:37, 1976. 8. Bagdade, J. D., Porte, D., and Bierman, E. L.: Steroid induced lipemia. Arch. Intern. Med., 125:129, 1970. 9. Baliah, T., Kim, K. H., Anthone, S., et al.: Recurrence of Henoch-Schiinlein purpura glomerulonephritis in transplanted kidneys. Transplantation, 18:343, 1974. 10. Banowsky, L. H. W.: Current results and future expectations in renal transplantation. Urol. Clin. North Am., 10:337, 1983. H. Baron, M., and Wechsler, H. L.: Low dose cytarabine therapy for herp~s zoster with pneumonia. Arch. Dermatol., 111 :910, 1975. 12. Beleil, O. M., Coburn, J. W., Shinaberger, J. H., et al.: Recurrent glomerulonephritis due to antiglomerular basement membrane antibodies in two successive allografts. Clin. Nephrol., 1:377, 1973. 13. Belzer, F. 0., and Kountz, S. L.: Preservation and transplantation of human cadaver kidneys: A two year experience. Ann. Surg., 172:394, 1970. 14. Berger, J., Yaneua, H., Nabarra, B., et al.: Recurrence of mesangial deposition of 19A after renal transplantation. Kidney Int., 7:232, 1975. 15. Berkowitz, J. S., David, D. S., Sakai, S., et al.: Ocular complications in renal transplant recipients. Am. J. Med., 55:492, 1973. 16. Berne, T. V., Gustafson, L. A., and Chatterjee, S. N.: Early severe renal allograft rejection. Arch. Surg., 111 :758, 1976. 17. Besarab, A., Jarrell, B., Ihle, B. U., et al.: Adverse effects of prophylactic irradiation and acute tubular necrosis on renal graft function and survival. Nephron, 31:347, 1982. 18. Bore, P. J., Basu, P. K., Rudge, C. J., et al.: Contaminated renal allografts. Arch. Surg., 115:755, 1980. 19. Braun, W. E., and Merrill, J. P.: Urine protein selectivity in human renal allografts. In Manuel, Y., Revillard, J. P., and Betuel, H.: (eds.): Proteins in Normal and Pathological Thine. Baltimore, University Park Press, 1970, pp. 271-280. 20. Braun, W. E., Phillips, D., Vidt, D. G., et al.: Coronary arteriography and coronary artery disease in 99 diabetic and nondiabetic patients on chronic hemodialysis or renal transplantation programs. Transplant. Proc., 13:128, 1981. 21. Briggs, J. D., Timbury, M. C., Paton, et al.: Viral infection and renal transplant rejection. Br. Med. J., 4:520, 1972. 22. Brown, E. A., Siegel, N. J., and Finkelstein, F. 0.: Symptomless acute renal transplant rejections. J.A.M.A., 239:2256, 1978. 23. Butt, K. M. H., Zielinski, C. M., Parsa, I., et al.: Trends in immunosuppression for kidney transplantation. Kidney Int., 13(Suppl. 8):S95, 1978. 24. Calne, R. Y., Rolles, K., White, D. J. G., et al.: Cyclosporin-A in clinical organ grafting. Transplant. Proc., 13:349, 1981. 25. Carroll, R. N. P., Marsh, S. D., O'Donoghue, E. P. N., et al.: Response to influenza vaccine by renal transplant patients. Br. Med. J., 2:701, 1974. 26. Cattran, D. C., Steiner, G., Wilson, D. R., et al.: Hyperlipidemia after renal transplantation: Natural history and pathophysiology. Ann. Intern. Med., 91:554, 1979. 27. Chatterjee, S. N., and Jordan, G. W.: Prospective study of the prevalence and symptomatology of cytomegalovirus infection in renal transplant recipients. Transplantation, 28:457, 1979. 28. Chatterjee, S. N., Payne, J. E., Bischel, M. D., et al.: Successful renal transplantation in patients positive for hepatitis B antigen. N. Engl. J. Med., 291 :62, 1974. 29. Cheigh, J. S., Stenzel, K. H., Susin, M., et al.: Kidney transplant nephrotic syndrome. Am. J. Med., 57:730, 1974.

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