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Emergencies Associated with Clinical Renal Transplantation
Emergencies Associated with Clinical Renal Transplantation ANTHONY P. MONACO, M.D. * PAUL S. RUSSELL, M.D., F.A.C.S.**
For over a decade there has been a progressive increase in interest in clinical renal transplantation. l • 2 The transplantation of an organ from one individual to another involves a number of serious moral and ethical considerations as well as unusual medical problems. With the present methods of immunosuppressive therapy the degree of success is clearly dependent on the genetic relationship between the donor and the recipient which determines the attendant degree of histocompatability difference involved and the violence of the subsequent rejection reaction. Although the results as measured by patient survival are surprisingly good and continue to improve,3 the procedure is still an experimental one, to be reserved for those patients afflicted with terminal uremia who have exhausted all forms of available conventional therapy. Furthermore, the availability of peritoneal dialysis and hemodialysis assures that renal allotransplantation (old terminology, homotransplantation) is never really an emergency procedure. Rarely, in association with severe trauma, one normal kidney may be sheared off its vascular pedicle. Under such circumstances, emergency operation to control hemorrhage is life-saving and reanastomosis of the devascularized organ at its usual site (orthotopic autotransplantation) or to different site (heterotopic autotransplantation) may save the otherwise undamaged kidney. The authors are aware of at least one instance in which this latter operation has been done. From the Department of Surgery, Harvard Medical School, and the General Surgical Services, Massachusetts General Hospital, Boston, Massachusetts This work was supported in part by grants AM 07055, AI 06320, T4 CA 5018 and CRTY 5018 from the United States Public Health Service. This is publication No. 1252 of the Cancer Commission of Harvard University. * Instructor in Surgery, Harvard Medical School; Assistant in Surgery, Massachusetts General Hospital ** John Homans Professor of Surgery, Harvard Medical School; Chairman, Surgical Services, Massachusetts General Hospital
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For the most part, however, the emergencies involved with renal transplantation are those related to the technical considerations of the operation itself and to the associated medical and immunological problems. For purposes of discussion, such emergencies will be considered arbitrarily as usually occurring in the preoperative period or in the immediate postoperative or late postoperative periods, although it will be obvious that, for the most part, all or any of the emergencies considered could occur at any time. Also, the emergency evaluation of cessation of function of the transplanted organ is considered. Unquestionably, one of the most serious emergencies is a sustained rejection crisis. Management of this emergency requires manipulation of current immunosuppressive drug therapy and institution of new immunosuppressive maneuvers and will not be considered in detail.
PREOPERATIVE EMERGENCIES
Patients referred for renal transplantation are invariably in an adval'lced state of uremia, frequently with associated fluid retention, cardiac failure, hyponatremia, hyperkalemia and acidosis. For this reason, a hemodialysis unit is an indispensable part of any renal transplantation program since major surgical procedures cannot be performed until major metabolic resuscitative measures are carried out. Appropriate hemodialysis readily corrects all of the above abnormalities. Localized collections of fluids in various serous cavities may necessitate emergency pericardiocentesis (secondary to uremic pericarditis) or emergency thoracentesis (secondary to uremic pleuritis and pneumonitis). Generalized fluid retention may produce cardiac failure and pulmonary edema and congestion, and may represent a clear-cut indication for emergency hemodialysis. As much as 6 kg. of body fluid can be removed by increasing the osmolarity of the bath (i.e., increased glucose concentration) and by constricting the outflow tract of the dialysis coil (to raise filtration pressure). In the management of cardiac failure, digitalis is to be avoided if possible in the patient requiring dialysis, since rapid falls in serum potassium and rapid shifts in extracellular electrolytes occurring during hemodialysis may accentuate digitalis intoxication and produce cardiac arrhythmia. Hyperkalemia is frequently a serious problem. Three commonly accepted means for controlling rises in serum potassium without resorting to dialysis are the use of cation exchange resins either orally or by rectum (sodium cycle resins if the serum sodium is low, ammonia cycle resins if serum sodium is above normal, and half-and-half mixtures if the serum sodium is normal), administration of sodium bicarbonate (particularly if the CO 2 combining power is low), and administration of hypertonic glucose and insulin intravenously. In spite of these measures, marked elevations of serum potassium levels frequently require emergency dialysis for control.
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Hypertension is treated by salt restriction and antihypertensive agents such as reserpine and ganglionic blocking agents. Under rare circumstances, malignant hypertension with associated hypertensive encepholopathy requires intravenous trimethaphan camsylate (Arfonad) therapy on an emergency basis for blood pressure control.
EMERGENCIES ASSOCIATED WITH THE IMMEDIATE POSTOPERATIVE PERIOD
Kidney transplantation is generally accomplished as a heterotopic allograft, the kidney being placed retroperitoneally in the iliac fossa (right kidney to left iliac fossa, and vice versa) with the renal artery of the donor usually anastomosed end-to-end to the divided recipient hypogastric artery and the donor renal vein anastomosed end-to-side to the recipient common iliac vein. The authors prefer to establish ureteral continuity by ureteropelvic anastomosis after the technique developed by Drs. Wyland and Guy Leadbetter, although many groups employ ureteroneocystostomy. (See Fig. 1.) In general, patients undergoing renal transplantation are markedly debilitated from uremia. Accordingly, such patients are especially prone to a number of complications and emergencies which can afflict all surgical patients. The hemorrhagic disorders and bleeding tendencies associated
Figure 1. Heterotopic Renal Allotransplantation. The donor kidney is transplanted retroperitoneally to the iliac fossa, the right kidney being placed in the left fossa and vice versa. Arterial continuity is usually established by end-to-end anastomoses of the donor renal artery with the recipient hypogastric artery which is divided and rotated upward (A). Venous reconstruction utilizes an endto-side anastomoses of the donor renal vein to the recipient common iliac or external iliac vein (V). Ureteral continuity is established by ureteropelvic anastomoses, although some still prefer ureteroneocystostomy.
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with uremia can lead to postoperative bleeding and accumulation of retroperitoneal hematoma. The singular complication which represents a serious emergency is postoperative atelectasis. Such patients are started on immunosuppressive therapy immediately preoperatively, and atelectasis can lead to serious pulmonary infection. For this reason, transplant patients are given vigorous preoperative and postoperative pulmonary physiotherapy. Furthermore, every effort is made to avoid infecting the tracheobronchial tree. Thus, spinal or continuous epidural anesthesia, supplemented by light inhalation anesthesia without endotracheal intubation, is the anesthesia of choice with this consideration in mind. If atelectasis does occur, vigorous therapy in the form of humidified oxygen, expectorants, chest physiotherapy and even bronchoscopy is indicated. Aside from the usual complications and emergencies associated with major surgery, certain emergencies specifically related to the transplanted organ also occur. Of these by far the most important is the usual massive diuresis which may begin on the operating table after the kidney is revascularized. The mean time interval after revascularization and appearance of urine on the operating table is usually approximately 30 minutes. For the first 12 to 24 hours after operation, urine output averages 250 to 450 cc./hour with some outputs reaching as high as 1000 cc./hour. When urine outputs rise toward this latter figure, the magnitude of the diuresis constitutes a serious postoperative emergency. Careful management of fluid replacement is necessary in order to avoid severe electrolyte imbalance and possible associated ventricular arrhythmia. In preparation for massive fluid replacement, adequate provision for intravenous fluid replacement is made. Patients are maintained on humidified oxygen and cardiac action continually monitored by a suitable cardiac monitor-pacemaker unit. In the immediate postoperative diuretic period, fluid volume is in general replaced hourly in an amount equal to the urine output, with adjustment made for the preoperative state of the patient's hydration. Accurate knowledge of urinary electrolyte concentrations is mandatory for correct replacement. These urinary electrolyte concentrations are usually predictable, the sodium averaging 95 mEq./liter and the chloride averaging 70 mEq./liter. Urinary potassium values are usually 10 to 20 mEq./liter. Intravenous fluid replacement is given in the form of 5 per cent glucose in 0.45 per cent saline. Although potassium is not usually replaced, in the presence of a massive diuresis 10 to 20 mEq./liter is added to intravenous fluids. Serial determinations of urinary and blood electrolytes are necessary for careful regulation of the replacement program. Calcium and sodium bicarbonate replacement intravenously is frequently needed and intramuscular magnesium sulfate may be required for falling serum magnesium levels. During a massive diuresis following renal transplantation, because of the large volumes of fluid involved, relatively small deviations in composition of the replacement fluid from the urine electrolytes can greatly magnify
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the total electrolyte replacement error. Furthermore, a number of electrolytes ordinarily in trace concentration in the urine and serum are not measured or replaced. Thus, electrolyte imbalance with cardiac arrest secondary to ventricular arrhythmia is a possible outcome. Figure 2 illustrates this unfortunate result in a six year old boy (weight 20 kg.) who received a renal transplant from his father (weight 66 kg.). The transplanted organ functioned immediately and a massive diuresis ensued with urine volumes rising to over 1000 cc./hour. In view of the small size of the recipient, the massive fluid shifts involved were further magnified. During the fourteenth hour post-transplantation the patient died from cardiac K. McC.
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Figure 2. Massive Post-transplantatim Diuresis Ending in Death. A 6 year old boy weighing 20 kg. received a renal allograft from his 32 year old father (weight 66 kg.) because of terminal uremia secondary to chronic pyelonephritis. At operation the donor kidney was found to have two small renal arteries, one of which was anastomosed end-to-end to the divided recipient hypogastric artery and one was anastomosed end-to-side to the external iliac artery. The total ischemia time was 102 minutes. The kidney functioned immediately postoperatively, and there was a rapid and progressive increase in the hourly urine output. Only 4 hours after completion of the anastomosis, the total urine output was 1000 cc. and had reached a rate of 400 cc./hour. Because of some fluid retention preoperatively, it was planned to maintain the patient at an output deficit which would total about 1000 cc. over the first 24.'hours postoperatively. By 6 hours postoperatively the total output was 2400 cc., the total intake 1660 cc., and the rate 650cc./hour. Eight hours after operation the rate was 850 cc./hour, the cumulative total about 3700 cc. and the total intake 2700 cc. Over the following 4 hours the level of diuresis continued at 1000 cc./hour. Serial determination of serum sodium, potassium, chloride, carbon dioxide, calcium and phosphorus, and magnesium through this time revealed normal values. However, 12 hours postoperatively, at the height of the diuresis, the patient had a sudden cardiac arrest and expired, presumably secondary to a cardiac arrhythmia related to an electrolyte disturbance.
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arrest, presumably from arrhythmia secondary to electrolyte imbalance. In general, the diuretic phase begins to subside 8 to 24 hours after transplantation. At this time, the volume of intravenous fluid therapy is reduced to avoid maintenance of the diuresis by excess water load. Less severe emergencies in the immediate post-transplantation period include occasional urinary leakage, particularly during the diuretic phase. In the case of ureteropelvic anastomosis, such leaks usually close as the suture line swells postoperatively. Rarely, if urinary fistulas persist beyond several days, retrograde catheterization with placement of an indwelling ureteral catheter through the ureteropelvic anastomosis or ureteroneocystostomy site is necessary until the fistula closes. Occasionally, severe genitourinary bleeding may occur from the site of ureteroneocystostomy or from an area of hemorrhagic cystitis associated with an indwelling urethral Foley catheter. In general, this bleeding is treated conservatively, occasionally requiring transfusion, although in the latter instance removal of the indwelling Foley catheter invariably results in cessation of bleeding.
EMERGENCY EVALUATION OF CESSATION OF FUNCTION OF RENAL ALLOGRAFTS
Among the several reasons which make the kidney an unusually good organ for experimental, clinical transplantation, one of the most important is the fact that the function of the transplanted organ can be continually monitored by serial urinalysis. Cessation or diminution of renal function as determined by frank anuria or oliguria can be caused by obstruction of the urinary outflow tract, thrombosis of the arterial or venous anastomosis, or by intrinsic failure of the kidney parenchyma either due to nonrejection factors such as ischemia and parenchymal swelling, or secondary to immunologic rejection. Since vascular problems constitute real hazards to the survival of the transplanted organ requiring rapid and active therapy, determination of the etiology of cessation of urine flow is an emergency. The sequence of events is important. Dramatic early function with excellent diuresis and progressive improvement in renal function following transplantation followed by gradual diminution of urine volume to oliguric but not anuric levels suggests rejection. Associated with this may be other signs of rejection such as rises in blood urea nitrogen and creatinine levels after initial gratifying falls, systemic temperature rise, clinically apparent transplant swelling, increased proteinuria and lymphocyturia. Under these circumstances, this emergency is managed by appropriate antirejection therapy. The etiology of sudden onset of anuria, in contrast to gradual progression to oliguria, may be more difficult to determine. Atony of the bladder secondary to residual uremic neuropathy may result in a functional obstruction. Urethral catheterization, in the absence of an indwelling Foley
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catheter, settles the question. Obstruction at the level of ureteroneocystostomy or uteropelvic anastomosis is more difficult to confirm. In general, renal vein thrombosis occurs with gradual production of anuria associated with increased hematuria and proteinuria, although this is not invariable. Complete arterial thrombosis produces a fairly sudden anuria, and can be confirmed by retrograde femoral arteriography by the Seldinger technique, with placement of the arterial catheter retrograde up to the level of the recipient hypogastric artery. Exploration of the wound with exposure of the transplant and its vascular pedicle provides the most definite evidence for proper status of the vascular supply of the transplanted organ, particularly if arteriography is not performed or is unsatisfactory. Unfortunately, severe swelling of a transplanted kidney secondary to ischemia during the transplantation surl!iery with or without acute tubular necrosis is a frequent cause for anuria. Under such circumstances, progression to the anuric state is usually gradual, rather than abrupt, although the latter can occur. A special circumstance in this regard occurs with cadaveric transplants which are subjected to long periods of hypotension and relative ischeInia prior to donor death and during transplantation so that the transplanted organ may not function for long periods postoperatively. Under such conditions evaluation of the status of such transplants is extremely difficult. Finally, acute swelling with secondary anuria may be secondary to rejection. Anuria secondary to swelling from any cause can be diagnosed only by exclusion from negative studies described above or by exploration and biopsy of the swollen, well vascularized organ (Fig. 3). The instrumentation studies described above for diagnosing the etiology of anuria have the fundamental drawback of being time-consuming and carrying the possibility of introducing infection. For this reason, simple maneuvers requiring no instrumentation have been sought. The so-called "radioactive renogram" has been utilized by several groups for the followup study of renal allografts. 5 The renogram provides a complicated curve of radioactivity which can be influenced by many factors. Recently, the Cleveland Clinic group has introduced the radioactive scintigram to study the etiology of oliguria and anuria after renal transplantation in man. 4 No special preparation of the patients is necessary. When severe oliguria and anuria appear, 150 micro curies of chloromerodin (Hg203) is injected intravenously. Approximately an hour later the abdominal wall area over the transplanted kidney is counted with a scintillating detector. The scintigram achieved represents a simple shadow of the radioactivity in the kidney entirely dependent upon vascular patency and tubular uptake. Nonvisualization of the kidney by scintigram is usually secondary to arterial occlusion or tubular cell death. The important point is that, if there is anuria and a normal scan is obtained, arteriography and re-exploration and biopsy are unnecessary to rule out other severe conditions. Obstructive uropathy may be a cause for the anuria, however, but can be ruled out by cystoscopy. In contrast, a rejection crisis in general gives a good uptake
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Figure 3. Anuria Secondary to Severe Edema and Early Rejection After Initial Period of Function Post-transplantation. A 20 year old man underwent renal allotransplantation because of terminal uremia and malignant hypertension secondary to chronic glomerulonephritis and pyelonephritis. The donor was the patient's 46 year old father. The total ischemia time for revascularization of the transplanted organ was 33 minutes. The kidney functioned within an hour of completion of the anastomosis. For the first 48 hours the urine output average was 150 cc./hour and there was a progressive fall in blood urea nitrogen and creatinine. During the third day postoperative there was a sudden appearance of hematuria and rapid fall in hourly urine output to anuric levels. Because of persistent anuria, the patient underwent cystoscopy and right ureteral catheterization which showed no obstruction at the ureteropelvic anastomosis and urinary extravasation (A). The patient then underwent exploration at which time the arterial and venous anastomoses were found to be open and satisfactory. The kidney was severely swollen, tense, and obviously extremely edematous. The renal capsule was incised and a biopsy taken. With the biopsy there was a release of a copious amount of edema fluid. Immediately after re-exploration the patient was started on intravenous steroids and within 4 hours the urine output was 50 cc./hour. B (magnification X21O) shows that at the time of biopsy the renal parenchyma was markedly swollen and edematous with only a small number of infiltrating mononuclear cells associated with rejection. The swelling could be secondary to ischemia alone or infiltration and immunological rejection, or both. Fortunately, the treatment for both causes of renal swelling is immediate steroid therapy.
and scintigram. However, with a radioactive renogram, rejection crises result in a nonfunctioning pattern and therefore do not rule out the other severe causes of anuria described above. In general, most groups involved in renal transplantation would consider progressive decrease in urine output after an initial period of excellent function as evidence for rejection and institute appropriate antirejection therapy without further investigation. In this regard it is important to realize that anuria secondary to swelling as a result of ischemia or im-
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munologic rejection are in fact both treated initially with steroids. The diagnostic procedures described above are used only when a high suspicion of mechanical or technical failure exists, i.e. the abrupt onset of anuria very early postoperatively while excellent diuresis is in progress and in the case of an allograft which fails to function at all after satisfactory transplantation. Furthermore, if a radioactive scintigram technique is available and familiar to the group concerned, a number of instrumentation techniques can be omitted.
EMERGENCIES ASSOCIATED WITH THE LATER POSTOPERATIVE PERIOD
As stated above, renal transplant patients are more susceptible to all the usual postoperative surgical complications and emergencies than routine surgical patients, a situation no doubt due to the debilitating effects of uremia and the stresses imposed by immunosuppressive therapy. Certain emergency situations arise frequently because of the nature of the operation, the immunosuppressive therapy involved, or the previous condition of the patient. Abdominal Emergencies
Normally, only a brief period of ileus follows the retroperitoneal transplantation of a kidney, with or without the performance of bilateral recipient nephrectomies. Usually, the nasogastric tube can be removed after 24 hours and progressive alimentation begun on the second day postoperatively. A number of instances of post-transplantation small bowel obstruction requiring emergency laparotomy, usually secondary to adhesions, have been reported. Lower abdominal dense adhesions, running from the posterior parietes to the site of a previous peritoneal dialysis catheter insertion in the lower anterior abdominal wall, are frequently the cause of such obstruction (Fig. 4). Other abdominal emergencies result from steroid immunosuppressive therapy. Most renal transplant patients who receive allografts sustain one or more rejection crises which require intensive steroid therapy for control and steroid maintenance therapy to prevent recurrence. Patients on such therapy are prone to develop duodenal and gastric ulceration with the obvious potential for acute perforation and bleeding. Acute perforations have usually been treated with pyloroplasty and vagotomy. Patients in severe rejection with secondary uremia on massive steroid therapy not uncommonly bleed from gastrointestinal ulceration and the associated uremic bleeding diathesis only compounds the difficulty. Acute pancreatitis has occurred in a number of patients, long after successful transplantation, while on steroids and Imuran (Burroughs-Wellcome Co., B.W. 57-322) therapy. Such pancreatitis may be a result of an idiosyncratic reaction to Imuran, but more likely is related to steroid therapy. Pan-
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Figure 4. Small Bowel Obstruction in the Postoperative Transplantation Period. This 22 year old man received a renal allograft from his father because of terminal uremia secondary to chronic glomerulonephritis. The patient had had numerous peritoneal dialyses via an indwelling lower abdominal catheter over a period of several months prior to transplantation. The transplanted kidney functioned immediately while the patient was still on the operating table. Over the succeeding 3 days there was an excellent diuresis and blood urea nitrogen and creatinine fell to normal levels. There was a brief period of illness for 48 hours postoperatively after which the gastrointestinal tract resumed normal function. On the seventeenth postoperative day, the patient complained of diffuse, crampy, lower abdominal pain. The x-ray picture shown developed over the succeeding 24 hours. At laparotomy the lower ileum was obstructed by a dense adhesion running from the posterior, parietal peritoneum to the site of insertion of the previously indwelling lower abdominal wall peritoneal dialysis catheter.
creatitis has been seen in animals on prolonged steroid treatment and in patients on prolonged steroids, particularly when the level of steroids has been recently changed. Nonseptic Emergencies Related to Immunosuppressive Therapy
Thrombophlebitis with one or more pulmonary emboli occurs more commonly than would be expected in renal transplant patients, and at least one such patient has undergone emergency pulmonary embolectomy. The cause of this increased incidence of thrombotic complications may be a combination of factors. All recipients are invariably in terminal uremia with muscle wasting, debility and inactivity which, with postoperative weight loss and dehydration secondary to rapid diuresis, all augment the possibility for venous thrombosis. With renal transplantation direct manipulation and anastomosis of the external iliac vein create further dangers. Finally, a number of groups employ splenectomy as an adjunctive immunosuppressive procedure. The known postsplenectomy thrombocytosis may indeed contribute to the observed increased thrombotic tendency. Prolonged steroid therapy results in the usual complications of iatrogenic Cushing's syndrome with steroid-induced diabetes, hypertension,
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moon facies, acne and osteoporosis. Steroid osteoporosis in transplantation patients, along with excessive weight gain, has resulted in spontaneous fractures of the lumbar vertebrae and femoral shafts requiring operative treatment. Furthermore, spontaneous aseptic necrosis of the femoral heads has been observed in osteoporotic transplant patients. Fatty infiltration of the liver in patients on steroids is well known. Recently, Najarian's group 6 has shown that cerebral nervous system and peripheral fat emboli can occur in renal transplantation patients on steroid treatment in the absence of any known trauma. A young female underwent renal transplantation and was treated with steroids for 10 months, following which they were gradually eliminated. Shortly after cessation of steroid therapy marked increases in serum triglyceride levels were noted and she complained of malaise, anorexia, nausea, extreme drowsiness, lethargy, pain in the right upper quadrant of the abdomen, and symptoms and signs of peripheral neuritis. Renal function also deteriorated and prednisone was resumed. Shortly thereafter the patient developed signs of disseminated skin infarction and later small bowel infarction requiring emergency laparotomy and intestinal resection. She subsequently became comatose and never recovered. At autopsy, the important findings were a large fatty infiltrated liver with fat in the form of fine droplets and large fatty cysts, some measuring 75 to 100 microns in diameter. Fat emboli, but not bone marrow emboli, were found in the lungs, myocardium, glomeruli of the transplanted kidney, and basal ganglia of the brain. The postmortem findings in this case suggested that all factors in the clinical course could be explained by multiple fat emboli. Furthermore, the finding of fat emboli may explain some of the so-called "transplantation pneumonias" seen in transplant patients on steroids. Decrease in kidney function with reduction of steroids may be due to renal fat embolization rather than rejection, as previously considered. Other cases of fat emboli in transplant patients have been observed. The induction of fatty livers in patients on steroids is well known; it is also well established that systemic fat embolism can occur in such patients without sustaining trauma. It is quite possible, therefore, that the source of fat emboli in steroid-treated transplantation patients is a fatty infiltrated liver. Furthermore, clinical signs of fat embolization appeared to coincide with the rise in serum triglycerides associated with rapid tapering of steroids. Steroid-induced fat embolism may masquerade as nephritis, pneumonitis, or encephalopathy as well as cause clear-cut ischemic embolization. Because of the high mortality and morbidity associated with hypercortisonism and possible fat embolization, it has been suggested that lower doses of prednisone be used and that they be tapered gradually, rather than very large doses tapered abruptly, in an effort to prevent this presently untreatable emergency complication.
Septic Emergencies Related to Immunosuppressive Therapy The renal transplantation patient on continuous immunosuppressive therapy is unusually susceptible to infection. Immunological studies of patients on Imuran and other immunosuppressive or cytotoxic drugs show
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that all modalities of the immune response are depressed, i.e., both the ability to make humoral antibody and the ability to express delayed cellular sensitivity. Aside from demonstrated depression of the immune responses, such treated patients are frequently leukopenic, usually with varying degrees of granulocytopenia. Furthermore, patients on cytotoxic drugs and steroids have been shown to be markedly or relatively hypogammaglobulinemic. Finally, steroid-induced diabetes carries with it the same susceptibility to infections seen in ordinary diabetic patients. This combination of factors clearly disposes the transplant recipient to infection and in turn renders the diagnosis and treatment a crucial emergency. Diagnosis may frequently be a problem, since rejection and infection can present as "fever of unknown origin." In general, high fever associated with rejection is accompanied by oliguria, rising creatinine, and falling creatinine clearance. The laboratory and clinical phenomena of specific infection are usually absent. Institution of high steroid dosage frequently causes prompt defervescence, as well as improvement in renal function. In contrast, septic fevers are usually not associated with the loss of renal function and signs of localized infection are frequently present and culture data are frequently positive. Of importance is the fact that the white blood cell count is rarely of value in differentiating between rejection and infection, since the peripheral white count is under control by constant daily adjustment in Imuran and steroid dosage. Leukocytosis along with rejection or infection while the patient is on cytoxic drug therapy is most likely only a reflection of a bone marrow reserve rather than a response characteristic of either process. A number of programs have been followed to avoid these emergencies. Originally, post-transplantation patients were treated with strict precautions. It became obvious, however, that infections noted were most likely of endogenous origin. At present most groups practice only clean precautions, permitting patients to walk about defined areas with the only precaution being the wearing of a mask to protect against nosocomial infection. Preoperative cultures of the respiratory, gastrointestinal and genitourinary tracts are obtained and repeated serially in the postoperative period. Specific carrier states are eliminated prior to transplantation with appropriate, specific antibiotic therapy. In the earlier postoperative period, gram-positive wound infection and mixed bacterial urinary tract infections are the predominant type of infectious problems. Therapy with specific antibiotics and appropriate surgical drainage when necessary are the indicated treatment. The increased frequency of such pyogenic infection probably reflects the depression of ability to form humoral antibody caused by immunosuppressive therapy. In the later postoperative period, after long-term immunosuppressive therapy, a number of serious infections occur which are characteristically seen in young patients with leukemia treated with steroids and cytotoxic drugs, and in old, debilitated patients. Pulmonary infections such as gram-
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negative pneumonia, fungal infections (i.e., Candida albicans), and primary and reactivation pulmonary tuberculosis have been seen. An unusual type of pneumonia in long-term transplantation patients has been observed in which none of the common bacterial and fungal agents can be implicated. Such pneumonias are characterized by abrupt fever and insidious onset of pulmonary symptoms, culminating in severe nonproductive cough, cyanosis and tachypnea. Physical examination of the chest is usually unremarkable, although chest x-rays reveal diffuse bilateral infiltrates without significant pleural reaction or hilar lymphadenopathy. In a number of fatal cases, histological examination of the lungs has shown enlarged alveolar cells with intranuclear inclusions characteristic of cytomegalic infection. In addition, the alveoli were filled with a foamy eosinophilic exudate which contained numerous Pneumocystis carinii. This latter organism is believed to be a protozoan parasite which characteristically causes pneumonia in older patients with malignant lymphatic disease treated with cytotoxic drugs and steroids. Apparently this agent frequently coexists with cytomegalic virus in pneumonia. The frequency and number of Pneumocystis carinii and cytomegalic virus in clinical "transplantation pneumonia" remains to be demonstrated conclusively. What appears clear, however, is that prolonged immunosuppressive therapy leads to defects in cellular type immunity rather than humoral antibody formation. This results in appearance of peculiar infections as described above rather than pyogenic infections which predominate in the earlier postoperative period. The possibility that certain "transplantation pneumonias" are unrecognized cases of fat embolization has been mentioned above. A recent observation in kidney transplantation patients on maintenance Imuran therapy is important. Such patients usually have a stable white blood cell count after a maintenance dose has been arrived at. On occasion the maintenance dose, even though previously well tolerated for several months, may cause profound and dangerous leukopenia if the recipient contracts anyone of the usually benign epidemic respiratory or gastrointestinal virus infections. The appearance of the vague symptoms characteristic of the prodrome of viral infection is an important indication for careful watching of the white cell count and judicious tapering of Imuran dosage for a temporary period. Profound and dangerous leukopenia has been observed by the authors in such instances of presumed intercurrent virus infection.
REFERENCES 1. Barnes, B. A.: Survival data of renal transplantations in patients. Transplantation
3: 812, 1965. 2. Figueroa, J. E., Rodriguez-Antrinez, A., Nakamoto, S. and Kolff, W. J.: The scintigram after renal transplantation in man. New England J. Med. 26: 1406, 1965. 3. Jones, J. P. Jr., Engelman, E. P. and Najarian, J. S.: Systemic fat embolism after
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renal homotransplantation and treatment with corticosteroids. New England J. 1ied. 27: 1453, 1965. 4. Loken, 1i. K., Staak, E. V., Vernier, R. L. and Kelly, W. D.: Radioisotope renogram in kidney transplants. J. Nuclear 1ied. 5: 807, 1964. 5. Russell, P. S. and 1ionaco, A. P.: The Biology of Tissue Transplantation. Boston, Little, Brown & Co., 1965. 6. Starzl, T. E.: Experience in Renal Transplantation. Philadelphia and London, W. B. Saunders Co., 1964. 1iassachusetts General Hospital Boston, 1iassachusetts 02114
For over a decade there has been a progressive increase in interest in clinical renal transplantation. l • 2 The transplantation of an organ from one individual to another involves a number of serious moral and ethical considerations as well as unusual medical problems. With the present methods of immunosuppressive therapy the degree of success is clearly dependent on the genetic relationship between the donor and the recipient which determines the attendant degree of histocompatability difference involved and the violence of the subsequent rejection reaction. Although the results as measured by patient survival are surprisingly good and continue to improve,3 the procedure is still an experimental one, to be reserved for those patients afflicted with terminal uremia who have exhausted all forms of available conventional therapy. Furthermore, the availability of peritoneal dialysis and hemodialysis assures that renal allotransplantation (old terminology, homotransplantation) is never really an emergency procedure. Rarely, in association with severe trauma, one normal kidney may be sheared off its vascular pedicle. Under such circumstances, emergency operation to control hemorrhage is life-saving and reanastomosis of the devascularized organ at its usual site (orthotopic autotransplantation) or to different site (heterotopic autotransplantation) may save the otherwise undamaged kidney. The authors are aware of at least one instance in which this latter operation has been done. From the Department of Surgery, Harvard Medical School, and the General Surgical Services, Massachusetts General Hospital, Boston, Massachusetts This work was supported in part by grants AM 07055, AI 06320, T4 CA 5018 and CRTY 5018 from the United States Public Health Service. This is publication No. 1252 of the Cancer Commission of Harvard University. * Instructor in Surgery, Harvard Medical School; Assistant in Surgery, Massachusetts General Hospital ** John Homans Professor of Surgery, Harvard Medical School; Chairman, Surgical Services, Massachusetts General Hospital
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RUSSELL
For the most part, however, the emergencies involved with renal transplantation are those related to the technical considerations of the operation itself and to the associated medical and immunological problems. For purposes of discussion, such emergencies will be considered arbitrarily as usually occurring in the preoperative period or in the immediate postoperative or late postoperative periods, although it will be obvious that, for the most part, all or any of the emergencies considered could occur at any time. Also, the emergency evaluation of cessation of function of the transplanted organ is considered. Unquestionably, one of the most serious emergencies is a sustained rejection crisis. Management of this emergency requires manipulation of current immunosuppressive drug therapy and institution of new immunosuppressive maneuvers and will not be considered in detail.
PREOPERATIVE EMERGENCIES
Patients referred for renal transplantation are invariably in an adval'lced state of uremia, frequently with associated fluid retention, cardiac failure, hyponatremia, hyperkalemia and acidosis. For this reason, a hemodialysis unit is an indispensable part of any renal transplantation program since major surgical procedures cannot be performed until major metabolic resuscitative measures are carried out. Appropriate hemodialysis readily corrects all of the above abnormalities. Localized collections of fluids in various serous cavities may necessitate emergency pericardiocentesis (secondary to uremic pericarditis) or emergency thoracentesis (secondary to uremic pleuritis and pneumonitis). Generalized fluid retention may produce cardiac failure and pulmonary edema and congestion, and may represent a clear-cut indication for emergency hemodialysis. As much as 6 kg. of body fluid can be removed by increasing the osmolarity of the bath (i.e., increased glucose concentration) and by constricting the outflow tract of the dialysis coil (to raise filtration pressure). In the management of cardiac failure, digitalis is to be avoided if possible in the patient requiring dialysis, since rapid falls in serum potassium and rapid shifts in extracellular electrolytes occurring during hemodialysis may accentuate digitalis intoxication and produce cardiac arrhythmia. Hyperkalemia is frequently a serious problem. Three commonly accepted means for controlling rises in serum potassium without resorting to dialysis are the use of cation exchange resins either orally or by rectum (sodium cycle resins if the serum sodium is low, ammonia cycle resins if serum sodium is above normal, and half-and-half mixtures if the serum sodium is normal), administration of sodium bicarbonate (particularly if the CO 2 combining power is low), and administration of hypertonic glucose and insulin intravenously. In spite of these measures, marked elevations of serum potassium levels frequently require emergency dialysis for control.
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Hypertension is treated by salt restriction and antihypertensive agents such as reserpine and ganglionic blocking agents. Under rare circumstances, malignant hypertension with associated hypertensive encepholopathy requires intravenous trimethaphan camsylate (Arfonad) therapy on an emergency basis for blood pressure control.
EMERGENCIES ASSOCIATED WITH THE IMMEDIATE POSTOPERATIVE PERIOD
Kidney transplantation is generally accomplished as a heterotopic allograft, the kidney being placed retroperitoneally in the iliac fossa (right kidney to left iliac fossa, and vice versa) with the renal artery of the donor usually anastomosed end-to-end to the divided recipient hypogastric artery and the donor renal vein anastomosed end-to-side to the recipient common iliac vein. The authors prefer to establish ureteral continuity by ureteropelvic anastomosis after the technique developed by Drs. Wyland and Guy Leadbetter, although many groups employ ureteroneocystostomy. (See Fig. 1.) In general, patients undergoing renal transplantation are markedly debilitated from uremia. Accordingly, such patients are especially prone to a number of complications and emergencies which can afflict all surgical patients. The hemorrhagic disorders and bleeding tendencies associated
Figure 1. Heterotopic Renal Allotransplantation. The donor kidney is transplanted retroperitoneally to the iliac fossa, the right kidney being placed in the left fossa and vice versa. Arterial continuity is usually established by end-to-end anastomoses of the donor renal artery with the recipient hypogastric artery which is divided and rotated upward (A). Venous reconstruction utilizes an endto-side anastomoses of the donor renal vein to the recipient common iliac or external iliac vein (V). Ureteral continuity is established by ureteropelvic anastomoses, although some still prefer ureteroneocystostomy.
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with uremia can lead to postoperative bleeding and accumulation of retroperitoneal hematoma. The singular complication which represents a serious emergency is postoperative atelectasis. Such patients are started on immunosuppressive therapy immediately preoperatively, and atelectasis can lead to serious pulmonary infection. For this reason, transplant patients are given vigorous preoperative and postoperative pulmonary physiotherapy. Furthermore, every effort is made to avoid infecting the tracheobronchial tree. Thus, spinal or continuous epidural anesthesia, supplemented by light inhalation anesthesia without endotracheal intubation, is the anesthesia of choice with this consideration in mind. If atelectasis does occur, vigorous therapy in the form of humidified oxygen, expectorants, chest physiotherapy and even bronchoscopy is indicated. Aside from the usual complications and emergencies associated with major surgery, certain emergencies specifically related to the transplanted organ also occur. Of these by far the most important is the usual massive diuresis which may begin on the operating table after the kidney is revascularized. The mean time interval after revascularization and appearance of urine on the operating table is usually approximately 30 minutes. For the first 12 to 24 hours after operation, urine output averages 250 to 450 cc./hour with some outputs reaching as high as 1000 cc./hour. When urine outputs rise toward this latter figure, the magnitude of the diuresis constitutes a serious postoperative emergency. Careful management of fluid replacement is necessary in order to avoid severe electrolyte imbalance and possible associated ventricular arrhythmia. In preparation for massive fluid replacement, adequate provision for intravenous fluid replacement is made. Patients are maintained on humidified oxygen and cardiac action continually monitored by a suitable cardiac monitor-pacemaker unit. In the immediate postoperative diuretic period, fluid volume is in general replaced hourly in an amount equal to the urine output, with adjustment made for the preoperative state of the patient's hydration. Accurate knowledge of urinary electrolyte concentrations is mandatory for correct replacement. These urinary electrolyte concentrations are usually predictable, the sodium averaging 95 mEq./liter and the chloride averaging 70 mEq./liter. Urinary potassium values are usually 10 to 20 mEq./liter. Intravenous fluid replacement is given in the form of 5 per cent glucose in 0.45 per cent saline. Although potassium is not usually replaced, in the presence of a massive diuresis 10 to 20 mEq./liter is added to intravenous fluids. Serial determinations of urinary and blood electrolytes are necessary for careful regulation of the replacement program. Calcium and sodium bicarbonate replacement intravenously is frequently needed and intramuscular magnesium sulfate may be required for falling serum magnesium levels. During a massive diuresis following renal transplantation, because of the large volumes of fluid involved, relatively small deviations in composition of the replacement fluid from the urine electrolytes can greatly magnify
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the total electrolyte replacement error. Furthermore, a number of electrolytes ordinarily in trace concentration in the urine and serum are not measured or replaced. Thus, electrolyte imbalance with cardiac arrest secondary to ventricular arrhythmia is a possible outcome. Figure 2 illustrates this unfortunate result in a six year old boy (weight 20 kg.) who received a renal transplant from his father (weight 66 kg.). The transplanted organ functioned immediately and a massive diuresis ensued with urine volumes rising to over 1000 cc./hour. In view of the small size of the recipient, the massive fluid shifts involved were further magnified. During the fourteenth hour post-transplantation the patient died from cardiac K. McC.
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Figure 2. Massive Post-transplantatim Diuresis Ending in Death. A 6 year old boy weighing 20 kg. received a renal allograft from his 32 year old father (weight 66 kg.) because of terminal uremia secondary to chronic pyelonephritis. At operation the donor kidney was found to have two small renal arteries, one of which was anastomosed end-to-end to the divided recipient hypogastric artery and one was anastomosed end-to-side to the external iliac artery. The total ischemia time was 102 minutes. The kidney functioned immediately postoperatively, and there was a rapid and progressive increase in the hourly urine output. Only 4 hours after completion of the anastomosis, the total urine output was 1000 cc. and had reached a rate of 400 cc./hour. Because of some fluid retention preoperatively, it was planned to maintain the patient at an output deficit which would total about 1000 cc. over the first 24.'hours postoperatively. By 6 hours postoperatively the total output was 2400 cc., the total intake 1660 cc., and the rate 650cc./hour. Eight hours after operation the rate was 850 cc./hour, the cumulative total about 3700 cc. and the total intake 2700 cc. Over the following 4 hours the level of diuresis continued at 1000 cc./hour. Serial determination of serum sodium, potassium, chloride, carbon dioxide, calcium and phosphorus, and magnesium through this time revealed normal values. However, 12 hours postoperatively, at the height of the diuresis, the patient had a sudden cardiac arrest and expired, presumably secondary to a cardiac arrhythmia related to an electrolyte disturbance.
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arrest, presumably from arrhythmia secondary to electrolyte imbalance. In general, the diuretic phase begins to subside 8 to 24 hours after transplantation. At this time, the volume of intravenous fluid therapy is reduced to avoid maintenance of the diuresis by excess water load. Less severe emergencies in the immediate post-transplantation period include occasional urinary leakage, particularly during the diuretic phase. In the case of ureteropelvic anastomosis, such leaks usually close as the suture line swells postoperatively. Rarely, if urinary fistulas persist beyond several days, retrograde catheterization with placement of an indwelling ureteral catheter through the ureteropelvic anastomosis or ureteroneocystostomy site is necessary until the fistula closes. Occasionally, severe genitourinary bleeding may occur from the site of ureteroneocystostomy or from an area of hemorrhagic cystitis associated with an indwelling urethral Foley catheter. In general, this bleeding is treated conservatively, occasionally requiring transfusion, although in the latter instance removal of the indwelling Foley catheter invariably results in cessation of bleeding.
EMERGENCY EVALUATION OF CESSATION OF FUNCTION OF RENAL ALLOGRAFTS
Among the several reasons which make the kidney an unusually good organ for experimental, clinical transplantation, one of the most important is the fact that the function of the transplanted organ can be continually monitored by serial urinalysis. Cessation or diminution of renal function as determined by frank anuria or oliguria can be caused by obstruction of the urinary outflow tract, thrombosis of the arterial or venous anastomosis, or by intrinsic failure of the kidney parenchyma either due to nonrejection factors such as ischemia and parenchymal swelling, or secondary to immunologic rejection. Since vascular problems constitute real hazards to the survival of the transplanted organ requiring rapid and active therapy, determination of the etiology of cessation of urine flow is an emergency. The sequence of events is important. Dramatic early function with excellent diuresis and progressive improvement in renal function following transplantation followed by gradual diminution of urine volume to oliguric but not anuric levels suggests rejection. Associated with this may be other signs of rejection such as rises in blood urea nitrogen and creatinine levels after initial gratifying falls, systemic temperature rise, clinically apparent transplant swelling, increased proteinuria and lymphocyturia. Under these circumstances, this emergency is managed by appropriate antirejection therapy. The etiology of sudden onset of anuria, in contrast to gradual progression to oliguria, may be more difficult to determine. Atony of the bladder secondary to residual uremic neuropathy may result in a functional obstruction. Urethral catheterization, in the absence of an indwelling Foley
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catheter, settles the question. Obstruction at the level of ureteroneocystostomy or uteropelvic anastomosis is more difficult to confirm. In general, renal vein thrombosis occurs with gradual production of anuria associated with increased hematuria and proteinuria, although this is not invariable. Complete arterial thrombosis produces a fairly sudden anuria, and can be confirmed by retrograde femoral arteriography by the Seldinger technique, with placement of the arterial catheter retrograde up to the level of the recipient hypogastric artery. Exploration of the wound with exposure of the transplant and its vascular pedicle provides the most definite evidence for proper status of the vascular supply of the transplanted organ, particularly if arteriography is not performed or is unsatisfactory. Unfortunately, severe swelling of a transplanted kidney secondary to ischemia during the transplantation surl!iery with or without acute tubular necrosis is a frequent cause for anuria. Under such circumstances, progression to the anuric state is usually gradual, rather than abrupt, although the latter can occur. A special circumstance in this regard occurs with cadaveric transplants which are subjected to long periods of hypotension and relative ischeInia prior to donor death and during transplantation so that the transplanted organ may not function for long periods postoperatively. Under such conditions evaluation of the status of such transplants is extremely difficult. Finally, acute swelling with secondary anuria may be secondary to rejection. Anuria secondary to swelling from any cause can be diagnosed only by exclusion from negative studies described above or by exploration and biopsy of the swollen, well vascularized organ (Fig. 3). The instrumentation studies described above for diagnosing the etiology of anuria have the fundamental drawback of being time-consuming and carrying the possibility of introducing infection. For this reason, simple maneuvers requiring no instrumentation have been sought. The so-called "radioactive renogram" has been utilized by several groups for the followup study of renal allografts. 5 The renogram provides a complicated curve of radioactivity which can be influenced by many factors. Recently, the Cleveland Clinic group has introduced the radioactive scintigram to study the etiology of oliguria and anuria after renal transplantation in man. 4 No special preparation of the patients is necessary. When severe oliguria and anuria appear, 150 micro curies of chloromerodin (Hg203) is injected intravenously. Approximately an hour later the abdominal wall area over the transplanted kidney is counted with a scintillating detector. The scintigram achieved represents a simple shadow of the radioactivity in the kidney entirely dependent upon vascular patency and tubular uptake. Nonvisualization of the kidney by scintigram is usually secondary to arterial occlusion or tubular cell death. The important point is that, if there is anuria and a normal scan is obtained, arteriography and re-exploration and biopsy are unnecessary to rule out other severe conditions. Obstructive uropathy may be a cause for the anuria, however, but can be ruled out by cystoscopy. In contrast, a rejection crisis in general gives a good uptake
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RUSSELL
Figure 3. Anuria Secondary to Severe Edema and Early Rejection After Initial Period of Function Post-transplantation. A 20 year old man underwent renal allotransplantation because of terminal uremia and malignant hypertension secondary to chronic glomerulonephritis and pyelonephritis. The donor was the patient's 46 year old father. The total ischemia time for revascularization of the transplanted organ was 33 minutes. The kidney functioned within an hour of completion of the anastomosis. For the first 48 hours the urine output average was 150 cc./hour and there was a progressive fall in blood urea nitrogen and creatinine. During the third day postoperative there was a sudden appearance of hematuria and rapid fall in hourly urine output to anuric levels. Because of persistent anuria, the patient underwent cystoscopy and right ureteral catheterization which showed no obstruction at the ureteropelvic anastomosis and urinary extravasation (A). The patient then underwent exploration at which time the arterial and venous anastomoses were found to be open and satisfactory. The kidney was severely swollen, tense, and obviously extremely edematous. The renal capsule was incised and a biopsy taken. With the biopsy there was a release of a copious amount of edema fluid. Immediately after re-exploration the patient was started on intravenous steroids and within 4 hours the urine output was 50 cc./hour. B (magnification X21O) shows that at the time of biopsy the renal parenchyma was markedly swollen and edematous with only a small number of infiltrating mononuclear cells associated with rejection. The swelling could be secondary to ischemia alone or infiltration and immunological rejection, or both. Fortunately, the treatment for both causes of renal swelling is immediate steroid therapy.
and scintigram. However, with a radioactive renogram, rejection crises result in a nonfunctioning pattern and therefore do not rule out the other severe causes of anuria described above. In general, most groups involved in renal transplantation would consider progressive decrease in urine output after an initial period of excellent function as evidence for rejection and institute appropriate antirejection therapy without further investigation. In this regard it is important to realize that anuria secondary to swelling as a result of ischemia or im-
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munologic rejection are in fact both treated initially with steroids. The diagnostic procedures described above are used only when a high suspicion of mechanical or technical failure exists, i.e. the abrupt onset of anuria very early postoperatively while excellent diuresis is in progress and in the case of an allograft which fails to function at all after satisfactory transplantation. Furthermore, if a radioactive scintigram technique is available and familiar to the group concerned, a number of instrumentation techniques can be omitted.
EMERGENCIES ASSOCIATED WITH THE LATER POSTOPERATIVE PERIOD
As stated above, renal transplant patients are more susceptible to all the usual postoperative surgical complications and emergencies than routine surgical patients, a situation no doubt due to the debilitating effects of uremia and the stresses imposed by immunosuppressive therapy. Certain emergency situations arise frequently because of the nature of the operation, the immunosuppressive therapy involved, or the previous condition of the patient. Abdominal Emergencies
Normally, only a brief period of ileus follows the retroperitoneal transplantation of a kidney, with or without the performance of bilateral recipient nephrectomies. Usually, the nasogastric tube can be removed after 24 hours and progressive alimentation begun on the second day postoperatively. A number of instances of post-transplantation small bowel obstruction requiring emergency laparotomy, usually secondary to adhesions, have been reported. Lower abdominal dense adhesions, running from the posterior parietes to the site of a previous peritoneal dialysis catheter insertion in the lower anterior abdominal wall, are frequently the cause of such obstruction (Fig. 4). Other abdominal emergencies result from steroid immunosuppressive therapy. Most renal transplant patients who receive allografts sustain one or more rejection crises which require intensive steroid therapy for control and steroid maintenance therapy to prevent recurrence. Patients on such therapy are prone to develop duodenal and gastric ulceration with the obvious potential for acute perforation and bleeding. Acute perforations have usually been treated with pyloroplasty and vagotomy. Patients in severe rejection with secondary uremia on massive steroid therapy not uncommonly bleed from gastrointestinal ulceration and the associated uremic bleeding diathesis only compounds the difficulty. Acute pancreatitis has occurred in a number of patients, long after successful transplantation, while on steroids and Imuran (Burroughs-Wellcome Co., B.W. 57-322) therapy. Such pancreatitis may be a result of an idiosyncratic reaction to Imuran, but more likely is related to steroid therapy. Pan-
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RUSSELL
Figure 4. Small Bowel Obstruction in the Postoperative Transplantation Period. This 22 year old man received a renal allograft from his father because of terminal uremia secondary to chronic glomerulonephritis. The patient had had numerous peritoneal dialyses via an indwelling lower abdominal catheter over a period of several months prior to transplantation. The transplanted kidney functioned immediately while the patient was still on the operating table. Over the succeeding 3 days there was an excellent diuresis and blood urea nitrogen and creatinine fell to normal levels. There was a brief period of illness for 48 hours postoperatively after which the gastrointestinal tract resumed normal function. On the seventeenth postoperative day, the patient complained of diffuse, crampy, lower abdominal pain. The x-ray picture shown developed over the succeeding 24 hours. At laparotomy the lower ileum was obstructed by a dense adhesion running from the posterior, parietal peritoneum to the site of insertion of the previously indwelling lower abdominal wall peritoneal dialysis catheter.
creatitis has been seen in animals on prolonged steroid treatment and in patients on prolonged steroids, particularly when the level of steroids has been recently changed. Nonseptic Emergencies Related to Immunosuppressive Therapy
Thrombophlebitis with one or more pulmonary emboli occurs more commonly than would be expected in renal transplant patients, and at least one such patient has undergone emergency pulmonary embolectomy. The cause of this increased incidence of thrombotic complications may be a combination of factors. All recipients are invariably in terminal uremia with muscle wasting, debility and inactivity which, with postoperative weight loss and dehydration secondary to rapid diuresis, all augment the possibility for venous thrombosis. With renal transplantation direct manipulation and anastomosis of the external iliac vein create further dangers. Finally, a number of groups employ splenectomy as an adjunctive immunosuppressive procedure. The known postsplenectomy thrombocytosis may indeed contribute to the observed increased thrombotic tendency. Prolonged steroid therapy results in the usual complications of iatrogenic Cushing's syndrome with steroid-induced diabetes, hypertension,
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moon facies, acne and osteoporosis. Steroid osteoporosis in transplantation patients, along with excessive weight gain, has resulted in spontaneous fractures of the lumbar vertebrae and femoral shafts requiring operative treatment. Furthermore, spontaneous aseptic necrosis of the femoral heads has been observed in osteoporotic transplant patients. Fatty infiltration of the liver in patients on steroids is well known. Recently, Najarian's group 6 has shown that cerebral nervous system and peripheral fat emboli can occur in renal transplantation patients on steroid treatment in the absence of any known trauma. A young female underwent renal transplantation and was treated with steroids for 10 months, following which they were gradually eliminated. Shortly after cessation of steroid therapy marked increases in serum triglyceride levels were noted and she complained of malaise, anorexia, nausea, extreme drowsiness, lethargy, pain in the right upper quadrant of the abdomen, and symptoms and signs of peripheral neuritis. Renal function also deteriorated and prednisone was resumed. Shortly thereafter the patient developed signs of disseminated skin infarction and later small bowel infarction requiring emergency laparotomy and intestinal resection. She subsequently became comatose and never recovered. At autopsy, the important findings were a large fatty infiltrated liver with fat in the form of fine droplets and large fatty cysts, some measuring 75 to 100 microns in diameter. Fat emboli, but not bone marrow emboli, were found in the lungs, myocardium, glomeruli of the transplanted kidney, and basal ganglia of the brain. The postmortem findings in this case suggested that all factors in the clinical course could be explained by multiple fat emboli. Furthermore, the finding of fat emboli may explain some of the so-called "transplantation pneumonias" seen in transplant patients on steroids. Decrease in kidney function with reduction of steroids may be due to renal fat embolization rather than rejection, as previously considered. Other cases of fat emboli in transplant patients have been observed. The induction of fatty livers in patients on steroids is well known; it is also well established that systemic fat embolism can occur in such patients without sustaining trauma. It is quite possible, therefore, that the source of fat emboli in steroid-treated transplantation patients is a fatty infiltrated liver. Furthermore, clinical signs of fat embolization appeared to coincide with the rise in serum triglycerides associated with rapid tapering of steroids. Steroid-induced fat embolism may masquerade as nephritis, pneumonitis, or encephalopathy as well as cause clear-cut ischemic embolization. Because of the high mortality and morbidity associated with hypercortisonism and possible fat embolization, it has been suggested that lower doses of prednisone be used and that they be tapered gradually, rather than very large doses tapered abruptly, in an effort to prevent this presently untreatable emergency complication.
Septic Emergencies Related to Immunosuppressive Therapy The renal transplantation patient on continuous immunosuppressive therapy is unusually susceptible to infection. Immunological studies of patients on Imuran and other immunosuppressive or cytotoxic drugs show
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RUSSELL
that all modalities of the immune response are depressed, i.e., both the ability to make humoral antibody and the ability to express delayed cellular sensitivity. Aside from demonstrated depression of the immune responses, such treated patients are frequently leukopenic, usually with varying degrees of granulocytopenia. Furthermore, patients on cytotoxic drugs and steroids have been shown to be markedly or relatively hypogammaglobulinemic. Finally, steroid-induced diabetes carries with it the same susceptibility to infections seen in ordinary diabetic patients. This combination of factors clearly disposes the transplant recipient to infection and in turn renders the diagnosis and treatment a crucial emergency. Diagnosis may frequently be a problem, since rejection and infection can present as "fever of unknown origin." In general, high fever associated with rejection is accompanied by oliguria, rising creatinine, and falling creatinine clearance. The laboratory and clinical phenomena of specific infection are usually absent. Institution of high steroid dosage frequently causes prompt defervescence, as well as improvement in renal function. In contrast, septic fevers are usually not associated with the loss of renal function and signs of localized infection are frequently present and culture data are frequently positive. Of importance is the fact that the white blood cell count is rarely of value in differentiating between rejection and infection, since the peripheral white count is under control by constant daily adjustment in Imuran and steroid dosage. Leukocytosis along with rejection or infection while the patient is on cytoxic drug therapy is most likely only a reflection of a bone marrow reserve rather than a response characteristic of either process. A number of programs have been followed to avoid these emergencies. Originally, post-transplantation patients were treated with strict precautions. It became obvious, however, that infections noted were most likely of endogenous origin. At present most groups practice only clean precautions, permitting patients to walk about defined areas with the only precaution being the wearing of a mask to protect against nosocomial infection. Preoperative cultures of the respiratory, gastrointestinal and genitourinary tracts are obtained and repeated serially in the postoperative period. Specific carrier states are eliminated prior to transplantation with appropriate, specific antibiotic therapy. In the earlier postoperative period, gram-positive wound infection and mixed bacterial urinary tract infections are the predominant type of infectious problems. Therapy with specific antibiotics and appropriate surgical drainage when necessary are the indicated treatment. The increased frequency of such pyogenic infection probably reflects the depression of ability to form humoral antibody caused by immunosuppressive therapy. In the later postoperative period, after long-term immunosuppressive therapy, a number of serious infections occur which are characteristically seen in young patients with leukemia treated with steroids and cytotoxic drugs, and in old, debilitated patients. Pulmonary infections such as gram-
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negative pneumonia, fungal infections (i.e., Candida albicans), and primary and reactivation pulmonary tuberculosis have been seen. An unusual type of pneumonia in long-term transplantation patients has been observed in which none of the common bacterial and fungal agents can be implicated. Such pneumonias are characterized by abrupt fever and insidious onset of pulmonary symptoms, culminating in severe nonproductive cough, cyanosis and tachypnea. Physical examination of the chest is usually unremarkable, although chest x-rays reveal diffuse bilateral infiltrates without significant pleural reaction or hilar lymphadenopathy. In a number of fatal cases, histological examination of the lungs has shown enlarged alveolar cells with intranuclear inclusions characteristic of cytomegalic infection. In addition, the alveoli were filled with a foamy eosinophilic exudate which contained numerous Pneumocystis carinii. This latter organism is believed to be a protozoan parasite which characteristically causes pneumonia in older patients with malignant lymphatic disease treated with cytotoxic drugs and steroids. Apparently this agent frequently coexists with cytomegalic virus in pneumonia. The frequency and number of Pneumocystis carinii and cytomegalic virus in clinical "transplantation pneumonia" remains to be demonstrated conclusively. What appears clear, however, is that prolonged immunosuppressive therapy leads to defects in cellular type immunity rather than humoral antibody formation. This results in appearance of peculiar infections as described above rather than pyogenic infections which predominate in the earlier postoperative period. The possibility that certain "transplantation pneumonias" are unrecognized cases of fat embolization has been mentioned above. A recent observation in kidney transplantation patients on maintenance Imuran therapy is important. Such patients usually have a stable white blood cell count after a maintenance dose has been arrived at. On occasion the maintenance dose, even though previously well tolerated for several months, may cause profound and dangerous leukopenia if the recipient contracts anyone of the usually benign epidemic respiratory or gastrointestinal virus infections. The appearance of the vague symptoms characteristic of the prodrome of viral infection is an important indication for careful watching of the white cell count and judicious tapering of Imuran dosage for a temporary period. Profound and dangerous leukopenia has been observed by the authors in such instances of presumed intercurrent virus infection.
REFERENCES 1. Barnes, B. A.: Survival data of renal transplantations in patients. Transplantation
3: 812, 1965. 2. Figueroa, J. E., Rodriguez-Antrinez, A., Nakamoto, S. and Kolff, W. J.: The scintigram after renal transplantation in man. New England J. Med. 26: 1406, 1965. 3. Jones, J. P. Jr., Engelman, E. P. and Najarian, J. S.: Systemic fat embolism after
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renal homotransplantation and treatment with corticosteroids. New England J. 1ied. 27: 1453, 1965. 4. Loken, 1i. K., Staak, E. V., Vernier, R. L. and Kelly, W. D.: Radioisotope renogram in kidney transplants. J. Nuclear 1ied. 5: 807, 1964. 5. Russell, P. S. and 1ionaco, A. P.: The Biology of Tissue Transplantation. Boston, Little, Brown & Co., 1965. 6. Starzl, T. E.: Experience in Renal Transplantation. Philadelphia and London, W. B. Saunders Co., 1964. 1iassachusetts General Hospital Boston, 1iassachusetts 02114