Pseudorejection - NCBI - NIH

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plant renal function at most centers. A significant eleva- ... Treatment of rejection episodes differs from center. 6ocenter, but most protocols call for an increase in bteroid medication. ...... Advisory Committee, ACS/NIH Renal Transplant Registry.
Pseudorejection: Factors Mimicking Rejection in Renal Allograft Recipients ARTHUR J. MATAS, M.D., RICHARD L. SIMMONS, M.D., CARL M. KJELLSTRAND, M.D., JOHN S. NAJARIAN, M.D.

From the Department of Surgery, University of Minnesota, Minneapolis, Minnesota

creatinine level is used as a major measure of postplant renal function at most centers. A significant elevaof creatinine level suggests allograft rejection. However, r factors affect renal function in the transplant recipient each may cause an elevation in serum creatinine level, esting a rejection episode. It is important to make the t diagnosis and not treat these episodes with antition therapy. We reviewed the course of patients transted between 1969 and 1974 to determine the patho's of creatinine elevations retrospectively found to be due causes other than rejection. Six distinct causes were found: rglycemia, ureteral obstruction, infection, lymphocele, rial stenosis, and recurrence of the original disease. of these is discussed individually. In order to make diagnosis of pseudorejection, a high index of suspicion is

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an elevation in creatinine is due to something other than a true rejection episode. We reviewed the course of patients transplanted at the University of Minnesota between 1969 and 1974 to elucidate what conditions frequently coincide with an elevated serum creatinine so that rejection is suspected. Six distinct syndromes were associated with significant elevations (>25%) in serum creatinine. Each will be discussed separately.

osay.' ENAL ALLOGRAFT REJECTION episodes require

Patients and Methods Between January, 1969 and December, 1974, 515 renal transplants were performed at the University of Minnesota. Patient selection, operative technique, and postoperative management have been previously described.935 In brief, following evaluation and acceptance into the program, bilateral nephrectomy and splenectomy were performed prior to transplantation. Posttransplantation antilymphocyte globulin (ALG), 20-30 mg/kg/day was given intravenously to all patients for two weeks. All patients received azathioprine 5 mg/kg/day initially and this was tapered to 2.5 mg/kg/day within one week. Recipients of nonHLA identical transplants received prednisone 2 mg/ kg/day initially while recipients of HLA identical kidneys received 1 mg/kg/day. This was gradually tapered to 0.3 mg/kg/day and 0.2 mg/kg/day, respectively. All patients received methylprednisolone 20 mg/kg/day intravenously for the first three posttransplant days. Following discharge patients had blood drawn for blood urea nitrogen, serum creatinine, hemoglobin, hematocrit, and white blood count three times per week for the first three months. This was gradually reduced to once a week and then once every two

early diagnosis and aggressive management to vent loss of renal function. Serum creatinine level recommended as the single measure of renal funcn with greatest reliability and availability in medical nters and is utilized as the major parameter of renal ction on routine long-term follow up of transplant tients at most institutions. A significant elevation of m creatinine (>25%) suggests allograft rejection d requires further evaluation and treatment. HowI ver, renal function is affected by factors other IIban rejection, and many of these may cause an eleion of serum creatinine, leading to an erroneous josis of rejection. I Treatment of rejection episodes differs from center I6o center, but most protocols call for an increase in Ibteroid medication. These drugs are associated with gnificant morbidity and mortality;33'77'92 increased Dsages therefore, must be limited to true rejection fisodes. So as to not use these drugs unnecessarily, ere must always be a high level of suspicion that

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Supported by USPHS Grant #AM 13083. Repnnt Requests: Dr. Matas, Box #319, Mayo Memorial hiding, University of Minnesota, Minneapolis, MN 55455. Submitted for publication: August 6, 1976.

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MATAS AND OTHERS TABLE 1. Pathogenesis of Elevated Serum Creatinine Levels Without Rejection in Renal Transplant Recipients I) Hyperglycemia

2) 3) 4) 5) 6)

Ureteral obstruction Lymphocele Arterial stenosis Infection Recurrence of original disease

weeks in stable patients. Only after a long period of stability was this reduced to monthly for the life of the graft. 1311 ortho-hippurate renograms were obtained immediately posttransplant and whenever there was a suspicion of rejection. Rejection episodes were diagnosed by elevations in serum creatinine, fall in creatinine clearance, and delayed extraction or excretion on renogram. Currently, they are frequently confirmed by percutaneous needle biopsy of the transplant. Following diagnosis, rejection episodes were treated with local irradiation (150 rads every other day to a total of 450 rads) one gram of methylprednisolone intravenously daily for three days, and an increased dosage of orally administered prednisone. Pseudorejection was defined as an episode of significant elevation of serum creatinine (>25%) that retrospectively was not caused by true rejection. The charts of all patients were reviewed to determine the incidence of this phenomenon. Many of these patients were initially treated for rejection as will be discussed later. However, as knowledge and experience with some of these phenomena increased, these episodes are now more frequently recognized and treated appropriately without rejection therapy. Six categories of pseudorejection were identified (Table 1). Each will be discussed separately. Case Reports Hyperglycemia There were 19 episodes of significant creatinine elevations in association with hyperglycemia in diabetic transplant recipients. Creatinine level returned to normal as blood sugar was corrected. Before this phenomenon was recognized, many of these patients were admitted to hospital and evaluated for rejection. On admission they were found to have normal renograms and to be asymptomatic with none of the clinical findings associated with rejection (fever, pain and swelling of the graft, leukocytosis, edema and hypertension). Since this phenomenon has been recognized, when the asymptomatic stable diabetic patient presents with an elevation of serum creatinine in association with hyperglycemia, the hyperglycemia is first corrected while changes in creatinine level are moni-

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tored. This can be accomplished on an out-patient basis. If serum creatinine falls as the plasma glucose falls, the patient is not admitted to hospital; however, if creatinine continues to climb in spite of a fall or stabilization of plasma glucose level, the patient is admitted to hospital and evaluated further. Case 1. A 36-year-old, juvenile-onset diabetic female received a kidney transplant from her sister. Following an uncomplicated,, postoperative course she was discharged from the hospital wit4i a serum creatinine level of 1.1 mg/100 ml. For the first threei months the serum creatinine level remained stable at 1.1-1.3 mg/100 ml. Three months following transplantation, serum creati nine level was reported to be 1.6 mg/100 ml. Following hospital admission for possible rejection, serum creatinine was found to b 1.8 mg/100 ml in association with a plasma glucose of 795 mg/l1 ml. Renogram was normal. Blood glucose was controlled wil regular insulin and the following day the plasma glucose wa 147 mg/100 ml and the creatinine was 1.2 mg/100 ml. Followil stabilization of her diabetes she was discharged without requin rejection therapy.

Comment. Serum creatinine in most laboratories' measured by an automated version of the total chrom gen method of Jaffe.6' Many factors, including gluco are known to affect creatinine determination by t' method.4099 We have shown that the glucose leve found clinically cannot explain the associated risei serum creatinine.55 More likely, it is the hype osmolarity due to the hyperglycemia that results elevation of serum creatinine. An elevation of blo glucose of 500 mg/100 ml will increase osmolaril 27.8 mOsm/L resulting in an increase of extracellul osmolarity.49 This will draw water from the cells sulting in a relative intracellular dehydration. As renal threshold for glucose is exceeded, gluco induced osmotic diuresis results in losses of wat and electrolytes. These losses result in a contract plasma volume. The combination of hyperosmolan and relative intracellular and extracellular dehyd tion may impair renal function and thus may expl the elevated serum creatinine values associated wi hyperglycemia. Ureteric Obstruction Two patients with stenosis of the transplant uretz initially presented with elevations in serum creatinin and responded to increased steroid administration therapy for rejection. Several other patients have h stenosis of the transplant ureter since recognition the syndrome and were not treated for rejection. Case 2. A 10-year-old male with familial nephrosis received cadaver transplant in 1965. Following rapid rejection of the kidn he received a transplant from his father in the same year. kidney was removed in 1969 because of chronic rejection and 1970 he received an allograft from his mother. After an u

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eventful postoperative course he was discharged. One month later he was readmitted because of rising serum creatinine. 131I orthohippurate renogram showed good uptake but delayed dye excretion and he was treated for rejection with a temporary fall in his serum creatinine level. However, 8 days later his serum creatinine began to rise again and continued to rise despite a second course of rejection therapy. A retrograde ureterogram performed at this time was interpreted as normal. He then received a third course of rejection therapy. A repeat retrograde ureterogram showed an obstruction at the uretero-vesical junction. A ureteral catheter was placed retrograde into the renal pelvis and an immediate diuresis ensued. Rejection therapy was stopped and serum creatinine rapidly fell. Two weeks later he underwent ureteral reimplantation. Biopsy at the time of surgery revealed no evidence of rejection. He is now well four years post-transplantation.

Comment. Ureteral problems are the most frequently reported technical complications associated with transplantation, 3-27% in different series 3,5,14,29,37,41,43-46,54,72,73,75,76,84,97,100-102,104 This is reflected in the fact that no consensus has yet been reached on a perfect method for directing the urine into the bladder. Ureteroneocystostomy (used routinely in this institution,3'5'14 29'37'72'73'100 ureteroureterostomy, 43,44,46,103 and pyeloureterostomy43 each have their advocates although the comparative reviews by Weil, Starzl and others have suggested that ureteroneocystostomy is associated with fewer

complications.97'10 Most ureteral complications occur early in the posttransplant period, urinary fistula being the most frequent. Late complications have been reported by a number of centers and include stenosis,45,54'97'100 cutaneous urinary fistula, 45,54,76,84,100 nephrolithiasis or ureterolithiasis,7 periureteral abscess,104 and periureteral fibrosis.41 Urinary fistulas are evident on presentation. The other entities can be diagnosed by routine urologic investigation (intravenous pyelogram, retrograde studies) or by radioisotope studies. However, the possibility must be considered and the studies asked for-thus a high index of suspicion is necessary. Ureteric obstruction mimicking rejection has previously been reported by Weiss et al.101 In their case "dynamic radioisotope study" with 131I hippuran revealed the ureteric obstruction. Surgical relief of the obstruction, as in our cases, resulted in prompt decrease in serum creatinine. In our two patients serum creatinine temporarily fell in response to treatment for rejection. However, subsequent renal biopsy revealed no evidence of rejection. It is possible, although unlikely, that the two events were occuring simultaneously. Why then did serum creatinine fall in response to anti-rejection treatment? One possible explanation is that there was an inflammatory component to the obstruction. The steroids administered

TABLE 2. Origin of Bacterial Sepsis in 8 Patients Who Had Elevated Serum Creatinine in Association with Bacterial Infection

Septic shoulder Orchitis Septicemia (unknown origin) Stitch abscess Infected tooth Tonsillitis Tonsillitis Tonsillitis

for rejection treatment may have reduced the inflammation, thus increasing the radius (r) of the ureter. As flow is proportional to r4, a small increase in radius will result in a significantly increased flow. Infection Bacterial infections. There were 8 documented episodes of creatinine elevations in association with bacterial infection in this group of patients. Successful treatment of the infection resulted in a fall in creatinine level in all cases (Table 2). Case 3. A 16-year-old male with renal failure secondary to chronic glomerulonephritis received a cadaver transplant. Following an uneventful postoperative course he was discharged with a serum creatinine of 1.2 mg/100 ml. One month later he was readmitted due to elevation in blood urea nitrogen and creatinine levels. Temperature was 38.20. Physical examination revealed an erythematous swollen incision, and the transplant wound was opened releasing a subcutaneous collection of purulent material. The infection did not appear to extend beneath the fascia. Cultures were obtained and he was started on appropriate antibiotics. Serum creatinine was monitored daily and fell with the institution of appropriate antibiotic therapy.

Comment. Elevated serum creatinine levels associated with bacterial infection may be due to one or a combination of many factors. First, as febrile patients require increased fluids, dehydration alone may be responsible. In addition when the cause of the fever is tonsillitis, oral intake may be limited because of the pain associated with swallowing. In some cases, elevated creatinine may also be due to deposition of antigen-antibody complexes in the kidney,18 either specifically22 or nonspecifically. Creatinine elevations in these patients were usually not severe (