Immunosuppressed Renal Transplant Patients Research Articles

Utility of bronchoalveolar lavage in assessing pneumonia in immunosuppressed renal transplant recipients

purpose: To determine if initial results obtained from diagnostic bronchoalveolar lavage (BAL) in immunosuppressed renal transplant patients with pulmonary infiltrates, fever, or hypoxemia can affect therapeutic decisions, morbidity, and mortality. design: A retrospective study of all BAL specimens obtained from renal transplant patients from January 1985 through June 1991. Initial results of Gram stain, cytology, cell differential count, and semi-quantitative bacterial cultures, all available within 24 hours of bronchoscopy, were compared with clinical outcomes and final diagnosis. setting: University hospital nephrology-transplant/pulmonary service. patients: Seventy renal transplant patients with a suspected pneumonia were stratified into 3 groups. A total of 48 patients underwent 58 bronchoscopies. Group 1 was comprised of 32 BALS that yielded 1 or more infectious organisms and was considered diagnostic. Group 2 (n = 26) were those BALs in which no organism was isolated and were thus nondiagnostic. Twenty-two additional immunosuppressed renal transplant recipients with pneumonia were considered by the admitting transplant nephrologist to have an uncomplicated community-acquired lung infection and thus were empirically treated and did not undergo BAL (Group 3). methods: BAL fluid analysis included cell differential count, cytopathologic examination, and culture for mycobacteria, legionella, fungi, viruses, and bacteria using a semi-quantitative technique. Etiologic diagnosis and the time of onset of the infectious processes were recorded. Therapeutic outcome and mortality were determined for each group. results: Thirty-nine etiologic organisms were found in 32 patients, with 6 patients having more than 1 infection. Twenty-two patients had 26 negative BALs, and 8 of these patients were clinically believed to have a volume overload state. Eight of 13 (61%) patients with bacterial pneumonia had BAL neutrophil counts greater than 20%, whereas 11 of 13 (84%) patients without bacterial pneumonia had neutrophil counts less than 20% (p <0.05). Those patients with an infectious etiology remained in the hospital longer than patients without a specific etiologic organism identified (p <0.02). Therapeutic decisions leading to the institution of specific antibiotics were more frequently made in patients with a diagnostic BAL (p <0.0001). An overall 3-month mortality (16%) was low compared with the historical rate (30%). conclusion: BAL is a useful procedure in the diagnosis of an infectious process in immunosuppressed renal transplant patients where initial results can alter therapy in more than 70% of cases.

Hypoglycemia Secondary to Trimethoprim/Sulfamethoxazole Administration in a Renal Transplant Patient

To report a case of trimethoprim/sulfamethoxazole (TMP/SMX)-induced hypoglycemia in an immunosuppressed renal transplant patient. English-language journal articles and reference texts identified via a MEDLINE search and a bibliographic review of pertinent data sources. Hypoglycemia resulting from the combination of sulfonylureas and sulfonamides is a recognized drug interaction. Hypoglycemia induced by sulfonamides alone may be encountered less frequently. Previously reported cases of TMP/SMX-induced hypoglycemia postulated that the sulfonamide mimics hypoglycemic sulfonylurea agents and stimulates pancreatic islet cells to secrete insulin. We report a case of hypoglycemia following the administration of high-dose TMP/SMX in a renal transplant patient. Elevated C-peptide concentrations following the hypoglycemic episode indicate that hypoglycemia resulted from increased endogenous insulin secretion. Hypoglycemia has been a rarely encountered result of TMP/SMX use. Patients receiving TMP/SMX, particularly those with impaired renal function and those receiving high doses, should be monitored closely for hypoglycemia.

Sequence rearrangement in JC virus DNAs molecularly cloned from immunosuppressed renal transplant patients

From nonimmunocompromised individuals, we have recently identified a possible archetypal JC virus DNA sequence from which various regulatory sequences of JC virus isolates derived from patients with progressive multifocal leukoencephalopathy (PML) could have evolved. In this study, we analyzed the regulatory sequences of JCV DNAs cloned from urine samples of a PML risk group (renal transplant patients on immunosuppressive therapy). A number of JC virus DNAs were molecularly cloned from virions excreted in the urine of eight patients. Furthermore, fragments containing the regulatory region were amplified by the polymerase chain reaction and subsequently molecularly cloned from cell-associated JC virus excreted in the urine of two patients. The regulatory regions in all clones were analyzed with restriction enzymes, and those in representative clones were sequenced. We found that clones with the archetypal regulatory sequence were predominant in all urine samples, but a few clones carried regulatory sequences that diverged from the archetypal sequence by deletion or duplication. The finding that sequence rearrangement in the archetypal regulatory region occurs in the course of infection in immunosuppressed hosts is consistent with the adaptation hypothesis which has been put forward to explain the divergence of the regulatory regions in PML-derived JC virus isolates.

Role of monoclonal antibody therapy in the treatment of infectious disease

The past, present, and emerging roles of immunotherapy, including the use of monoclonal antibodies for diagnosis and treatment, are discussed. Although immunotherapy has been used for more than 100 years, it became less important when antimicrobial agents came into widespread use. In the 1970s investigators began to re-examine immunotherapy for potential use in gram-negative infections. Polyclonal antiserum against the J5 mutant of Escherichia coli (gram-negative lipid A) has been shown to be effective in treating patients with bacteremia and septic shock. The discovery of monoclonal antibodies and the creation of hybridoma technology by the fusion of immortal cells with antibody-producing cells have resulted in the production of large amounts of monoclonal antibodies of desired specificities. More recently, murine monoclonal antibodies have been used clinically for immunosuppression in renal-transplant patients (OKT3 antibody) and for prevention of septic complications in patients with suspected gram-negative infection and evidence of systemic response (E5 IgM antibody). E5 antibody directed against gram-negative bacterial endotoxin has been reported to significantly reduce morbidity and mortality from gram-negative sepsis and to be well tolerated. The application of new treatment modalities such as monoclonal antibodies is expected to enhance the therapeutic options available to treat infectious diseases.

Candida norvegensis peritonitis and invasive disease in a patient on continuous ambulatory peritoneal dialysis

We report a case of Candida norvegensis invasive disease in an immunosuppressed renal transplant patient on continuous ambulatory peritoneal dialysis. Multiple cultures of peritoneal fluid, blood, and tracheal suction done over a 2-week period were positive for this unusual isolate. Despite treatment with amphotericin B and flucytosine the patient died. This is the first report of C. norvegensis fungemia documented by culture.

Total hip replacement in the renal transplant recipient.

Osteonecrosis of the femoral head is a severely disabling complication of steroid immunosuppression in renal transplant patients. We report 31 total hip arthroplasties in 21 renal transplant recipients with an average follow-up of six years. There were no problems with wound healing or infection despite full immunosuppression. Four hips developed symptomatic loosening but the other results were excellent, comparing well with other methods of treatment for osteonecrosis. Ten patients died during the follow-up period. Total hip replacement is a safe and effective treatment for transplant recipients and, in view of their limited life expectancy, should be considered at an early stage in their treatment.

The Occurrence of a Peripheral T-Cell Lymphoma in a Chronically Immunosuppressed Renal Transplant Patient

A 32-year-old man received a cadavaric renal transplant in 1975 for end-stage renal disease and, thereafter, was treated with azathioprine and methylprednisolone for chronic immunosuppression. In 1985, he presented with fever and pancytopenia that persisted despite withdrawal of the immunosuppressive agents. Lymph node and liver biopsies demonstrated malignant lymphoma within the sinuses of the node and the sinusoids of the liver. A splenectomy was performed for persistent pancytopenia, and the spleen demonstrated malignant lymphoma of the diffuse mixed large and small cell type exclusively within the cords of the red pulp. The immunophenotype of the tumor cells was obtained by frozen section immunoperoxidase staining with monoclonal antibodies and flow cytometric analysis. The tumor cells were positive for the Pan T cell markers CD3 and CD2, but were negative for the subset markers CD4 and CD8. A DNA hybridization study conducted on the splenic tissue conclusively identified the clonal nature of the malignant T cells by demonstrating rearrangement of the T cell receptor beta gene. In spite of multiple chemotherapeutic regimens, the patient developed increasing peripheral blood involvement and died with disseminated lymphoma. This case appears to be unique in that it is the first report of a chronically immunosuppressed transplant recipient to develop a malignant lymphoma of the mature T cell type, and several of the pathologic features of the tumor have not been observed previously.

THE IMPACT OF RENAL TRANSPLANTATION ON THE COURSE OF HEPATITIS B LIVER DISEASE

To establish the impact of transplantation on the course of chronic hepatitis B liver disease we performed a prospective study of the clinical and pathological sequelae of hepatitis B disease in all 22 patients who had renal allografts that functioned for more than 1 year and who were hepatitis B surface antigen (HBsAg)-positive following transplantation. No patient converted to HBsAg-negative. During a mean follow-up of 83 months serial liver biopsies were performed in 20 patients and 1 liver biopsy was available in the remaining 2 patients. Eleven patients died of liver disease, 5 of whom died of hepatic failure, 3 with hepatoma, 2 of gastrointestinal hemorrhage, and 1 of ascites with pleuroperitoneal fistula. Aggressive liver disease was observed in the vast majority of patients: 12 ultimately developed cirrhosis, (mean follow-up 81 months), 6 chronic active hepatitis (mean follow-up 93 months), 3 chronic persistent hepatitis (mean follow-up 89 months), and in 1 patient the presence of HB virus in hepatocytes was the sole morphologic alteration (follow-up 42 months). There was a marked tendency to progression in that 82% of patients with virus only, reactive hepatitis, or chronic persistent hepatitis on initial biopsy subsequently developed chronic active hepatitis or cirrhosis. For comparison, 10 HBsAg-positive patients whose renal failure had been treated by hemodialysis were also studied over a comparable period. Four patients converted to the negative state. Biochemical evidence of persistent liver dysfunction occurred in only 1 patient and no patient has died from complications of liver disease. We conclude that in the immunosuppressed renal transplant patient HB infection often results in the development of cirrhosis, leading to death from hepatoma and hepatic failure. This course is worse than that in dialysis patients. Renal transplantation of HBsAg-positive patients with end-stage renal failure may be inadvisable.

Nephrostomy Drainage for Renal Transplant Complications

The use of temporary diverting nephrostomy drainage in the management of immunosuppressed renal transplant patients with supravesical urinary extravasation, fistulas or ureteral obstruction is reviewed. In a literature survey covering an 11-year interval and 4,307 transplants there were 204 cases (4.7 per cent) of ureteral extravasation or fistula and 113 cases (2.6 per cent) of ureteral obstruction. Attempts at urologic repair in these 317 cases resulted in a 30.9 per cent failure rate (98 cases), of which 86.7 per cent (85 cases) occurred in patients without nephrostomy compared to 13.3 per cent (13 cases) in patients with nephrostomy. In our 255 consecutive renal transplant patients there were 7 (2.7 per cent) with ureteral extravasation or fistula and 14 (5.5 per cent) with ureteral obstruction. Temporary nephrostomy was done in all 21 patients to protect the urologic repair and, when necessary, to control sepsis and allow for patient stabilization before delayed urinary tract reconstruction. In our series there was no mortality and only 1 renal unit (4.7 per cent) was lost as a consequence of urologic complications. The use of nephrostomy in transplant patients with ureteral extravasation, fistulas or ureteral obstruction is encouraged strongly to optimize patient and renal unit survival.

Rapidly Expanding Pulmonary Nodule Caused by Pittsburgh Pneumonia Agent

PITTSBURGH pneumonia agent (PPA), also known as TATLOCK and HEBA, and tentatively ascribed to the genus<i>Legionella (L micdadei)</i>, has recently been identified as a cause of pneumonia in patients receiving high-dose steroid therapy for rejection of renal transplants.^1-4We report a case of a rapidly expanding pulmonary nodule caused by PPA in an immunosuppressed renal transplant patient. <h3>Report of a Case</h3> A 59-year-old man had a cadaveric renal transplantation because of renal failure caused by familial polycystic kidney disease. After transplantation, he was given prednisone, 2 mg/kg/day, and azathioprine, 3 mg/kg/day. During the next six weeks of hospitalization, he had four episodes of acute graft rejection, each treated with methylprednisolone sodium succinate pulse therapy, 30 to 90 mg/kg/day for three days. He was discharged from the hospital with instructions to take prednisone, 70 mg/day, and azathioprine, 50 mg/day, but was readmitted one week later for a rising serum

Management and treatment of the immunosuppressed renal transplant patient

Kidney transplants are being performed with increasing success, and the dental profession has the responsibility of providing outpatient oral care for these patients. A case is presented in which an acute alveolar abscess is treated by endodontic therapy in an immunosuppressed kidney transplant patient. The special problems in treating these patients are also discussed.

Human polyomavirus infections with JC virus and BK virus in renal transplant patients.

Infection with the human polyomaviruses JC virus and BK virus was studied in 61 immunosuppressed renal transplant patients. Urine cytologic studies, indirect immunofluorescence microscopy, electron microscopy, and serologic studies were used to assess viral activity. Patients records were abstracted for events associated with polyomavirus infections. Polyomavirus excretion in urine was detected in 12 of 61 patients (20%). Eleven excreted JC virus and nine, BK virus. Fourfold hemagglutination-inhibition antibody titer rises occurred in 25 of 61 patients (41%). The serologic data suggested that most JC virus infections were primary, whereas most BK virus infections resulted from virus reactivation. During this 2-year study, 32 of 61 patients (52%) had evidence of active viral replication. Urinary tract excretion was associated with drug-requiring diabetes mellitus (P = 0.001), arterial occlusive disease (P = 0.03), and ureteral stricture with loss of renal function (P = 0.02). Antibody increases to BK virus were associated with a rising seurum creatinine (P = 0.02) and need for transplant biopsy (P = 0.02). Polyomavirus replication was therefore associated with an increased frequency of transplant related complications.

Prolonged Herpes-Zoster Infection Associated with Immunosuppressive Therapy

Unusually prolonged zoster was observed in four patients, two with cardiac transplants, one with acute lymphocytic leukemia, and one with diffuse histiocytic lymphoma. Lesions increased in number and persisted for 5 to 24 weeks before beginning to resolve. Specific cellular-immune responsiveness to varicella-zoster virus was markedly depressed during these infections. Absolute numbers of T lymphocytes were also very low. Reducing immunosuppressive therapy to increase immune responses appeared to initiate resolution of zoster lesions and halt dissemination. In one patient treatment with adenine arabinoside was also needed for resolution of disseminated zoster. This syndrome appears to be counterpart of the prolonged mucocutaneous herpes-simplex infection previously reported in immunosuppressed cardiac and renal transplant patients.

Oral lesions in renal transplant patients.

Plaque-like lesions of the oral mucosa have been observed in seven immunosuppressed renal transplant patients. Whilst bearing a superficial resemblance to acute pseudomembranous candidiasis (thrush), these lesions have been shown to be associated with bacterial overgrowth and not with fungi. Treatment has depended on the use of appropriate antibiotics and antiseptics together with the adoption of measures to cause disintegration of the mucoid matrix of the lesions.

Listeria monocytogenes

A brain abscess caused by Listeria monocytogenes developed in an immunosuppressed renal transplant patient. Meningitis and meningoencephalitis from this organism were encountered in three other renal transplant recipients at this medical center during the past 4 years. Focal neurologic deficits occurred in patients with either Listeria abscess or meningoencephalitis. Computerized tomography was a rapid aid to the diagnosis of abscess. Immunosuppression has increased the incidence of central nervous system Listeria infections, but ampicillin still provides effective treatment, even when immunosuppressive therapy is continued. Limited experience with Listeria brain abscess suggests that surgical intervention improves the prognosis.

Foley catheter tip cultures: A valuable diagnostic aid in the immunosuppressed patient

Cultures of forty-three Foley catheter tips from immunosuppressed renal transplant patients have been analyzed and correlated with the subsequent development of urinary tract infection. Fifteen cultures produced no growth and two showed only coagulase-negative staphylococci; none of these patients subsequently developed a urinary tract infection. Twenty-four of the cultures showed at least one organism known to be a frequent urinary pathogen; sixteen (67 per cent) of these patients developed a urinary tract infection within ten days of the culture, and all sixteen had an infection caused by an organism present on the Foley tip. None of the organisms were identified by simultaneous catheter specimen urine cultures. Foley tip cultures in the immunosuppressed renal transplant patients are predictive of urinary sepsis and diagnostic of the causative organism.

Oral infection in immunosuppressed renal transplant patients

The most common cause of death in patients taking immunosuppressive (IS) drugs is infection. Many of the microorganisms which infect these IS patients may be found in the mouth, but the mouth has not been investigated as a potential source of lethal infection. In view of this, we studied twenty-seven IS patients taking Imuran and prednisone for 6 to 61 weeks and eighteen normal controls. The patients were followed monthly, and the incidence of oral and systemic complications was recorded. There were no deaths due to infection during the 10-month study period. Oral infection occurred as frequently as pneumonia or urinary tract infection. Systemic factors which were related to the development of dental infection were lymphocyte count and length of time on immunosuppressive drug therapy.

Hodgkin's disease in human renal transplantation

After transplantation Hodgkin's disease developed in two recipients of related donor renal allografts. Only one case of Hodgkin's disease had previously been reported in this specific patient population and these two cases demonstrate the very atypical biologic behavior of Hodgkin's disease in the immunosuppressed renal transplant patient.

Discontinuance of Immunosuppression

To the Editor .—Our experience at the University of Wisconsin permits me to agree with Dr Najarian's editorial comments on the article by Owens et al concerning the discontinuance of immunosuppression in renal transplant patients ( Arch Surg 110:1450-1451, 1975). We have recently reviewed our immunosuppressive protocol at the University of Wisconsin, after finding that several patients had voluntarily stopped taking the drugs without informing the physician. Eight patients (five living related donor recipients and three cadaver recipients) stopped all immunosuppression against medical advice. This represents a 4% incidence of major lapses in immunosuppression, and is probably lower than the actual incidence. In addition, several other transplantation patients had their immunosuppressive therapy removed by medical advice due to severe infection or leukopenia. Two of the mixed leukocyte culture (MLC)-nonidentical living related donor recipients underwent severe rejection following cessation of immunosuppressive therapy; this was ultimately fatal to both. This occurred despite the

THE NITROBLUE-TETRAZOLIUM TEST: Usefulness in Detecting Bacterial Infections in Uræmic and Immunosuppressed Renal Transplant Patients

The nitroblue-tetrazolium test was performed on a group of uræmic patients and a group of renal transplant patients in an attempt to assess its ability to identify bacterial infection. The data suggest that this test is useful in monitoring the infectious-disease status of uræmic patients. The test is not affected by large doses of steroids nor by transplant rejection, and is therefore useful in the diagnosis and differential diagnosis of infection and/or rejection in the transplant patient.