James R. Johnston

A randomized trial of staphylococcus aureus prophylaxis in peritoneal dialysis patients: Mupirocin calcium ointment 2% applied to the exit site versus cyclic oral rifampin

The objective of this study was to compare prophylaxis for Staphylococcus aureus infections in peritoneal dialysis patients using 600 mg cyclic oral rifampin for 5 days every 3 months versus mupirocin calcium ointment 2% applied daily to the exit site. The study design was a prospective randomized trial, controlling for S aureus nasal carriage. Eighty-two continuous ambulatory and continuous cyclic peritoneal dialysis patients (54% male, 71 % white, 34% insulin-dependent, mean prestudy time on peritoneal dialysis 1.2 years) were randomly assigned to cyclic rifampin (n = 41 patients) or daily exit site mupirocin prophylaxis (n = 41 patients). Mean follow-up was 1 year. S aureus catheter infection rates were 0.13/yr with mupirocin and 0.15/yr with rifampin (P = NS). Both rates were significantly lower than the centers historical rate (the period between 1983 and 1992) of 0.46/yr prior to the study (P < 0.001). S aureus peritonitis rates were 0.04/yr with mupirocin and 0.02/yr with rifampin (P = NS), both significantly lower than the centers historical rate of 0.16/yr (P < 0.02). Catheter loss due to S aureus infections was 0.02/yr with mupirocin and 0/yr with rifampin (P = NS), both significantly lower than the centers historical rate of 0.12/yr (P < 0.001). There were no side effects in patients using mupirocin, but 12% were unable to continue rifampin due to side effects. We conclude that mupirocin ointment at the exit site and cyclic oral rifampin are equally effective in reducing S aureus catheter infections. In addition, rifampin or mupirocin significantly reduced S aureus peritonitis and catheter loss due to S aureus infections. Mupirocin at the exit site provides an excellent alternative prophylaxis for S aureus infections, particularly in patients who cannot tolerate oral rifampin therapy.

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS IN ADULT AND PEDIATRIC RENAL TRANSPLANT PATIENTS RECEIVING TACROLIMUS-BASED IMMUNOSUPPRESSION

Between March 27, 1989 and December 31, 1997, 1316 kidney transplantations alone were performed under tacrolimus-based immunosuppression at our center. Posttransplant lymphoproliferative disorders (PTLD) developed in 25 (1.9%) cases; the incidence in adults was 1.2% (15/1217), whereas in pediatric patients it was 10.1% (10/99; P<.0001). PTLD was diagnosed 21.0+/-22.5 months after transplantation, 25.0+/-24.7 months in adults and 14.4+/-18.2 months in pediatric patients. Of the 4 adult cases in whom both the donor and recipient Epstein Barr virus (EBV) serologies were known, 2 (50%) were seropositive donor --> seronegative recipient. Of 7 pediatric cases in whom both the donor and recipient EBV serologies were known, 6 (86%) were EBV seropositive donor --> seronegative recipient. Acute rejection was observed before the diagnosis of PTLD in 8 (53%) of 15 adults and 3 (30%) of 10 pediatric patients. Initial treatment of PTLD included a marked decrease or cessation of immunosuppression with concomitant ganciclovir therapy; two adults and two pediatric patients required chemotherapy. With a mean follow-up of 24.9+/-30.1 months after transplantation, the 1- and 5-year actuarial patient and graft survival rates in adults were 93% and 86%, and 80% and 60%, respectively. Two adults died, 3.7 and 46.2 months after transplantation, of complications related to PTLD, and 10 (including the 2 deaths) lost their allograft 3.7-84.7 months after transplantation. In children, the 1- and 5-year actuarial patient and graft survival rates were 100% and 100%, and 100% and 89%, respectively. No child died; one child lost his allograft 41.3 months after transplantation. One child had presumed recurrent PTLD that responded to discontinuation of tacrolimus and reinitiation of antiviral therapy. The mean serum creatinine level in adults was 2.5+/-1.2 mg/dl, and in children, it was 1.3+/-0.6 mg/ dl. Under tacrolimus-based immunosuppression, PTLD is less common after renal transplantation in adults than in children, but PTLD in children is associated with more favorable outcomes than in adults.

A PROSPECTIVE, RANDOMIZED TRIAL OF TACROLIMUS/PREDNISONE VERSUS TACROLIMUS/PREDNISONE/MYCOPHENOLATE MOFETIL IN RENAL TRANSPLANT RECIPIENTS

BACKGROUND Between September 20, 1995 and September 20, 1997, 208 adult patients undergoing renal transplantation were randomized to receive tacrolimus/prednisone (n=106) or tacrolimus/prednisone/mycophenolate mofetil (n=102), with the goal of reducing the incidence of rejection. METHODS The mean recipient age was 50.7+/-13.7 years. Sixty-three (30.3%) patients were 60 years of age or older at the time of transplantation. The mean donor age was 34.5+/-21.7 years. The mean cold ischemia time was 30.5+/-9.2 hr. The mean follow-up is 15+/-7 months. RESULTS The overall 1-year actuarial patient survival was 94%; the overall 1-year actuarial graft survival was 87%. When the patient and graft survival data were stratified to recipients under the age of 60 who did not have delayed graft function, the overall 1-year actuarial patient survival was 97%, and the corresponding 1-year actuarial graft survival was 93%. There were no differences between the two groups. The overall incidence of rejection was 36%; in the double-therapy group, it was 44%, whereas in the triple therapy group, it was 27% (P=0.014). The mean serum creatinine was 1.6+/-0.8 mg/dl. A total of 36% of the successfully transplanted patients were taken off prednisone; 32% of the patients were taken off antihypertensive medications. The incidence of delayed graft function was 21%, the incidence of cytomegalovirus was 12.5%, and the initial and final incidences of posttransplant insulin-dependent diabetes mellitus were 7.0% and 2.9%; again, there was no difference between the two groups. CONCLUSIONS This trial suggests that the combination of tacrolimus, steroids, and mycophenolate mofetil is associated with excellent patient and graft survival and a lower incidence of rejection than the combination of tacrolimus and steroids.

An Analysis of Early Renal Transplant Protocol Biopsies - the High Incidence of Subclinical Tubulitis

To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one‐week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2 ± 2.6 d (range 3–18 d) after transplantation (n = 28). Six (21%) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one‐week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.

Hepatic expression of macrophage inflammatory protein-1α and macrophage inflammatory protein-1β after liver transplantation

Two local events that are crucial for T cell emigration into tissue are (1) activation of T cell integrins to permit binding to endothelial counter-receptors and (2) directed migration through the endothelium and into tissue in response to chemotactic factors. Because the chemokines macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta can activate adhesion and induce migration of T cells in vitro, we investigated their expression in human liver allografts to determine whether they might be involved in regulating the recruitment of T cells to allografts in vivo. Both chemokines were expressed strongly by infiltrating leukocytes during rejection and could be detected immunohistochemically on biliary epithelium, an important target for T cell mediated graft damage. Both chemokines, but particularly MIP-1 beta, were detected on the vascular and sinusoidal endothelium of rejecting liver allografts, where they were coexpressed with the T cell beta 1-integrin receptor vascular cell adhesion molecule-1. In situ hybridization with complementary ribonucleic acid probes showed no MIP-1 alpha or MIP-1 beta mRNA in normal liver but dramatic expression of both chemokines in infiltrating leukocytes and graft endothelium during rejection. Expression was reduced after successful corticosteroid treatment of rejection but persisted in patients progressing to chronic rejection. Increased MIP-1 alpha and MIP-1 beta mRNA expression was already found in biopsies taken at the end of the transplant operation, suggesting that early induction of chemokines, possibly in response to graft reperfusion, might promote the subsequent development of graft rejection. These data demonstrate for the first time that MIP-1 alpha and MIP-1 beta are (1) expressed in human liver allografts, (2) produced by endothelial cells in vivo, and (3) induced early after transplantation. They suggest that MIP-1 alpha and MIP-1 beta produced by graft infiltrating leukocytes and graft endothelium might play a crucial role in regulating T cell recruitment to liver allografts in vivo.

Hospitalization in peritoneal dialysis patients

Hospitalization rates are declining more rapidly for peritoneal dialysis (PD) than for hemodialysis patients. This has been postulated to be caused in part by lower peritonitis rates. However, the causes of admission have not been reexamined in the setting of declining rates. We prospectively examined our hospitalization rates, causes of admission, and impact of peritonitis on hospitalization in adult PD patients at a single center over a 4-year period. There were 274 admissions in 168 patient-years for a rate of 1.6 admissions and 13.0 hospital days per patient-year. Rates were greater for men (1.8 v 1.5; P = 0.013), patients with diabetes (2.2 v 1.4, P < 0.001), and those with a higher peritoneal equilibration test result. Creatinine clearance and sex were independent predictors in a multivariate analysis. The most common causes for admission were cardiac disease (14.6%) and peritonitis (13.5%). Peritonitis accounted for 0.21 admissions and 2.0 hospital days per patient-year. Thirty percent of the incident patients were admitted during the first 90 days of dialysis. Admissions for dehydration and glucose abnormalities were more common in the first 90 days. Overall admission rates, as well as admission rates for peritonitis, did not change over time, although hospital days per year decreased. Those admitted for peritonitis had higher peritonitis rates, more time on PD, and were more likely to be black. Eighty-one percent of the admissions for peritonitis were caused by Staphylococcus aureus, Streptococcus spp, or gram-negative/fungal peritonitis. Patients with peritonitis caused by Staphylococcus epidermidis were less likely to be admitted than patients with peritonitis caused by other organisms. To conclude, peritonitis remains a common cause of hospitalization, despite low peritonitis rates. To decrease admissions for peritonitis, attention should be focused on preventing peritonitis caused by organisms other than S epidermidis.

Hemoperitoneum complicating chronic peritoneal dialysis: single-center experience and literature review.

Hemoperitoneum is a well-recognized, if uncommon, complication of chronic peritoneal dialysis. In this review of 424 patients maintained on peritoneal dialysis at a single center during an 11-year period, 26 patients (6.1%) developed one or more episodes of hemoperitoneum. Three patients had hemoperitoneum on two separate occasions with different etiologies. One additional patient was seen on a hospital consultative service. Three types of bleeding episodes were observed. Twenty-one of 30 (70%) were benign, consisting of pink-tinged dialysate with little clinical consequence (group 1). Three (10%) consisted of minor hemoperitoneum associated with significant intra-abdominal pathology (group 2), and six (20%) required active intervention (group 3). The most frequent cause of hemoperitoneum was bleeding related to menstruation or ovulation; hemoperitoneum was more common in women than in men. Two patients had hemoperitoneum occurring after more than 6 years on dialysis. In both, the etiology was sclerosing peritonitis, an association not previously noted. The less common etiologies of hemoperitoneum encountered in our patients were similar to those in reports from other centers and are compiled here.

Interferon-induced reversible acute renal failure with nephrotic syndrome

Although there has been considerable experience with interferons in clinical trials during the past decade, acute renal failure as a side effect of interferon treatments has rarely been reported. We report a case in which acute renal failure with nephrotic syndrome was associated with therapy with two types of interferons. We note incomplete return of renal function upon withdrawal of therapy.

A PROSPECTIVE, RANDOMIZED TRIAL TO COMPARE TACROLIMUS AND PREDNISONE WITH AND WITHOUT MYCOPHENOLATE MOFETIL IN PATIENTS UNDERGOING RENAL TRANSPLANTATION: FIRST REPORT

PURPOSE Between September 20, 1995 and September 20, 1996, 120 patients were entered into a prospective, randomized trial comparing tacrolimus and prednisone with (61) and without (59) 2 gm. mycophenolate mofetil daily to determine whether mycophenolate mofetil was associated with a lower incidence of rejection. MATERIALS AND METHODS Mean recipient age plus or minus standard deviation was 50.8+/-14.1 years (range 18.8 to 84.1). Mean donor age was 34.3+/-21.7 years (range 0.01 to 76). Of the donors 18 (15%) were older than 60 years. Mean cold ischemia time was 30.9+/-8.4 hours (range 14.2 to 49). Median followup was 8.6+/-0.5 months. RESULTS The 6-month actuarial patient survival was 95%, 92% in the double therapy group and 98% in the triple therapy group (not significant). The 6-month actuarial graft survival was 88%, 84% in the double therapy group and 92% in the triple therapy group (not significant). The overall incidence of rejection and steroid resistant rejection was 34.2 and 4.2%, respectively. There was a strong trend toward less rejection in the mycophenolate mofetil group than in the double therapy group (26.2 versus 42.4%). Crossover was common, and was 42.6% from triple to double therapy and 18.6% from double to triple therapy. The reasons for discontinuation of mycophenolate mofetil were gastrointestinal toxicity, primarily diarrhea, or less commonly hematological toxicity, primarily neutropenia or thrombocytopenia. Gastrointestinal toxicity was ameliorated by separating the doses of tacrolimus and mycophenolate mofetil by 2 to 4 hours, and reducing the dose to 1 gm. daily. CONCLUSIONS Mycophenolate mofetil appears to be a useful third agent with tacrolimus in patients undergoing renal transplantation, and is associated with a reduction in the rate of rejection and a low incidence of steroid resistant rejection. There is a high incidence of gastrointestinal toxicity associated with the 2 gm. daily dose but this complication is relatively straightforward to manage.

The Use of Streptokinase to Treat Renal Artery Thromboembolism

The effects of streptokinase are difficult to determine. Furthermore, it has toxic side effects, and renal function may not recover from its use. However, because of favorable experiences with this drug in the early treatment of venous thromboembolism and following myocardial infarction, as well as the favorable findings with early perfusion in the dog model, the use of local streptokinase may be justified if the infusion is begun early, preferably within four to six hours.