Intravenous immunoglobulin therapy in the treatment of BK viremia and nephropathy in pediatric renal transplant recipients.

Polyoma BKVN is a significant cause of allograft dysfunction and loss in renal transplant recipients. Reduction in immunosuppression is accepted as first-line therapy to decrease viral load and prevent allograft injury and dysfunction. We report our experience with persistent BKV after reduction in immunosuppression followed by successful clearance of BKV in three pediatric renal transplant recipients and histological resolution of BKVN in a fourth patient following therapy with IVIG. Once BKV was detected, immunosuppression was reduced and BKV was monitored until clearance was achieved. All four patients were given IVIG in a dose of 2 g/kg. Allograft function remained stable in all patients. Early routine screening for BKV allows early intervention to prevent the development of BKVN and permanent allograft damage. While immunosuppression reduction is a logical first-line therapy, second-line therapy is not well established. IVIG seems to be an effective treatment for persistent BKV after reduction in immunosuppression and for BKVN and can therefore be considered as a therapeutic option in these patients.

A new technique for resecting 'unresectable' liver tumors.

BACKGROUND/PURPOSE: Liver tumors that surround the three major hepatic veins traditionally have been considered unresectable. This report describes an extended atypical left hepatectomy technique for tumors around the major hepatic veins. METHODS: Three children with tumors surrounding the 3 hepatic veins underwent intraoperative evaluation for extended atypical left hepatectomy. The left hepatic artery, left branch of the portal vein, and the 3 hepatic veins are occluded with vascular clamps. Perfusion of the remaining liver is through the right hepatic artery and portal vein into the retrohepatic vena cava via the retro hepatic veins. If the liver remains soft and does not become mottled, division of the 3 hepatic veins and resection of the tumor are carried out. RESULTS: Extended atypical left hepatectomy was successful in 2 children. Bile leak occurred in 1 instance and healed spontaneously. Both patients had transiently elevated serum bilirubin and transaminase levels and an elevated prothrombin time for 2 weeks. Both survived after treatment with chemotherapy. In the third child the liver became tense and mottled, and the procedure was abandoned. CONCLUSIONS: Successful extended atypical left hepatectomy depends on the ability of the retro hepatic veins to adequately drain blood into the vena cava after interruption (clamping) of the main hepatic veins. If the liver becomes mottled and tense the procedure must be abandoned and the patient should be considered for hepatic transplantation.

Experience with the Rex shunt (mesenterico-left portal bypass) in children with extrahepatic portal hypertension.

BACKGROUND/PURPOSE: Extrahepatic portal vein thrombosis (EPVT) in children can lead to severe bleeding from gastrointestinal varices, ascites, thrombocytopenia from hypersplenism, and other coagulation disorders. The authors have used the superior mesenteric vein to intrahepatic left portal vein (Rex) shunt in 5 children with symptomatic EPVT and report their results with this novel technique. METHODS: Children with symptomatic portal hypertension were screened for the underlying cause. All children with essentially normal livers and obstruction of the extrahepatic portal vein were considered for the Rex shunt. Evaluation included liver function tests, liver biopsy, and radiological evaluation of the intrahepatic vascular anatomy. RESULTS: Five patients between the ages of 2.8 and 10.5 years underwent evaluation for portal hypertension secondary to extrahepatic portal vein obstruction. Three patients had idiopathic extra hepatic portal vein thrombosis with cavernous transformation, 1 had thrombosis after a living-related liver transplant, and 1 had compression and obstruction of the main portal vein from enlarged lymph nodes after treatment of systemic histoplasmosis. All patients were symptomatic. Three patients had intermittent bleeding from esophageal and gastric varices, and all 5 had relative degrees of hypersplenism with enlarged spleens and thrombocytopenia (11,000 to 77,000). Three patients had significant leukopenia. Results of imaging studies suggested that 3 patients had inadequate intrahepatic portal veins for shunting, but all patients at exploration underwent successful shunting. There were no serious intraoperative complications. Postoperative complications included ascites in 2 patients that resolved within 1 month. There were no early shunt thromboses. The median postoperative length of stay was 7 days. Clinical follow-up ranged from 7 to 21 months. Gastrointestinal bleeding did not recur in any patient, and ascites resolved in all. Spleen size decreased significantly (P < .01) from 9.4 +/- 4.0 cm to 5.0 +/- 3.7 cm below the left costal margin. Mean platelet count and white blood cell count rose after shunting from 79 +/- 42 to 176 +/- 73 (P < .02) and 5.4 +/- 2.3 to 7.5 +/- 3.9 (P = .06), respectively. All shunts were studied at 1 and 7 days, and 3 and 6 months after the procedure. Shunt patency was documented in all cases. Subsequently, shunt blockage occurred in 2 patients. CONCLUSIONS: The Rex shunt has proven to be an effective method of resolving portal hypertension caused by EPVT including thrombosis after living donor transplantation. This shunt is preferable to other surgical procedures because it eliminates portal hypertension and its sequelae by restoring normal portal flow to the liver.

Pretransplant exposure to donor HLA-DR antigen in random transfusion units and the development of donor antigen-specific hyporeactivity.

Our previous studies have shown that the in vitro assay of donor antigen-specific hyporeactivity is a useful marker for identifying solid organ transplant recipients (kidney, lung and heart) at low risk for immunologic complications (i.e., late acute rejection episodes and chronic rejection). Donor antigen-specific hyporeactivity is defined as a significantly decreased post- vs. pretransplant proliferative response to donor antigens while response to third-party controls remains unchanged. We analyzed whether exposure to the same HLA-DR antigen pretransplant via random blood transfusion and posttransplant via the transplanted organ influenced the development of hyporeactivity. Thirty previously nontransfused recipients, each receiving two 150 ml pretransplant random blood transfusions, were assessed for hyporeactivity at 1 year posttransplant. Of the 12 recipients with pretransplant exposure to kidney HLA-DR via transfusions, 6 (50%) developed hyporesponsiveness; in contrast, of the 18 recipients who were not preexposed, only 3 (15%) exhibited this form of immunomodulation. Of interest, 2 of the 3 hyporesponsive recipients who were not preexposed, received units containing HLA-DR antigens previously shown to share crossreactive epitopes with the kidney HLA-DR. In conclusion, these results suggest a increased incidence in the development of hyporeactivity in patients receiving pretransplant transfusions which share an HLA-DR antigen with the transplanted kidney.

Effect of cyclosporine on renal function in kidney transplant recipients: a 12-year follow-up.

Nephrotoxicity remains a concern for patients on long-term cyclosporine. We have previously reported on renal function in a cohort of kidney transplant recipients followed up to 10 years posttransplant. The current study extends the analysis to 12 years. We find no evidence of cyclosporine-induced renal failure.

Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. The multivariate analysis.

The impact of delayed graft function on outcome after cadaver renal transplantation has been controversial, but most authors fail to control their analyses for the presence or absence of rejection. We studied 457 adult recipients of primary cadaver allografts at a single institution during the cyclosporine era. All patients received sequential immunosuppression. The incidence of delayed graft function (defined as dialysis being required during the first week after transplant) was 23%. There was a significant association between delayed graft function and cold ischemia time > 24 hr (P = 0.0001) and between delayed graft function and the occurrence of at least one biopsy-proven rejection episode (P = 0.004). Actuarial graft survival was not significantly different when comparing delayed graft function versus no delayed graft function for patients without rejection (P = 0.02). However, it was significantly worse for patients with both delayed graft function and rejection versus those with delayed graft function but no rejection (P = 0.005), as well as for grafts preserved > 24 hr versus < or = 24 hr (P = 0.007). By multivariate analysis, delayed graft function per se was not a significant risk factor for decreased graft survival for patients without rejection (P = 0.42). In contrast, rejection significantly decreased graft survival for grafts with immediate function (relative risk = 2.3, P = 0.0002), particularly in combination with delayed graft function (relative risk = 4.2, P < 0.0001). While cold ischemia time > 24 hr was also a significant risk factor (relative risk = 1.9, P = 0.02), other variables (preservation mode, 0 HLA Ag mismatch, age at transplantation, gender, diabetic status, and panel-reactive antibody at transplantation) had no impact on graft survival. Patient survival was significantly affected by the combination of delayed graft function and rejection (relative risk = 3.1, P < 0.0001), age at transplantation > 50 years (relative risk = 2.6, P < 0.0001), and diabetes (relative risk = 1.8, P = 0.006). Further studies are necessary to elucidate the mechanisms linking delayed graft function and rejection, which, in combination, lead to poor allograft outcome.

Prolonged survival without posttransplant immunosuppression in a large animal model.

BACKGROUND: T cells that receive T-cell antigen receptor signals but do not undergo mitosis become unresponsive to subsequent antigenic stimulation. This can be achieved by antigen presentation to T cells in the absence of critical costimulatory signals from antigen-presenting cells (APC) or in the presence of the antiproliferative drug rapamycin. In mice, peritransplant infusion of adherent APC-depleted splenocytes, which do not provide costimulatory signals to T cells in vitro, leads to T-cell unresponsiveness in vivo and specifically prolongs the survival of skin grafts that express the major histocompatibility complex (MHC) molecules expressed by the transfused cells. Our goal was to determine whether in vivo infusion of adherent APC-depleted donor peripheral blood mononuclear cells (PBMC), with or without rapamycin, induces prolonged kidney allograft survival in a large animal model. METHODS: MHC homozygous inbred miniature swine (SLAcc) were transfused with dendritic cell-monocyte-depleted (G10-passed) PBMC (2.5 x 10(8) cells) from MHC disparate SLAdd donors, with and without three peritransfusion infections of rapamycin (0.25 mg/kg/day intramuscularly) the day before, the day of, and the day after the transfusion. SLAcc recipients received an SLAdd kidney transplant 6 days later. No posttransplant immunosuppression was given. RESULTS: In contrast to donor-specific whole blood transfusions, which uniformly resulted in sensitization and hyperacute rejection (less than 1 day), renal allograft survival in animals that received a transfusion of G10-passed PBMC from their eventual kidney donor was similar (mean, 8.1 +/- 4.5 days) to untreated controls (mean, 7.8 +/- 5.0 days). Pretransplant rapamycin alone also had no effect on survival (mean, 7.7 +/- 8.1 days) versus controls. The combination of G10-passed blood and peritransfusion rapamycin, however, increased survival significantly (mean, 27.3 +/- 10.4 days) (p = 0.01 versus untreated recipients or recipients of only G10-passed PBMC; p = 0.03 versus recipients of rapamycin alone). CONCLUSIONS: Pretransplant transfusion with costimulator-deficient donor PBMC plus peritransfusion rapamycin treatment, but neither alone, prolongs renal allograft survival in pigs without posttransplant immunosuppression. This strategy, once optimized, may be applicable to human transplant tolerance.

Rapamycin: immunosuppression, hyporesponsiveness, and side effects in a porcine renal allograft model.

Rapamycin prolongs allograft survival and induces donor-specific tolerance in some small animal transplant models. Large animal studies, however, are limited. We studied rapamycin in a porcine renal allograft model. Donor-recipient combinations were chosen based on high response in pretransplant MLCs. Allografts were anastomosed to the aorta and vena cava and the native kidneys removed. There were 5 treatment groups: (a) no immunosuppression; (b) triple therapy (CsA, 1 mg/kg/day; AZA, 2-3 mg/kg/day; and PRED, 3-4 mg/kg/day); (c) rapamycin (0.75 mg/kg/day i.m.) in carboxymethylcellulose (CMC); (d) rapamycin (0.25 mg/kg/day i.m. in CMC); and (e) a vehicle (CMC) control. Serum creatinine levels were determined every other day. Most allografts were biopsied once a week. Immunosuppression was stopped after 30 days. Mean graft survival in nonimmunosuppressed recipients was 6.8 +/- 3.6 days. Mean graft survival in triple therapy recipients (n = 10) was 45.7 +/- 36 days vs. 59.6 +/- 11.4 days in rapamycin (0.25 mg/kg/day) recipients (n = 7) (P = 0.51). Both triple therapy and rapamycin improved renal allograft survival versus nonimmunosuppressed controls (P = 0.0025 and 0.001, respectively). Serum creatinine levels were significantly lower (P < 0.05) in rapamycin versus triple therapy recipients. We conclude that rapamycin is a potent immunosuppressant in a porcine renal allograft model and may avoid the elevated serum creatinine levels associated with CsA.

Risk factors for chronic rejection in renal allograft recipients.

Chronic rejection is a major barrier to long-term renal allograft survival. Cyclosporine, though effective at reducing graft loss to acute rejection, has had little impact on the incidence of chronic rejection. Between June 2, 1986 and January 22, 1991, 587 kidney-alone transplants (566 patients) were performed, and had been entered into our renal transplant database and had at least 1 year of follow-up: 103 with biopsy-proven chronic rejection (37 living-related donor, 66 cadaver) and 484 without chronic rejection (236 LRD 248 CAD). The 5-year patient survival was 84% for recipients with biopsy-proven chronic rejection vs. 89% without (P = .08). The 5-year graft survival was 31% for recipients with biopsy-proven chronic rejection vs. 81% without (P < .0001). Using multivariate analysis, we determined the impact on the incidence of chronic rejection of these variables: transplant number, age at transplant (< 18 years, 18 to 50 years, > 50 years), gender, human leukocyte antigen matching, peak and transplant panel-reactive antibody, acute rejection episodes, infections (including cytomegalovirus, viral, and bacterial), donor age, and CsA dosage at 1 year (< 5 mg/kg vs. > or = 5 mg/kg). Logistic regression models were fit to the data using a forward stepwise selection procedure. In this analysis, risk factors included an acute rejection episode (P < .001), CsA dosage < 5 mg/kg/day at 1 year (P = .007), infection (P = .023), female gender (P = .042), and retransplant (P = .103). Individual analyses were done for CAD and LRD recipients. For both groups, important variables were acute rejection, infection, CsA dosage at 1 year, and age at transplant. In conclusion, acute rejection, CsA dosage < 5 mg/kg/day at 1 year, and infection are the major risk factors for the development of chronic rejection, suggesting that chronic rejection may be the result of inadequate immunosuppression (acute rejection episodes and low CsA dosage) or the production of inflammatory cytokines (infections).

Renal transplantation for infantile cystinosis: long-term follow-up.

Renal transplantation for infantile cystinosis corrects renal failure and prolongs survival. However, after transplantation, the disease may develop in the allograft and continue to progress in nonrenal organs. We studied seven children (6 boys, 1 girl) with infantile cystinosis who received 11 renal transplants (3 cadaver, 8 living-related) between May 1969 and December 1986. The age at transplant ranged from 6 to 12 years (mean, 9.1 years). Four children received second renal transplants at a mean age of 17 years (range, 16 to 22 years). The mean period of follow-up was 138 +/- 47 months. Three children received cysteamine therapy prior to transplantation. Nonrenal complications of infantile cystinosis present before transplantation were photophobia (n = 3), corneal crystals (n = 5), hypothyroidism (n = 1), rickets (n = 6), and short stature (n = 7). Graft and patient survival did not differ from controls matched for the time of transplantation. Two patients died (1 pneumococcal sepsis, 1 respiratory failure due to pulmonary fibrosis) with functioning grafts 5 and 14 years posttransplant. Complications that developed posttransplant included photophobia (n = 1), corneal crystals (n = 2), hypothyroidism (n = 4), polyneuropathy (n = 1), pulmonary fibrosis (n = 1), abnormal electroencephalogram without clinical seizures (n = 1), bladder stones (n = 1), and diabetes mellitus (n = 2). One patient received a corneal transplant. All seven children failed to show improvement in growth following transplantation. Cystine crystals are present in graft-infiltrating cells, but do not seem to affect kidney allograft function.(ABSTRACT TRUNCATED AT 250 WORDS)