Anne M. Wiland

Clinical Course of Polyoma Virus Nephropathy in 67 Renal Transplant Patients

Polyoma virus (PV) can cause interstitial nephritis and lead to graft failure in renal transplant recipients. The clinical course of patients with polyoma virus nephritis (PVN) is not well understood, partially due to its relatively low incidence. This study is a retrospective analysis of our experience over 4 yr. The specific purpose is to outline the clinical course and outcome of patients with PVN and to study the relationship between immunosuppression and the disease process. Between June 1997 and March 2001, 67 patients with graft dysfunction were found to have biopsy-proven PVN. The diagnosis was made at a mean of 12.8 +/- 9.9 mo posttransplantation. The majority of patients were men (79%) with a mean age of 54 +/- 14 yr (range, 28 to 75). All patients received immunosuppression with a calcineurin inhibitor (tacrolimus in 89% of patients). All patients except two received mycophenolate mofetil and prednisone. After the diagnosis of PVN, maintenance immunosuppression was reduced in 52 patients and remained unchanged in 15 patients. After reduction of immunosuppression, eight patients (15.3%) developed acute rejection and six (11.5%) became negative for PV in biopsy and urine. After a mean observation period of 12.6 mo (mean of 26 mo posttransplantation), 16.4% of patients had lost their grafts (8 of 52 in the reduction group and 3 of 15 in the no change group). In comparison to a case-matched polyoma virus-negative control group, the PVN patients were older (P =.0004) and there was a predominance of men (P = 0.02). Kaplan-Meier analysis demonstrated that patients with PVN had reduced graft survival compared with negative controls (P =.0004). It is concluded that PVN is a serious hazard for renal transplant recipients and contributes directly to graft loss. Antiviral drugs are needed, as the reduction of immunosuppression alone may not significantly improve graft function in patients with already established PVN. Although multiple factors probably play a role in the development of PVN, judicious use of immunosuppressive agents is indicated to minimize the occurrence of this infection.

A comparison of recipient renal outcomes with laparoscopic versus open live donor nephrectomy.

Background. Laparoscopic donor nephrectomy (laparoNx) has the potential to increase living kidney donation rates by reducing the pain and suffering of the donor. However, renal function outcomes of a large series of recipients of laparoNx have not been studied. Methods. We retrospectively reviewed the records of 132 recipients of laparoNx done at our center between 3/96 and 11/97 and compared them to 99 recipients of kidneys procured by the open technique (openNx) done between 10/93 and 3/96. Results. Significantly more patients in the laparoNx group (25.2%) were taking tacrolimus within the first month than those in the openNx group (2.1%). Mean serum creatinine was higher in laparoNx compared with openNx at 1 week (2.860.3 and 1.860.2 mg/dl, respectively; P50.005) and at 1 month (2.060.1 and 1.660.1 mg/dl, P50.05) after transplant. However, by 3 and 6 months, the mean serum creatinine was similar in the two groups (1.760.1 versus 1.560.05 mg/dl, and 1.760.1 versus 1.760.1, respectively). By 1 year posttransplant, the mean serum creatinine for laparoNx was actually less than that for openNx (1.460.1 and 1.760.1 mg/dl, P50.03). Although patients in the laparoNx compared to the openNx group were more likely to have delayed graft function (7.6 versus 2.0%) and ureteral complications (4.5 versus 1.0%), the rate of other complications, as well as hospital length of stay, patient and graft survival rates were similar in the two groups. Conclusion. Although laparoNx allografts have slower initial function compared with openNx, there was no significant difference in longer term renal function. Kidney transplantation is considered to be the treatment of choice for end-stage renal failure. Insufficient supply of organs for donation has produced long waiting times for many patients who may benefit from transplantation (1). During this period patients accumulate the morbidity of renal failure, they must endure the lifestyle limitations of dialysis, and they often die while waiting for the organ sharing system to grant them this resource. Live donor renal transplantation represents a large potential supply of organs that may relieve much of this shortage. Additionally, recipients of live renal transplants may reap benefits of improved patient and allograft survival that have been clearly demonstrated in this population (2,3). Although unilateral nephrectomy has proven to be safe and the solitary kidney state has been found to be well tolerated in a carefully chosen candidate for donation (4,5), substantial disincentives to donation exist. These include a significant hospitalization, prolonged convalescence period with time away from jobs, intractable perioperative pain, and, for some, cosmetic concerns of the resulting

A high panel-reactive antibody rescue protocol for cross-match-positive live donor kidney transplants.

Background. Alloimmunization can present a virtually insurmountable barrier to kidney transplantation. Past protocols to desensitize patients using plasmapheresis and cyclophosphamide have not been broadly applied because of the fear of complications, including high rates of immunologic failure. Methods. Fifteen patients with a positive donor-recipient cross-match were desensitized with plasmapheresis to permit live donor (LD) transplantation under newer maintenance immunosuppressants. Pretransplant the patients received plasmapheresis three times weekly for a planned maximum of six treatments, plus intravenous hyperimmune globulin, tacrolimus, mycophenolate mofetil, and prednisone. Patients who were successfully desensitized and received transplants were given 10 days of OKT3 postoperatively. Results. Eleven of the 15 patients became anti-human globulin cross-match-negative after one to five plasmapheresis treatments and underwent LD transplantation. Relatively low initial titers of donor-specific antibody were predictive of successful attainment of a negative cross-match. Few side effects and rejection episodes were observed. All transplant patients remain dialysis-free after 3–26 months of follow-up. Conclusion. A positive cross-match is not necessarily a contraindication to LD transplantation, especially for patients with low donor-specific alloantibody titers.

Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation: a retrospective study.

ObjectiveTo compare portal and systemic venous drainage of pancreas transplants and demonstrate an immunologic and survival superiority of portal venous drainage. Summary Background DataTraditionally, solitary pancreas transplants have been performed using systemic venous and bladder drainage, but more recently, the advantages of enteric drainage have been well documented. Although physiologic benefits for portal venous drainage have been described, the impact of portal venous drainage, especially with solitary pancreas transplants, has yet to be determined. MethodsSince August 1995, 280 pancreas transplants with enteric duct drainage were analyzed. One hundred and seventeen were simultaneous pancreas and kidney (SPK), 63 with systemic venous drainage (SV) and 54 with portal venous drainage (PV). The remainder were solitary transplants; 97 pancreas after kidney (PAK; 42 SV and 55 PV) and 66 transplants alone (PTA; 26 SV and 40 PV). Immunosuppressive therapy was equivalent for both groups. ResultsThe groups were similar with respect to recipient characteristics and HLA matching. Thirty-six month graft survival for all transplants was 79% for PV and 65% for SV (P = .008). By category, SPK graft survival was 74% for PV and 76% for SV, PAK graft survival was 70% for PV and 56% for SV, and PTA graft survival was 84% for PV and 50% for SV. The rate of at least one rejection episode was also significantly higher in the SV group. At 36 months, for all pancreas transplants, the rejection rate was 21% for PV and 52% for SV (P < .0001). For SPK, rejection rates were 9% for PV and 45% for SV. For PAK, rejection rates were 16% for PV and 65% for SV, and for PTA 36% for PV and 51% for SV. The rejection rates for kidneys following SPK were also lower in the PV group (26% versus 43% for SV). Furthermore, the grades of rejection were milder in PV for all transplants (P = .017). By multivariate analysis, portal venous drainage was the only parameter that significantly affected rejection. ConclusionGraft survival and rejection is superior for PV. These clinical findings are consistent with published reports of experimentally induced portal tolerance and strongly argue that PV drainage should be the procedure of choice for pancreas transplantation.

Pancreas transplantation: the histologic morphology of graft loss and clinical correlations.

Background. Graft losses due to leaks, bleeding, thrombosis, infections, and early pancreatitis are grouped together under the category of technical failure. Among these complications, massive vascular thrombosis continues to be the most important cause of early graft loss due to technical failure. Pathological evaluation of most allografts lost early in the posttransplantation period shows vascular thrombosis with associated proportional parenchymal necrosis. The morphological findings in allografts that are considered to be lost due to technical failure has not been systematically addressed. In particular, the role of acute rejection in early graft loss has not been well studied. Methods. Seventy-four consecutive pancreas graft pancreatectomies were studied histologically to evaluate for thrombosis (recent versus organized), type of vessel involved by thrombosis (arteries, veins, or both), acute rejection grade, chronic rejection grade, endotheliitis, transplant arteritis, coagulation necrosis, acute pancreatitis, presence of infectious organisms, transplant (obliterative) arteriopathy, neoplasia, relative proportions of alpha and beta islet cells, and immunoglobulin and complement deposition. The histological findings were correlated with donor and recipient data as well as clinical presentation. Results. In 23 out of 39 grafts lost in the first 4 weeks posttransplantation, the only pathological changes found were vascular thrombosis and bland ischemic parenchymal necrosis. In these cases, no underlying vascular pathology or any other specific histological change was identified. Most of these grafts (78%) were lost in less than 48 hr and all in the first 2 weeks posttransplantation. Massive vascular thrombosis occurring in an otherwise histologically normal pancreas was the most common cause of graft loss in the first 4 weeks posttransplantation (59%). In most of the remaining cases (33%), although the clinical presentation suggested technical failure, there was clear histological evidence that the massive thrombosis resulted from vascular injury due to immune damage (acute and hyperacute rejection). Increased incidence of early graft thrombosis was seen in grafts from older donors and longer cold ischemia times. After the first month posttransplantation, graft pancreatectomies revealed a wider variety of pathological processes that included severe acute rejection, combined acute and chronic rejection, chronic rejection, and infections. Acute and chronic vascular thrombosis in large and small vessels was commonly seen at all times posttransplantation; chronic, organized thrombosis was strongly associated with chronic rejection. Conclusions. (a) Early acute thrombosis occurring in a histologically normal pancreas defines a true technical failure. This study showed that acute rejection leading to massive thrombosis, which clinically simulates technical failure, results in a significant proportion of early graft losses. (b) Systematic histological evaluation of failed grafts is absolutely necessary for the accurate classification of the cause of graft loss. (c) There is morphological evidence that chronically ongoing thrombosis is an important, common, contributing factor for late graft loss.

Histologic grading of acute allograft rejection in pancreas needle biopsy: correlation to serum enzymes, glycemia, and response to immunosuppressive treatment

BACKGROUND Allograft rejection continues to be the most common cause of graft failure in technically successful pancreas transplants. Early diagnosis and treatment of rejection is essential for long-term graft survival. Pancreas graft biopsies are now used routinely for the diagnosis of acute allograft rejection. The correlation between clinical evidence of graft dysfunction (increased serum enzymes and glucose), severity of acute rejection on biopsy (rejection grade), and response to treatment has not been previously studied. METHODS A total of 151 pancreas transplant needle biopsy specimens from 57 patients were evaluated. Statistical correlation was done between the histologic rejection grade (O-V) and the peak level of enzymes in serum, glycemia, type of antirejection treatment instituted, and response to treatment. Differentiation between grades was also evaluated statistically. RESULTS Response to antirejection treatment was 25%, 40%, 88%, 78%, 50%, and 17% for grades O-V, respectively. The response for grades II and III was better than for grades 0-I and IV-V (P=0.0003 and 0.0008, respectively). The response to corticosteroids alone was 36%, 86%, 68%, and 0% for grades I, II, III, and IV, respectively. The response to antilymphocyte regimen was 50%, 89%, 85%, 71%, and 17% for grades I, II, III, IV, and V, respectively. Overall correlation between the mean levels of enzymes and rejection grade was seen; the increase of lipase was statistically significant (r=0.24, P=0.012). Amylase and lipase correlated very well with each other (r=0.84, P=0.0001). No correlation was found in the mean values of blood glucose with the serum enzyme increase and with severity of rejection. Hyperglycemia was present in 12 patients; this abnormality in patients with grades II-IV responded promptly to treatment, whereas in patients with grade V, hyperglycemia persisted despite antirejection treatment. Other causes of increased enzymes were found in patients with biopsy specimens showing no rejection (grades 0 and I, 43% and 31%, respectively). CONCLUSIONS Increased serum enzymes, particularly lipase, correlate with the grade of acute rejection, but their lack of specificity precludes their use as sole markers of acute rejection. Glucose levels are not a sensitive marker for acute rejection. Rejection grades II and III are the most responsive to treatment, and a significant proportion of these cases respond to treatment with corticosteroids only. The higher rejection grades (IV and V) require treatment with antilymphocytic regimens, and their overall response to treatment is moderate to poor, respectively.

Increased incidence of postoperative infections associated with peritoneal dialysis in renal transplant recipients.

BACKGROUND Infection is a frequent postoperative complication in renal transplant recipients. However, little information is available concerning the effect of pretransplantation dialysis modality on posttransplantation complications including infection. We therefore evaluated the effect of hemodialysis (HD) versus peritoneal dialysis (PD) on the incidence of postoperative infection as well as several other posttransplantation outcomes. METHODS A retrospective analysis was performed using medical records covering the period 30 days after transplantation of 156 dialysis patients who underwent renal transplantation at a single center during a 22-month period. Of these patients, 103 received only HD, 32 received only PD, 13 received PD in the past and HD immediately before transplantation (PH/HD), and 8 received HD in the past and PD immediately before transplantation (HD/PD). The presence of culture-proven infection, types of infecting organisms, length of initial hospital stay, and incidence of rejection during the first 30 days after transplantation were determined for each patient. RESULTS All groups were similar with regard to age, race, gender, underlying disease, donor type, incidence of delayed graft function, and perioperative antibiotic prophylaxis. There were more infectious complications within 30 days after transplantation in patients on PD just prior to transplantation (PD and HD/PD) than in HD patients (67.5% vs. 25.9%, P<0.00001). When types of infectious organisms were assessed, PD patients were found to have a greater incidence of infections with microorganisms that colonize human skin (P<0.0001). The median length of hospital stay was 3 days longer for PD patients and 6.5 days longer for HD/PD patients than for patients receiving HD (P=0.01 and 0.04), and PD and HD/PD patients were more likely to have an episode of rejection than HD patients (P=0.02). CONCLUSIONS Renal replacement therapy with PD immediately before transplantation negatively affects outcome as compared with HD, predisposing patients to a greater incidence of postoperative infections and rejection and a longer hospital stay. Further study in a randomized controlled trial may help determine how adjustment of the dialysis method can optimize transplantation outcome.

Should living-unrelated renal transplant recipients receive antibody induction? Results of a clinical experience trial.

Background. Living-donor kidney transplant recipients generally do not receive antibody induction. Induction avoidance may not be appropriate, particularly for living-unrelated renal transplant (LURT) recipients, in whom matching may not be optimal. We compared the incidence of acute rejection and graft outcome of LURT recipients who were administered no induction and cadaveric renal transplant (CRT) recipients who were administered anti-CD25 antibody. These groups both had immediate graft function and similar maintenance immunosuppression. Methods. This retrospective analysis included patients who received kidney transplants between 1999 and 2000. CRT recipients received basiliximab, corticosteroids, mycophenolate mofetil (MMF), and delayed tacrolimus (serum creatinine <3 mg/dL). LURT recipients received tacrolimus (initiated pretransplantation), MMF, and corticosteroids. Results. The analysis included 136 LURT recipients and 126 CRT recipients. CRT recipients included more African Americans (52.4% vs. 30.9%, P <0.01). LURT recipients included more patients with at least one human leukocyte antigen mismatch (97.8% vs. 85.7%, P <0.01). A higher acute rejection rate was observed in LURT recipients at both 6 months (LURT recipients 19.1% vs. CRT recipients 3.2%, P <0.01) and 1 year (21.3% vs. 4.0%, P <0.0004); a higher rate also was observed in African American LURT recipients compared with African American CRT recipients (35.7% vs. 4.5%, P <0.0015) at 1 year. LURT recipients demonstrated a threefold greater rejection risk than CRT recipients who were administered basiliximab (relative risk: 3.6, P <0.002). Graft survival was similar at 1 year. Conclusion. The higher rejection rates in LURT recipients (no induction) compared with CRT recipients (basiliximab induction), despite similar chronic immunosuppression (tacrolimus, MMF, and steroids) and immediate graft function, indicate the potential advantage of anti-CD25 induction in LURT protocols to reduce the risk of acute rejection.

The shrinking renal replacement therapy 'break-even' point

BACKGROUND This study examines the current cost of live donor (LD) transplantation at our institution, and compares it with that of dialysis. METHODS The study population consisted of 184 consecutive adult recipients of laparoscopically procured LD kidney transplants. Cost-containment measures instituted during this series included elimination of routine postoperative antilymphocyte induction and an accelerated discharge clinical pathway with planned discharge of the recipient on postoperative day (POD) 2. Costs of the transplants to Medicare were estimated from hospital charges, readmission rates, and immunosuppressant usage. These were compared with published costs of dialysis to Medicare in terms of a fiscal transplant-dialysis break-even point. RESULTS Kaplan-Meier patient and graft survival rates at 1 year were 97 and 93%, respectively. Among patients followed for at least 90 days and treated with no induction and either cyclosporine-mycophenolate mofetil or tacrolimus-mycophenolate mofetil, acute rejection rates were low (27.6 and 13.9%, respectively). In the last 124 patients, 32.3% were discharged by POD 3 and 71.8% by POD 6, with corresponding mean transplant hospital charges (excluding organ acquisition) of

Early steroid withdrawal in solitary pancreas transplantation results in equivalent graft and patient survival compared with maintenance steroid therapy

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