Carl Cardella

ABO-Incompatible heart transplantation in infants

BACKGROUND Transplantation of hearts from ABO-incompatible donors is contraindicated because of the risk of hyperacute rejection mediated by preformed antibodies in the recipient to blood-group antigens of the donor. This contraindication may not apply to newborn infants, who do not yet produce antibodies to T-cell-independent antigens, including the major blood-group antigens. METHODS We studied 10 infants 4 hours to 14 months old (median, 2 months) who had congenital heart disease or cardiomyopathy and who received heart transplants from donors of incompatible blood type between 1996 and 2000. Serum isohemagglutinin titers were measured before and after transplantation. Plasma exchange was performed during cardiopulmonary bypass; no other procedures for the removal of antibodies were used. Standard immunosuppressive therapy was given, and rejection was monitored by means of endomyocardial biopsy. The results were compared with those in 10 infants who received heart transplants from ABO-compatible donors. RESULTS The overall survival rate among the 10 recipients with ABO-incompatible donors was 80 percent, with 2 early deaths due to causes presumed to be unrelated to ABO incompatibility. The duration of follow-up ranged from 11 months to 4.6 years. Two infants had serum antibodies to antigens of the donors blood group before transplantation. No hyperacute rejection occurred; mild humoral rejection was noted at autopsy in one of the infants with antibodies. No morbidity attributable to ABO incompatibility has been observed. Despite the eventual development of antibodies to antigens of the donors blood group in two infants, no damage to the graft has occurred. Because of the use of ABO-incompatible donors, the mortality rate among infants on the waiting list declined from 58 percent to 7 percent. CONCLUSIONS ABO-incompatible heart transplantation can be performed safely during infancy before the onset of isohemagglutinin production; this technique thus contributes to a marked reduction in mortality among infants on the waiting list.

A Randomized Controlled Trial of Prednisone in Patients with Idiopathic Membranous Nephropathy

We conducted a prospective randomized study in which patients with biopsy-confirmed idiopathic membranous nephropathy were assigned to receive either a six-month course of prednisone given on alternate days (45 mg per square meter of body-surface area; n = 81) or no specific treatment (n = 77). The mean duration of follow-up was 48 months. Patients in the prednisone group (median age, 46 years) entered with a mean disease duration of 15 months, a median creatinine clearance of 1.2 ml per second per 1.73 m2 (range, 0.25 to 2.6), and a median rate of urinary protein excretion of 6.8 g per day (0.3 to 26). The annual change in the corrected creatinine clearance at six months did not differ between the prednisone group and the control group (0.10 vs. 0.06 ml per second; P = 0.8), or at the last follow-up evaluation (-0.07 vs. -0.02 ml per second; P = 0.2; 95 percent confidence interval on the difference, -0.03 to 0.13). The proportion of patients with complete remission of proteinuria was also similar in the groups at 6 and 12 months and after a mean of 48 months. Outcomes were similar in the two groups with respect to progression to renal failure (3 vs. 4 patients), death (3 vs. 1 patient), complete remission of proteinuria at 36 months (16 vs. 19 patients), and a decline of 25 percent or more in the creatinine clearance at 60 months (32 vs. 25 percent of patients). A multivariate analysis, which adjusted for differences at entry in sex distribution, urinary protein excretion, and creatinine concentration, as well as other prognostic variables, failed to provide an explanation for the lack of effect of prednisone. We conclude that a six-month course of therapy in which prednisone is given on alternate days is of no benefit to patients with idiopathic membranous nephropathy.

Treatment of Kaposi's sarcoma after solid organ transplantation.

PURPOSE This retrospective review of all patients who developed Kaposis sarcoma (KS) after solid organ transplantation at a single institution was undertaken to define the clinical presentation of this malignancy in the setting of iatrogenic immunodeficiency, and to determine the most appropriate treatment for patients in this clinical setting. MATERIALS AND METHODS The records of 2,099 patients who underwent heart, lung, liver, or kidney transplantation at The Toronto Hospital between January 1, 1981 and June 30, 1995, were reviewed. Twelve patients were identified who developed biopsy-proven KS in the posttransplantation period. Five patients who had disseminated KS who had not responded to either reduction or withdrawal of immunosuppression or to local radiotherapy were treated with combination chemotherapy consisting of doxorubicin 20 to 30 mg/m2, bleomycin 10 mg/m2, and vincristine 2 mg (ABV) administered intravenously every 3 weeks. RESULTS Eight of 12 patients were male and nine were of Italian origin. KS was limited to a localized area of the skin for only six patients, all after kidney transplantation. Visceral KS was present in three patients. Four of five patients responded to ABV chemotherapy (two complete and two partial remissions). The fifth patient responded to second-line etoposide and cisplatin. The median duration of response was in excess of 13 months (range, 8+ to 45+ months). Toxicity was limited to grade 1 neurotoxicity and grade 1 skin toxicity. CONCLUSION KS is an uncommon but recognized complication of solid organ transplantation. Combination chemotherapy is a safe and effective treatment for patients with disseminated or visceral KS that fails to respond to changes in immunosuppression.

A report of the Lisbon Conference on the care of the kidney transplant recipient

An International Conference on the Care of the Kidney Transplant Recipient was convened in Lisbon, Portugal from February 2– 4, 2006 under the auspices of the National Kidney Foundation and Kidney Disease: Improving Global Outcomes (KDIGO), and in cooperation with The Transplantation Society. Conference participants included over 100 experts and leaders in kidney transplantation, representing more than 40 countries from around the world, including participants from Africa, Asia, Australia, Europe, North American, and South America (Appendix). The goal of the conference was to develop recommendations to improve the outcomes of kidney transplant recipients worldwide with regard to the following basic medical issues: cardiovascular disease (Work Group I), cancer and infection (Work Group II), and anemia, bone disease, reproductive issues, growth and development (Work Group III). Work Groups I, II, and III addressed the preand posttransplant care of kidney transplant recipients by the following components: timelines of preand posttransplantation, immunosuppression, level of kidney allograft function, and burden of disease (prior history of dialysis or preemptive transplant and how that history affects outcome). A graft maintenance section (Work Group IV) addressed: 1) recipient (and donor) selection; 2) surgical aspects and immediate posttransplant care of recipients including consideration of minimal surgical infrastructure; 3) immunosuppression including an assessment of the incremental expected value of more complex and expensive regimens in comparison to simpler and less expensive regimens, generics, midand long-term immunosuppression; 4) living donor versus deceased donor transplantation; and 5) midand long-term posttransplant care and monitoring of allograft function. In addition, conference participants were asked to examine the issue of applicability of the recently published Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for chronic kidney disease (CKD) in kidney allograft recipients (1). Specifically, Work Group V addressed the role of estimated glomerular filtration rate (eGFR) in monitoring kidney function after transplantation, as well as the stratification for intervention according to eGFR values.

The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline.

This guideline for the use of immunoglobulin (IG) for sensitized patients undergoing solid organ transplantation (SOT) is an initiative of the Canadian Blood Services and the National Advisory Committee on Blood and Blood Products of Canada to (1) provide guidance for Canadian practitioners involved in the care of patients undergoing SOT and transfusion medicine specialists on the use of IG and (2) standardize care, limit adverse events, and optimize patient care. A systematic expert and bibliography literature search up to July 2008 was conducted, with 791 literature citations and 45 reports reviewed. To validate the recommendations, the guideline was sent to physicians involved in SOT in Canada and a patient representative. The recommendations identify (1) sensitized patients undergoing SOT that would have a better survival and decreased morbidity by receiving IG preoperatively, postoperatively, and for the treatment of organ rejection; (2) patients who may not have any benefit from receiving IG; and (3) potential adversities to IG.

Reduced Incidence of New-Onset Diabetes Mellitus after Renal Transplantation with 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors (Statins)

Statins have anti‐inflammatory effects, modify endothelial function and improve peripheral insulin resistance. We hypothesized that statins influence the development of new‐onset diabetes mellitus in renal transplant recipients. The records of all previously non‐diabetic adults who received an allograft in Toronto between January 1, 1999 and December 31, 2001 were reviewed with follow‐up through December 31, 2002. All patients receiving cyclosporine or tacrolimus, mycophenolate mofetil and prednisone were included. New‐onset diabetes was diagnosed by the Canadian Diabetic Association criteria: fasting plasma glucose ≥7.0 mmol/L or 2‐h postprandial glucose ≥11.1 mmol/L on more than two occasions. Statin use prior to diabetes development was recorded along with other variables. Cox proportional hazards models analyzing statin use as a time‐dependent covariate were performed. Three hundred fourteen recipients met study criteria, of whom 129 received statins. New‐onset diabetes incidence was 16% (n = 49). Statins (p = 0.0004, HR 0.238[0.109–0.524]) and ACE inhibitors/ARB (p = 0.01, HR 0.309[0.127–0.750]) were associated with decreased risk. Prednisone dose (p = 0.0001, HR 1.007[1.003–1.010] per 1 mg/d at 3 months), weight at transplant (p = 0.02, HR 1.022[1.003–1.042] per 1 kg), black ethnicity (p = 0.02, HR 1.230[1.023–1.480]) and age ≥45 years (p = 0.01, HR 2.226[1.162–4.261]) were associated with increased diabetes. Statin use is associated with reduced new‐onset diabetes development after renal transplantation.

Coronary sinus sampling of cytokines after heart transplantation: Evidence for macrophage activation and interleukin-4 production within the graft

OBJECTIVES This study was undertaken to evaluate the organ-specific release of cytokines after heart transplantation and to assess any correlation with transplant rejection. This cytokine profile should document the relative activation of mononuclear cell subsets within the graft. BACKGROUND Up to 60% of mononuclear cells infiltrating the cardiac allograft during rejection are macrophages, but their role is undetermined. The T lymphocytes are activated, but the activity of specific T cell subsets is not known. We sought to assess for the first time in humans the in vivo activation of mononuclear cell subsets by measuring coronary sinus cytokine levels after heart transplantation. METHODS Paired superior vena cava and coronary sinus serum samples were assayed for interleukin (IL)-2, IL-4 and IL-6, soluble IL-2 receptors, tumor necrosis factor-alpha and neopterin in 10 patients at the time of 40 routine endomyocardial biopsy procedures. All cytokine measurements were made by using enzyme-linked immunosorbent assay; neopterin was measured by using radioimmunoassay. RESULTS Interleukin-2 levels were not detectable (< 0.8 U/ml) in either the superior vena cava or the coronary sinus in the presence or absence of rejection. Interleukin-2 receptor levels were uniformly elevated to 1,283 U/ml in the superior vena cava and to 1,232 U/ml in the coronary sinus, with no correlation with rejection severity. Interleukin-4 levels were consistently higher in coronary sinus serum than in peripheral blood (229 vs. 61 pg/ml, p < 0.0005), but there was no relation with rejection. Interleukin-6 levels were higher in the coronary sinus than in the superior vena cava (200 vs. 120 pg/ml, p < 0.05). Tumor necrosis factor-alpha showed consistently elevated levels in coronary sinus serum (68 vs. 17 pg/ml, p < 0.0005), with no relation with rejection. Neopterin, which is produced only by activated macrophages, was also consistently elevated in the coronary sinus (2.5 vs. 2.2 nmol, p = 0.08). CONCLUSIONS The cardiac allograft is a major source of cytokines after heart transplantation. The cytokine profile allows the activity of subsets of the mononuclear cell infiltrate to be investigated. Elevated coronary sinus activity of the macrophage-specific metabolite neopterin suggests macrophage activation within the allograft. This possibility is supported by elevated coronary sinus levels of tumor necrosis factor-alpha and IL-6. The T lymphocytes are activated, as evidenced by high soluble IL-2 receptor levels, but IL-2 production was suppressed by conventional immunosuppressive therapy. Coronary sinus IL-4 levels represent T helper-2 cell activation within the graft despite immunosuppression. We could find no temporal relation between the coronary sinus or superior vena cava cytokine concentration or profile and severity of rejection on concurrent biopsy studies.

Cutaneous Associations of Chronic Renal Failure and Dialysis

C renal failure (CRF) is associated with several dermatologic conditions. With better management, patients with CRF are living longer, and some of the cutaneous complications of CRF and dialysis are becoming more commonplace. Cutaneous changes associated with the following need to be considered: (1) drugs used to treat the underlying disease or manifestation of CRF; (2) CRF per se; (3) the treatment modality used in CRF, for example, hemodialysis or peritoneal dialysis; (4) renal transplantation, (5) primary disease process leading to CRF. This review is concerned with the first three categories. The cutaneous complications associated with renal transplantation are the subject of another paper; those associated with the primary disease process(es) leading to CRF have not been discussed. Table 1 lists the common causes of CRF in adults. Glomerulonephritis accounts for approximately 40% of the cases.

Monocyte procoagulant activity and plasminogen activator. Role in human renal allograft rejection.

Currently the mechanism of renal allograft rejection is not well understood. This study was designed to determine whether induction of monocyte procoagulant activity (MCPA) is important in the pathogenesis of renal allograft rejection. The MPCA assay was performed utilizing a one stage clotting assay both in normal and in factor-VII-deficient plasma. There was no increase in spontaneous MPCA in 20 patients with end-stage renal failure and in 10 patients following abdominal or orthopedic operation, as compared with 20 normal controls. MPCA was assessed daily in 18 patients who had received renal allografts. Rejection episodes (RE) were predicted on the basis of persistent elevation in MPCA as compared with pretransplant levels. Rejection was diagnosed clinically and treated on the basis of standard criteria. Treated RE were compared with those predicted by elevated MFCA, and 3 patients were assessed as having no RE by MPCA and by standard criteria. In 8 RE, MPCA correlated temporally with RE (same day) when compared with standard criteria. In 12 RE, MPCA was predictive of rejection preceding standard criteria by at least 24 hr. There were 7 false-positive predictions on the basis of MPCA; however, there was only 1 false negative. MPCA was shown to be a prothrombinase by its dependence only on prothrombin and fibrinogen for full activity. MPCA may be important in the pathogenesis of allograft rejection, and additionally it may be a useful adjunct in the clinical management of this disease.

A comparison of the effects of C2-cyclosporine and C0-tacrolimus on renal function and cardiovascular risk factors in kidney transplant recipients.

Background. There are few data directly comparing the effects of two-hour postingestion monitored cyclosporine (C2-CsA) vs. trough-monitored tacrolimus (C0-Tac) on renal function and cardiovascular risk factors. Methods. We studied 378 (202 C2-CsA vs. 176 C0-Tac) incident kidney transplant recipients in Toronto, Canada, from August 1, 2000 and December 31, 2003. Outcomes included changes in estimated glomerular filtration rate (eGFR at 1 and 6 months by modification of diet in renal disease four-variable equation), mean arterial pressure (MAP), total cholesterol (TC), and new-onset diabetes mellitus (NODM) at six months posttransplant. The independent effect of treatment/monitoring strategies on continuous outcomes and time-to-NODM was modeled using linear and Cox regression, respectively. Results. Mean eGFR was 59.5 vs. 62.9 ml/min at one month and 50.6 vs. 61.2 ml/min at six months for C2-CsA vs. C0-Tac, respectively. Multiple linear regression revealed the slope of eGFR to be 0.93 ml/min/month lower in C2-CsA patients. This was equivalent to an adjusted average eGFR difference of 4.64 ml/min between months one and six posttransplant. There was no significant difference in average MAP and TC. In a stepwise multivariable Cox model and a propensity score analysis, there was no significant association between the type of treatment/monitoring strategy and time-to-NODM. Conclusions. There was a greater decline in eGFR for patients on C2-CsA (vs. C0-Tac) between one and six months posttransplant. However, MAP, TC, and the risk of NODM were comparable in both treatment/monitoring groups. The long-term impact of short-term reductions in eGFR as a function of the type of treatment/monitoring strategy requires further study.