Angelo M. de Mattos

Nephrotoxicity of immunosuppressive drugs: Long-term consequences and challenges for the future

The calcineurin inhibitors cyclosporin A (CsA) and tacrolimus (FK506) are associated with dose- and efficacy-limiting adverse events, including nephrotoxicity, which may diminish their overall benefits for long-term graft survival. Nephrotoxicity is difficult to distinguish from chronic allograft rejection and is a particular problem in the setting of renal transplantation. Minimizing immunosuppressant-induced nephrotoxicity could improve long-term renal allograft survival. However, to obtain significant long-term improvement in renal allograft outcomes, it may be necessary to adopt new immunosuppressive regimens that rely less on calcineurin inhibitors. Recipients of other transplanted organs, as well as patients with autoimmune diseases who require immunosuppressant therapy, could also benefit from this change in immunosuppressive drug strategy because their healthy, native kidneys are particularly susceptible to the nephrotoxic effects of CsA and FK506. CsA- and FK506-sparing regimens, which use reduced doses of CsA and FK506 in combination with other nonnephrotoxic immunosuppressants, may be the best current option for reducing nephrotoxicity. The chemical immunosuppressant mycophenolate mofetil (MMF) has been used as part of CsA- and FK506-sparing regimens that provide improved renal function while maintaining adequate immunosuppression. Such regimens should reduce patient morbidity and mortality. Also, because immunosuppressant-induced nephrotoxicity has been associated with significant financial costs, CsA- and FK506-sparing regimens should result in substantial savings in health care costs.

Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients.

The introduction of mycophenolate mofetil (MMF) represented a major advance in transplant medicine, although optimal use may be limited by gastrointestinal (GI) side‐effects. An enteric‐coated formulation of mycophenolate sodium (EC‐MPS; myfortic®) has been developed with the aim of improving the upper GI tolerability of mycophenolic acid. Therapeutic equivalence of EC‐MPS (720 mg b.i.d.) and MMF (1000 mg MMF b.i.d.), with concomitant cyclosporine microemulsion (Neoral®) and corticosteroids, was assessed in 423 de novo kidney transplant patients recruited to a 12‐month, double‐blind study. Efficacy failure (biopsy‐proven acute rejection [BPAR], graft loss, death or loss to follow up) at 6 months (EC‐MPS 25.8% vs. MMF 26.2%; 95% CI: [−8.7, +8.0]) demonstrated therapeutic equivalence. At 12 months, the incidence of BPAR, graft loss or death was 26.3% and 28.1%, and of BPAR alone was 22.5% and 24.3% for EC‐MPS and MMF, respectively. Among those with BPAR, the incidence of severe acute rejection was 2.1% with EC‐MPS and 9.8% with MMF (p = ns). The safety profile and incidence of GI adverse events were similar for both groups. Within 12 months, 15.0% of EC‐MPS patients and 19.5% of MMF patients required dose changes for GI adverse events (p = ns). Enteric‐coated‐MPS 720 mg b.i.d. is therapeutically equivalent to MMF 1000 mg b.i.d. with a comparable safety profile.

Renal transplantation across the ABO barrier using A2 kidneys

BACKGROUND The waiting list for cadaveric kidney transplantation has continued to grow, and with the relative scarcity of cadaver donors, the median waiting time for patients in the United States increased to 824 days in 1994. The median waiting times for patients with blood groups B or O were 1329 and 1007 days, respectively. Allocation of blood group A2 kidneys (20% of group A) to blood group O and B patients expands their potential donor pool and shortens their waiting time for a kidney transplantation. METHODS Between May 1991 and June 1998, we transplanted 15 A2 kidneys into 6 blood group O and 9 blood group B patients. Anti-A isoagglutinins were measured before transplantation, and patients with anti-A1 titers > or = 1:8 underwent plasmapheresis (PP). RESULTS One patient with high titer anti-A antibodies, who did not receive PP, lost her allograft because of hyperacute rejection. Allograft function was excellent in the remaining 14 patients, with a mean serum creatinine level of 1.7 (+/-0.89) mg/dl at 1 month and 1.3 (+/-0.34) mg/dl at 1 year. The actuarial 1-year graft survival rate was 93.3+/-6.4% and the patient survival rate was 100%. CONCLUSION We conclude that the allocation of blood group A2 kidneys for blood group O and B recipients is a practical way to expand the donor pool for these transplant candidates. PP may be important for reducing the levels of anti-A1 and anti-A2 antibodies and for reducing the risk of hyperacute rejection. Splenectomy seems to be unnecessary.

Immunosuppressant-induced nephropathy: pathophysiology, incidence and management.

Immunosuppressant-induced nephrotoxicity, in particular chronic progressive tubulointerstitial fibrosis/arteriopathy induced by the calcineurin inhibitors cyclosporin and tacrolimus, has become the ‘Achilles heel’ of immunosuppressive agents. The use of calcineurin inhibitors as primary immunosuppressants in hepatic and cardiac transplantation has led to end-stage renal disease and dialysis. Calcineurin inhibitor—induced acute renal failure may occur as early as a few weeks or months after initiation of cyclosporin therapy. The clinical manifestations of acute renal dysfunction are caused by vasoconstriction of renal arterioles, and include reduction in glomerular filtration rate, hypertension, hyperkalaemia, tubular acidosis, increased reabsorption of sodium and oliguria. The acute adverse effects of calcineurin inhibitors on renal haemodynamics are thought to be directly related to the cyclosporin or tacrolimus dosage and blood concentration.However, new clinical data indicate that calcineurin inhibitor—induced chronic nephropathy can occur independently of acute renal dysfunction, cyclosporin dosage or blood concentration. Several strategies have been evaluated to attenuate cyclosporin-induced nephropathy, but their efficacy remains unknown.Cytokine release syndrome associated with the use of muronomab-CD3 (OKT-3) can also contribute to the pathogenesis of transient acute tubular necrosis and renal dysfunction following renal transplantation.Continued research and clinical experience should provide information regarding the aetiology of cyclosporin-induced chronic progressive tubulointerstitial fibrosis/arteriopathy and its potential treatment.

Detection of hepatitis C virus infection among cadaver organ donors: Evidence for low transmission of disease

OBJECTIVE To determine the prevalence of antibodies to hepatitis C virus (anti-HCV) and HCV RNA among cadaver organ donors and to correlate these results with donor liver histologic abnormalities and evidence for transmission of disease through organ transplantation. DESIGN Retrospective testing of stored serum samples from cadaver organ donors for anti-HCV and HCV RNA. SETTING Transplantation service of the University of Miami/Jackson Memorial Medical Center and other cooperative medical centers furnishing follow-up data. SUBJECTS Of 1096 cadaver organ donors harvested between 1 January 1979 and 28 February 1991, 484 had stored serum samples available for analysis. Recipients of organs from recombinant immunoblot assay (RIBA)-positive donors for whom adequate follow-up was available were also included in the analysis. MEASUREMENTS Samples were tested for anti-HCV by enzyme-linked immunosorbent assay (ELISA). Confirmatory testing was done using a second-generation RIBA. Hepatitis C viral RNA was detected in serum using the polymerase chain reaction. Liver biopsies were obtained from the organ donor and interpreted blindly by a pathologist unaware of the clinical data. Liver chemistry profiles and serum sample analysis for HCV RNA were done for transplant recipients. RESULTS From the 484 cadaver organ donors, 89 samples (18%; 95% Cl, 15% to 21%) were reactive by ELISA. Of these, 33 (6.8%; Cl, 4.6% to 9%) were RIBA seropositive. Hepatitis C viral RNA sequences were detected in 50% of the RIBA-positive serum samples tested. Liver tissue was available from 24 of the 33 RIBA-positive donors and showed chronic active hepatitis in 16, chronic persistent hepatitis in 2, and no abnormality in 6. Among the 46 recipients of a kidney from a RIBA-positive donor, 13 (28%; Cl, 15% to 41%) developed post-transplant liver disease, of which only 4 cases were highly suggestive of viral transmission from the donor. Little morbidity and no mortality could be attributed to liver disease in this cohort of recipients. CONCLUSIONS These data suggest that HCV transmission by organ transplantation is low and that the consequences of infection are small. If the medical condition of the potential recipient is so serious that other options no longer exist, the use of an organ from an anti-HCV-seropositive donor should be considered.

Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors

Background. HuM291 is a humanized anti-CD3 monoclonal antibody engineered to reduce binding to Fc&ggr; receptors and complement fixation.HuM291 has a long serum half-life and mediated profound depletion of circulating T cells in chimpanzees; HuM291 also has significantly less mitogenic and cytokine-releasing activity than OKT3 in vitro. Methods. A phase I dose-escalation study was conducted in 15 end-stage renal disease patients scheduled for renal allografts from living donors. Patients received one i.v. HuM291 injection before transplantation. Five doses were tested: 0.015 &mgr;g/kg, 0.15 &mgr;g/kg, 0.0015 mg/kg, 0.0045 mg/kg, and 0.015 mg/kg. Patients were followed for adverse events, laboratory abnormalities, serum cytokine levels, pharmacokinetics, and CD2+, CD3+, CD4+, and CD8+ T cell counts. Results. HuM291 was well tolerated; most adverse events were mild to moderate in severity and included headache, nausea, chills, and fever. These occurred within the first few hours after HuM291 administration, resolved within 24 to 48 hr, and were likely related to cytokine release. In general, peak tumor necrosis factor-&agr;, interferon-&ggr;, and interleukin-6 levels were detected 1 to 6 hr postdosing only at the three highest doses and were generally undetectable by 24-hr postdosing. Serious adverse events possibly related to HuM291 included clotting of a fistula (two patients), chemical cellulitis (one patient), and increased serum creatinine/decreased hematocrit (one patient). At doses ≥0.0015 mg/kg (0.1 mg/70 kg), HuM291 induced rapid, marked depletion of peripheral T cells within 2 hr; duration of T cell depletion was dose dependent. At the two highest dose levels, T cells remained depleted for approximately 1 week. Conclusions. A single HuM291 dose rapidly depleted circulating T cells in a dose-dependent manner and was associated with only mild to moderate symptoms of cytokine release.

Role of Myocardial Perfusion Imaging in Patients With End-Stage Renal Disease Undergoing Coronary Angiography

Patients with end-stage renal disease (ESRD) are at high risk of cardiovascular events. This study examined the prognostic power of stress myocardial perfusion imaging (MPI) in 150 patients with ESRD (mean age 53 +/- 9 years; 30% women; 66% with diabetes mellitus) being evaluated for renal transplantation with known coronary anatomy using angiography. Baseline data in addition to perfusion and angiographic parameters were compared between survivors and nonsurvivors. All-cause mortality was defined as the outcome measure. An abnormal MPI result was present in 85% of patients, 30% had left ventricular (LV) ejection fraction (EF) < or =40%, and 40% had multivessel coronary artery disease using angiography. At a mean follow-up of 3.4 +/- 1.5 years, 53 patients died (35%). LVEF < or =40%, LV dilatation (LV end-diastolic volume >90 ml), and diabetes mellitus were associated with higher mortality (all p <0.05). Both total perfusion defect size and mean number of narrowed coronary arteries using angiography were significantly higher in those who died (p <0.05). In a multivariate model, abnormal MPI results (low LVEF or abnormal perfusion) and diabetes alone were independent predictors of death, whereas number of narrowed arteries using coronary angiography was not. Thus, MPI was a strong predictor of all-cause mortality in patients with ESRD. In conclusion, abnormal MPI results independently predicted worse survival and provided more powerful prognostic data than coronary angiography.

Pharmacology of Immunosuppressive Medications Used in Renal Diseases and Transplantation

As understanding of the molecular basis for the immune response has expanded rapidly, so have the possibilities for designing therapeutic interventions that are more effective, more specific, and safer than current treatment options. The promise of therapeutic advances in the future is based on the rapidly expanding insights into the pathogenesis of abnormal immunologic reactions. Nowhere is the understanding of molecular mechanisms, pathophysiology, and targeted therapy more relevant than in the field of renal transplantation, which makes up much of the clinical database for the use of immunosuppressive therapy for renal disease. Despite the recent advances in basic immunology, clinical validation of new agents and approaches is lacking for most drugs at present. This review will focus in the pharmacology of agents used in the therapy of immunologic renal disease and in renal transplantation. It should be recognized that clinical pharmacology and experience with newer agents is limited, and potential utility is based largely on experimental data.

Systolic Dysfunction Portends Increased Mortality among Those Waiting for Renal Transplant

Individuals waiting for a renal transplant experience excessive cardiovascular mortality, which is not fully explained by the prevalence of ischemic heart disease in this population. Overt heart failure is known to increase the mortality of patients with ESRD, but the impact of lesser degrees of ventricular systolic dysfunction is unknown. For examination of the association between left ventricular ejection fraction(LVEF) and mortality of renal transplant candidates, the records of 2718 patients evaluated for transplantation at one institution were reviewed. During 6355 patient-years (median 27 mo) of follow-up, 681 deaths occurred. Patients with systolic dysfunction (LVEF <or= 0.40) had significantly lower survival than those with higher systolic function (median 49 +/- 3.1 versus 72 +/- 4.0 mo; P 0.001) but had similar survival to patients with ischemia (48 +/- 2.5 mo). Multivariate modeling showed that those with systolic dysfunction were nearly twice as likely to die as those with normal systolic function, adjusted for risk factors including diabetes, left ventricular hypertrophy, and ischemia (adjusted hazard ratio 1.7; 95%confidence interval 1.43 to 2.07). In addition, a graded, reverse association between LVEF and mortality was identified. In conclusion, systolic dysfunction is strongly associated with mortality, in a graded manner, in renal transplant candidates.

QT Prolongation Is an Independent Predictor of Mortality in End-Stage Renal Disease

Coronary artery disease (CAD) is the predominant cause of sudden cardiac death in the general population, and sudden cardiac death is the leading cause of mortality in end‐stage renal disease (ESRD).