Kathleen D. Lake

Increased immunosuppressive vulnerability in elderly renal transplant recipients.

The results of renal transplantation have improved steadily over the last 10 years. This improvement is in large part attributable to improvements in immunosuppressive pharmacotherapy. Several phase III clinical trials have demonstrated decreased acute rejection rates with relatively little, if any, increase in infectious complications in a broad cross-section of patients (1‐12). It is possible, however, that in certain subpopulations of patients, such as elderly renal transplant recipients, the risk/benefit ratio of acute rejection versus infection may be different from that of the general renal transplant population. If this were the case, the appropriate immunosuppressive regimen for that population should be reconsidered. Renal transplantation is a relatively safe option for renal replacement therapy in elderly patients with end-stage renal disease (ESRD). In 1976, Tersigni et al. (13) reported a series of nine ESRD patients above the age of 60 years successfully treated with renal transplantation. Shortly thereafter, Wedel et al. (14) published a series of 41 geriatric renal transplant recipients, and pointed out that the risk to these patients was not graft loss from rejection but, rather, death with a functioning graft. This author also reported that there was an increased risk for serious infectious complications in the older age group. With the advent of cyclosporine and more selective immunosuppression, the results of renal transplantation improved in high-risk groups, such as elderly patients. In 1989, Pirsch et al (15) concluded that cadaveric renal transplantation with cyclosporine immunosuppression was safe and an effective therapeutic modality in elderly ESRD patients. Subsequent studies have reinforced that concept (16) but have also reinforced the idea that elderly patients have a degree of immune incompetence (17) and require less aggressive immunosuppressive therapy (17). That theory was supported by the continuing observation of lower rejection rates (17, 18) and lower incidence of chronic rejection (18, 19), but higher risk of infections (19, 20) noted in elderly transplant recipients. Reinforcement of the practice of transplantation in elderly patients came from a study that showed significantly greater survival probability in ESRD patients over the age of 60 who received transplants as opposed to matched patients who remained on dialysis (9). Recent data demonstrate a very similar 5-year graft (54 ‐74%) and patient survival (52‐74%), confirming the improvement made but also the concept that most patients in this high-risk group die with functioning grafts (19). In this study, posttransplant morbidity was attributed primarily to infectious complications and an increased prevalence of malignancy (19). We demonstrated previously, in a single-center study, that intensification of immunosuppressive therapy in elderly transplant recipients increased infectious complications without decreasing the incidence of acute rejection or improvement in graft survival (21). Given the above data, it is possible that the vulnerability to immunosuppression of older renal transplant patients may be very different from that of younger patients. To test this hypothesis, we analyzed a large group of renal transplant recipients with regard to their balance of acute rejection versus death due to infection.

Report of the American Society of Transplantation conference on immunosuppressive drugs and the use of generic immunosuppressants.

Considerable economic and health‐related costs are associated with the life‐long maintenance immunosuppressive therapy required to prevent transplant rejection. Generic medications have the potential of providing equivalent therapeutic efficacy at a lower economic cost. In 2001, the American Society of Transplantation invited experts to review the data and issues associated with the approval and use of generic immunosuppressants. A summary of that meeting is reported here.

Efficacy and Safety of Low-Dose Valganciclovir in the Prevention of Cytomegalovirus Disease in Adult Liver Transplant Recipients

The efficacy and safety of valganciclovir (VGCV) for cytomegalovirus (CMV) prophylaxis in liver transplant recipients has not been established. We retrospectively compared the efficacy and safety of low‐dose oral VGCV (450 mg once daily for 90 days) and standard oral ganciclovir (1 g three times a day for 90 days, GCV) in preventing CMV disease in 109 adult liver transplant recipients who survived at least 1 month between January 2001 and April 2003 (49 GCV and 60 VGCV). The incidence of CMV disease at 1 year post‐transplant was similar among patients treated with VGCV and GCV (3% and 4%, respectively). Three of the four CMV disease cases occurred in high‐risk recipients with CMV serotype of donor+/recipient− (D+/R−) and all cases presented after completion of CMV prophylaxis, ranging 114‐152 days post‐transplant. Severe neutropenia was rare, and thrombocytopenia and anemia occurred at similar frequencies with both prophylaxis regimens. In conclusion, a 90‐day regimen of low‐dose oral VGCV has a similar efficacy and safety profile to high‐dose oral GCV in adult liver transplant recipients. D+/R− liver transplant recipients remain at risk of developing CMV disease after completion of antiviral prophylaxis. Additional prospective studies with close monitoring for CMV viremia and drug resistance are needed to further establish the optimal dose and duration of VGCV in liver transplant recipients. Liver Transpl 12:112–116, 2006.

Nefazodone and cyclosporine drug-drug interaction.

Depression is a significant post-transplant complication often necessitating drug therapy. Many of the newer selective serotonin reuptake inhibitor (SSRI) antidepressants are metabolized by the same cytochrome P450IIIA isoenzyme system that is responsible for the metabolism of cyclosporine, and these agents pose an interactive risk in transplant patients. We have observed nearly a 10-fold increase in whole blood cyclosporine concentrations in a cardiac transplant patient shortly after the addition of nefazodone antidepressant therapy. We suggest there is a clinically significant drug-drug interaction between nefazodone and cyclosporine due to inhibition of cytochrome P-450 IIIA4 isoenzymes by nefazodone.

Lack of Correlation Between MMF Dose and MPA Level in Pediatric and Young Adult Cardiac Transplant Patients: Does the MPA Level Matter?

To determine the correlation between mycophenolate mofetil (MMF) dose and mycophenolic acid (MPA) level as well as its impact on rejection among young cardiac transplant recipients (OHT), trough concentrations of MPA and its metabolite, mycophenolic acid glucuronide (MPAG), were measured following MMF doses of 1200 mg/m2/d (max 3000 mg/d). Corresponding endomyocardial biopsy (EMB) grades and calcineurin inhibitor levels were recorded with simultaneous MPA/MPAG levels. Correlation coefficients were derived between MMF dose and MPA/MPAG levels. Contingency analysis evaluated the relation between MPA level and EMB score.

Elevated Free Fractions of Valproic Acid in a Heart Transplant Patient with Hypoalbuminemia

OBJECTIVE: To report a case demonstrating the importance of monitoring unbound valproic acid (VPA) serum concentrations in a patient with hypoalbuminemia. CASE SUMMARY: A 53-year-old white woman status–post heart transplantation was admitted to the hospital for declining cardiac function, possible rejection, and increased lethargy requiring intubation. An extensive workup of the patients profound lethargy was initiated, including an evaluation of her VPA regimen. Initially, VPA dosages were adjusted based on the total serum concentration of VPA. Hypoalbuminemia compounded with increased lethargy prompted the measurement of unbound serum concentrations of VPA. The VPA dosage was then adjusted based on the unbound rather than the total VPA serum concentration; the patient eventually improved and was discharged from the hospital. DISCUSSION: Lethargy is a concentration-related adverse effect of VPA. The nonlinear pharmacokinetic and protein saturation characteristics of VPA may result in nonproportional elevations in unbound drug, and subsequent increases in adverse effects, when dosage adjustments are based solely on measurement of total VPA serum concentrations in patients with hypoalbuminemia. CONCLUSIONS: This case report suggests that appropriate monitoring of unbound drug concentrations of VPA may prevent unrecognized concentration-related adverse effects. Awareness of the pharmacokinetic relationship and adverse effects of VPA will aid clinicians in identifying the etiology of symptoms.

Ganciclovir pharmacokinetics during renal impairment.

Limited information is available concerning the use of ganciclovir (GCV) in patients with severe renal impairment. The pharmacokinetics of GCV were studied in a heart transplant recipient requiring hemodialysis. The total body clearance was calculated to be approximately 5% of that previously reported for patients with normal renal function. GCV was removed by hemodialysis; a single 4-h procedure decreased the concentration in plasma by approximately 50%. GCV can be safely administered to patients with renal insufficiency if concentrations in plasma are monitored.

Safety and efficacy of atorvastatin in heart transplant recipients

BACKGROUND Pravastatin and simvastatin prolong survival and reduce transplant-related coronary vasculopathy, although low-density lipoprotein (LDL) lowering with these agents is only modest. The objective of this study was to assess the safety of moderate dose atorvastatin and its efficacy when prior treatment with another statin had failed to lower LDL to < 100 mg/dl. METHODS Data from 185 patients were retrospectively evaluated for adverse events, duration of exposure (person-days), and the mean atorvastatin dose exposure. Changes in lipid parameters, and prednisone and cyclosporine doses were determined. RESULTS SAFETY 48 patients received atorvastatin for 24,240 person-days at a mean dose exposure of 21 +/- 10 mg. Rhabdomyolysis, myositis, myalgias, and hepatotoxicity occurred in 0, 2, 2, and 0 patients, respectively. All events occurred at the 10-mg dose, within the first 3 months, and were rapidly reversible with atorvastatin discontinuation. EFFICACY Thirty-four patients evaluable for efficacy analyses had a pre-atorvastatin LDL of 145 +/- 38 mg/dl on the following statins: pravastatin (n = 30, 40 +/- 0mg), fluvastatin (n = 3, 33 +/- 12 mg), simvastatin (n = 1, 40 mg). After atorvastatin (21 +/- 9 mg/day) for 133 +/- 67 days, LDL was reduced to 97 +/- 24 mg/dl (relative reduction 31 +/- 20%, p < 0.0001). At the end of the observation period (418 +/- 229 days, atorvastatin final dose 24 +/- 14 mg/day), LDL was further decreased to 88 +/- 23 mg (relative reduction 37 +/- 17%, p < 0.0001). CONCLUSION Atorvastatin, when used at moderate doses and with close biochemical and clinical monitoring, appears to be safe and is effective in aggressively lowering LDL in heart transplant recipients when treatment with other statins has failed to achieve LDL goals.

Practices of cardiothoracic transplant centers regarding hepatitis C-seropositive candidates and donors.

The purpose of this survey was to determine current practices of cardiothoracic transplant centers regarding transplantation of hearts and lungs into hepatitis C (HCV)-seropositive candidates and the use of organs from HCV-seropositive donors. A telephone survey of 48 cardiothoracic transplant centers was conducted in October 1992. Questions included the centers policy for listing HCV-seropositive candidates; if, and under what conditions, organs from HCV-seropositive donors would be used; and which HCV assays were used. Forty-five programs responded; 75% will list an HCV-seropositive candidate, either directly or by lack of routine screening to exclude such patients; only 16% will not accept HCV-seropositive candidates; 9% had no policy. Overall, 69% will accept organs from HCV-seropositive donors, at least for selected recipients (22% for any recipient, 45% for HCV-seropositive and/or status I recipients; 2% do not screen donors). A total of 27% will never accept organs from an HCV-seropositive donor, and 4% had no policy. Thirty centers provided information on HCV methodology. All but one use a second generation ELISA or EIA as a first-line test. A positive result will be followed by a confirmatory assay/liver biopsy in 42%. The variation in practices reflects the ambiguity in the literature. Adequate evaluation of morbidity and mortality due to HCV infection in this population has not yet been possible, although currently available reports do not show a substantial increase. Prospective controlled trials in cardiothoracic transplant patients are necessary.

Postmortem Changes and Pharmacokinetics: Review of the Literature and Case Report

OBJECTIVE: To review the mechanisms and sequence of events that occur during ischemia and cell death and following death of the human body. The impact of these postmortem events on the distribution and pharmacokinetic behavior of drugs is described. The case study presented illustrates a possible situation where such postmortem changes could have affected the pharmacokinetics of procainamide. DATA SOURCES: English-language journal articles and reference texts identified from pertinent data sources. DATA SYNTHESIS: Postmortem changes in the human body begin at the cellular level with the onset of ischemia. As the length of time of ischemia increases and death ensues, more changes occur and lead to deterioration in tissue and organ function. These changes may affect the pharmacokinetic and distribution behavior of certain drugs. Drugs particularly affected are those whose distribution is dependent on molecular size, lipophilicity, pH, energy-dependent transport, and tissue binding. Such drugs include the tricyclic antidepressants, digoxin, and cimetidine. Other drugs with similar characteristics, such as procainamide, may also demonstrate like changes in distribution and pharmacokinetics. CONCLUSIONS: When measuring drug concentrations after death, it is important to consider the phenomenon of postmortem redistribution. Postmortem drug concentrations may not be a true reflection of antemortem concentrations and as a result, wrong conclusions could be made about the cause of death. More studies characterizing the postmortem distribution and pharmacokinetic characteristics of specific drugs are necessary.