Elmahdi A. Elkhammas

Everolimus versus Mycophenolate Mofetil in the Prevention of Rejection in De Novo Renal Transplant Recipients: A 3-year Randomized, Multicenter, Phase Iii Study

Background. This 36-month, randomized, parallel-group study compared safety and efficacy of two doses of everolimus with mycophenolate mofetil (MMF) in de novo renal-transplant recipients. Methods. Renal-allograft recipients received 1.5 mg/day or 3 mg/day of everolimus or 2 g/day of MMF, plus full-dose cyclosporine (CsA) and corticosteroids after randomization. For at least their first year, patients received study medication according to a double-blinded, double-dummy design. Concerns over nephrotoxicity led to a protocol amendment to an open-label design with reduced CsA troughs. Results. Incidences of primary efficacy failure at 36 months (biopsy-proven acute rejection, graft loss, death, or loss to follow-up) were everolimus 1.5 mg/day, 33.7% (65/193); everolimus 3 mg/day, 34.0% (66/194); and MMF, 31.1% (61/196) (P=0.810). Antibody-treated acute rejection at 36 months was significantly lower with everolimus 1.5 mg (9.8%) than MMF (18.4%, P=0.014). Discontinuation for adverse events was more frequent with everolimus and hemolytic uremic syndrome, lymphoproliferative disease, and proteinuria, and higher serum creatinine occurred at increased frequency relative to the MMF arm. Creatinine levels in the everolimus arms were stable in follow-up: the mean rise in creatinine over the first 6 months of the open-label phase was 3 &mgr;mol/L or greater with everolimus and 7 &mgr;mol/L with MMF. However, serum creatinine levels were lower in the MMF group throughout. Death and graft loss were higher in the everolimus arms (not significant). Conclusions. As part of triple-drug immunosuppression, everolimus (1.5 or 3 mg/day) was as efficacious as MMF, although the side-effect profile featured increased adverse events. Nephrotoxicity/calcineurin–inhibitor-related adverse events will require judicious lowering of CsA exposure with monitoring of everolimus troughs.

The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation

Abstract: Background:  Mycophenolate mofetil (MMF) has proven to be a very effective drug for the prevention of acute rejection following renal transplantation when dosed as prescribed at 2 or 3 g/d. However, circumstances arise in clinical transplantation where the dose must be lowered, either to avoid drug toxicity or because of concurrent infection. The impact on the incidence of acute rejection and graft survival when the MMF dose must be lowered has not previously been investigated.

Impact of acute rejection and early allograft function on renal allograft survival

Both acute rejection and the function of a renal allograft early after transplantation correlate with long-term graft survival. In this study we assessed the relationship between these two factors in 843 adult recipients of first cadaveric renal grafts, transplanted at a single institution and followed for a minimum of 3.5 years. Patients were divided into four groups according to (1) history of acute rejection (AR) during the first 6 months after transplantation, and (2) concentration of serum creatinine at 6 months after transplantation (SCr(6mo) < or > or = 2 mg/dl). Death censored allograft survival was not significantly different among patients without AR and with low SCr(6mo) (group 1, n=376), patients without AR but with an elevated SCr(6mo) (group 2, n=117), and patients with AR but low SCr(6mo) (group 3, n=185). In contrast, graft survival was significantly worse in patients with AR and an elevated SCr(6mo) (group 4, n=165) compared with patients in the other three groups (Cox, P<0.0001). The elevated SCr(6mo) in group 4 patients was not necessarily the consequence of AR, as 32% of patients in group 4 had a SCr at 10 days after transplantation (SCr(10d)), before they had AR, that was equal to or higher than the SCr(6mo). Based on this observation we investigated the implications of the SCr(10d) concentration for graft prognosis. The SCr(10d) correlated weakly with graft survival (Cox, P=0.05). However, an elevated SCr(10d) correlated with other potential risk factors for graft survival including: Older donors (P<0.0001), male recipients (P<0.0001), and heavier recipients (P<0.0001, all by multivariate regression); and posttransplant factors such as, increasing numbers of AR (P<0.0001), higher posttransplant blood pressure (P<0.0001), and lower doses of cyclosporine (P<0.0001, all by multivariate regression). In conclusion, graft dysfunction predicts poor graft survival only when associated with AR. Similarly, AR predicts a poor renal allograft survival only when associated with graft dysfunction. The SCr(10d) is an indicator of risk factors from both the donor and recipient, and an elevated SCr(10d) predicts a higher risk of acquiring additional risk factors early after transplantation.

Renal transplantation in older people

Renal transplantation in people 60 years old or more is controversial due to the morbidity associated with immunosuppression and the scarcity of renal allografts. We have reviewed the outcome of 1222 consecutive renal transplants done at a single institution with a uniform immunosuppressive protocol over 10 years. 5-year graft survival was the same in the under sixties as in the sixties and over. Patient survival was worse in the older group (p = 0.0001), but there were significantly fewer immunological graft losses: 11% vs 31% (p = 0.0009; relative risk [RR] = 0.36 [95% confidence interval 0.19-0.66]). A majority of the deaths in both groups were secondary to cardiovascular disease, not due to complications of immunosuppression. We conclude that renal transplantation in people 60 and over has results equivalent to a younger population. Age 60 and over should not be a major factor in considering if a patient is eligible for renal transplantation.

Factors related to the donor organ are major determinants of renal allograft function and survival

In this study, we analyzed the relative impact of donor and recipient variables on cadaveric renal allograft function and survival. The unique feature of the study population is that each pair of recipients received their allografts from a single donor. The study includes 378 adult patients. In 129 pairs both recipients were Caucasian, and in 60 pairs one recipient was Caucasian and the other was African-American. All transplants were done in one center, thus minimizing differences in preservation time and providing uniform posttransplant management. The initial analysis showed a relationship between the function of the allograft 6 months after transplantation (serum creatinine [SCr]6 mo) and donor variables (P = 0.0004, analysis of variance). Furthermore, it was calculated that 64% of the variability in the SCr 6mo among patients was due to donor factors and 36% was due to recipient factors. An elevated SCr 6 mo was significantly associated with older donors, male recipients, and patients with acute rejection episodes. Furthermore, other unidentified donor factors may have an impact on allograft function. Reflecting the importance of donor factors, there was a significant relationship between SCr 6mo in paired recipients (P < 0.0008 by Spearman). Analysis of racially dissimilar pairs showed that the SCr 6mo and graft survival 6 months after transplantation were not significantly different between Caucasians and African-Americans. However, beyond 6 months, graft survival was worse in African-Americans (P < 0.0001 by Cox). Compared with Caucasians, graft survival was significantly worse in African-Americans with poorly controlled blood pressure (mean arterial pressure > 105 mmHg) (P = 0.002, Cox), but not in those patients with mean arterial pressure < 105 mmHg. In conclusion, donor factors are major determinants of renal allograft function. However, those factors may not be easily identifiable or quantifiable. Donor factors do not contribute to racial differences in allograft survival. However, poorly controlled hypertension correlates with poor renal graft survival in African-Americans.

The high prevalence of severe early posttransplant renal allograft pathology in hepatitis C positive recipients.

In the USA approximately 10% of candidates for renal transplantation have serum antibodies to hepatitis C (HCV). To assess the possible impact of HCV infection on early posttransplant events we assessed allograft complications during the first 6 months following renal transplantation in three groups of adult renal allograft recipients: (1) HCV antibody positive recipients (R-HCV) (n=32); (2) HCV negative recipients who received kidneys from HCV antibody positive donors (D-HCV) (n=48); and (3) HCV negative recipients of HCV negative allografts who were transplanted during the same time period as R-HCV (Ctrl) (n=204). Allograft biopsies were done for evaluation of allograft dysfunction during the first 6 months posttransplant in 58% of Ctrl, 42% of D-HCV, and 63% of R-HCV (not significantly different). The prevalence of acute tubulointerstitial rejection was similar among the 3 groups of patients. In contrast, compared with Ctrl, both R-HCV and D-HCV had a significantly higher prevalence of acute transplant glomerulopathy (Ctrl, 6%; R-HCV, 55%, P<.0001; D-HCV 40%, P=.0004). Acute vascular rejection was more common in R-HCV (60%) than in Ctrl (28%) (P=.009) and the prevalence of chronic vascular rejection was also higher in R-HCV (60%) than in Ctrl (31%) (P=.01). Furthermore, chronic vascular rejection was diagnosed earlier in R-HCV (64% of cases within one month posttransplantation) than in Ctrl (19% within one month) (P=.01). Death censored renal allograft losses occurred in 14% of Ctrl, 17% of D-HCV, and 26% of R-HCV (not significant). In conclusion, R-HCV patients have a high prevalence of severe acute pathologic findings in renal allograft biopsies obtained early after transplantation and develop chronic vascular rejection more often and earlier than HCV negative recipients. These studies also confirm the previously reported association of HCV with acute transplant glomerulopathy.

Impact of serum lipids on long-term graft and patients survival after renal transplantation

The results after primary cadaveric renal transplantation in 665 consecutive patients were reviewed with respect to posttransplant serum lipids. Data were available for 182 of 665 patients on serum total cholesterol and triglycerides at 1 year posttransplant. Hypercholesterolemia (cholesterol > 200 mg/dl) developed in 141 of 182 patients (77%) and hypertriglyceridemia developed in 73 of 166 patients (44%). At 1 year posttransplant, hypercholesterolemia and hypertriglyceridemia both correlated with age at transplant (P = 0.0001, P = 0.01). Hypercholesterolemia and hypertriglyceridemia were also correlated with obesity as determined by body mass index (kg/m2) (P = 0.006, P = 0.01). Hypertriglyceridemia at 1 year posttransplant correlated with pretransplant triglyceride level (P = 0.006), but hypercholesterolemia did not correlate with pretransplant cholesterol level (P = 0.53). Hyperlipidemia was not correlated with cyclosporine (CsA) or prednisone dose (mg/kg), CsA trough levels, number of rejection episodes, or serum creatinine at 1 year. Despite significant differences in serum cholesterol and triglycerides, actuarial graft and patient survival were similar between the normolipidemic and hyperlipidemic groups.

Transmission of hepatitis C by kidney transplantation--the risks.

The use of cadaveric organ donors with positive serologic tests for hepatitis C (HCV) has caused considerable debate. We have reviewed the clinical course of 43 EIA1 HCV-negative recipients who received kidney transplants from EIA1 HCV-positive donors (Study). We have attempted to define the rate of HCV-RNA transmission and to determine the frequency of HCV disease transmission as determined by abnormalities in liver function tests. Viral transmission was assessed using serologic assays for HCV antibody formation (EIA1, EIA2, and Matrix--an automated multiple antigen immunoblot assay) and with PCR testing for the presence of HCV-RNA on recipient sera. Liver function was followed longitudinally in the Study patients and compared with a group of 103 kidney recipients of organs from EIA1 HCV-negative donors (Control). Of the Study patients, 56% became PCR-positive for HCV-RNA, suggesting the transmission of HCV-RNA from the HCV-positive donor. Interpretation of serologic tests for HCV was complex. Currently available first (EIA1) and second (EIA2) generation serologic assays were always negative. The multiple antigen immunoblots assay (Matrix) had a high positive predictive value (93%) for the presence of HCV-RNA transmission, but one-third of Matrix-negative Study patients were PCR-positive (sensitivity = 66%). Currently, only 38% of recipients have HCV-RNA, suggesting that the virus may have been cleared by one-third of Study recipients who had circulating virus. Traditional tests of liver function (ALT, AST, AP, and GGT) were of limited use in predicting HCV-RNA transmission. Average AST, AP, and GGT were similar in the two groups. Average ALT was increased (93 I/U and 47 I/U) in Study and Control patients, respectively, but this difference was not significant. Episodes of abnormal liver function (ALT 60-99 IU for > or = 14 days) occurred in 22% of Study and 10% of Control patients (P = NS) and lasted longer in Study compared with Control patients (301 vs. 138 days; P < 0.02). Hepatitis (ALT > or = 100 IU for > 14 days) occurred with an equal frequency (6.5%) in both groups. The presence of HCV-RNA did not predict episodes of abnormal liver function. Fulminant hepatitis or rapidly progressive cirrhosis did not occur in the recipients of organs from HCV-positive donors. These data demonstrate a high efficiency of transfer of HCV-RNA by kidney transplantation from an HCV-positive donor to an HCV-negative recipient. A majority of the patients have asymptomatic HCV infection.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationships between arterial hypertension and renal allograft survival in African-American patients

In previous studies, we showed that in African-American patients arterial hypertension during the first 6 months after transplantation is associated with a high risk of renal allograft loss. In this study, we sought to examine the relationships between pretransplant blood pressure (preBP), blood pressure early after transplantation (postBP), and allograft function and survival. The study included 116 African-American recipients of first cadaveric renal allografts followed for 64 +/- 40 months. Prior to transplantation, 78% of the patients required antihypertensive medications and 59% had poorly controlled BP (average mean arterial pressure, > or =107 mm Hg). Blood pressure levels increased significantly during the first month posttransplant, particularly in patients with poorly controlled preBP. During the first 6 months posttransplant, 95% of patients required antihypertensive drugs; after the transplant, patients required significantly more and higher doses of antihypertensives compared with pretransplant. In 38% of the patients, postBP remained high despite therapy. The level of postBP correlated with the patients weight pretransplant and with the level of preBP. Pretransplant BP correlated with postBP 1 month after transplantation (r = 0.4, P < 0.0001), and 70% of the patients with poorly controlled postBP had uncontrolled preBP. Patients with poorly controlled preBP had worse graft survival than patients with well-controlled preBP (P = 0.03 by Cox regression). Furthermore, compared with patients with well-controlled postBP, patients with high postBP had higher serum creatinine at 10 days (P = 0.04) and at 6 months (P = 0.0004) posttransplant; these patients had reduced graft survival (P = 0.0006 by Cox). We found no objective evidence of differences in patient compliance between individuals with high postBP and those with well-controlled postBP. This study confirms the association between high postBP and reduced renal allograft survival in African-American patients. In addition, these results show that the level of preBP can be used to identify patients at high risk of developing severe hypertension immediately after transplantation and those at risk for renal allograft failure.

Prophylactic Cholecystectomy Is Not Indicated following Renal Transplantation

BACKGROUND The appropriate management of gallstones in patients undergoing renal transplantation is controversial. Screening for gallstones and subsequent prophylactic cholecystectomy has been recommended by some authors for kidney transplant candidates. Our program does not practice routine pretransplant screening for gallstones, and we reviewed our data to determine the outcome of our management approach. METHODS We reviewed the records of the 1,364 currently followed patients who have undergone kidney transplant at our institution since 1985 in order to evaluate the morbidity and mortality of biliary disease in the post-transplant period. We attempted to contact all patients by telephone or mail survey for the presence of biliary tract disease or operations. RESULTS Six hundred and sixty-two patients were fully evaluated. Fifty-two (7.85%) required cholecystectomy for stone disease. Seven patients underwent incidental cholecystectomy during other operations, 2 patients developed acalculus cholecystitis, and 14 patients with asymptomatic cholelithiasis are being followed up. Surgical indications included 38 biliary colic, 9 acute cholcystitis, 3 gallstone pancreatitis, and 2 patients who were asymptomatic. Fifty-two patients underwent 30 laparoscopic cholecystectomies, 20 open cholecystectomies, and 2 conversions. Surgery occurred from 7 days to 9.6 years following transplantation. Overall, the median hospital stay (no postoperative stay) was 4 days (range 1 to 57). Patients undergoing laparoscopy had a median stay of 2 days compared with 7 days for those undergoing an open procedure. Complications were seen in 6 patients (11.5%) with no morbidity and no graft loss. The 1-, 2-, and 5-year graft survival was 98%, 96%, and 85%, respectively, in patients undergoing cholecystectomy. CONCLUSIONS Transplant patients are not at an increased risk for developing biliary tract disease compared with nontransplant patients. Gallstone disease does not have a negative impact on graft survival. Treatment of gallstones has a low risk and does not represent an increased risk of complications in patients following renal transplantation.