Bryce Kiberd

Prevalence of Low Glomerular Filtration Rate in Nondiabetic Americans: Third National Health and Nutrition Examination Survey (NHANES III)

End-stage renal disease is an important and costly health problem. Strategies for its prevention are urgently needed. Knowledge of the population-based prevalence of renal insufficiency in nondiabetic adults would inform such strategies. Black and white nondiabetic adult participants in the Third National Health and Nutrition Examination Survey were analyzed. The analysis was stratified by age, gender, and race, and four clinically applicable methods were used to assess renal function. There were 13,251 complete records for analysis. By the Modification of Diet in Renal Diseases (MDRD) GFR (GFR) prediction Equation 7, 58% (95% confidence interval [CI], 56 to 60%) of the total adult nondiabetic black and white US population had MDRD GFR below 80 ml/min per 1.73m(2), 13% (95% CI, 11 to 14%) below 60 ml/min per 1.73m(2), and 0.26% (95% CI, 0.19 to 0.33%) below 30 ml/min per 1.73m(2). By the Cockcroft-Gault formula, the equivalent figures were 39% (95% CI, 37 to 41%), 14% (95% CI, 12% - 16%), and 0.81% (95% CI, 0.46 to 1.2%), respectively. The findings of an unexpectedly high prevalence of low clearance and the increased prevalence of low clearance with age were consistent across the four clearance estimation methods used and for each race-sex stratum. The absolute magnitude of the prevalence of low clearance was, however, dependent on the clearance method used. Assessed by estimation from serum creatinine, low clearance may be very common, particularly with advancing age. The prognosis (in terms of risk for progression and end-stage renal disease) of low clearance in unreferred populations may differ from that in referred populations and requires further study.

Is routine ureteric stenting needed in kidney transplantation? A randomized trial.

Background. Whether routine ureteric stenting in low-urological-risk patients reduces the risk of urological complications in kidney transplantation is not established. Methods. Eligible patients were recipients of single-organ renal transplants with normal lower urinary tracts. Patients were randomized intraoperatively to receive either routine stenting or stenting only in the event of technical difficulties with the anastomosis. All patients underwent Lich-Gregoire ureteroneocystostomy. Results. Between June 1994 and December 1997, 331 kidney transplants were performed at a single center, 305 patients were eligible, and 280 patients were enrolled and randomized. Donor and recipient age, sex, donor source, whether first or subsequent grafts, ureteric length, native renal disease, and immunosuppression were similar in each group. In the no-routine-stenting group 6 of 137 patients (4.4%) received stents after randomization for intraoperative events that in the surgeon’s opinion required use of a stent. In an intention-to-treat analysis there was no difference between groups in the primary outcome cluster of obstruction or leak [routine stenting 5 of 143 (3.5%) vs. no routine stenting 9 of 137 (6.6%);P =0.23], or in either of these complications analyzed separately. All urological complications were successfully managed without major morbidity. Living donor organs and shorter ureteric length (after trimming) were univariate risk factors for leaks, although increasing donor age was associated with obstruction. Conclusions. Routine ureteric stenting is unnecessary in kidney transplantation in patients at low risk for urological complications. Careful surgical technique with selective stenting of problematic anastomoses yields similar results.

A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients.

BACKGROUND Corticosteroids have been a mainstay of rejection prophylaxis for several decades, despite the multiple adverse effects of long-term use, including weight gain, hyperlipidemia, diabetes, hypertension, and bone disease. The detrimental effect of steroids on the metabolic profile begins in the early posttransplantation period, and the complete avoidance of steroids in transplantation would therefore be optimal. We hypothesized that the addition of mycophenolate mofetil (MMF) and a humanized monoclonal anti-CD25 antibody (daclizumab) to a cyclosporine (CsA microemulsion)-based immunosuppression protocol would permit transplantation without steroids. METHODS Steroid-free renal transplantation was attempted in 57 patients treated with daclizumab, MMF, and CsA. Twenty-eight patients received kidneys from living donors; the remaining 29 received cadaveric grafts. RESULTS At 1 year, patient and graft survival were 95% and 89%, respectively. Fourteen patients (25%) experienced rejections, of which 13 were readily reversed with steroids; 1 patient required OKT3. Mean serum creatinine at 12 months for patients not experiencing rejection was 149+/-58 micromol/L, compared with 158+/-102 micromol/L for those experiencing rejection. Five patients required hospitalization for infection; no patients developed lymphoproliferative disease. At baseline, 17 patients required 3 or more antihypertensive medications, compared with 2 patients at 1 year. Three of 43 nondiabetic patients developed diabetes during the study. There was no significant reduction in lumbar or femoral bone density. CONCLUSIONS On the basis of these positive results, we believe steroid avoidance with this immunosuppressive regimen merits further study.

Conversion to rapamycin immunosuppression in renal transplant recipients : Report of an initial experience

Background. The aim of thisstudy is to evaluate the effects of RAPA conversion in patients undergoing cyclosporine (CsA) or tacrolimus (Tac) toxicity. Methods. Twenty renal transplant recipients were switched to fixed dose rapamycin (RAPA) (5 mg/day) 0 to 204 months posttransplant. Drug monitoring was not initially used to adjust doses. The indications for switch were chronic CsA or Tac nephrotoxicity (12), acute CsA or Tac toxicity (3), severe facial dysmorphism (2), posttransplant lymphoproliferative disorder (PTLD) in remission (2), and hepatotoxicity in 1. Follow-up is 7 to 24 months. Results. In the 12 patients switched because of chronic nephrotoxicity there was a significant decrease in serum creatinine [233±34 to 210±56 &mgr;mol/liter (P <0.05) at 6 months]. Facial dysmorphism improved in two patients. No relapse of PTLD was observed. Five patients developed pneumonia (two Pneumocystis carinii pneumonia, one infectious mononucleosis with polyclonal PTLD lung infiltrate) and two had bronchiolitis obliterans. There were no deaths. RAPA was discontinued in four patients, because of pneumonia in two, PTLD in one, and oral aphtous ulcers in one. RAPA levels were high (>15 ng/ml) in 7 of 13 (54%) patients. Conclusions. RAPA conversion provides adequate immunosuppression to enable CsA withdrawal. However, when converting patients to RAPA drug levels should be monitored to avoid over-immunosuppression and adequate antiviral and Pneumocystis carinii pneumonia prophylaxis should be given.

Early Adequate Mycophenolic Acid Exposure is Associated with Less Rejection in Kidney Transplantation

This study examines the importance of early mycophenolic acid (MPA) exposure in the cyclosporine‐ and mycophenolate mofetil (MMF)‐treated kidney transplant population.

Cumulative Risk for Developing End-Stage Renal Disease in the US Population

The individual risk of developing end-stage renal disease (ESRD) and its overall impact on life expectancy is not known. This studys objectives were to determine the effect of ESRD on life expectancy for a cohort of 20-yr-olds and to compare this impact to that of several cancers for which population-based screening programs exist. A computer simulation, stratified by race (white, black) and by gender was used to calculate cumulative lifetime risk of ESRD, life-years lost to ESRD, and cumulative Medicare payments for ESRD. Similar calculations were made for breast, prostate, and colorectal cancer. The cumulative lifetime risk of ESRD for a 20-yr-old black woman is 7.8%. Equivalent risks for black men are 7.3%, white men 2.5%, and white women 1.8%. Lost years of life attributable to ESRD are 1.09, 1.10, 0.40, and 0.32 yr for black women, black men, white men, and white women, respectively. In blacks, ESRD is responsible for nearly as much loss of life-years as breast cancer in women and more loss of life-years than colorectal or prostate cancer in men. In addition, treatment costs for ESRD in this population are many-fold more expensive than cumulative treatment costs of these cancers. Exploring new screening and treatment strategies may be warranted to prevent ESRD, particularly in the US black population.

Adequate Early Cyclosporin Exposure is Critical to Prevent Renal Allograft Rejection: Patients Monitored by Absorption Profiling

This study used receiver operating characteristic analysis to investigate the properties of area under the concentration‐time curve during the first 4 h after cyclosporin‐microemulsion dosing (AUC0−4) and cyclosporin (CyA) levels immediately before and at 2 and 3 h after dosing (C0, C2 and C3) to predict the risk of biopsy‐proven acute rejection (AR) at 6 months. Ninety‐eight kidney transplant recipients treated with CyA‐microemulsion‐based triple therapy immunosuppression were studied on post‐transplant days 3, 5, and 7, and at increasing intervals thereafter.

Nucleic acid testing (NAT) of organ donors: is the 'best' test the right test? A consensus conference report.

Nucleic acid testing (NAT) for HIV, HBV and HCV shortens the time between infection and detection by available testing. A group of experts was selected to develop recommendations for the use of NAT in the HIV/HBV/HCV screening of potential organ donors. The rapid turnaround times needed for donor testing and the risk of death while awaiting transplantation make organ donor screening different from screening blood‐or tissue donors. In donors with no identified risk factors, there is insufficient evidence to recommend routine NAT, as the benefits of NAT may not outweigh the disadvantages of NAT especially when false‐positive results can lead to loss of donor organs. For donors with identified behavioral risk factors, NAT should be considered to reduce the risk of transmission and increase organ utilization. Informed consent balancing the risks of donor‐derived infection against the risk of remaining on the waiting list should be obtained at the time of candidate listing and again at the time of organ offer. In conclusion, there is insufficient evidence to recommend universal prospective screening of organ donors for HIV, HCV and HBV using current NAT platforms. Further study of viral screening modalities may reduce disease transmission risk without excessive donor loss.

Screening for prostate, breast and colorectal cancer in renal transplant recipients.

American Society of Transplantation guidelines recommend screening renal transplant recipients for breast, colorectal and prostate cancer. However there is a lack of evidence to support this practice.

Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics

An intravenous (i.v.) formulation of mycophenolate mofetil (MMF; CellCept®, Roche Pharmaceuticals, Inc., Palo Alto, CA) that will enable its administration to patients unable to tolerate oral medication is available. Two separate studies, an open‐labeled pharmacokinetic (PK) study and a double‐blind safety study, were performed. Within 24 h after transplant, 153 (safety study) and 45 (PK study) first or second renal transplant recipients were started on i.v. MMF 1 g Q12h or placebo (used in the safety study only, 2:1 MMF:placebo), given over 2 h via a dedicated peripheral venous catheter. In the safety study, per os (p.o.) MMF (1g Q12h) or placebo was administered, starting within 72 h after transplant, whereas in the PK study, p.o. MMF was started on the evening of day 5. Sequential blood samples obtained on study days 5 (i.v. MMF) and 6 (p.o. MMF) before and up to 12 h after the AM dose were analyzed for mycophenolic acid (MPA) and MPA glucuronide (MPAG) concentrations by high‐performance liquid chromatography. The area under the concentration curve (AUC) was calculated using the linear trapezoidal rule. The MPA AUC0–12 was higher for i.v. MMF than p.o. MMF (40.8±11.4 μg·h/mL vs. 32.9±15, p<0.001). There were no other significant PK differences for plasma MPA or MPAG. In the safety study (n=98 i.v. MMF vs. n=55 placebo), 11 patients (11%, i.v. MMF) and 4 patients (7%, placebo) discontinued their use of the drug because of an adverse event (AE). Overall, AEs were similar between i.v. MMF and placebo. Injection site phlebitis (4%) and thrombosis (4%) were observed only with i.v. MMF. MMF i.v. 1 g twice daily (b.i.d.) should provide efficacy at least equivalent to p.o. MMF without increased toxicity, and it provides an acceptable alternative dose form in the immediate period after transplant.