The impact of tacrolimus exposure on extrarenal adverse effects in adult renal transplant recipients.

AIMS: Tacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model-predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady-state tacrolimus area under the curve over a 12-h dosing period (AUCss,0-12h ). METHODS: All recipients receiving tacrolimus and mycophenolic acid ≥6 months completed a 12-h cross-sectional observational pharmacokinetic-pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. An LSS was determined using a Bayesian estimation method with the same patients. RESULTS: Dose-normalized tacrolimus AUCss,0-12h and apparent clearance were independently associated with diarrhoea, dyspepsia, insomnia and neurological AE ratio. Dose-normalized tacrolimus maximum concentration was significantly correlated with skin changes and acne. No AE associations were found with trough concentrations. Using limited sampling at 0, 2h; 0, 1, 4h; and 0, 1, 2, 4h provided a precise and unbiased prediction of tacrolimus AUC (root mean squared prediction error < 10%), which was not well characterized using trough concentrations only (root mean squared prediction error >15%). CONCLUSIONS: Several AEs (i.e. diarrhoea, dyspepsia, insomnia and neurological AE ratio) were associated with tacrolimus dose normalized AUCss,0-12h and clearance. Skin changes and acne were associated with dose-normalized maximum concentrations. To facilitate clinical implementation, a LSS was developed to predict AUCss,0-12h values using sparse patient data to efficiently assess projected immunosuppressive exposure and potentially minimize AE manifestations.

The impact of systematic review of status 7 patients on the kidney transplant waitlist.

BACKGROUND: Increased morbidity and mortality are well documented in Status 7(inactive list) patients. Delays in transplantation secondary to prolonged periods on inactive status also negatively impacts transplant outcomes. We developed an effective system to reduce the proportion of status 7 patients on our kidney transplant waitlist. This can easily be reproduced by other transplant centers since concerns about Status 7 list size are commonplace. METHODS: Meetings of a dedicated status 7 focus group were undertaken biweekly beginning in April 2016, each lasting for 1 hour or less. The group was led by a transplant physician and comprised of members from all disciplines of the kidney transplant department. Individual patient barriers to activation were systematically evaluated and action plans were developed to overcome those. The formal meetings were supplemented by updates to an electronic database accessible to all members of the team. RESULTS: In the first 2 years of the program, we were able to activate and eventually transplant 18% of the formerly inactive patients. Forty percent of all inactive patients were removed from the waitlist due to one or more unsurmountable barriers. The median time patients stayed inactive on the waitlist was shortened from 1344 days at the start of this initiative to 581 days at the end. CONCLUSION: This strategy of systematic reevaluation of status 7 patients resulted in successful disposition of a substantial number of inactive patients. Further, waitlist time was reduced and transplantation expedited for the appropriate individuals. This approach could easily be adapted by other transplant centers with minimum utilization of resources.

An observational study of the quality of care for chronic kidney disease: a Buffalo and Albany, New York metropolitan area study.

BACKGROUND: The database of a major regional health insurer was employed to identify the number and frequency of covered patients with chronic kidney disease (CKD). We then examined the characteristics of their care as defined, in part, by the frequency of physician visits and specialty referral, the characteristics of laboratory testing and total costs as indices of the quality of care of the subject population. METHODS: This retrospective, cross-sectional study analyzed insurance claims, laboratory results and medication prescription data. Patients with two estimated glomerular filtration rate readings below 60 ml/min/1.73 m(2) (n = 20,388) were identified and classified by CKD stage. RESULTS: The prevalence of CKD stages 3a and above was 12 %. Vascular comorbidities were common with prevalence increasing steadily from stage 3a through stage 5. Only 55.6 % of stage 4 CKD patients had claims for nephrology visits within one year of their index date. Fifty-nine percent of patients had claims for renin-angiotensin system (RAS) blockers. Twenty-five percent of patients in stage 3a CKD filled a prescription for non-steroidal anti-inflammatory drugs. Fifty-two percent of patients who developed end-stage renal disease received their first dialysis treatment as inpatients. CONCLUSIONS: The pattern of medical practice observed highlights apparent deficiencies in the care of CKD patients including inappropriate medication use, delayed nephrology referral, and a lack of preparation for dialysis. This study shows the potential value of using large patient databases available through insurers to assess and likely improve regional CKD care.

Validity and reliability of a novel immunosuppressive adverse effects scoring system in renal transplant recipients.

BACKGROUND: After renal transplantation, many patients experience adverse effects from maintenance immunosuppressive drugs. When these adverse effects occur, patient adherence with immunosuppression may be reduced and impact allograft survival. If these adverse effects could be prospectively monitored in an objective manner and possibly prevented, adherence to immunosuppressive regimens could be optimized and allograft survival improved. Prospective, standardized clinical approaches to assess immunosuppressive adverse effects by health care providers are limited. Therefore, we developed and evaluated the application, reliability and validity of a novel adverse effects scoring system in renal transplant recipients receiving calcineurin inhibitor (cyclosporine or tacrolimus) and mycophenolic acid based immunosuppressive therapy. METHODS: The scoring system included 18 non-renal adverse effects organized into gastrointestinal, central nervous system and aesthetic domains developed by a multidisciplinary physician group. Nephrologists employed this standardized adverse effect evaluation in stable renal transplant patients using physical exam, review of systems, recent laboratory results, and medication adherence assessment during a clinic visit. Stable renal transplant recipients in two clinical studies were evaluated and received immunosuppressive regimens comprised of either cyclosporine or tacrolimus with mycophenolic acid. Face, content, and construct validity were assessed to document these adverse effect evaluations. Inter-rater reliability was determined using the Kappa statistic and intra-class correlation. RESULTS: A total of 58 renal transplant recipients were assessed using the adverse effects scoring system confirming face validity. Nephrologists (subject matter experts) rated the 18 adverse effects as: 3.1 ± 0.75 out of 4 (maximum) regarding clinical importance to verify content validity. The adverse effects scoring system distinguished 1.75-fold increased gastrointestinal adverse effects (p=0.008) in renal transplant recipients receiving tacrolimus and mycophenolic acid compared to the cyclosporine regimen. This finding demonstrated construct validity. Intra-class correlation was 0.81 (95% confidence interval: 0.65-0.90) and Kappa statistic of 0.68 ± 0.25 for all 18 adverse effects and verified substantial inter-rater reliability. CONCLUSIONS: This immunosuppressive adverse effects scoring system in stable renal transplant recipients was evaluated and substantiated face, content and construct validity with inter-rater reliability. The scoring system may facilitate prospective, standardized clinical monitoring of immunosuppressive adverse drug effects in stable renal transplant recipients and improve medication adherence.

Nuclear translocation of nuclear factor of activated T cells (NFAT) as a quantitative pharmacodynamic parameter for tacrolimus.

Nuclear factor of activated T cells (NFAT) is a family of transcription factors involved in regulating the immune response. The canonical NFAT pathway is calcium-dependent and upon activation, NFAT is dephosphorylated by the phosphatase, calcineurin. This results in its translocation from the cytoplasm to the nucleus and transcription of downstream target genes that include the cytokines IL-2, IL-10, and IFNγ. Calcineurin inhibitors including tacrolimus inhibit the NFAT pathway and are used as immunosuppressants in transplant settings to prevent graft rejection. There is, as yet, no direct means to monitor tacrolimus pharmacodynamics. In this study, a rapid, quantitative, image cytometry-based measurement of nuclear translocation of NFAT1 is used to evaluate NFAT activation in T cells and its tacrolimus-induced inhibition. A strong dose-dependent correlation between NFAT1 inhibition and tacrolimus dose is demonstrated in vitro. Time kinetic analysis of NFAT1 inhibition in plasma from stable renal transplant recipients before and after an in vivo dose with tacrolimus correlated with the expected pharmacokinetic profile of tacrolimus. This was further corroborated by analysis of patients' autologous CD4 and CD8 T cells. This is the first report to show that the measurement of NFAT1 activation potential by nuclear translocation can be used as a direct, sensitive, reproducible and quantitative pharmacodynamic readout for tacrolimus action. These results, and the rapid turnaround time for this assay, warrant its evaluation in a larger clinical setting to assess its role in therapeutic drug monitoring of calcineurin inhibitors.

Age associations with tacrolimus and mycophenolic acid pharmacokinetics in stable Black and White kidney transplant recipients: Implications for health inequities.

Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and is dosed empirically in elderly kidney transplant recipients (KTRs) resulting in health inequities. Limited immunosuppressive pharmacokinetics are available comparing adult ages. This secondary analysis compared TAC and MPA pharmacokinetics and adverse effects (AEs) among young, middle-aged, and elderly Black and White KTRs. The 12-h TAC and MPA pharmacokinetics with AE evaluation were conducted in 67 stable KTRs greater than or equal to 6 months post-transplant. TAC regimens were adjusted to target troughs. MPA regimens were adjusted using clinical response. Participants were: young: less than or equal to 40 years; middle age: greater than 40 to 60 years, and elderly greater than 60 years. Noncompartmental pharmacokinetic analysis determined area under the concentration-time curve 0-12 h (AUC0-12h ), clearance (CL), and CL/body mass index (BMI) with 0-h troughs. MPA enterohepatic recirculation (EHR), MPA-AUC6-12h /MPA-AUC0-12h , and MPA glucuronide (MPAG)-AUC0-12h /MPA-AUC0-12h were determined. Univariate analysis of variance (ANOVA) was conducted using SAS version 9.4. No group differences were noted for estimated glomerular filtration rate, MPA, and TAC doses. EHR was reduced in elderly with decreased MPA-AUC6-12h /MPA-AUC0-12h (p = 0.049) and increased MPAG-AUC0-12h /MPA-AUC0-12h (p = 0.036). MPA troughs (p = 0.045) were reduced in the elderly. TAC CL/BMI (p = 0.043) was reduced in the elderly. For therapeutic MPA AUC0-12h : 30-60 mg·h/L, 34.3% KTRs achieved this target with 55.2% greater than the therapeutic range. 77.6% KTR were in the TAC AUC0-12h target: 100-190 ng·h/mL and 19.4% were below this range with no age relationship. In 44% young, 26% middle-age and 7.8% elderly subjects achieved target AUC0-12h for both medications (p = 0.036). Neurologic AEs were manifested in the elderly (p = 0.014). Immunosuppressive pharmacokinetics demonstrated age-related differences with reduced TAC CL/BMI and MPA EHR and increased neurologic AE in the elderly. This immunosuppressive regimen may require age-adjusted individualization to optimize allograft function.

Comparison of P-glycoprotein function in peripheral blood mononuclear cells ex vivo in stable Black and White male and female kidney transplant recipients.

Kidney allograft survival remains poorer in Black compared to White recipients due to racial differences in calcineurin inhibitor (CNI) pharmacology. P-glycoprotein (P-gp), an ABC efflux transporter expressed in peripheral blood mononuclear cells (PBMCs), modulates CNI pharmacokinetics and intracellular pharmacology. This study investigated P-gp function in PBMC ex vivo at 0 (trough), 4, 8, and 12 h in stable Black and White male and female kidney transplant recipients (n = 67) receiving tacrolimus and mycophenolic acid. Tacrolimus doses were adjusted to troughs of 4-10 ng/ml. P-gp function was quantified with flow cytometric measurement of cyclosporine (CYA; 2.5 µM)-reversible efflux of P-gp substrate, 3,3'-Diethyloxacarbocyanine iodide by determining the percentage change of mean fluorescent intensity (MFI) with CYA (% ΔMFI). The composite parameter of area under the concentration versus time (AUC)0-12h % ΔMFI estimated P-gp function. Data analysis examined race, sex, and race-sex associations to P-gp function. A secondary aim analyzed ABCB1 genotypes: 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642), and P-gp function. P-gp function (% ΔMFI) was higher in White patients at troughs (p = 0.031) compared to Black counterparts with similar trends at 4 and 8 h. Reduced AUC0-12h % ΔMFI was noted in Black recipients (N = 32) compared with Whites (N = 35, p = 0.029) with notable pairwise adjusted differences between Black and White women (p = 0.021). Higher AUC0-12h % ΔMFI was associated with ABCB1 2677 TT compared to GG variants (p = 0.035). The AUC0-12h % ΔMFI was greater in White than Black subjects. P-gp function was higher at troughs in White subjects and differed between race-sex groups. P-gp function in PBMC may influence intracellular tacrolimus exposure and inter-relating pharmacodynamic responses which may support race and sex pharmacologic differences.

Effect of steroid-free low concentration calcineurin inhibitor maintenance immunosuppression regimen on renal allograft histopathology and function.

BACKGROUND: The most common cause of late kidney transplant failure is insidiously progressive renal dysfunction associated with organ scarring and fibrosis. Advanced donor age, delayed graft function, calcineurin toxicity and repeated acute rejection episodes are risk factors for this pathophysiology. METHODS: We employed 3, 12 and 24 months surveillance renal biopsies, scored using the Chronic Allograft Damage Index (CADI), with periodic estimates of glomerular filtration rate (eGFR) to assess the effect of a steroid-free maintenance immunosuppression regimen on allograft histology and function. Ninety-one patients were induced with Alemtuzumab and then treated with mycophenolate sodium and low trough concentrations of tacrolimus. RESULTS: Fifty-six of 91 patients followed for 24 months showed no clinical rejection and in 16 more only minimal histological or borderline changes as defined by Banff criteria were observed. Histologically acute rejection was observed in 14 patients including two detected on surveillance biopsy. Five patients refused biopsies but showed stable eGFR for 24 months. Graft histopathology in the group with no rejection did not worsen. In contrast, nearly half the patients with acute rejection showed progression of CADI scores and a total of four grafts were lost over the 2 years. The 16 patients with borderline rejection changes exhibited stable glomerular filtration rate throughout, but 12.5% showed progression of CADI scores in the 12- to 24-month period. CONCLUSIONS: Following Alemtuzumab induction and in conjunction with low-dose tacrolimus and mycophenolate, continuous steroid therapy was not required to prevent progressive injury or preservation of graft function in patients without biopsy-proven acute rejection. Scored surveillance renal biopsies provide a useful tool to monitor transplanted kidneys.

The MDRD equation underestimates the prevalence of CKD among blacks and overestimates the prevalence of CKD among whites compared to the CKD-EPI equation: a retrospective cohort study.

BACKGROUND: Black individuals are far more likely than white individuals to develop end stage renal disease (ESRD). However, earlier stages of chronic kidney disease (CKD) have been reported to be less prevalent among blacks. This disparity remains poorly understood. The objective of this study was to evaluate whether the lower prevalence of CKD among blacks in early stages of CKD might be due in part to an inability of the MDRD equation to accurately determine early stages of CKD in both the black and white population. METHODS: We conducted a retrospective cohort study of 97, 451 patients seen in primary care clinic in Veterans Integrated Service Network 2 (VISN 2) over a 7 year period to determine the prevalence of CKD using both the Modification of Diet in Renal Disease (MDRD) Study equation and the more recently developed CKD Epidemiology Collaboration (CKD-EPI) equation. Demographic data, comorbid conditions, prescription of medications, and laboratory data were recorded. Logistic regression and quantile regression models were used to compare the prevalence of estimated glomerular filtration rate (eGFR) categories between black and white individuals. RESULTS: The overall prevalence of CKD was lower when the CKD-EPI equation was used. Prevalence of CKD in whites was 53.2% by MDRD and 48.4% by CKD-EPI, versus 34.1% by MDRD and 34.5% by CKD-EPI in blacks. The cumulative logistic regression and quantile regression showed that when eGFR was calculated by the EPI method, blacks were as likely to present with an eGFR value less than 60 mL/min/1.73 m2 as whites. Using the CKD-EPI equation, blacks were more likely than white individuals to have stage 3b, 4 and 5 CKD. Using the MDRD method, the prevalence in blacks was only higher than in whites for stage 4 and 5 CKD. Similar results were obtained when the analysis was confined to patients over 65 years of age. CONCLUSIONS: The MDRD equation overestimates the prevalence of CKD among whites and underestimates the prevalence of CKD in blacks compared to the CKD-EPI equation.

Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients.

STUDY OBJECTIVE: This study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients. DESIGN AND SETTING: A cross-sectional, open-label, single center, 12-h pharmacokinetic-pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration-time curve (AUC0-12 ), AUC0-4 , 12-h troughs (C12 h ), maximum concentrations (Cmax ), oral clearance (Cl), with dose-normalized AUC0-12 , troughs, and Cmax with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate-adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms. PATIENTS: 65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post-transplant were evaluated. MEASUREMENTS AND MAIN RESULTS: Black recipients exhibited higher tacrolimus AUC0-12 (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC0-12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC0-12 was <100 ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%-19% of tacrolimus variability in dose (p = 0.002); AUC0-12 h * (p < 0.001), and Cl (p < 0.001). CONCLUSIONS: Tacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC0-12 h .

Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients.

Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance-associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes -24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross-sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0-12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0-12h . The wild-type haplotype ABCC2 CGC had greater mycophenolic acid AUC0-12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0-12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine-mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.

Beyond Single Nucleotide Polymorphisms: CYP3A5∗3∗6∗7 Composite and ABCB1 Haplotype Associations to Tacrolimus Pharmacokinetics in Black and White Renal Transplant Recipients.

Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both CYP3A5 or ABCB1. Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both CYP3A5 and ABCB1. A metabolic composite based upon the CYP3A5 polymorphisms: ∗3(rs776746), ∗6(10264272), and ∗7(41303343), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of ABCB1 on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: 1236C > T (rs1128503), 2677G > T/A(rs2032582), and 3435C > T(rs1045642). Finally, a combined analysis using both CYP3A5 and ABCB1 polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three CYP3A5 loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P < 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance (P < 0.001) with 50% lower AUC∗ (P < 0.001) than Poor metabolizers. No differences in C12 h were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The ABCB1 haplotype analysis detected significant associations of the wildtype 1236T-2677T-3435T haplotype to tacrolimus dose (P = 0.03), CL (P = 0.023), CL/LBW (P = 0.022), and AUC∗ (P = 0.078). Finally, analysis combining CYP3A5 and ABCB1 genotypes indicated that the presence of the ABCB1 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite CYP3A5∗3∗4∗5 and ABCB1 haplotypes. Consideration of multiple alleles using CYP3A5 metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks.

CKD in MYH9-related disorders.

MYH9-related disorders are rare causes of chronic kidney disease (CKD) presenting as chronic glomerulonephritis and derive from mutations of the MYH9 gene, which encodes for the nonmuscle myosin heavy chain IIA. These disorders are autosomal dominant and include May-Hegglin anomaly and Sebastian, Fechtner, and Epstein syndromes. Diagnosis of these disorders is made first in early childhood because of the characteristic peripheral-blood smear findings of thrombocytopenia, giant platelets, and variably detected basophilic cytoplasmic inclusion bodies in leukocytes. CKD typically develops later in adulthood and may progress to end-stage renal disease. MYH9-related disorders may be associated with deafness and cataract; hence, Alport syndrome becomes important in the differential diagnosis. However, the autosomal dominance pattern of inheritance and characteristic peripheral-blood smear findings in the former help differentiate the two conditions. New evidence suggests that MYH9 gene alterations also are associated with a greater risk of focal segmental glomerulosclerosis and hypertensive nephrosclerosis in African Americans. The purpose of this review is to focus on the known, but rarely recognized association of MYH9-related disorders with CKD and highlight the recent discoveries related to the MYH9 gene that may explain the reason for a high CKD burden in African Americans.

Cross Reactive Epitope Group antibodies in sensitized kidneys transplant recipients was associated with early acute Antibody Mediated Rejection.

BACKGROUND: Antibody Mediated Rejection (AMR) is a major cause of early graft loss, graft dysfunction, and chronic allograft nephropathy. Patients with elevated pre-transplant Panel Reactive Antibodies (PRA) are at much higher risk to develop AMR. We, retrospectively, studied the attack rate of AMR in sensitized recipients and evaluated whether preformed antibodies to donor Cross Reactive Epitope Group (CREG) and/or choice of induction immunosuppressive agent affected the frequency of this complication. METHODS: From the period between September 2002 and March 2008, we identified 19 sensitized renal transplant recipients (with mean PRA of 44.5+/-26%) and recorded the induction agent, number of HLA antigen mismatches, CREG match, CREG antibodies, PRA levels, clinical course, biopsy proven rejection episodes and presence of donor specific antibody. Nine patients were induced with Alemtuzumab (Campath-1H) and ten received horse or rabbit derived polyclonal antithymocyte antibody ATGAM (Pharmacia) or Thymoglobulin (Genzyme). All recipients were cross-match negative at time of transplant. RESULTS: Out of the 19 patients, 9 patients developed acute rejection (47.4%), 4 had AMR and 5 had Acute Cellular Rejection (ACR). Out of 19 patients, 9 patients had existing CREG antibodies (as per CREG Model proposed by McKenna, Takemoto et al.). All patients who developed AMR were found of have preformed antibodies to donor CREG. The median time interval for the development of acute humoral rejection was only 6 days and biopsies showed acute vascular rejection with Complement (C(4)D) deposition. CONCLUSIONS: Pre-existing CREG antibodies in sensitized renal transplant patients appear to identify a group at high risk to develop AMR.

Kidney transplantation and pregnancy.

PURPOSE OF REVIEW: The purpose of this review is to improve the basis upon which advice on pregnancy is given to renal transplant recipients in the reproductive age group. The review attempts to impart up-to-date evidence-based information on the predictable outcome and the risk of pregnancy after kidney transplantation. RECENT FINDINGS: A current change in the consensus opinion of American Society of Transplantation regarding timing of pregnancy after transplantation. There are conflicting data regarding the utility of drug monitoring and dose adjustments of immunosuppressive medications during pregnancy and breast feeding. There is a recent change in the U.S. Food and Drug Administration category of mycophenolate mofetil from pregnancy Class C to D based on recent adverse fetal and neonatal outcome. SUMMARY: Counseling regarding pregnancy should be an integral part of caring for the kidney transplant patient in the reproductive age group. Ethical concerns exist about advising pregnancy and fertility treatment for a woman whose life expectancy may be affected by outcome of pregnancy. Toxic effects of newer immunosuppressive medications exposed in utero and during breast feeding and its long-term effects in the offspring have to be clearly defined. The need for longitudinal studies and multicenter observational studies cannot be over emphasized to help answer our considerable gaps in this area.

Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post-Renal Transplant.

Tacrolimus or cyclosporine is prescribed with mycophenolic acid posttransplant and contributes to interpatient variability in mycophenolic acid pharmacokinetics and response. Cyclosporine inhibits enterohepatic circulation of the metabolite mycophenolic acid glucuronide, which is not described with tacrolimus. This study investigated mycophenolic acid pharmacokinetics and adverse effects in stable renal transplant recipients and the association with calcineurin inhibitors, sex, and race. Mycophenolic acid and mycophenolic acid glucuronide area under the concentration-time curve from 0 to 12 hours (AUC0-12h ) and apparent clearance were determined at steady state in 80 patients receiving cyclosporine with mycophenolate mofetil and 67 patients receiving tacrolimus with mycophenolate sodium. Gastrointestinal adverse effects and hematologic parameters were evaluated. Statistical models evaluated mycophenolic acid pharmacokinetics and adverse effects. Mycophenolic acid AUC0-12h was 1.70-fold greater with tacrolimus (68.9 ± 30.9 mg·h/L) relative to cyclosporine (40.8 ± 17.6 mg·h/L); P < .001. Target mycophenolic acid AUC0-12h of 30-60 mg·h/L was achieved in 56.3% on cyclosporine compared with 34.3% receiving tacrolimus (P < .001). Mycophenolic acid clearance was 48% slower with tacrolimus (10.6 ± 4.7 L/h) relative to cyclosporine (20.5 ± 10.0 L/h); P < .001. Enterohepatic circulation occurred less frequently with cyclosporine (45%) compared with tacrolimus (78%); P < 0.001; with a 2.9-fold greater mycophenolic acid glucuronide AUC0-12h to mycophenolic acid AUC0-12h ratio (P < .001). Race did not affect mycophenolic acid pharmacokinetics. Gastrointestinal adverse effect scores were 2.2-fold higher with tacrolimus (P < .001) and more prominent in women (P = .017). Lymphopenia was more prevalent with tacrolimus (52.2%) than cyclosporine (22.5%); P < 0.001. Calcineurin inhibitors and sex contributed to interpatient variability in mycophenolic acid pharmacokinetics and adverse effects post-renal transplant, which could be attributed to differences in enterohepatic circulation.

Mycophenolate mofetil in the treatment of retroperitoneal fibrosis.

The pathogenesis of idiopathic retroperitoneal fibrosis (IRPF) has been attributed to an autoimmune response to atherosclerotic lipid material leaking from blood vessels. Corticosteroids and cytotoxic agents have been used for therapy. Based on the immunosuppressive and anti-fibrotic action of mycophenolate, we administered this agent to a patient with biopsy-proven IRPF and achieved a rapid, complete and sustained remission with a 6-year follow-up.

Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients.

Tacrolimus exhibits inter-patient pharmacokinetic variability attributed to CYP3A5 isoenzymes and the efflux transporter, P-glycoprotein. Most black renal transplant recipients require higher tacrolimus doses compared to whites to achieve similar troughs when race-adjusted recommendations are used. An established guideline provides tacrolimus genotype dosing recommendations based on CYP3A5*1(W/T) and loss of protein function variants: CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343) and may provide more comprehensive race-adjusted dosing recommendations. Our objective was to develop a tacrolimus population pharmacokinetic model evaluating demographic, clinical, and genomic factors in stable black and white renal transplant recipients. A secondary objective investigated race-based tacrolimus regimens and genotype-specific dosing. Sixty-seven recipients receiving oral tacrolimus and mycophenolic acid ≥6 months completed a 12-hour pharmacokinetic study. CYP3A5*3,*6,*7 and ABCB1 1236C>T, 2677G>T/A, 3435C>T polymorphisms were characterized. Patients were classified as extensive, intermediate, and poor metabolizers using a novel CYP3A5*3*6*7 metabolic composite. Modeling and simulation was performed with computer software (NONMEM 7.3, ICON Development Solutions; Ellicott City, Maryland). A 2-compartment model with first-order elimination and absorption with lag time best described the data. The CYP3A5*3*6*7 metabolic composite was significantly associated with tacrolimus clearance (P value < .05), which was faster in extensive (mean: 45.0 L/hr) and intermediate (29.5 L/hr) metabolizers than poor metabolizers (19.8 L/hr). Simulations support CYP3A5*3*6*7 genotype-based tacrolimus dosing to enhance general race-adjusted regimens, with dose increases of 1.5-fold and 2-fold, respectively, in intermediate and extensive metabolizers for comparable exposures to poor metabolizers. This model offers a novel approach to determine tacrolimus dosing adjustments that maintain comparable therapeutic exposure between black and white recipients with different CYP3A5 genotypes.

Utility of Serial Protocol Biopsies Performed After 1 Year in Predicting Long-Term Kidney Allograft Function According to Histologic Phenotype.

OBJECTIVES: Prognostic implications of early protocol biopsies have been studied; however, the value of late protocol biopsy in predicting graft outcome has not been well defined. Here, we compared the effects of early and late protocol biopsy histologic findings in stable kidney allografts and aimed to understand the significance of "borderline" rejection on allograft function. MATERIALS AND METHODS: We studied 261 biopsies from 159 renal transplant recipients who were on a steroid-free, calcineurin inhibitor and mycophenolate mofetil regimen and who received transplants between 2004 and 2012 with mean follow-up of 5 years. Early (between 3 and 9 mo) and subsequent late (between 12 and 24 mo) protocol biopsies were performed. Biopsies were classified as normal, interstitial fibrosis and/or tubular atrophy, subclinical acute rejection with interstitial fibrosis and/or tubular atrophy, and borderline rejection with interstitial fibrosis and/or tubular atrophy. A linear mixed-effects model was used to determine the effects of early and late protocol biopsies on estimated glomerular filtration rate changes, with baseline time for estimated glomerular filtration rate fixed at 12 months. RESULTS: The adjusted model showed that estimated glomerular filtration rate at 3 months, donor age, delayed graft function, and early protocol biopsies were associated with baseline estimated glomerular filtration rate at 12 months. Estimated glomerular filtration rate changes over time were associated with findings of interstitial fibrosis and/or tubular atrophy at early biopsy and subclinical acute rejection and borderline rejection at late biopsy. At last follow-up, final estimated glomerular filtration rate was significantly associated with interstitial fibrosis and/or tubular atrophy at early biopsy and with subclinical acute rejection at late biopsy. CONCLUSIONS: Although early protocol biopsy predicted baseline estimated glomerular filtration rate, late biopsy was important for predicting changes in function over time. In addition, a diagnosis of "borderline" rejection on protocol biopsies predicted long-term graft function.