Henrik Ekberg

Dose Optimization Of Mycophenolate Mofetil When Administered With A Low Dose Of Tacrolimus In Cadaveric Renal Transplant Recipients

Background. Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. Methods. Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. Results. At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P =0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P <0.05). Conclusions. Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

Minimization of Immunosuppressive Therapy After Renal Transplantation: Results of a Randomized Controlled Trial

Modern immunosuppressive regimens reduce the acute rejection rate by combining a cornerstone immunosuppressant like tacrolimus or cyclosporine with adjunctive agents like corticosteroids, mycophenolate mofetil (MMF) or azathioprine, often associated with untoward side effects.

Association of four DNA polymorphisms with acute rejection after kidney transplantation

Renal transplant outcomes exhibit large inter‐individual variability, possibly on account of genetic variation in immune‐response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open‐label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal‐toxicity (CAESAR)] investigating renal function and biopsy‐proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50–6.67]; P = 0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42–8.09]; P = 0.006). BPAR was almost fivefold more likely in patients homozygous for IL‐10 ‐592A (OR: 4.71, 95% CI [1.52–14.55]; P = 0.007) and twice as likely in patients with at least one A allele of TNF‐α G‐308A (OR: 2.18, 95% CI [1.08–4.41]; P = 0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant.

Serum Cystatin C Is a More Sensitive and More Accurate Marker of Glomerular Filtration Rate than Enzymatic Measurements of Creatinine in Renal Transplantation

Background/Aims: Serum creatinine has several drawbacks as marker of glomerular filtration rate (GFR), and therefore serum cystatin C has been proposed as a more optimal GFR marker. Previous reports have suggested benefits of serum cystatin C measurements in patients with renal transplants. The purpose of the present study was to evaluate the diagnostic accuracy of cystatin C measurements compared with enzymatic creatinine measurements as serum markers of GFR (established from plasma clearance of iohexol) in a large cohort of stable renal transplant recipients and in the early postoperative phase. Methods: Renal transplant patients (n = 125) with stable graft function were evaluated from reciprocals of serum creatinine and cystatin C compared with iohexol clearance. Fourteen patients were examined immediately after the onset of renal function. Cystatin C was measured by a particle-enhanced turbidimetric method and creatinine by an enzymatic method. Results: In stable renal transplant recipients, serum cystatin C showed a significantly (p = 0.033) closer correlation (r = 0.89 or 79% co-variance) with iohexol clearance than did serum creatinine (r = 0.81 or 66% co-variance). Using the χ2 test and a cut-off at 60 ml/min/1.73 m2, serum cystatin C levels demonstrated significantly higher sensitivity for early GFR impairment (p = 0.0045) compared with serum creatinine measurements. On the first day after transplantation, serum cystatin C fell more rapidly than serum creatinine. Conclusion: Serum cystatin C levels correlate significantly closer to accurate measurements of GFR and are significantly more sensitive to detect early GFR impairment than enzymatic measurements of creatinine in serum.

Co-administration of tacrolimus and mycophenolate mofetil in cadaveric renal transplant recipients

Co-administration of tacrolimus and mycophenolate mofetil in cadaveric renal transplant recipients.

Do drug transporter (ABCB1) SNPs and P‐glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study

The function of the efflux pump P‐glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was evaluated in PBMC using the Rhodamine 123 efflux assay. TT carrier patients on C3435T, G2677T, and C1236T SNPs (Pgp‐low pumpers) showed lower Pgp activity than noncarriers. Pgp‐high pumpers treated with cyclosporine showed lower values of Pgp function than macrolides. There was a negative correlation between cyclosporine AUC and Pgp activity at 3 months. Results did not show any correlation between tacrolimus and sirolimus AUC and Pgp activity at 3 months. We found an important role of the ABCB1 SNPs Pgp function in CD3+ peripheral blood lymphocytes from renal transplant recipients. Pgp activity was influenced by cyclosporine but not macrolides exposure.

Accuracy of Noninvasive Ultrasonic Volume Measurements on Human Kidney Transplants

Purpose: To evaluate the precision in volume measurement on human kidney transplants with the aid of noninvasive ultrasonic technique. Material and Methods: A Philips P700 ultrasound machine was used for noninvasive volume determination of 28 porcine kidneys compared to plethysmography. Also, the volume of 46 human transplanted kidneys in situ were measured by ultrasound. Since the configuration of the two types of kidneys differed, a new formula for volume measurement, suitable for kidney transplants, was developed with the aid of clay model experiments. Results: With the standard ellipsoid formula the accuracy of ultrasonic volume determination of the porcine kidneys was good compared with plethysmography, with intra- and interobserver variability of 10.9 and 9.2%, respectively. However, since the width and depth in relation to length of the transplanted kidneys were greater than in the porcine ones (55 vs. 47.5% and 54 vs. 28%, p < 0.01), a new ellipsoid formula was created (r = 1.0, p < 0.0001). Conclusion: Noninvasive ultrasonic kidney volume measurements show an acceptable reproducibility (CV 10%). Since the previously used formula for calculating kidney volume was inaccurate on human kidney transplants, a new and accurate ellipsoid formula fitting for human transplanted kidneys is suggested.

Small Islets are Essential for Successful Intraportal Transplantation in a Diabetes Mouse Model

Optimization of islet transplantation protocols is necessary for improved success of treatment for type 1 diabetes. Here, we investigated whether the size of islets transplanted into the portal vein (PV) of the liver can affect engraftment in the early post‐transplantation in an experimental mouse model. Small (average diameter < 250 μm, group A) or large (average diameter > 250 μm, group B) islets (400 islet equivalents/recipient) purified from normal BALB/c mice were transplanted into syngenic recipients with diabetes induced by STZ. The percentage of mice returning to a non‐diabetic status was higher in group A (100%) than that of group B (62.5%). Focal areas of liver necrosis associated with the islets emboli were observed in both groups, but the pathology in group B was significantly worse. Multiple proinflammatory cytokines were significantly higher in group B than that of A at 3 h post‐transplantation. Our study determined that the size of islets plays a critical role in the success of intraportal islet transplantation (IPIT) and should be taken into account in future IPIT protocols for the treatment of diabetes.

Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1

We have recently described the immunosuppressive properties of AR‐C117977 and AR‐C122982, representatives of a group of compounds identified as inhibitors of lactate transporters (monocarboxylate transporters; MCTs). These compounds demonstrate the potential therapeutic usefulness of inhibiting MCT‐1, but their physical and metabolic properties made them unsuitable for further development. We have therefore tried to find analogues with similar immunosuppressive efficacy and a more suitable profile for oral administration. Five analogues of AR‐C117977 were synthesised and screened for binding to the transporter, for inhibition of proliferation of both human and rat lymphocytes, for in vivo activity in a model of graft‐versus‐host (GvH) response in the rat, and in high‐ and low‐responder cardiac transplant models in the rat. There was a good correlation between levels of binding of the five analogues to MCT and their inhibition of lymphocyte proliferation in human and rat cells. Furthermore, activity in both the GvH response and the cardiac transplant models correlated well with the determined concentrations of test compound in plasma. These findings on new analogues of MCT‐1 inhibitors have taken us further towards defining the pharmacokinetic properties that may help to identify future drug candidates among inhibitors of MCT‐1.

Increased Prevalence of Apolipoprotein E3/E4 Genotype among Swedish Renal Transplant Recipients

There is increasing evidence that lipoproteins are involved in the progression of kidney diseases and in the deterioration of kidney transplant function, although the exact mechanism is still not known. Common polymorphisms of apolipoprotein E genotype associate with the variability of lipoprotein levels and composition. We have, therefore, determined the apolipoprotein E genotype in a group of 112 renal transplant patients, of whom 27 had had an episode of acute vascular rejection, while 85 had not. We found no difference in apolipoprotein E genotype distribution or in relative allele frequency in the vascular rejection group as compared with the group without vascular rejection. The apolipoprotein E genotype distribution in the transplant group was also compared with that in a group of 407 healthy Swedish individuals. The E3/E4 genotype occurred with a significantly increased frequency in the transplant group: 38.3 versus 16% in the control group (p < 0.001). The prevalence of individuals carrying the Ε4 allele among the transplant group was also significantly higher (44%) as compared with the control group (30%; p < 0.01). This increase was entirely due to the predominant increase of E3/E4, as the E4/E4 genotype was less frequent in transplant recipients than in normal controls (3.5 vs. 10.6%; p < 0.05). The relative frequencies of Ε2 (0.044), Ε3 (0.716), and Ε4 (0.238) alleles in the renal transplant group were not different from those of normal controls (0.078, 0.718, and 0.202, respectively). With regard to the prevalence of E4/E4 in the two groups, the lack of difference in the relative frequency of the Ε4 allele must be interpreted with caution. The results thus suggest that the E3/E4 genotype may be associated with the progression of kidney disease leading to renal insufficiency. However, the apolipoprotein E genotype does not seem to influence the risk of vascular rejection among transplant recipients.