Regimen In Kidney Transplantation Research Articles

Lowering the Dose of Corticosteroid Regimen in Kidney Transplantation: Is It Effective in Decreasing Post-operative Surgical Complications?

To investigate the impact of reducing post-operative oral corticosteroid regimen on associated postoperative surgical complication rate, patient and graft survival in kidney transplant patients. In this retrospective cohort study, we enrolled patients who received a kidney transplant during two periods of distinct corticosteroid protocols. 592 patients in group 1 received prednisone 2 mg/kg (maximum dose 120 mg) on post-operative days (POD) 1, 2 and 3, 1mg/kg for a week, and tapered it to 10 mg by 3 months post-transplant and sustained the daily 10mg from 3 months post-transplant as maintenance therapy. 639 patients in group 2 received prednisone 50 mg on POD 1, 40mg on POD 2, 30mg on POD 3, 20mg on POD 4, 15mg on POD 5 and continued with 10mg daily from POD 6, as maintenance therapy. The two groups were similar in terms of other immunosuppression drug regimens. 75 (12.7%) patients in group 1 and 24 (3.4%) patients in group 2 developed corticosteroid-related postoperative surgical complications (P < .001). Wound infection (P = .035), incisional hernia (P = .003), infectious collection (P = .004), post-op hemorrhage (P = .005) and ureteral fistula (P = .076) occurred with lower frequency in group 2. Patient survival (1-year: 97.3% vs 97.1%, respectively; P = .85, 5-year: 89.9% vs 94.9%, respectively; P = .06) and graft survival (1-year: 94.6% vs 93.3%, respectively; P = .29, 5-year: 81.2% vs 85.1%, respectively; P = .39) were similar in both groups. Post-operative corticosteroid dosage decrement through our protocol would lessen the serious associated postoperative surgical complications, without negative impacts on overall patient and graft survival.

MO1021: Long-Term Outcomes After Conversion to a Belatacept-Based Immunosuppression in Kidney Transplant: A Matched Cohort Study

Abstract BACKGROUND AND AIMS Conversion to a belatacept regimen after transplant seems to be safe. However, no studies have reported the long-term efficacy and safety outcomes after conversion to a belatacept regimen and compared it with patients treated with a CNI-based regimen in kidney transplantation. This study aims to investigate the long-term outcomes of patients converted to a belatacept regimen compared with matched patients under a CNI regimen. METHOD Kidney transplant recipients transplanted between 1998 and 2019 from two French academic transplant canters were recruited. We used a propensity score to match with a 1:1 ratio of patients at the time of the biopsy, which indicates the conversion to a belatacept regimen to control patients under a CNI regimen with a biopsy after transplant. We used 11 parameters associated with graft survival for the matching, 4 baseline transplant characteristics (recipient age, prior transplant status, donor type and dgf) and 7 at time of the biopsy (time after transplant, eGFR, proteinuria, DSA and Banff scores cv, ah, IFTA). Transplant outcomes defined by graft and patient survival, as well as safety outcomes, were compared between the matched patients. RESULTS From 3215 kidney transplant recipients transplanted during the study period with the inclusion criteria (311 patients under belatacept and 2904 patients under CNI). A total of 243 patients under belatacept were matched with 243 controls under CNI. All prognostic parameters were well-balanced before conversion between the two groups, with a mean age of 54.7 ± 15.1 years (P = .4543), a mean time of 2.2 ± 3.2 years after transplant (P = .586), a mean eGFR of 33.0 ± 13.3 mL/min/1.73 m2 (P = .976), a median proteinuria of 0.23 (0.12–0.50) g/g (P = .278) and 30.9% of positive anti-HLA DSA (P = 1.0) in the belatacept group. After a mean follow-up time after conversion of 4.4 ± 2.5 years, 36 (14.8%) patients lost their grafts and 39 (16.0%) patients died in the belatacept cohort. After conversion to a belatacept regimen, the graft survival was significantly improved when we compared with the matched patients’ under CNI P &amp;lt; .0001 (Fig. 1). Patients converted to Belatacept showed a lower death rate of 16.0% compared with 30.0% for the CNI treated patients (P &amp;lt; .001). The safety outcomes showed a similar rate of biopsy proven rejection (P = .08), major adverse cardiovascular events and cancer between the two groups, while a significant higher rate of CMV disease was observed among the belatacept treated patients P &amp;lt; .01). CONCLUSION This study confirms that conversion to belatacept post-transplant is associated with improved long-term graft outcome and acceptable safety. Conversion to belatacept after transplant should be considered as a valuable therapeutic option for kidney recipients.

UNOS/OPTN Data-guided Assessment of Focal Segmental Glomerulosclerosis After Kidney Transplantation and Evaluation of Immunosuppressive Protocols in a Steroid-free Center.

Background.Focal segmental glomerulosclerosis (FSGS) is a common recurrent glomerulopathy associated with graft loss and patient survival after kidney transplantation (KT). However, its natural history, clinical predictors, and treatment response are still poorly understood. Steroid withdrawal regimens in KT have been associated with improvements in cardiovascular risk and patient outcomes. The Scripps Center for Organ Transplantation (SCOT) uses a rapid low-dose steroid withdrawal immunosuppression (IS) protocol for KT maintenance.Methods.We assessed the impact of our protocol on FSGS disease recurrence over a 10-y period to reassess our steroid and IS protocols and to evaluate if our patient outcomes diverge from published data. We compared 4 groups: steroids always, steroid free, steroid switch on, and steroid weaned off. We used IS and induction-matched retrospective data from United Network for Organ Sharing (UNOS) to investigate patient and graft survival for FSGS at SCOT.Results.Our analysis results differ from earlier studies showing that FSGS was associated with a higher risk of graft loss, perhaps because of selection of a UNOS data set filtered to match the SCOT IS protocol for making direct comparisons. Overall outcomes of graft failure and recipient death did not differ between SCOT patients and steroid-free transplant patient data from the UNOS data for FSGS. SCOT recurrence rate for FSGS was 7.5%, which was lower than in most published single-center studies.Conclusions.Based on our results, we believe that it is safe to continue the steroid avoidance protocols at SCOT and the steroid-free protocol may not be detrimental when the adverse effects and toxicities associated with steroid use are considered.

UNOS/OPTN data guided assessment of IgA nephropathy recurrence after kidney transplantation and evaluation of immunosuppressive protocols in a steroid free center

Immunoglobulin A (IgA) Nephropathy (IgAN) is one of the most common recurrent glomerulopathies associated with graft loss and patient survival after kidney transplantation (KT). Steroid withdrawal regimens in KT have been associated with improvements of patient outcomes. The Scripps Center for Organ Transplantation (SCOT) utilizes a rapid low-dose steroid withdrawal immunosuppression (IS) protocol for KT maintenance. We assessed the impact of our protocol on IgAN recurrence over a 10-year period to reassess our steroid withdrawal and IS protocols to see if outcomes diverged from available UNOS data. Therefore, we used IS and induction matched retrospective data from UNOS to investigate patient and graft survival for IgAN. SCOT recurrence rates for IgAN was 13.6%. Overall outcomes of graft failure and recipient death did not differ between SCOT patients and data obtained from steroid free transplants from UNOS. Our results differ from earlier studies showing IgAN was associated with a higher risk of graft loss, perhaps due to selection of a SCOT IS matched dataset. Based on our analysis, we believe that it is safe to continue the steroid avoidance protocols at SCOT and think that it may be beneficial, given the adverse effects and toxicities associated with steroid use.

Role of CD28 Signaling on T cell Phenotype following Lymphodepletion and Homeostatic Reconstitution

Calcineurin inhibitors, the current standard of care in immunosuppression for transplant patients, leads to nephrotoxicity and loss of graft function over time. Preclinical studies have shown selective CD28 blockade (CD28 dAb, Lulizumab) to be superior to calcineurin inhibitors in reducing toxicity and prolonging allograft survival. Emory University will soon commence a Phase 2 clinical trial testing the efficacy of a Lulizumab‐based immunosuppression regimen in kidney transplantation. Patients in the trial will be T cell depleted (TCD), rendering them lymphopenic at the time of transplant and will therefore undergo homeostatic reconstitution in the weeks following transplantation. Lulizumab prevents T cell activation by selectively targeting CD28 signaling, but it is presently unclear what effect blocking this pathway will have on T cell phenotypes following homeostatic reconstitution (HR) in these patients. Previous studies have shown that HR leads to increased differentiation of naïve T cells into memory cells and to premature senescence. We hypothesized that blocking CD28 signaling in T cells during this process could prevent memory differentiation and senescence. We investigated this question using a murine model of TCD and skin transplantation. Four groups of mice were established: no treatment control, TCD alone, CD28 dAb alone, and both TCD and CD28 dAb (n = 4). Mice were sacrificed at 6 weeks post‐depletion and transplantation, and blood and tissues were collected for flow cytometric analysis. Using both traditional flow cytometry analysis and an unsupervised machine‐learning approach, we found that TCD CD4+ T cells have significantly elevated expression of the memory markers CD27, CD103, and CD69 when compared to no treatment control CD4+ T cells, indicating HR‐induced differentiation into memory T cells. In addition, TCD CD4+ T cells also expressed significantly higher levels of PD‐1, TIGIT, and CD226 (DNAM‐1) when compared to no treatment control CD4+ T cells, indicating a higher degree of senescence. Finally, we found that treating TCD mice with CD28 dAb restored expression of both memory markers and costimulatory markers to baseline levels. As such, we believe CD28 dAb presents a viable method to control HR‐induced differentiation and senescence of CD4+ T cells. These results were consistent across the blood, lung, and spleen. Our future directions include using murine models to determine whether the selective CD28 blockade‐mediated rescue of the HR‐induced phenotypic changes significantly affects protective immunity to infection.Support or Funding InformationResearch reported here was supported by the National Institutes of Health under award number R25 DK 101390 ‐ Title: Summer Undergraduate Program in Renal Research (SUPERR).

Effect of Panel-Reactive Antibody on Graft Survival in Living Kidney Donor Transplantation: Analysis of 10 Years in a Transplant Center in Veracruz, Mexico

BackgroundPretransplant anti-HLA antibodies are a risk factor for graft rejection and loss, and its percentage estimate is known as panel-reactive antibody (PRA). Our objective was to evaluate the influence of PRA on the survival of renal grafts from living donors over a period of 10 years. MethodsRetrospective analysis was completed in all living donor transplants with PRA class I and class II from October 2008 to December 2018 with follow-up until June 2019. The methods used for the PRA were flow cytometry and Luminex. Graft survival (not censored) was evaluated by Kaplan-Meier (log-rank) and Cox regression. P < .05 was considered significant. ResultsThe study included 393 patients. PRA class I mean was 9.8 ± 20% (0%-98%) and class II mean was 8.6 ± 17.8% (0%-97.8%). Of the patients, 81.9% had a PRA <20% for any class. Uncensored graft survival at 1, 5, and 10 years was 90.3%, 76.2%, and 69.3%, respectively. Mean estimated uncensored graft survival in PRA <20% patients (103.9 ± 2.7, 95% confidence interval [CI] 96.6-11.2) was higher than that of PRA >20% patients (61.5 ± 5.7, 95% CI 50.3-72.8) (P = .005 log-rank). Cox regression (univariate) was statistically significant for PRA class I (Exp [B] 1.01, 95% CI 1.003-1.02, P = .009) and for PRA >20% any class (Exp [B] 2.074, 95% CI 1.222-3.520, P = .007). ConclusionPRA class I and PRA >20% any class are associated with lower graft survival. PRA must be considered to determine immunologic risk and to choose an immunosuppressive regimen in kidney transplantation.

Preliminary assessment of safety and adherence to a once-daily immunosuppression regimen in kidney transplantation: Results of a randomized controlled pilot study.

Medication non-adherence is common after transplant and a major contributor to graft loss. The objective of this pilot study was to obtain preliminary safety and adherence data of a complete once-daily immunosuppression regimen of Extended-release-tacrolimus (LCP-tac), everolimus, and prednisone vs LCP-tac, mycophenolate Twice daily (BID), and prednisone through a randomized controlled pilot study of 40 patients (20 in each arm). At 3±2months post-transplant, patients were randomized to receive LCP-tac and everolimus once daily or LCP-tac and mycophenolate BID (control arm) for 6months; 80 met eligibility, and 40 were randomized. Mean age was 51±14years, 33% were female, 45% African American, and 55% had a Calculated panel reactive antibody (cPRA) >20%. Both regimens were well-tolerated, and medication side effect burden tended to be less severe in the intervention group. Self-reported high medication adherence decreased in the control arm from baseline to 6months (80%-59%), while remaining the same in the intervention arm throughout the study (45%-47%). For safety assessment, there was no rejection, graft loss, or death in either arm. These results provide preliminary evidence of the safety of a novel once-daily immunosuppression regimen. The impact of this once-daily regimen on medication adherence requires a larger long-term study.

Short-Term Intensified Dosage Regimen of Mycophenolic Acid is Associated with Less Acute Rejection in Kidney Transplantation from Donation after Circulatory Death

Introduction: Whether an early, short-term, adequate exposure to mycophenolic acid (MPA) under tacrolimus-based immunosuppression regimen in kidney transplantation from donation after circulatory death (DCD) was effective and safe is yet unknown. Material and Methods: The study was a single-center, retrospective, cohort study of DCD transplantation in China. Intensified and standard dosage regimens of enteric-coated mycophenolate sodium (EC-MPS) were week 1, 2,160 vs. 1,440 mg/day. The incidences of biopsy-proven acute rejection (BPAR), delayed graft function, infection, and patient and graft survival were compared between the 2 groups. Results: A total of 209 patients (n = 82 in intensified group and n = 127 in standard group) were enrolled from August 2013 to December 2014. The incidence of BPAR at 12 months was significantly lower in the intensified group as compared to that of the standard group. (2.4 vs. 10.2%, p = 0.035). The mean MPA area under curve (AUC) levels at day 7 was significantly higher in the intensified group than that in the standard group (66.18 ± 35.48 vs. 45.30 ± 23.5 mg·h/L, p < 0.001). MPA AUC levels were significantly decreased in patients with BPAR as compared to those with NO-BPAR. Conclusion: An early, short-term regimen of intensified EC-MPS with tacrolimus increased early MPA exposure and achieved a low rate of BPAR in kidney transplantation from DCD.

Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Tacrolimus in Kidney Transplantation.

Background: Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immu-nosuppressant which consists of the footstone as immunosuppressive regimens in kidney transplantation. However, the drug toxicity and the significant differences of pharmacokinetics (PK) and pharmacodynam-ics (PD) among individuals are hidden troubles for clinical application. Recently, emerging evidences of Tac pharmacogenetics (PG) regarding drug absorption, metabolism, disposition, excretion and response are discovered for better understanding of this drug.Method: We reviewed the published articles regarding the Tac PG and its effects on PK and PD in kidney transplantation. In addition, we summarized information on polygenic algorithms.Results: The polymorphism of genes encoding metabolic enzymes and transporters related to Tac were largely investigated, but the results were inconsistent. In addition to CYP3A4, CYP3A5 and P-gp (also known as ABCB1), single nucleotide polymorphisms (SNPs) might also affect the PK and PD parameters of Tac.Conclusion: The correlation between Tac PK, PD and PG is very complex. Although many factors need to be verified, it is envisaged that thorough understanding of PG may assist clinicians to predict the optimal starting dosage, help adjust the maintenance regimen, as well as identify high risk patients for adverse ef-fects or drug inefficacy

Interleukin-2 receptor antagonist compared with antithymocyte globulin induction therapy in kidney transplantation from donors after cardiac death.

The aim of this study was to compare the efficacy and safety of induction therapy using the interleukin-2 receptor antagonist (IL-2RA) with antithymocyte globulin (ATG) under a tacrolimus-based immunosuppression regimen in kidney transplantation from donors after cardiac death. It was a single-centre, retrospective, cohort study design to evaluate the efficacy and safety of IL-2RA vs. ATG induction therapy in adult renal transplant recipients from donors after cardiac death. The primary end-point was the incidence of biopsy-proven acute rejection (BPAR) at 6 months, and the secondary end-point included the incidence of delayed graft function (DGF), the renal function, and the patient and graft survival at 6 months. The safety end-point was the incidence of infectious complications. A total of 132 patients (n = 37 in the IL-2RA group and n = 95 in the ATG group) were enrolled from March 2013 to April 2014. The BPAR at 6 months was similar between the two groups (IL-2RA vs. the ATG group, 5.4% vs. 12.6%, respectively, p = 0.228). There were no differences in the DGF, renal function at 1 and 3 months, and the patient and graft survival at 6 months between the two groups, but the renal function at 6 months in the IL-2RA group was superior to that of the ATG group (p = 0.02). The IL-2RA group experienced less infection than the ATG group (p = 0.025). The efficacy of IL2-RA and ATG induction under a tacrolimus-based immunosuppression regimen in low-risk DCD transplantation did not differ, but the safety of the IL2-RA induction was better than that of the ATG induction.

Safety and Efficacy of Induction Treatment with Low Thymoglobulin Doses in Kidney Transplantation from Expanded-Criteria Donors

BackgroundInduction treatment has been recommended as part of the initial immunosuppressive regimen in kidney transplantation, and antithymocyte globulin is one of the drugs used for it, but at usual dosage it has been related to an increase of infectious and neoplastic complications. Our aim was to analyze the safety and efficacy of induction treatment with low doses of antithymocyte globulin, compared to basiliximab. MethodsIn this retrospective cohort study of 321 kidney transplant patients with a minimum follow-up of 2 years, 162 were treated with low doses of antithymocyte globulin (1.25 mg/kg, every other day) and 159 with basiliximab. Mean follow-up was 76.6 ± 37.51 months (range, 24–187 mo) and was similar for the 2 groups. ResultsMean number of antithymocyte globulin doses was 1.89 ± 0.32 mg/kg (range, 1–3). The globulin group received a higher proportion of kidneys from donors >70 years old (25.3% vs 13.8%; P = .010) and donors with higher creatinine levels (1.01 ± 0.62 vs 0.86 ± 0.28 mg/dL; P = .006). The basiliximab group presented a higher incidence of acute rejection (22.1% vs 9.1%; P = .010). Cytomegalovirus disease was more frequent in the globulin group (18.6% vs 8.1%; P = .011) without an increase of infectious hospitalizations. Graft (P = .214) and patient (P = .533) survivals were similar. ConclusionsInduction with low doses of antithymocyte globulin resulted in a lower incidence of acute rejection with graft and patient survivals similar to that obtained with basiliximab induction, in spite of a worse donor profile. CMV disease was more frequent with antithymocyte globulin, without an increase of infectious hospitalizations or cancer development, in long-term follow-up.

Risk of Metabolic Complications in Kidney Transplantation After Conversion From Calcineurin Inhibitor to mTOR Inhibitor: A Systematic Review and Meta-Analysis.

Background: Mammalian target of rapamycin (mTOR) inhibitors (sirolimus/everolimus) have been used in calcineurin inhibitor (CNI)-sparing regimens in kidney transplantation to minimize CNI-induced vasoconstriction and nephrotoxicity. However, the incidence of metabolic complications after conversion from CNI to mTOR inhibitor is not fully documented. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials reporting incidences of new-onset diabetes after transplant (NODAT) and hypercholesterolemia in transplant recipients converted from CNI- to mTOR inhibitor-based immunosuppressive regimen. The endpoints included relative risks (RR) and incidences of these metabolic complications. Results: A total of 109 publications were identified, of which 9 trials (published from 2005 to 2012), involving a total of 2,312 patients, met the pre-defined eligibility criteria and were included in meta-analysis. The mean follow-up duration of these studies was 17 months. By using the random-effects model, the incidence of NODAT was calculated as 5.7% (95% confidence interval (CI) 3.42-9.3%) in patients receiving mTOR inhibitors in comparison to 4.9% (95% CI 3.2-7.6%) in those receiving CNI, while the incidence of hypercholesterolemia was 29.0% (95% CI, 15.6-47.3%) and 13.8% (95% CI, 4.8-33.5%), respectively. The conversion from CNI-based to mTOR inhibitor-based regimen was associated with a non-significantly increased risk of NODAT (RR, 1.32; 95% CI, 0.92-1.89, p=0.11) and a significantly increased risk of hypercholesterolemia (RR, 1.91; 95% CI, 1.26-2.93, p=0.007).Table: No Caption available.Table: No Caption available.Conclusions: To our knowledge, this is the first meta-analysis to evaluate the risk of metabolic complications associated with conversion from CNIs to mTOR inhibitors in post-kidney transplant recipients in contemporary immunosuppressive regimens. Since cardiovascular mortality is the leading cause of long-term graft loss, clinicians should be aware of these risks when switching from CNI to mTOR inhibitor.

Corticosteroid and calcineurin inhibitor sparing regimens in kidney transplantation

Chronic kidney disease is a major public health problem that is associated with increased risks of kidney disease progression, cardiovascular disease and death. Kidney transplantation remains the renal replacement therapy of choice for patients with end-stage kidney disease. Despite impressive strides in short-term allograft survival, there has been little improvement in long-term kidney graft survival, and rates of death with a functioning allograft remain high. Long-term safety profiles of existing immunosuppressive regimens point to a need for continued search for alternative agents. This overview discusses emerging evidence on a few promising therapeutic approaches, juxtaposes conflicting findings and highlights remaining knowledge gaps.

René Küss (1913–2006)–A Transplant Pioneer in Paris

René Küss (1913–2006), an outstanding urologic surgeon, was one of the leading pioneers in kidney transplantation. He suggested and perfected the retroperitoneal placement of the donor kidney into the iliac fossa and its anastomosis to the iliac vessels in the early 1950s. He was one of the first to introduce an immunosuppressive regimen in kidney transplantation a decade later. Küss established the first multiple department of urology at the Paris hospitals, served as General Secretary and later as President for the Société Internationale d'Urologie from 1952 until 1985, and founded “La Société Francaise de Transplantation” as the first scientific society dedicated to transplantation medicine in Europe in 1971. Moreover, Küss was an art connoisseur and collector, an automobiliste, and a medical historian.

Quality of Life Outcomes Reported in Randomised Controlled Trials of Immunosuppressive Drug Regimens in Kidney Transplantation: A Systematic Review

Quality of Life Outcomes Reported in Randomised Controlled Trials of Immunosuppressive Drug Regimens in Kidney Transplantation: A Systematic Review

Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation

Calcineurin-inhibitor-sparing strategies in kidney transplantation may spare patients the adverse effects of these drugs, but the efficacy of these strategies is unknown. Here, we conduct a meta-analysis to assess outcomes associated with reducing calcineurin inhibitor exposure from the time of transplantation. We search Medline, Embase, and Cochrane Register of Controlled Trials for randomized controlled trials published between 1966 and 2010 that compared de novo calcineurin-inhibitor-sparing regimens to calcineurin-inhibitor-based regimens. In this analysis, we include 56 studies comprising data from 11337 renal transplant recipients. Use of the contemporary agents belatacept or tofacitinib, in combination with mycophenolate, decreased the odds of overall graft failure (OR 0.61; 95% CI 0.39-0.96; P = 0.03). Similarly, minimization of calcineurin inhibitors in combination with various induction and adjunctive agents reduces the odds of graft failure (OR 0.73; 95% CI 0.58-0.92; P = 0.009). Conversely, the use of inhibitors of mammalian target of rapamycin (mTOR), in combination with mycophenolate, increases the odds of graft failure (OR 1.43; 95% CI 1.08-1.90; P = 0.01). Calcineurin-inhibitor-sparing strategies are associated with less delayed graft function (OR 0.89; 95% CI 0.80-0.98; P = 0.02), improved graft function, and less new-onset diabetes. The more contemporary protocols did not seem to increase rates of acute rejection. In conclusion, this meta-analysis suggests that reducing exposure to calcineurin inhibitors immediately after kidney transplantation may improve clinical outcomes.

Conversion to Proliferation Signal Inhibitors–Based Immunosuppressive Regimen in Kidney Transplantation: To Whom and When?

Background Despite significant advances in kidney transplantation, long-term graft survival has not dramatically improved leading to strategies to change immunosuppression during the posttransplantation period. Proliferation signal inhibitors (PSI) sirolimus or everolimus possess immunosuppressive and antiproliferative properties. Methods We evaluated 62 kidney transplant recipients who underwent conversion from a calcineurin inhibitors (CNI)– to a PSI-based regimen for various reasons. The statistical analysis used SPSS v.15.0 software. We compared calculated glomerular filtration rates (GFRs) before initiation of PSI (baseline) and at 6 months after conversion. Results We converted to a PSI-based triple regimen at 172.0 ± 116.5 days after transplantation. The mean serum creatinine at the time of conversion was 2.0 ± 1.1 mg/dL, and it was 1.5 ± 0.7 mg/dL at 6 months after conversion. The rate of change in serum creatinine was −17.1 ± 23.5%. The mean calculated GFR at the time of conversion was 53.6 ± 25.5 mL/min and at 6 months after conversion was 65.8 ± 23.7 mL/min. The rate of change in calculated GFR was 37.9 ± 71.7% (16.4/59.4) at 6 months. Thus we observed significant improvements in creatinine and GFR ( P values <.001) after conversion. The Improved GFR significantly correlated with prior dialysis duration and time to conversion ( P = .025; P = .012). Patients who had a shorter duration on dialysis and shorter time to conversion experienced more benefit from conversion. Four of the 62 patients reported gastrointestinal toxicity, which resolved with dose reduction in 3 patients: 15 patients experienced acne; 16 reported oral ulcers. None of these toxicities resulted in discontinuation of PSI therapy. Serum cholesterol and tryglyceride levels tended to increase among the conversion group, but they did not show statistical significance. Conclusion We observed that minimization or withdrawal of CNI with addition of a PSI was a good treatment for deterioration of renal allograft function.

Urinary hepatocyte growth factor indicates ischemia/reperfusion injury after kidney transplantation

Despite the development of immunosuppressive regimens in kidney transplantation, long-term graft survival rates have not increased significantly. One of the causes of long-term graft loss is ischemia-reperfusion insult. Hepatocyte growth factor (HGF) is a regenerative factor produced in response to injury. Our aim was to assess the effect of HGF and xanthine oxidase (indicators of ischemia/reperfusion insult) on early and late kidney function. In 17 patients, HGF levels in urine and xanthine oxidase activity in blood were examined 1, 7, 14, 30 days, 3 and 6 months after kidney transplantation. We also measured 24-hour diuresis and serum creatinine levels after transplantation. Urinary HGF levels were highest 1 day after transplantation. During the following week, it rapidly decreased and was maintained at similar levels in the later period. Creatinine at 1 day showed a positive correlation with urinary HGF levels at 1 day and at 3 months (R = 0.54, P <0.05 and R = 0.82, P <0.01, respectively). Creatinine at 7 days positively correlated with HGF levels at 6 months (R = 0.82, P <0.05). HGF levels at 1 day and at 6 months positively correlated with xanthine oxidase activity at 1 day (R = 0.73, P <0.001 and R = 0.77, P <0.02, respectively). A negative correlation was observed between HGF levels at 6 months and diuresis 1 and 7 days after transplantation (R = -0.99, P <0.00 001 and R = -0.77, P <0.05, respectively). Urinary HGF is a good marker of perioperative kidney damage and may affect long-term graft function.

Sirolimus-based calcineurin inhibitor withdrawal immunosuppressive regimen in kidney transplantation: a single center experience

This observational study was conducted to evaluate the safety and efficacy of the conversion from calcineurin inhibitors (CNIs) to sirolimus (SRL)-based immunosuppressive therapy in kidney transplantation. Sixty-four kidney recipients of mean age 38.3 +/- 14.6 years were converted to SRL. The main reasons for conversion were elective in 45 (70.3%) and biopsy-proven chronic allograft nephropathy in 11 (17.2%). The primary CNI used was cyclosporine A in 51 patients. Mean time to conversion was 50.5 months. After conversion, 61 patients received mycophenolate mofetil. We evaluated the impact of conversion on renal function for 5 years post-conversion. The overall mean follow-up time was 72.8 months. The analysis showed significant improvement in renal function at month 3 post-conversion (P < 0.05) with stabilization thereafter. Lipid parameters and blood sugar levels were similar pre- and post-conversion. Abnormal liver function test was transient in 12.8%. Reasons for SRL discontinuation were nephrotic range proteinuria in two patients and mouth ulceration in one. We compared patients with serum creatinine <140 micromol/l and those with serum creatinine > or = 140 micromol/l, and found that serum creatinine was an independent risk factor for chronic allograft dysfunction (P = 0.02). Graft loss occurred in three patients because of cardiovascular death in two and an acute rejection episode in one. We concluded that conversion from CNIs to SRL is an option and of benefit without significant acute rejection episodes or chronic allograft dysfunction especially in well-selected kidney transplant recipients with good graft function.

Clinicopathologic evaluation of short‐term outcome after early corticosteroid discontinuation in kidney transplantation

Steroids have been a gold-standard drug of immunosuppressive regimens in kidney transplantation. Steroid minimization protocols have been applied to minimize the adverse effects of steroids. We have evaluated the short-term outcomes of our early steroid discontinuation regimen. A total of 128 recipients who received kidney from ABO-compatible, flow crossmatch-negative living-related donors were included in this study. Immunosuppressive regimens consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), and basiliximab. In a cohort of recipients, designated as a steroid early discontinuation (ESD) group, only three doses of methylprednisolone (MP) were given (500, 250, 125 mg). In the other cohort of recipients, designated as a chronic steroid (CS) group, MP was given chronically, being tapered to 4 mg at one month post-transplant. TAC and mycophenolic acid (MPA) blood levels were monitored. The following data were retrospectively compared between the two groups at 1, 3, 6, 9, 12 months post-transplant: serum creatinine (sCr), urine protein per gCr (uP/Cr), the incidence of biopsy-proven acute rejection (BPAR), graft survival (GS), area-under-the-curve of blood levels of tacrolimus (TAC-AUC(0-12), ng h/mL) and mycophenolic acid (MPA-AUC(0-12), mug h/mL), MMF dose (mg), the incidence of opportunistic infection, post-transplant diabetes mellitus (PTDM), and histopathologic findings of protocol biopsy according to the Banff '07 classification. sCr and uP/Cr were comparable between the two groups up to 12 months except for sCr at one month (ESD group > CS group). TAC-AUC(0-12) was significantly higher in ESD group at one month but was equivalent thereafter, while the prevalence of biopsy-proven tubulotoxicity was not different. MMF dose was comparable throughout the period between two groups. The incidence of BPAR until 12 months was equivalent. Of note, 60% of BPAR cases in ESD group occurred within one month. Prevalence of opportunistic infection or PTDM was equivalent. Graft survival was 100% in both groups. The following histopathologic scores up to 12 months were also equivalent: t, i, g, v, ci, ct, cg, cv, mm, ah, and ptc. Favorable short-term outcomes were achieved both clinically and histologically using our early steroid discontinuation protocol compared with the conventional protocol with chronic steroid treatment.