Presence of a survival benefit of HLA-incompatible living donor kidney transplantation compared to waiting or HLA-compatible deceased donor kidney transplantation with a long waiting time.

HLA-incompatible living donor kidney transplantation (LDKT) is one of efforts to increase kidney transplantation opportunity for sensitized patients with kidney failure. However, there are conflicting reports for outcomes of HLA-incompatible kidney transplantation compared to patients who wait for HLA-compatible deceased donor kidney transplantation (DDKT) in the United States and United Kingdom. Waiting for an HLA-compatible DDKT is relatively disadvantageous in Korea, because the average waiting time is more than five years. To study this further, we compared outcomes of HLA-incompatible LDKT with those who wait for HLA-compatible DDKT in Korea. One hundred eighty nine patients underwent HLA-incompatible LDKT after desensitization between 2006 and 2018 in two Korean hospitals (42 with a positive complement-dependent cytotoxicity cross-match, 89 with a positive flow cytometric cross-match, and 58 with a positive donor-specific antibody with negative cross-match). The distribution of matched variables was comparable between the HLA-incompatible LDKT group and the matched control groups (waiting-list-only group; and the waiting-list-or-HLA-compatible-DDKT groups; 930 patients each). The HLA-incompatible LDKT group showed a significantly better patient survival rate compared to the waiting-list-only group and the waiting-list-or-HLA-compatible-DDKT groups. Furthermore, the HLA-incompatible LDKT group showed a significant survival benefit as compared with the matched groups at all strength of donor-specific antibodies. Thus, HLA-incompatible LDKT could have a survival benefit as compared with patients who were waitlisted for HLA-compatible DDKT or received HLA-compatible DDKT in Korea. This suggests that HLA-incompatible LDKT as a good option for sensitized patients with kidney failure in countries with prolonged waiting times for DDKT.

Effects of bisphosphonates on long-term kidney transplantation outcomes.

BACKGROUND: Bisphosphonates are administered to post-transplantation patients with mineral and bone disorders; however, the association between bisphosphonate therapy and long-term renal graft survival remains unclear. METHODS: This nested case-control study investigated the effects of bisphosphonates on long-term graft outcomes after kidney transplantation. We enrolled 3836 kidney transplant recipients treated from April 1979 to June 2016 and matched patients with graft failure to those without (controls). Annual post-transplant bone mineral density assessments were performed and recipients with osteopenia or osteoporosis received bisphosphonate therapy. The associations between bisphosphonate use and long-term graft outcomes and graft survival were analyzed using conditional logistic regression and landmark analyses, respectively. RESULTS: A landmark analysis demonstrated that death-censored graft survival was significantly higher in bisphosphonate users than in non-users in the entire cohort (log-rank test, P < 0.001). In the nested case-control matched cohort, bisphosphonate users had a significantly reduced risk of graft failure than did non-users (odds ratio = 0.38; 95% confidence interval 0.30-0.48). Bisphosphonate use, increased cumulative duration of bisphosphonate use >1 year and increased cumulative bisphosphonate dose above the first quartile were associated with a reduced risk of graft failure, after adjustments. CONCLUSIONS: Bisphosphonates may improve long-term graft survival in kidney transplant recipients.

Glomerular subepithelial microparticles - a footprint for podocyte injury.

The aim of this study was to clarify the nature and clinical significance of glomerular subepithelial microparticles (SMPs), located between the basal surface of the podocytes and the glomerular basement membrane. Ultrastructural morphology of 79 renal biopsy samples (obtained from 25 native and 54 transplanted kidneys), showing SMPs in the last 3 years, was reevaluated with regard to the podocyte changes and clinical condition of the patients. One hundred and nine SMPs were identified, with 32.9% of the samples having two or more per glomerulus. Overall, they were most frequently located in the open capillary loops (55%). However, in the native kidney samples with mesangial deposits, 64.3% of SMPs were present in the mesangium-bound areas. Each vesicle ranged from 46.9 to 87.1 nm, and vesicles were admixed with curved strands in larger SMPs. Diffuse effacement of the foot processes and condensation of the actin filaments were present in 56.0% and 62.4% of the samples, respectively. SMPs were associated with hematuria, proteinuria of ≥ 1 gm, and immune complex deposition in the patients with native kidneys, whereas they were related to hyperglycemia and elevated serum creatinine levels in the patients with renal allografts. Patients with native and transplanted kidneys most commonly presented with IgA nephropathy and allograft rejection, respectively. Finding SMPs in the renal biopsy samples is not rare and they may act as a footprint of podocyte injury caused by diverse etiologies. Considering their size, podocyte exosomes could be a possible source of SMPs.

Transplant outcomes in positive complement-dependent cytotoxicity- versus flow cytometry-crossmatch kidney transplant recipients after successful desensitization: a retrospective study.

BACKGROUND: Despite the obvious survival benefit compared to that among waitlist patients, outcomes of positive crossmatch kidney transplantation (KT) are generally inferior to those of human leukocyte antigen (HLA)-compatible KT. This study aimed to compare the outcomes of positive complement-dependent cytotoxicity (CDC) crossmatch (CDC + FC+) and positive flow cytometric crossmatch (CDC-FC+) with those of HLA-compatible KT (CDC-FC-) after successful desensitization. METHODS: We retrospectively analyzed 330 eligible patients who underwent KTs between June 2011 and August 2017: CDC-FC- (n = 274), CDC-FC+ (n = 39), and CDC + FC+ (n = 17). Desensitization protocol targeting donor-specific antibody (DSA) involved plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab with/without bortezomib for positive-crossmatch KT. RESULTS: Death-censored graft survival and patient survival were not different among the three groups. The median estimated glomerular filtration rate was significantly lower in the CDC + FC+ group than in the compatible group at 6 months (P < 0.001) and 2 years (P = 0.020). Biopsy-proven rejection within 1 year of CDC-FC-, CDC-FC+, and CDC + FC+ were 15.3, 28.2, and 47.0%, respectively. Urinary tract infections (P < 0.001), Pneumocystis jirovecii pneumonia (P < 0.001), and cytomegalovirus viremia (P < 0.001) were more frequent in CDC-FC+ and CDC + FC+ than in CDC-FC-. CONCLUSIONS: This study showed that similar graft and patient survival was achieved in CDC-FC+ and CDC + FC+ KT compared with CDC-FC- through DSA-targeted desensitization despite the higher incidence of rejection and infection than that in compatible KT.

Enhanced immune-modulatory effects of thalidomide and dexamethasone co-treatment on T cell subsets.

Thalidomide (TM) has been reported to have anti-cancer and anti-inflammatory properties, and dexamethasone (DX) is known to reduce inflammation and inhibit production of inflammatory cytokines. Many studies have reported that combinatorial therapy with TM and DX is clinically used to treat multiple myeloma and lupus nephritis, but the mechanism responsible for its effects has not been elucidated. In this study, we determined that TM and DX co-treatment had an enhanced immune-modulatory effect on T cells through regulating the expression of co-stimulatory molecules. Splenic naive T cells from C57BL/6 mice were sort-purified and cultured for CD4+ T cell proliferation and regulatory T (Treg) cell conversion in the presence of TM and/or DX. Following incubation with the drugs, cells were collected and OX40, 4-1BB, and glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) expression was quantified by flow cytometry. TM (1 or 10 µm) decreased CD4+ T cell proliferation in a dose-dependent manner, whereas TM/DX (0·1 or 1 nm) co-treatment further decreased proliferation. Treg cell populations were preserved following drug treatment. Furthermore, expression of co-stimulatory molecules decreased upon TM/DX co-treatment in effector T (Teff) cells and was preserved in Treg cells. Splenic CD4+ T cells isolated from TM- and DX-treated mice exhibited the same patterns of Teff and Treg cell populations as observed in vitro. Considering the selective effect of TM on different T cell subsets, we suggest that TM may play an immunomodulatory role and that TM/DX combinatorial treatment could further enhance these immunomodulatory effects by regulating GITR, OX40, and 4-1BB expression in CD4+ T cells.

Rituximab and hepatitis B reactivation in HBsAg-negative/ anti-HBc-positive kidney transplant recipients.

Background: Hepatitis B virus (HBV) reactivation is a well-known complication of immunosuppressive therapy. Although rituximab is increasingly used for desensitization of ABO-incompatible or positive crossmatch kidney transplantation, the risk of HBV reactivation in hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (anti-HBc)-positive kidney transplant patients receiving rituximab desensitization remains undetermined. Methods: We analysed 172 resolved HBV patients who underwent living donor kidney transplantation between 2008 and 2014. Patients were divided into rituximab ( n = 49) or control ( n = 123) groups. All patients were observed for HBV reactivation, which was defined as the reappearance of hepatitis B surface antigen or HBV DNA. Results: During the follow-up period (median, 58 months; range, 4-95 months), five patients (10.2%) in the rituximab group and two patients (1.6%) in the control group experienced HBV reactivation (P = 0.003). In the rituximab group, two patients experienced HBV-related severe hepatitis, and one patient died due to hepatic failure. The median time from rituximab desensitization to HBV reactivation was 11 months (range, 5-22 months). By contrast, no patients in the control group experienced severe hepatitis. The status of hepatitis B surface antibody was similar between groups. Rituximab desensitization [hazard ratio (HR), 9.18; 95% confidence interval (CI), 1.74-48.86; P = 0.009] and hepatitis B surface antibody status (HR, 4.74; 95% CI, 1.05-21.23, P = 0.04) were significant risk factors for HBV reactivation. Conclusions: Rituximab desensitization for incompatible kidney transplantation significantly increased the risk of HBV reactivation in HBsAg-negative/anti-HBc-positive patients. Therefore, close monitoring of HBV DNA is required in these patients.

De novo low-dose sirolimus versus mycophenolate mofetil in combination with extended-release tacrolimus in kidney transplant recipients: a multicentre, open-label, randomized, controlled, non-inferiority trial.

BACKGROUND: Most of the previous studies reported that tacrolimus (TAC) with sirolimus (SRL) was associated with worse post-transplant outcomes in kidney transplantation, compared with TAC with mycophenolate mofetil (MMF). These might be attributable to high-dose SRL. However, outcomes using low-dose SRL with TAC for kidney transplantation are uncertain. The aim of this study was to assess the efficacy and safety of low-dose SRL with extended-release tacrolimus (ER-TAC) versus MMF with ER-TAC. METHODS: We randomly assigned 158 renal transplant patients to receive low-dose SRL or MMF in combination with ER-TAC and corticosteroid. The primary endpoint was the composite efficacy failure rate, including biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up, within 12 months post-transplantation. This trial is registered with ClinicalTrial.gov (number NCT01680952). RESULTS: The efficacy failure rate was 6.6% in the low-dose SRL group and 13.3% in the MMF group in the intention-to-treat population (absolute difference, 6.8%; 95% confidence interval, -2.8% to 16.3%). The incidence of BPAR within 12 months post-transplantation was 5.3% in the low-dose SRL group and 13.3% in the MMF group (P = 0.09). The mean estimated glomerular filtration rate at 12 months post-transplantation was 53.2 mL/min/1.73 m2 in the low-dose SRL group and 52.4 mL/min/1.73 m2 in the MMF group (P = 0.76). The incidences of adverse events and serious adverse events were similar between groups. CONCLUSION: Low-dose SRL with ER-TAC was not inferior to MMF with ER-TAC with respect to efficacy and safety. When used for immunosuppression in kidney transplantation, low-dose SRL with ER-TAC can effectively prevent acute rejection and preserve renal function.

The clinicopathological relevance of pretransplant anti-angiotensin II type 1 receptor antibodies in renal transplantation.

BACKGROUND: Anti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been suggested as a risk factor for graft failure and acute rejection (AR). However, the prevalence and clinical significance of pretransplant AT1R-Abs have seldom been evaluated in Asia. METHODS: In this multicenter, observational cohort study, we tested the AT1R-Abs in pretransplant serum samples obtained from 166 kidney transplant recipients. Statistical analysis was used to set a threshold AT1R-Abs level at 9.05 U/mL. RESULTS: Pretransplant AT1R-Abs were detected in 98/166 (59.0%) of the analyzed recipients. No graft loss or patient death was reported during the study period. AT1R-Abs (+) patients had a significantly higher incidence of biopsy-proven AR than AT1R-Abs (-) patients (27.6 versus 10.3%, P = 0.007). Recipients with pretransplant AT1R-Abs had a 3.2-fold higher risk of AR within a year of transplantation (P = 0.006). Five study subjects developed microcirculation inflammation (score ≥2). Four of them were presensitized to AT1R-Abs. In particular, three patients had a high titer of anti-AT1R-Abs (>22.7 U/mL). CONCLUSIONS: Pretransplant AT1R-Abs is an independent risk factor for AR, especially acute cellular rejection, and is possibly associated with the risk of antibody-mediated injury. Pretransplant assessment of AT1R-Abs may be useful for stratifying immunologic risks.

Successful launch of an ABO-incompatible kidney transplantation program to overcome the shortage of compatible living donors: experience at a single center
.

AIMS: ABO-incompatible (ABOi) kidney transplantation (KT) is being increasingly performed to overcome donor shortages. However, debate persists regarding the post-transplant outcomes of ABOi KT vs. that of ABO-compatible (ABOc) KT. METHODS: A total 454 recipients who underwent living-donor KT (LDKT) between June 2010 and July 2014 at Severance Hospital (Seoul) were retrospectively reviewed. 100 ABOi and 354 ABOc KTs were compared. Recipients with a pretransplant positive crossmatch to their donors, pretransplant donor-specific anti-HLA antibody (DSA), or high panel reactive antibody (PRA ≥ 50%) were excluded from both the ABOi and ABOc KT groups. Finally, the authors compared the transplant outcomes of 95 of these ABOi KTs and 121 ABOc KTs performed over the same period. RESULTS: No significant difference in incidence of biopsy-proven acute rejection was observed between the ABOi and ABOc KT groups (p = 0.230), and group glomerular filtration rate of ABOi KT was comparable to that of ABOc KT (p > 0.05 at all time points). 3-year death-censored graft survival rates were similar (96.8 vs. 96.6%, respectively; p = 0.801). However, the incidences of postoperative bleeding, cytomegalovirus infection, fungal infection, and serious infection rates were significantly higher after ABOi KT. CONCLUSIONS: In this study, graft renal function and survival after ABOi KT were excellent, and the incidence of acute rejection was similar to that of ABOc KT. However, efforts are needed to reduce hemorrhagic and infectious complications after ABOi KT. ABOi KT can be a good strategy to overcome ABO antibody barriers and relieve donor shortage.
.

The effect of rituximab dose on infectious complications in ABO-incompatible kidney transplantation.

BACKGROUND: Rituximab (RIT) improves the outcomes of ABO-incompatible (ABOi) kidney transplantation (KT), but it has been associated with infectious complications. The aim of this study was to investigate infectious complications according to the dose of RIT in ABOi KT. METHODS: We analyzed 213 recipients [118 ABO-compatible (ABOc) KT and 95 ABOi KT] who underwent living donor KT between 2010 and 2014. ABOi KT patients were categorized by RIT dose: standard RIT (375 mg/m(2), n = 76) versus reduced RIT (200 mg, n = 19). All patients received basiliximab and maintained on triple immunosuppression consisting of tacrolimus, prednisone and mycophenolate mofetil. Infectious complications and post-transplant outcomes were analyzed for 1 year following KT. RESULTS: The rates of overall infectious complications among the three groups were comparable (22.9% in ABOc KT, 38.2% in standard RIT and 26.3% in reduced RIT, P = 0.069). In the standard RIT group, hepatitis B virus reactivation occurred in three recipients (3.9%) with hepatitis B surface antigen[-]/anti-hepatitis B core antibody[+]. Three cases (3.9%) of Pneumocystis jirovecii pneumonia occurred in the standard RIT group. Serious infections developed in 13 of the ABOc KT (11.0%), 20 from the standard RIT group (26.3%) and 2 from the reduced RIT group (10.5%, P = 0.015). Standard-dose RIT was found to be an independent risk factor for serious infections [hazard ratio: 2.59 (95% confidence interval: 1.33-5.07), P = 0.005]. There were no significant differences in rejection, renal function, graft survival and patient survival between standard and reduced RIT groups. CONCLUSIONS: Standard RIT increased the risk of serious infection when compared with reduced-dose RIT. Reduced-dose RIT might be sufficient for ABOi KT without increasing the risk of serious infection.

The clinical outcomes of second kidney transplantation in IgA nephropathy: a multicenter retrospective study.

BACKGROUND: Recurrent IgA nephropathy (IgAN) after kidney transplantation (KT) has been reported to range between 12 and 65%. However, few data are available on second transplantation in recurrent IgAN. Therefore, this study aimed to build bottom-line data for the possibility of second transplantation in patients who lost first transplanted kidney due to recurrent IgAN. METHODS: Patients who received KT twice due to recurrent IgAN at four large academic hospitals in Korea between March 1985 and December 2013 were reviewed. They were followed up until October 2014. All patients were identified as having recurrent IgAN in the first graft biopsies. The clinical outcomes of the second KT in these patients were compared with the first KT and with all cases of second KT (n = 169) performed at one center in the same period. RESULTS: 28 patients were enrolled in this study. First grafts failed after 106.64 ± 48.72 months (mean ± SD). Following the second transplantation, recurrent IgAN was identified in only 2 patients during the follow-up of 61.61 ± 47.23 months. In 1 patient, the second graft was lost due to chronic rejection without mesangial IgA deposit. The second KT showed comparable graft survival compared with the first KT and the overall second KT (p = 0.308 by log-rank test). At the final follow-up, the serum creatinine level was 1.16 ± 0.33 mg/dL in the second graft except in 1 patient. CONCLUSIONS: Second KT in recurrent IgAN showed reasonably good long-term results. Therefore, clinicians might be able to suggest second transplantation as an option for patients who lost the first graft due to recurrent IgAN.

Low-dose mycophenolate mofetil in tablet form or capsule form combined with tacrolimus in the early period after kidney transplantation: a prospective randomized trial
.

AIMS: The tablet form (500 mg) of mycophenolate mofetil (MMF) provides more convenience of taking drugs and cost-effectiveness than the capsule form (250 mg). We examined the efficacy and safety of MMF in its different forms combined with tacrolimus in kidney transplant recipients. METHODS: This multicenter, 26-week, randomized trial was performed to compare the efficacy and safety of the tablet form of MMF versus the capsule form of MMF in 156 kidney transplant recipients. Allograft function, the incidence of efficacy failure (biopsy-proven acute rejection (BPAR), death, graft loss, or loss to follow-up), and adverse events were compared. RESULTS: The mean dose (mg/day) of MMF at 26 weeks was comparable: 1,052.6 ± 194.2 in the tablet group vs. 1,155.6 ± 298.1 in the capsule group (p = 0.063). Trough levels of tacrolimus at 26 weeks were comparable. The mean estimated glomerular filtration rate of the tablet group at 26 weeks post-transplant was not inferior to that of the capsule group. The incidence of efficacy failure was similar in the two groups: tablet group, 5.2% and capsule group, 7.7% (difference -2.5%; 95% confidence interval -5.22 - 10.21%). The incidence of BPAR until 26 weeks post-transplant in the tablet group was 3.9%, compared to 7.7% in the capsule group (p = 0.346). There was no significant difference in the incidence of discontinuations and serious adverse events between the groups. CONCLUSION: Low-dose MMF in tablet form combined with tacrolimus can be considered as an efficacious and safe immunosuppressive regimen in the early period after kidney transplantation.
.

De novo C3 glomerulonephritis in a renal allograft.

C3 glomerulonephritis (C3GN) is a recently described, rare glomerular disease characterized by predominant or sole glomerular C3 deposits. Morphologic features of C3GN are similar to those of dense deposit disease (DDD); however, ribbon-like intramembranous electron-dense deposits are absent in the former. We report a case of de novo C3GN in a renal allograft with morphologic transformation to DDD. A 6-year-old boy presented with congenital left renal agenesis and right ureteropelvic junction obstruction. The patient underwent pyeloplasty but experienced recurrent urinary tract infections. At the age of 22 years, he received a renal allograft from a living related donor. C3GN was diagnosed after 1 year of transplantation; initial histology showed minimal mesangiopathy and this progressed to mesangial proliferation and membranoproliferative features over the next 7 years. Serum creatinine levels were stabilized with anti-rejection treatments for combating repeated episodes of acute rejection; however, glomerular and tubular band-like electron-dense deposits became evident.

A 12-month single arm pilot study to evaluate the efficacy and safety of sirolimus in combination with tacrolimus in kidney transplant recipients at high immunologic risk.

The optimal immunosuppressive strategy for renal transplant recipients at high immunologic risk remains a topic of investigation. This prospective single arm pilot study was undertaken to evaluate the safety and efficacy of a combined tacrolimus and sirolimus regimen in recipients at immunological high risk and to compare outcomes with a contemporaneous control group received tacrolimus and mycophenolate mofetil. Patients that received a renal allograft between 2010 and 2011 at high risk (defined as panel reactive antibodies > 50%, 4 or more human leukocyte antigen mismatches, or retransplantation) were enrolled. All patients received basiliximab induction and corticosteroids. A total of 28 recipients treated with tacrolimus and sirolimus were enrolled in this study and 69 recipients were retrospectively reviewed as a control group. The sirolimus group showed a higher, but not statistically significant, incidence of biopsy proven acute rejection and a lower glomerular filtration rate than the control group. Furthermore, sirolimus group was associated with significant increases in BKV infection (P = 0.031), dyslipidemia (P = 0.004), and lymphocele (P = 0.020). The study was terminated prematurely due to a high incidence of adverse events. A de novo tacrolimus/sirolimus combination regimen may not be an ideal choice for recipients at high immunological risk.

KNOW-KT (KoreaN cohort study for outcome in patients with kidney transplantation: a 9-year longitudinal cohort study): study rationale and methodology.

BACKGROUND: Asian patients undergoing kidney transplantation (KT) generally have better renal allograft survival and a lower burden of cardiovascular disease than those of other racial groups. The KNOW-KT aims to explore allograft survival rate, cardiovascular events, and metabolic profiles and to elucidate the risk factors in Korean KT patients. METHODS: KNOW-KT is a multicenter, observational cohort study encompassing 8 transplant centers in the Republic of Korea. KNOW-KT will enroll 1,000 KT recipients between 2012 and 2015 and follow them up to 9 years. At the time of KT and at pre-specified intervals, clinical information, laboratory test results, and functional and imaging studies on cardiovascular disease and metabolic complications will be recorded. Comorbid status will be assessed by the age-adjusted Charlson co-morbidity index. Medication adherence and information on quality of life (QoL) will be monitored periodically. The QoL will be assessed by the Kidney Disease Quality of Life Short Form. Donors will include both living donors and deceased donors whose status will be assessed by the Kidney Donor Risk Index. Primary endpoints include graft loss and patient mortality. Secondary endpoints include renal functional deterioration (a decrease in eGFR to <30 mL/min/1.73 m2), acute rejection, cardiovascular event, albuminuria, new-onset diabetes after transplant, and QoL. Data on other adverse outcomes including episodes of infection, malignancy, recurrence of original renal disease, fracture, and hospitalization will also be collected. A bio-bank has been established for the acquisition of DNA, RNA, and protein from serum and urine samples of recipients at regular intervals. Bio-samples from donors will also be collected at the time of KT. KNOW-KT was registered in an international clinical trial registry (NCT02042963 at http://www.clinicaltrials.gov) on January 20th, 2014. CONCLUSION: The KNOW-KT, the first large-scale cohort study in Asian KT patients, is expected to represent the Asian KT population and provide information on their natural course, complications, and risk factors for complications.

Sirolimus conversion efficacy for graft function improvement and histopathology in renal recipients with mild to moderate renal insufficiency.

This study was designed to evaluate whether sirolimus (SRL) conversion effectively improves renal function and histopathology in calcineurin inhibitor (CNI)-treated renal recipients with mild to moderate renal insufficiency. SRL conversion from CNI was performed in patients who underwent kidney transplantation from 6 months to 5 yr prior to screening. Forty-five patients were enrolled. The effect of SRL conversion on graft function was evaluated, and protocol biopsies were performed preconversion and 1 yr after conversion. Overall graft function after SRL conversion gradually improved, and the improvement in renal function was closely associated with the shorter duration of CNI exposure. When we divided the patients by the duration of CNI exposure, the patients with less than 1 yr of CNI exposure demonstrated significant improvement, but patients with a greater than 1 yr CNI exposure did not exhibit significant improvement. In contrast, protocol biopsies demonstrated no significant improvements in the modified "ah" score or other Banff scores after SRL conversion. Furthermore, the duration of CNI treatment prior to SRL conversion was not associated with histological findings 1 yr after SRL conversion. SRL conversion improved graft function in renal recipients with mild to moderate renal insufficiency, but this effect is not accompanied by histological improvement.

Association of clinical events with everolimus exposure in kidney transplant patients receiving reduced cyclosporine.

BACKGROUND: The association between clinical events and everolimus exposure in patients receiving reduced-exposure calcineurin inhibitor therapy is poorly explored. METHODS: In a pre-planned, descriptive analysis of data from a randomized controlled trial, events were correlated with everolimus trough concentrations in 556 newly transplanted kidney transplant patients receiving everolimus with reduced-exposure cyclosporine (CsA) and steroids. Influence of everolimus exposure on clinical events was stratified according to predefined time-normalized concentrations. RESULTS: The incidence of treated biopsy-proven acute rejection and graft loss at month 12 was highest in patients with everolimus <3 ng/mL (36.4% and 28.6%, respectively, vs. 9.1-15.3% and 0.9-5.0% with higher concentration ranges). A higher mortality rate was observed in patients with an everolimus trough concentration ≥ 12 ng/mL (10.0% vs. 1.7-5.6% with lower concentration ranges). The lowest rates of renal dysfunction (defined as poor renal function [estimated GFR, serum creatinine] or proteinuria), wound healing events, peripheral edema, new-onset diabetes mellitus, hypercholesterolemia and hypertriglyceridemia were generally observed with everolimus trough concentration in the range 3-8 ng/mL and CsA <100 ng/mL. Proteinuria occurred most frequently in patients with very low or very high everolimus trough concentrations. CONCLUSIONS: These results support an exposure-response relationship between clinical events and everolimus trough concentrations in kidney transplant patients receiving reduced-exposure CsA.

Changes in glucose metabolism among recipients with diabetes 1 year after kidney transplant: a multicenter 1-year prospective study.

Background: Diabetes mellitus is a common and crucial metabolic complication in kidney transplantation. It is necessary to analyze the course of glucose metabolism in patients who already have diabetes after receiving a transplant. In this study, we investigated the changes in glucose metabolism after transplantation, and a detailed analysis was performed on some patients whose glycemic status improved. Methods: The multicenter prospective cohort study was conducted between 1 April 2016 and 31 September 2018. Adult patients (aged 20 to 65 years) who received kidney allografts from living or deceased donors were included. Seventy-four subjects with pre-transplant diabetes were followed up for 1 year after kidney transplantation. Diabetes remission was defined as the results of the oral glucose tolerance test performed one year after transplantation and the presence or absence of diabetes medications. After 1-year post-transplant, 74 recipients were divided into the persistent diabetes group (n = 58) and the remission group (n = 16). Multivariable logistic regression was performed to identify clinical factors associated with diabetes remission. Results: Of 74 recipients, 16 (21.6%) showed diabetes remission after 1-year post-transplant. The homeostatic model assessment for insulin resistance numerically increased in both groups throughout the first year after transplantation and significantly increased in the persistent diabetes group. The insulinogenic index (IGI30) value significantly increased only in the remission group, and the IGI30 value remained low in the persistent diabetes group. In univariate analysis, younger age, newly diagnosed diabetes before transplantation, low baseline hemoglobin A1c, and high baseline IGI30 were significantly associated with remission of diabetes. After multivariate analysis, only newly diagnosed diabetes before transplantation and IGI30 at baseline were associated with remission of diabetes (34.00 [1.192-969.84], P = 0.039, and 17.625 [1.412-220.001], P = 0.026, respectively). Conclusion: In conclusion, some kidney recipients with pre-transplant diabetes have diabetes remission 1 year after transplantation. Our prospective study revealed that preserved insulin secretory function and newly diagnosed diabetes at the time of kidney transplantation were favorable factors for which glucose metabolism did not worsen or improve 1 year after kidney transplantation.

Outcome of kidney allograft in patients with adulthood-onset focal segmental glomerulosclerosis: comparison with childhood-onset FSGS.

BACKGROUND: Idiopathic focal segmental glomerulosclerosis (FSGS) occurring at young age is known to predispose to poor graft outcome, but the outcome of adulthood-onset FSGS (A-FSGS) has not been thoroughly investigated. Here, we compared the graft outcomes between kidney recipients with A-FSGS and childhood-onset FSGS (C-FSGS). METHODS: We enrolled 47 A-FSGS recipients and 60 C-FSGS recipients with an onset age of ≤ 15, from four of the largest transplant centers in Korea. RESULTS: The baseline characteristics were similar between two groups. The 1- and 3-year cumulative recurrence rates were 20.0 and 22.1%, respectively. FSGS was recurrent in 19 C-FSGS patients [median duration, 2 months (interquartile range, IQR, 1-35)], and 11 patients had recurrent disease in A-FSGS [5 months (IQR, 3-37)]. The recurrence rate was similar between two groups (P = 0.126). The 5- and 10-year graft survival rates were 90.0 and 78.5%, respectively. The overall graft survival rates were not different between two groups. After adjusting baseline characteristics, the development of major outcomes was similar between two groups except acute rejection that was more frequent in A-FSGS. The age of disease onset did not affect recurrence in both groups. While grafts with recurrence had poorer graft survival in the A-FSGS group (P = 0.005), the recurrence was not associated with graft loss in the C-FSGS group (P = 0.558). CONCLUSIONS: The onset age did not affect the graft outcome in patients with FSGS, and the recurrence significantly affected graft survival in A-FSGS. Therefore, the main focus should aim for the management of recurrence.