Association of physical activity with fractures in kidney transplant recipients: A Korean nationwide cohort study.

Kidney transplant recipients are at high risk for fractures, primarily due to post-transplant bone disease. This retrospective cohort study analyzed data from the Korean National Health Insurance Service, including 10 083 kidney transplant recipients examined from 2009 to 2017. We assessed fracture incidence, emphasizing vertebral and hip fractures, and the association of physical activity and traditional risk factors with fracture risk. Kidney transplant recipients were categorized into three groups according to physical activity levels: non-activity, metabolic equivalent of task (MET) 1-499, and MET ≥500. Physical activity was associated with a decreased risk of all types of fractures: any (MET 1-499: adjusted hazard ratio (aHR) .75; 95% confidence interval (CI) .62-.92, MET ≥500: aHR .84; 95% CI .70-1.00), vertebral (MET 1-499: aHR .69; 95% CI .49-.98, MET ≥500: aHR .67; 95% CI .49-.91), and hip (MET 1-499: aHR .43; 95% CI .23-.81) fractures. Additionally, older age, female sex, and diabetes were associated with an increased fracture risk. The assessment of physical activity and traditional risk factors could improve fracture risk prediction. Our findings emphasize the need for further research to establish optimal physical activity recommendations for fracture prevention in kidney transplant recipients.

Acute kidney injury in bortezomib-treated patients with multiple myeloma.

BACKGROUND: The nephrotoxicity of bortezomib, a proteasome inhibitor, has not yet been elucidated, although tumor lysis syndrome (TLS) associated with multiple myeloma (MM) has been reported to increase after introduction of the drug. This study compared the incidence and risk factors for acute kidney injury (AKI) and TLS in patients with MM after bortezomib-based chemotherapy to investigate drug-related nephrotoxicity. METHODS: From 2006 to 2017, 276 patients who underwent a first cycle of bortezomib-based chemotherapy for MM were identified in a single tertiary hospital. Laboratory TLS was defined according to the Cairo-Bishop definition. Development of AKI was assessed by AKI Network criteria within 7 days of the first chemotherapy. RESULTS: The median (interquartile range) age was 65 (56-72) years, and baseline estimated glomerular filtration rate (eGFR) was 61.3 (34.1-89.1) mL/min/1.73 m2. The incidences of AKI and laboratory TLS were 17% (n = 47) and 13% (n = 36), respectively. Ten (3.6%) subjects met both AKI and TLS criteria. Multivariate analyses showed that lower eGFR category [30-59, odds ratio (OR) 3.005 (95% confidence interval 1.163-7.976); 15-29, OR 4.225 (1.183-15.000); <15, OR 16.154 (3.831-70.920) vs ≥60, P < .001], lower serum albumin level [per 1 increase, OR 0.479 (0.256-0.871), P = .018], renal amyloidosis [OR 13.039 (4.108-44.041), P < .001] and use of acyclovir during bortezomib treatment [OR 3.689 (1.133-14.469), P = .042] were predictors of AKI. MM stages and ß-2-microglobulin were not associated with increased risk of AKI. Regarding laboratory TLS, MM stage and ß-2-microglobulin were higher in those with TLS than in others. In multivariate analyses, ß-2-microglobulin level [OR 1.204 (1.005-1.461), P = .038] and absence of high-risk chromosome abnormalities [OR 0.143 (0.022-0.588), P = .016] were associated with higher risk of TLS. CONCLUSIONS: Development of AKI was often observed in the absence of TLS in patients with MM after treatment with bortezomib. In addition, the risk factors for AKI and TLS varied widely. These findings indicate the potential nephrotoxicity of bortezomib irrespective of TLS in patients with decreased kidney function.

The impact of preoperative kidney replacement therapy on kidney outcome and survival in patients with left ventricular assist device.

Left ventricular assist device (LVAD) has been highlighted as a new treatment option in the end-stage heart failure (HF). Kidney outcome after LVAD in severe cardiorenal syndrome (CRS) patients requiring kidney replacement therapy (KRT) is unclear. We investigated the impact of preoperative KRT on kidney function and survival in LVAD patients with severe CRS. A total of 50 patients followed up for at least 1 year after LVAD implantation was analyzed. The primary outcomes were estimated glomerular filtration rate and survival rate. Patients were divided into two groups depending on in-hospital KRT before LVAD implantation: the control group (n = 33) and the KRT group (n = 17). Postoperative KRT was performed for 76.5% of patients in the KRT group, and all of them discontinued KRT before discharge. There were no statistically significant differences in the degree of eGFR decline in survivors according to preoperative KRT. Although there were no statistically significant differences in the degree of eGFR decline in survivors regardless of preoperative KRT, old age (ß -0.94, p < 0.01), preexisting chronic kidney disease (ß -21.89, p < 0.01), and high serum creatinine (ß -13.95, p < 0.01) were identified as independent predictors of post-LVAD eGFR decline. Mortality rate was higher, and more patients progressed to end-stage kidney disease in KRT group than control group. However, LVAD still can be considered as the treatment option in end-stage HF patients with severe CRS requiring KRT, especially in those with young age and previous normal kidney function.

Recoverability of Diabetic Nephropathy of Donor Kidney After Kidney Transplantation.

Some kidney donors have diabetes, and little of their natural course of diabetic nephropathy (DN) is known. The aim of this study was to analyze the changes in pathologic lesions in the diabetic donor kidney after KT by performing protocol biopsy two weeks and one year after KT. This retrospective study included 103 patients who underwent KT, with kidneys from donors with a history of diabetes mellitus (DM). Among them, data of 34 patients who underwent biopsy two weeks and one year after KT were reviewed. Biopsy specimens were reviewed using light microscopy and electron microscopy. Glomerular basement membrane (GBM) thickness at 2 weeks and 1 year was compared. Biopsy showed that DN occurred in 29 of the 34 patients. Only trivial histological changes were observed in 22 patients (64.7%), including 5 patients who did not show DN. At one year after transplantation, there was no change in the DN histologic class in 26 patients (76.5%), and there was no statistically significant difference in the change in GBM thickness. This pattern was observed regardless of the recipient's DM or glycemic control. With this understanding, clinicians can use kidneys from DM donors with more comfort, thereby reducing the kidney discard rate.

A Scoring Model with Simple Clinical Parameters to Predict Successful Discontinuation of Continuous Renal Replacement Therapy.

BACKGROUND: Continuous renal replacement therapy (CRRT) is the standard treatment for severe acute kidney injury in critically ill patients. However, a practical consensus for discontinuing CRRT is lacking. We aimed to develop a prediction model with simple clinical parameters for successful discontinuation of CRRT. METHODS: Adult patients who received CRRT at Samsung Medical Center from 2007 to 2017 were included. Patients with preexisting ESRD and patients who progressed to ESRD within 1 year or died within 7 days after CRRT were excluded. Successful discontinuation of CRRT was defined as no requirement for renal replacement therapy for 7 days after discontinuing CRRT. Patients were assigned to either a success group or failure group according to whether discontinuation of CRRT was successful or not. RESULTS: A total of 1,158 patients were included in the final analyses. The success group showed greater urine output on the day before CRRT discontinuation (D-1) and the discontinuation day (D0). Multivariable analysis identified that urine output ≥300 mL on D-1, and mean arterial pressure 50∼78 mm Hg, serum potassium <4.1 mmol/L, and BUN <35 mg/dL (12.5 mmol/L) on D0 were predictive factors for successful discontinuation of CRRT. A scoring system using the 4 variables above (area under the receiver operating curve: 0.731) was developed. CONCLUSIONS: Scoring system composed of urine output ≥300 mL/day on D-1, and adequate blood pressure, serum potassium <4.1 mmol/L, and BUN <35 mg/dL (12.5 mmol/L) on D0 was developed to predict successful discontinuation of CRRT.

Predialysis predictors for identifying patients requiring dialysis at a higher glomerular filtration rate.

BACKGROUND: Current evidence suggests that the initiation of maintenance hemodialysis should not be based on a specific glomerular filtration rate (GFR) but on symptoms or signs attributable to kidney disease. However, it is difficult to predict the time point at which overt uremic syndrome develops in individuals. The estimated GFR is poorly correlated with occurrence of uremic symptoms, and some patients require dialysis at a higher eGFR than others. In this case, patients are more likely to be improperly prepared for dialysis. We investigated the predialysis characteristics of patients who require dialysis at a higher eGFR. METHODS: A total of 453 incident dialysis patients being monitored by a nephrologist from January 2013 to December 2018 were included. The predialysis characteristics when eGFR decreased to 20 mL/min/1.73 m2 were obtained. RESULTS: The mean age was 61 years, and 65.7% were men. Overall, the median eGFR at the first dialysis was 5.8 (interquartile range 4.6-7.3) mL/min/1.73 m2 and initiation of dialysis at the first quintile (≥7.8 mL/min/1.73 m2) was defined as 'early initiation of dialysis' Among the predialysis characteristics, heart failure (adjusted odds ratio 3.68; 95% confidence interval, 1.59-8.03), serum albumin <4.0 mg/dL (2.22; 1.30-3.77), blood urea nitrogen (BUN)/creatinine (Cr) ratio >15 mg/mg (1.92, 1.16-3.18), and hyperuricemia (1.84; 1.05-3.23) were independent predictors of early initiation. Diabetes mellitus and the causes of kidney disease were not independent predictors of early initiation. The early initiation group was less likely to initiate dialysis with a permanent vascular access than the late initiation group. CONCLUSIONS: For patients with heart failure, low serum albumin level, high BUN/Cr ratio, or hyperuricemia, clinicians can provide predialysis counseling in advance and consider early creation of vascular access.

The combination of area under the curve and percentage change in estimated glomerular filtration rate predicts long-term outcome of kidney transplants.

The development of surrogate markers for long-term outcomes of kidney transplant (KT) is a focus of attention. We examined the possibility of using a combination of the area under the curve of estimated glomerular filtration rate (eGFR) for 2 years (AUCeGFR2yrs ) and percent change in eGFR between 1 and 2 years after KT (% changeeGFR1/2yr ) as a surrogate marker. We compared the predictive power of death-censored graft failure with various combinations. The combination of >2% vs ≤2% for % changeeGFR1/2yr and >1300 vs ≤1300 mL/min/month for AUCeGFR2yr had the highest Harrell C-index (0.647; 95% confidence interval [95% CI], 0.604-0.690). The death-censored graft survival rate of the group with ≤2% changeeGFR1/2yr and ≤1300 mL/min/month AUCeGFR2yr was significantly lower than those of other groups. The AUC/% change eGFR had comparable predictive power to the previously identified marker ≥30% decline in eGFR between years 1 and 3 after KT (≤-30% changeeGFR1/3yr ) (Harrell's C-index = 0.645 [95% CI 0.628-0.662] for ≤-30% changeeGFR1/3yr ). The proposed combination might be useful as a surrogate marker in KT trials because it requires a shorter surveillance period than the established marker while having comparable predictive power.

Hepatitis B reactivation after kidney transplantation in hepatitis B surface antigen-negative, core antibody-positive recipients.

Nowadays, intensive immunosuppressive therapy including rituximab is commonly used prior to kidney transplantation (KT), raising concerns over hepatitis B virus (HBV) reactivation among hepatitis B surface antigen (HBsAg)-negative and anti-hepatitis B core (HBc)-positive KT recipients. Recent practice guidelines suggested watchful monitoring or antiviral prophylaxis for the first 6-12 months, the period of maximal immunosuppression. However, the actual risk for HBV reactivation, and whether short-term antiviral therapy in the early period is necessary, remains unclear. A total of 449 HBsAg-negative and anti-HBc-positive KT recipients were analysed for HBV reactivation. During a median follow-up of 6.7 (interquartile range: 4.2-9.4) years, HBV reactivation was observed in 9 patients (2.0%). The median time of HBV reactivation from KT was 2.8 years (range: 1.4-11.5 years), with cumulative incidence rates of 0%, 1% and 2% for 1, 3 and 5 years, respectively. There were no severe adverse outcomes, including liver transplantation or mortality related to HBV reactivation. The risk of HBV reactivation was not high, even in anti-HBs-negative patients (n = 60, 4% at 5 years), ABO mismatch (n = 92, 4% at 5 years), use of rituximab (n = 66, 3% at 5 years) or plasmapheresis (n = 17, 7% at 5 years), and acute rejection (n = 169, 3% at 5 years). In conclusion, the HBV reactivation risk was not high and the time of detection was not clustered in the early post-KT period. Our findings favour continued watchful monitoring over antiviral prophylaxis in the early period.

Urinary angiotensinogen as a surrogate marker predicting the antiproteinuric effects of angiotensin receptor blockers in patients with overt proteinuria: a multicenter prospective study.

BACKGROUND: Although urinary angiotensinogen (AGT) and renin reflect intrarenal renin-angiotensin system activity and are enhanced in proteinuric chronic kidney disease, the clinical value of urinary AGT and renin levels during antiproteinuric treatment has yet to be determined. We investigated the clinical usefulness of initial urinary AGT or renin to determine the antiproteinuric effects of angiotensin receptor blockers (ARBs). METHODS: This multicenter, prospective, single-arm study included 205 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] ≥ 1 mg/mg) enrolled between April 2009 and December 2011. All patients were treated with valsartan. The urinary AGT/creatinine ratio (uAGT/Cr) was measured at the baseline and 24 weeks, and the renin/creatinine ratio (uR/Cr) was measured at the baseline. Fifty-six patients were followed-up for 5 years. RESULTS: The mean age was 47.6 years and 51.2% were male. The mean uPCR was 2.32 mg/mg and the mean eGFR was 63.2 mL/min/1.73m2. Natural logarithms (ln) (uAGT/Cr), ln(uR/Cr), and diabetes mellitus were associated with proteinuria decrement (decrease in uPCR ≥1 mg/mg). Ln(uAGT/Cr) was an independent predictor for proteinuria decrement (OR 1.372, 95% CI, 1.068-1.762, P = 0.013). Among the 56 patients followed-up for 5 years, Δln(uAGT/Cr) at 24 weeks was an independent predictor for uPCR < 1 mg/mg at 5 years (OR 0.379, 95% CI, 0.20-0.715, P = 0.003). CONCLUSIONS: Our study demonstrates the potential role of both baseline urinary AGT and changes in urinary AGT during the initial 24 weeks as surrogate markers predicting the antiproteinuric effects of ARBs in patients with overt proteinuria.

Creatinine- and cystatin C-based estimated glomerular filtration rate slopes for the prediction of kidney outcome: a comparative retrospective study.

BACKGROUND: Many studies have evaluated the usefulness of creatinine- (eGFRcr) and cystatin C-based estimated glomerular filtration rate (eGFRcys) at specific time points in predicting renal outcome. This study compared the performance of both eGFR changing slopes in identifying patients at high risk of end-stage renal disease (ESRD). METHODS: From 2012 to 2017, patients with more than three simultaneous measurements of serum creatinine and cystatin C for 1 year were identified. Rapid progression was defined as eGFR slope < - 5 mL/min/1.73 m2/year. The primary outcome was progression to ESRD. RESULTS: Overall, 1323 patients were included. The baseline eGFRcr and eGFRcys were 39 (27-48) and 38 (27-50) mL/min/1.73 m2, respectively. Over 2.9 years (range, 2.0-3.8 years) of follow-up, 134 subjects (10%) progressed to ESRD. Both the eGFRcr and eGFRcys slopes were associated with a higher risk of ESRD, independently of baseline eGFR (hazard ratio [HR] = 0.986 [0.982-0.991] and HR = 0.988 [0.983-0.993], respectively; all p <  0.001). The creatinine- and cystatin C-based rapid progressions were associated with increased risk of ESRD (HR = 2.22 [1.57-3.13], HR = 2.03 [1.44-2.86], respectively; all p <  0.001). In the subgroup analyses, the rapid progression group, defined on the basis of creatinine levels (n = 503), showed no association between the eGFRcys slope and ESRD risk (p = 0.31), whereas the eGFRcr slope contributed to further discriminating higher ESRD risk in the subjects with rapid progression based on eGFRcys slopes (n = 463; p = 0.003). CONCLUSIONS: Both eGFR slopes were associated with future ESRD risk. The eGFRcr slope was comparable with the eGFRcys slope in predicting kidney outcome.

Arteriovenous graft patency outcomes and prognostic factors.

OBJECTIVES: Arteriovenous graft for hemodialysis shows poorer outcomes than arteriovenous fistula, due to frequent stenosis and thrombosis. We investigated arteriovenous graft patency outcomes and prognostic factors for these outcomes. METHODS: We included a single-center cohort of patients receiving arteriovenous graft for hemodialysis access from 2010 to 2014. Demographics, laboratory data, comorbidities, and medications were collected from medical records. Surgical factors related to graft operation including the type and diameter of connected vessels, graft location, and type of operation (elective or emergency) were also recorded. Outcomes included primary and secondary patency. Survival analysis was conducted using the Kaplan-Meier method; univariate and multivariate analyses were used to evaluate the prognostic factors. RESULTS: Data from 225 grafts were analyzed. During the follow-up period (mean: 583 days, range: 1-1717 days), 138 (61%) grafts required intervention and 46 (20%) permanently failed. Primary patency at one, two, and three years was 42%, 20%, and 16%, respectively. Secondary patency at one, two, and three years was 85%, 72%, and 64%, respectively. Multivariate analysis showed that primary patency was negatively associated with increasing age and location of vessel anastomosis (reference-brachiobrachial anastomosis; brachiobasilic - HR, 0.569; 95% CI, 0.376-0.860; p = 0.007; brachioaxillary anastomosis - HR 0.407; 95% CI, 0.263-0.631; p < 0.0001); secondary patency was positively associated with diastolic blood pressure, serum albumin level, and hemoglobin over 10 g/dL. Adverse events other than stenosis or thrombosis, such as infection/inflammation or pseudoaneurysm were observed in approximately 20% of grafts. CONCLUSIONS: Factors associated with diminished primary arteriovenous graft patency included increased patient age and location of vessel anastomosis (brachiobrachial type compared to brachiobasilic or brachioaxillary type); diminished secondary patency was associated with low diastolic blood pressure, low serum albumin, and hemoglobin level under 10 g/dL. Among these factors, diastolic blood pressure, serum albumin, and hemoglobin level may be modifiable and could improve arteriovenous graft patency outcomes.

Comparative Evaluation of QuantiFERON-TB Gold In-Tube and QuantiFERON-TB Gold Plus in Diagnosis of Latent Tuberculosis Infection in Immunocompromised Patients.

QuantiFERON-TB Gold Plus (QFT-Plus) is a new-generation QuantiFERON-TB Gold In-Tube (QFT-GIT) assay which has two antigen-coated tubes called TB1, which contains long peptides derived from ESAT-6 and CFP-10, and TB2, which contains the same components as TB1 and additional short peptides which potentially stimulate CD8+ T cells through the presentation of major histocompatibility complex class I. This is the first study to compare QFT-Plus and QFT-GIT for use in the diagnosis of latent tuberculosis infection (LTBI) among immunocompromised patients in the Republic of Korea. Among 317 consecutive patients who underwent screening for LTBI before solid organ or hematopoietic stem cell transplantation and tumor necrosis factor alpha inhibitor treatment, LTBI was identified in 92 (29.0%) and 88 (27.8%) patients by QFT-GIT and QFT-Plus, respectively. The rate of concordance between QFT-GIT and QFT-Plus was 93.7% (κ value, 0.860), and the indeterminate rate (3.2%) was similar between QFT-GIT and QFT-Plus. Of 20 (6.3%) samples with discordant results, 11 (55.0%) and 7 (35.0%) were positive by QFT-GIT alone and QFT-Plus alone, respectively, and 2 (15.0%) were indeterminate by each assay. The interferon gamma level in samples with discordant results ranged from 0.39 to 1.10 IU/ml, except for one sample, in which the gamma interferon level was 2.97 IU/ml only in TB2. Conclusively, there was a high degree of agreement between the results of QFT-GIT and QFT-Plus for the screening of immunocompromised patients for LTBI. The reactivity in TB2 contributed substantially to the difference between QFT-GIT and QFT-Plus, particularly in solid organ transplant candidates. The significance of the discrete responses in TB1 and TB2 of QFT-Plus needs to be explored further by means of an immunological and clinical approach in different patient groups and clinical settings.

First-year GFR slope and long-term renal outcome in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most frequent primary glomerular disease and the leading cause of end-stage renal disease. We investigated clinicopathologic predictors of renal survival in patients with IgAN with a focus on glomerular filtration rate (GFR) decline slope. MATERIALS AND METHODS: We screened all patients with primary IgAN between 1995 and 2012. Renal progression was defined as doubling of serum creatinine. Using serial serum creatinine levels during the first-year, we calculated the GFR decline slopes. Further, we defined patients in the steepest GFR slope quartile as rapid decliners and those in the second steepest GFR slope quartile as slow decliners. Others were defined as nondecliners. RESULTS: Of 214 participants, baseline GFR was 81 (62, 100) mL/min/1.73 m2 , which was not different among the 3 groups. Rapid decliners and slow decliners had higher levels of urinary protein/creatinine ratio (0.88, 0.89 and 0.58 g/gCr, respectively, P < .001). Five-year renal survival was 76% in rapid decliners, 91% in slow decliners and 100% in nondecliners (P < .001, rapid or slow decliners vs nondecliners). After adjustment for clinicopathologic variables, slow decliners were associated with an 8.8-fold higher risk of progression (P = .011), and rapid decliners were associated with a 10.2-fold increased risk of progression (P = .007) compared with nondecliners. CONCLUSIONS: First-year GFR slope was associated with increased risk of renal progression, independent of proteinuria and histologic findings. Further studies are needed to investigate whether early GFR change can identify high-risk patients who benefit from immunosuppressive treatment in IgAN.

Ten-year observational follow-up of a randomized trial comparing cyclosporine and tacrolimus therapy combined with steroid withdrawal in living-donor renal transplantation.

Although various strategies for steroid withdrawal after transplantation have been attempted, there are few reports of the long-term results of steroid withdrawal regimens in kidney transplantation. Earlier, we reported on a 5-year prospective, randomized, single-center trial comparing the safety and efficacy of cyclosporine (CsA) plus mycophenolate mofetil (MMF) with that of tacrolimus (TAC) plus MMF, when steroids were withdrawn 6 months after kidney transplantation in low-risk patients. We now report the 10-year observational data on the study population. We collected data from the database of the Organ Transplantation Center, Samsung Medical Center for 5 years after completion of the original study (TAC group n = 62; CsA group n = 55). The 10-year patient survival, death-censored graft survival, and acute rejection-free survival did not differ between groups (98% vs 96%; P = 0.49, 78% vs 85%; P = 0.75 and 84% vs 76%; P = 0.14 in the TAC group vs CsA group, respectively). In low-risk patients, there was no difference in long-term patient and graft survival between TAC- and CsA-based late steroid withdrawal regimens that included MMF treatment. More long-term randomized clinical trials are needed to clarify the benefits of late steroid withdrawal in kidney transplantation.

Association between diuretics and successful discontinuation of continuous renal replacement therapy in critically ill patients with acute kidney injury.

BACKGROUND: Despite aggressive application of continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury (AKI), there is no consensus on diuretic therapy when discontinuation of CRRT is attempted. The effect of diuretics on discontinuation of CRRT in critically ill patients was evaluated. METHODS: This retrospective cohort study enrolled 1176 adult patients who survived for more than 3 days after discontinuing CRRT between 2009 and 2014. Patients were categorized depending on the re-initiation of renal replacement therapy within 3 days after discontinuing CRRT or use of diuretics. Changes in urine output (UO) and renal function after discontinuing CRRT were outcomes. Predictive factors for successful discontinuation of CRRT were also analyzed. RESULTS: The CRRT discontinuation group had a shorter duration of CRRT, more frequent use of diuretics after discontinuing CRRT, and greater UO on the day before CRRT discontinuation [day minus 1 (day - 1)]. The diuretics group had greater increases in UO and serum creatinine elevation after discontinuing CRRT. In the CRRT discontinuation group, continuous infusion of furosemide tended to increase UO more effectively. Multivariable regression analysis identified high day - 1 UO and use of diuretics as significant predictors of successful discontinuation of CRRT. Day - 1 UO of 125 mL/day was the cutoff value for predicting successful discontinuation of CRRT in oliguric patients treated with diuretics following CRRT. CONCLUSIONS: Day - 1 UO and aggressive diuretic therapy were associated with successful CRRT discontinuation. Diuretic therapy may be helpful when attempting CRRT discontinuation in critically ill patients with AKI, by inducing a favorable fluid balance, especially in oliguric patients.

Case Report of Kidney Paired Donation (KPD) with Desensitization: the Strategy and Experience of 3-Way KPD in Samsung Medical Center.

As the need for the organ donation increases, strategies to increase kidney transplantation (KT) through expanded living donation have become essential. These include kidney paired donation (KPD) programs and desensitization in incompatible transplantations. KPD enables kidney transplant candidates with incompatible living donors to join a registry with other incompatible pairs in order to find potentially compatible living donor. Positive cross match and ABO incompatible transplantation has been successfully accomplished in selective cases with several pre-conditionings. Patients who are both difficult-to-match due to broad sensitization and hard-to-desensitize because of donor conditions can often be successfully transplanted through a combination of KPD and desensitization. According to the existing data, KPD can increase the number of KTs from living donors with excellent clinical results. This is also a cost-effective treatment as compared with dialysis and desensitization protocols. We carried out 3-way KPD transplantation with one highly sensitized, positive cross match pair and with two ABO incompatible pairs. Herein we report our first successful 3-way KPD transplantation in a single center. To maximize donor-recipient matching and minimize immunologic risk, KPD programs should use proper algorithms with desensitization to identify optimal donor with simultaneous two-, three- or more complex multi-way exchanges.

Early, but not late, treatment with human umbilical cord blood-derived mesenchymal stem cells attenuates cisplatin nephrotoxicity through immunomodulation.

Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin-induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUCB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered on day 1 (early treatment) or day 3 (late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores on day 3 Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1 and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2-fold higher than baseline levels) showed no renoprotective effects on day 6 Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AKI progression or alter the intrarenal inflammatory micromilieu.

Aging has small effects on initial ischemic acute kidney injury development despite changing intrarenal immunologic micromilieu in mice.

Inflammatory process mediated by innate and adaptive immune systems is a major pathogenic mechanism of renal ischemia-reperfusion injury (IRI). There are concerns that organ recipients may be at increased risk of developing IRI after receiving kidneys from elder donors. To reveal the effects of aging on the development of renal IRI, we compared the immunologic micromilieu of normal and postischemic kidneys from mice of three different ages (9 wk, 6 mo, and 12 mo). There was a higher number of total T cells, especially effector memory CD4/CD8 T cells, and regulatory T cells in the normal kidneys of old mice. On day 2 after IRI, the proportion of necrotic tubules and renal functional changes were comparable between groups although old mice had a higher proportion of damaged tubule compared with young mice. More T cells, but less B cells, trafficked into the postischemic kidneys of old mice. The infiltration of NK T cells was similar across the groups. Macrophages and neutrophils were comparable between groups in both normal kidneys and postischemic kidneys. The intrarenal expressions of TNF-α and VEGF were decreased in normal and postischemic kidneys of aged mice. These mixed effects of aging on lymphocytes and cytokines/chemokines were not different between the two groups of old mice. Our study demonstrates that aging alters the intrarenal micromilieu but has small effects on the development of initial renal injury after IRI. Further study investigating aging-dependent differences in the repair process of renal IRI may be required.

Comparison of intrarenal renin-angiotensin system activity in diabetic versus non-diabetic patients with overt proteinuria.

AIM: The intrarenal renin-angiotensin system (RAS) has been reported to be activated in chronic proteinuria patients. This study aimed to compare intrarenal RAS activity between diabetic nephropathy (DN) and non-diabetic nephropathy (NDN) patients with overt proteinuria. METHODS: A multicenter, cross-sectional study was conducted in 116 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] > 1 mg/mg Cr). To estimate intrarenal RAS activity we measured urinary excretion of angiotensinogen (uAGT) and renin (uRenin) in patients with DN (n = 38) and NDN (n = 78). RESULTS: Both natural logarithms of uAGT/urinary creatinine (ln[uAGT/uCr]) and uRenin (ln[uRenin/uCr]) levels were significantly higher in patients with DN compared with those with NDN (ln[uAGT/uCr]: 4.16 ± 1.13 in DN vs. 3.52 ± 1.21 in NDN, P = 0.007; ln[uRenin/uCr]: 5.66 ± 1.60 in DN vs. 4.29 ± 1.48 in NDN, P < 0.001), when estimated glomerular filtration rate (eGFR) and uPCR showed no significant difference between the two groups. In a subgroup analysis, according to amount of proteinuria, both uAGT and uRenin were higher in DN in patients with subnephrotic-range proteinuria (uPCR < 3.5 mg/mg Cr). However, in patients with nephrotic-range proteinuria (uPCR ≥ 3.5 mg/mg Cr), only uRenin was higher in DN compared to NDN. In a multiple regression analysis, diabetes showed independent association with uRenin. CONCLUSION: Consistently elevated uRenin in DN, regardless of the amount of proteinuria, indicates that intrarenal RAS activity may be higher in DN compared to NDN in patients with overt proteinuria.

Multiple-Dose Study to Evaluate Pharmacokinetics, Pharmacodynamics, and Safety in Healthy Subjects: A Comparison of Controlled-Release Sarpogrelate and Immediate-Release Sarpogrelate.

AIMS: To compare the pharmacokinetics, pharmacodynamics, and safety of sarpogrelate between controlled-release (CR) and immediate-release (IR) formulations after multiple-dose administration. METHODS: This study was a randomized, open-label, 2-period, 2-treatment, crossover study in healthy subjects. All subjects received CR sarpogrelate 300 mg once daily and IR sarpogrelate 100 mg three times daily by random order each for 3 days with a 7-day washout period. Serial blood sampling was performed over 24 h. Pharmacokinetic parameters were determined by noncompartmental methods. Platelet aggregation to collagen, measured by light transmission aggregometry, was reported as maximal platelet aggregation. RESULTS: Thirty-two subjects completed the study. CR sarpogrelate increased rapidly, reaching Cmax in 1.25 h (vs. 1.00 h in IR sarpogrelate) and declined with a t1/2 of 3.59 h (vs. 1.12 h in IR sarpogrelate). The 90% CIs for the geometric mean ratio of AUCτ and Cmax,ss between IR and CR formulations were 1.18 to 1.40 and 0.99 to 1.29, respectively. The degree of inhibition of platelet aggregation was similar between two formulations. CONCLUSIONS: CR sarpogrelate showed slightly higher systemic exposure and similar peak concentration compared with IR sarpogrelate. The profiles of pharmacodynamics and safety were comparable between two formulations.