Association of Serum Osteoprotegerin With Vascular Calcification, and Cardiovascular and Graft Outcomes in Kidney Transplant Patients: Results From the KNOW-KT.

BACKGROUND: Vascular calcification and stiffness contribute to increased cardiovascular morbidity in patients with chronic kidney disease. This study investigated associations between serum osteoprotegerin (OPG) levels and vascular calcification or stiffness to assess cardiovascular and graft outcomes in kidney transplant patients. METHODS: The KoreaN cohort study for Outcome in patients With Kidney Transplantation was a prospective multicenter cohort study. Serum OPG levels were measured at baseline and 3 y after transplantation in 1018 patients. Patients were classified into high and low OPG groups according to median serum OPG levels. The median follow-up duration was 93.5 mo. RESULTS: The mean age was 45.8 ±â€…11.7 y and 62.9% were men. Patients with high OPG had significantly higher coronary artery calcium scores, abdominal aortic calcification scores, and brachial-ankle pulse wave velocities than those with lower OPG; these parameters remained significant for 5 y after transplantation. The 3-y OPG levels were lower than baseline values ( P < 0.001) and were positively correlated ( r = 0.42, P < 0.001). Multivariate Cox regression analysis showed that high OPG levels were significantly associated with posttransplant cardiovascular events ( P = 0.008) and death-censored graft loss ( P = 0.004). Similar findings regarding posttransplant cardiovascular events ( P = 0.012) and death-censored graft loss ( P = 0.037) were noted in patients with high OPG at the 3-y follow-up. Mediation analyses revealed that coronary artery calcium scores, abdominal aortic calcification scores, and brachial-ankle pulse wave velocities could act as mediators between serum OPG levels and posttransplant cardiovascular events. CONCLUSIONS: Serum OPG concentration is associated with vascular calcification and stiffness and could be a significant risk factor for cardiovascular outcomes and graft loss in patients undergoing kidney transplantation.

A Standardized Education Program on Deceased Organ and Tissue Donation for Premedical and Medial Students in Korea.

Background: As the imbalance in organ demand and supply is getting worse, <1000 patients waiting for organ transplants die each year in South Korea. To enhance positive attitudes to deceased organ-tissue donation through systematic education, we developed an educational program with delivery pathways for premedical and medical students. Methods: Online and offline self-learning educational materials on deceased organ-tissue donation were generated and posted on the Vitallink Academy YouTube site. Thirty-two pre- and 15 posteducation questionnaires were developed using a web-based survey platform, and conducted before and immediately after the education process. The education proceeded in 3 steps: (1) group study sessions on selected topics, (2) poster submissions by each group and the selection of excellent poster by the organizing committee, and (3) excellent poster presentation and questions and answers. Results: A total of 141 students in the first year of premedical classes at the Seoul National University College of Medicine participated in this program. Only 24.2% of responders agreed that anyone who was diagnosed with brain death should donate. The proportion of students with positive attitudes toward organ-tissue donation increased from 74.7% to 97.7% (P < 0.001) with our education. Likewise, interest in deceased organ-tissue donation-related issues increased from 33.3% to 84.9% (P < 0.001). The expressed willingness for organ-tissue donation also increased from 76.8% to 96.5% (P < 0.001). The proportion of accepting brain death as the determination of death increased from 61.6% to 89.5% (P < 0.001). Moreover, 81.4% changed their approach and planned to register with an organ donor card. Conclusions: In this study, significant improvements were observed in knowledge, awareness, and attitude toward organ-tissue donation with our newly developed co-participatory education program for premedical students. Hence, target-specific education can be regarded as a valuable approach to enhancing public awareness of deceased organ-tissue donation.

Vitamin D and narrowband ultraviolet B phototherapy for chronic kidney disease-associated pruritus.

BACKGROUND: In addition to improving the serum vitamin D balance, narrowband ultraviolet B (NB-UVB) phototherapy can effectively treat chronic kidney disease-associated pruritus (CKD-aP). We investigated the degree of CKD-aP amelioration according to changes in the serum vitamin D level after NB-UVB phototherapy. METHODS: This was a before-after clinical study in patients with refractory CKD-aP on hemodialysis. NB-UVB phototherapy was administered thrice weekly for 12 weeks. The response of CKD-aP to NB-UVB phototherapy was assessed as the change in pruritus intensity over time. A rapid response was defined as a reduction in the visual analog scale (VAS) score of ≥50% within the first 6 weeks of NB-UVB phototherapy. RESULTS: We included 34 patients in this study. Although serum 25-hydroxy vitamin D [25(OH)D] concentrations increased significantly, by a median of 17.4 ng/mL, after the phototherapy course, other serologic parameters did not change. NB-UVB phototherapy reduced the VAS score for pruritus intensity over time significantly more in patients with Δ25(OH)D of >17.4 ng/mL than in patients with Δ25(OH)D of ≤17.4 ng/mL (p = 0.001). Ten patients were rapid responders. Multivariate logistic regression analysis showed that Δ25(OH)D was independently associated with rapid response (odds ratio, 1.29; 95% confidence interval, 1.02-1.63; p = 0.04). CONCLUSION: The effect of NB-UVB phototherapy on patients with CKD-aP correlated with their increase in serum vitamin D levels. Further well-designed clinical and experimental studies are needed to clarify the relationship between NB-UVB phototherapy and serum vitamin D levels in patients with CKD-aP.

High pretransplant FGF23 level is associated with persistent vitamin D insufficiency and poor graft survival in kidney transplant patients.

Vitamin D3 (25[OH]D3) insufficiency and fibroblast growth factor 23 (FGF23) elevation are usually attenuated after kidney transplantation (KT). However, elevated FGF23 may be associated with poor graft outcomes and vitamin D insufficiency after KT. This study investigated the effect of pretransplant FGF23 levels on post-KT 25(OH)D3 status and graft outcomes. Serum FGF23 levels from 400 participants of the KoreaN Cohort Study for Outcome in Patients With Kidney Transplantation were measured. Annual serum 25(OH)D3 levels, all-cause mortality, cardiovascular event, and graft survival were assessed according to baseline FGF23 levels. Serum 25(OH)D3 levels were initially increased 1 year after KT (12.6 ± 7.4 vs. 22.6 ± 6.4 ng/mL). However, the prevalence of post-KT vitamin D deficiency increased again after post-KT 3 years (79.1% at baseline, 30.8% and 37.8% at 3 and 6 years, respectively). Serum FGF23 level was decreased 3 years post-KT. When participants were categorized into tertiles according to baseline FGF23 level (low, middle, high), 25(OH)D3 level in the low FGF23 group was persistently low at a median follow-up of 8.3 years. Furthermore, high baseline FGF23 level was a risk factor for poor graft survival (HR 5.882, 95% C.I.; 1.443-23.976, P = 0.013). Elevated FGF23 levels are associated with persistently low post-transplant vitamin D levels and poor graft survival.

Direct oral anti-Xa anticoagulants versus warfarin in newly diagnosed atrial fibrillation and CKD: the Korean National Health Insurance Data.

Introduction: Despite the benefits of direct oral anti-Xa anticoagulants (DOACs), the risk-benefit profile of DOAC therapy compared to warfarin therapy in patients with non-valvular atrial fibrillation (AF) and chronic kidney disease (CKD), including end-stage renal disease (ESRD), is uncertain. Methods: We conducted a retrospective study using the Korea National Health Insurance Database from 2013 to 2018. We evaluated patients with incident non-valvular AF and CKD. The primary and secondary effectiveness outcomes were ischemic stroke and all-cause mortality. The primary safety outcomes included intracranial hemorrhage, gastrointestinal bleeding, and extracranial or unclassified major bleeding. Results: Among the 1,885 patients evaluated, 970 (51.5%) initiated warfarin therapy, and 915 (48.5%) initiated DOAC therapy. During a mean follow-up period of 23.8 months, there were 293 and 214 cases of ischemic stroke and all-cause death, respectively. Kaplan-Meier survival analysis showed significantly lower all-cause mortality in DOAC users than in warfarin users. In multivariate Cox regression analyses, DOAC therapy had a hazard ratio for all-cause mortality of 0.41 (95% CI, 0.30-0.56; p < 0.001) compared to warfarin therapy. Additionally, DOAC therapy significantly reduced intracranial hemorrhage and gastrointestinal bleeding. Discussion: Our study demonstrates that DOAC therapy has a better risk-benefit profile than warfarin therapy in patients with AF and CKD. Further well-designed clinical trials are needed to clarify the benefits of DOACs in this patient population.

Fibroblast growth factor-23 and cardiovascular disease among prevalent hemodialysis patients focusing on residual kidney function.

Background: In patients undergoing incident hemodialysis, increased fibroblast growth factor-23 (FGF-23) levels are associated with the development of cardiovascular disease (CVD), but the influence of residual kidney function (RFK) on this association is unclear. This study aimed to investigate the association between FGF-23 levels, RKF, and CVD in patients undergoing prevalent hemodialysis. Methods: This cross-sectional and longitudinal observational study included 296 patients undergoing maintenance hemodialysis for at least three months who were followed up for a median of 44 months. RKF was defined as 24-h urine output >200 mL, left ventricular (LV) diastolic dysfunction as E/E' >15 on echocardiographic parameters. CVD was defined as hospitalization or emergency room visits due to cardiovascular causes, such as angina, myocardial infarction, or congestive heart failure. Results: The median intact FGF-23 (iFGF-23) level was 423.8 pg/mL (interquartile range, 171-1,443). Patients with an FGF-23 level > 423.8 pg/mL significantly had a lower proportion of RKF (39.2% vs. 60.1%, P < 0.001) and a higher proportion of LV diastolic dysfunction (54. 1% vs. 29.1%, P < 0.001) than those with an iFGF-23 level ≤ 423.8 pg/mL. The odds ratio (OR) for LV diastolic dysfunction was significantly higher in patients with RFK (OR per one-unit increase in the natural log-transformed iFGF-23 levels, 1.80; 95% confidence interval [CI]: 1.11-2.93) than in patients without RKF (OR per one-unit increase in the natural log-transformed iFGF-23 levels: 1.42; 95% CI: 1.01-1.99) in multivariate analysis (p < 0.001). During the follow-up period, 55 patients experienced CVD. The hazard ratio (HR) for CVD development was also significantly higher in patients with RKF (HR per one-unit increase in the natural log-transformed iFGF-23 levels, 2.64; 95% CI: 1.29-5.40) than those without RKF (HR per one-unit increase in the natural log-transformed iFGF-23 levels: 1.44; 95% CI: 1.04-1.99) in multivariate analysis (p = 0.05). Conclusions: Increased iFGF-23 levels were associated with LV diastolic dysfunction and CVD development in patients undergoing prevalent hemodialysis; however, the loss of RKF attenuated the magnitude of these associations. Therefore, in these patients, RKF strongly influenced the detrimental role of iFGF-23 in the development of CVD.

The Korean Organ Transplantation Registry (KOTRY): an overview and summary of the kidney-transplant cohort.

BACKGROUND: As the need for a nationwide organ-transplant registry emerged, a prospective registry, the Korean Organ Transplantation Registry (KOTRY), was initiated in 2014. Here, we present baseline characteristics and outcomes of the kidney-transplant cohort for 2014 through 2019. METHODS: The KOTRY consists of five organ-transplant cohorts (kidney, liver, lung, heart, and pancreas). Data and samples were prospectively collected from transplant recipients and donors at baseline and follow-up visits; and epidemiological trends, allograft outcomes, and patient outcomes, such as posttransplant complications, comorbidities, and mortality, were analyzed. RESULTS: From 2014 to 2019, there were a total of 6,129 registered kidney transplants (64.8% with living donors and 35.2% with deceased donors) with a mean recipient age of 49.4 ± 11.5 years, and 59.7% were male. ABO-incompatible transplants totaled 17.4% of all transplants, and 15.0% of transplants were preemptive. The overall 1- and 5-year patient survival rates were 98.4% and 95.8%, respectively, and the 1- and 5-year graft survival rates were 97.1% and 90.5%, respectively. During a mean follow-up of 3.8 years, biopsy-proven acute rejection episodes occurred in 17.0% of cases. The mean age of donors was 47.3 ± 12.9 years, and 52.6% were male. Among living donors, the largest category of donors was spouses, while, among deceased donors, 31.2% were expanded-criteria donors. The mean serum creatinine concentrations of living donors were 0.78 ± 0.62 mg/dL and 1.09 ± 0.24 mg/dL at baseline and 1 year after kidney transplantation, respectively. CONCLUSION: The KOTRY, a systematic Korean transplant cohort, can serve as a valuable epidemiological database of Korean kidney transplants.

Urinary Retinol-Binding Protein 4 is Associated With Renal Function and Rapid Renal Function Decline in Kidney Transplant Recipients.

BACKGROUND: Urinary retinol-binding protein 4 (RBP4) has been known as a biomarker of chronic kidney disease. In this study, we evaluated the association of urinary RBP4 with renal function and progression of renal function in kidney transplant recipients (KTRs). METHODS: A total 50 KTRs were included in this study. Proteomic analysis with liquid chromatography-mass spectrometry and tandem mass spectrometry was performed to discover potential urinary biomarkers. Several urinary proteins including RBP4 were identified and then validated by enzyme-linked immunosorbent assay. Rapid renal function decline was defined as estimated glomerular filtration rate (eGFR) decline of >3 mL/min/1.73 m2/year or initiation of dialysis, and 19 (38%) were included in rapid renal function decline group. RESULTS: Urinary RBP4/creatinine was inversely correlated with allograft function (r = -0.54, P < .001 with eGFR, and r = 0.49, P < .001 with serum creatinine, respectively). Urinary RBP4/creatinine was higher in rapid renal function decline group than in stable renal function group (184.9 ± 156.7 vs 83.1 ± 99.9, P = .017). Log-transformed urinary RBP4/creatinine was significantly associated with rapid renal function decline in univariate logistic regression analysis (Odds ratio [OR] 7.59, confidence interval [CI] 2.04-36.70, P = .005). In multivariate logistic regression adjusted with recipient age and sex, donor age, number of HLA mismatch, and acute rejection episode, urinary RBP4/creatinine remained a significant factor for rapid renal function decline (OR 9.43, CI 1.99-65.65, P = .010). Receiver operating characteristic analysis showed that the area under the curve of urinary RBP4/creatinine was 0.747 (CI 0.608-0.886, P < .001) for rapid renal function decline. CONCLUSIONS: Urinary RBP4 levels are associated with renal function and might be used to predict rapid renal function decline in KTRs.

Hypochromic red cells as predictors of anemia in patients undergoing hemodialysis: an observational retrospective study.

The percentage of hypochromic red blood cells (%HRC) estimates the availability of iron by evaluating the degree of hemoglobinization. We investigated whether %HRC was a predictor of anemia in patients undergoing hemodialysis. We recruited 142 patients undergoing routine hemodialysis between 2017 and 2019. Delta hemoglobin level (ΔHb)1mo-baseline was calculated as the difference between the hemoglobin level at 1 month after study enrollment and that at the time of study enrollment. Development of anemia was defined as hemoglobin level ≤ 15% of baseline. The median %HRC was 3.1%. There was a significant negative correlation between (ΔHb)1mo- baseline and %HRC (r = - 0.63, P < 0.001). The incidence of anemia was significantly higher in patients with %HRC > 3.1% than in those with %HRC ≤ 3.1%. In the multivariate logistic regression analysis, %HRC was significantly related to the development of anemia (odds ratio 2.57, 95% confidence interval [CI] 1.72-3.85, P < 0.001). The best cutoff value for %HRC to predict the development of anemia was 4.3%, with a sensitivity and specificity of 67.74 (95% CI, 54.7-79.1) and 97.50 (95% CI, 91.3- 99.7), respectively. %HRC is an independent predictor of anemia in patients undergoing hemodialysis. %HRC ≤ 4.3% is an early marker to consider changing the anemia treatment.

Dyschloremia is associated with failure to restore renal function in survivors with acute kidney injury: an observation retrospective study.

Dyschloremia is common in critically ill patients. However, little is known about the effects of dyschloremia on renal function in patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). A total of 483 patients who received CRRT for AKI were selected and divided into three groups according to their serum chloride concentrations at the time of CRRT initiation. At 90 days after initiating CRRT, renal outcome, i.e., non-complete renal recovery, or renal failure, was assessed in the three groups. The hypochloremia group (serum chloride concentrations < 96 mEq/L, n = 60), the normochloremia group (serum chloride concentrations, 96-111 mEq/L, n = 345), and the hyperchloremia group (serum chloride concentrations > 111 mEq/L, n = 78) were classified. The simplified acute physiology score III was higher in the hyperchloremia and hypochloremia groups than in the normochloremia group. Multivariate logistic regression analyses showed that hypochloremia (odds ratio, 5.12; 95% confidence interval [CI], 2.56-10.23; P < 0.001) and hyperchloremia (odds ratio, 2.53; 95% CI, 1.25-5.13; P = 0.01) were significantly associated with non-complete renal recovery. Similar trends were observed for renal failure. This study showed that dyschloremia was independently associated with failure in restoring renal function following AKI.

Post-traumatic stress symptoms in hemodialysis patients with MERS-CoV exposure.

BACKGROUND: Post-traumatic stress symptoms can occur in patients with medical illness. During the Middle East Respiratory Syndrome (MERS) outbreak in South Korea in 2015, some dialysis patients in three centers who were incidentally exposed to patients or medical staff with confirmed MERS-CoV infection were isolated to interrupt the spread of the infection. We aimed to investigate post-traumatic stress symptoms and risk factors among these patients. MATERIALS AND METHODS: In total, 116 hemodialysis (HD) patients in contact with MERS-CoV-confirmed subjects were isolated using three strategies, namely, single room isolation, cohort isolation, and self-quarantine. We used the Impact of Event Scale-Revised-Korean (IES-R-K) to examine post-traumatic stress symptoms at 12 months after the isolation period. RESULTS: Of the 116 HD patients, 27 were lost to follow-up. Of the 89 patients, 67 (75.3%) completed the questionnaires. Single room isolation was used on 40 (58.8%) of the patients, cohort isolation on 20 (29.4%), and self-imposed quarantine on 8 (11.8%). In total, 17.9% of participants (n = 12) reported post-traumatic stress symptoms exceeding the IES-R-K's cutoff point (≧18). Prevalence rates of IES-R-K ≧18 did not differ significantly according to isolation method. However, isolation duration was linearly associated with the IES-R-K score (standardized ß coefficient - 0.272, P = 0.026). Scores in Avoidance, Emotional numbing and Dissociation subscale were higher in patients with longer isolation period. CONCLUSION: MERS was a traumatic experience for quarantined HD patients. IES-R-K scores were not significantly different by isolation methods. However, short isolation was associated with post-traumatic stress symptoms.

Effect of isolation practice on the transmission of middle east respiratory syndrome coronavirus among hemodialysis patients: A 2-year prospective cohort study.

Hemodialysis (HD) patients had a high rate of infection transmission and mortality during the middle east respiratory syndrome coronavirus (MERS-CoV) outbreak in Saudi Arabia. A standardized guideline on isolation technique for exposed HD patients is not available. Thus, this study aimed to evaluate the effect of different isolation strategies on the prevention of secondary viral transmission and clinical outcomes among exposed HD patients.During the 2015 MERS-CoV outbreak in Korea, 116 patients in 3 HD units were incidentally exposed to individuals with confirmed MERS-CoV infection and underwent different types of isolation, which were as follows: single-room isolation (n = 54, 47%), cohort isolation (n = 46, 40%), and self-imposed quarantine (n = 16, 13%). The primary outcome was rate of secondary viral transmission. The secondary outcome measures were changes in clinical and biochemical markers during the isolation period, difference in clinical and biochemical markers according to the types of isolation practice, and effect of isolation practice on patient survival.During a mean isolation period of 15 days, no further cases of secondary transmission were detected among HD patients. Plasma hemoglobin, serum calcium, and serum albumin levels and single-pool Kt/V decreased during the isolation period but normalized thereafter. Patients who were subjected to self-imposed quarantine had higher systolic and diastolic blood pressure, lower total cholesterol level, and lower Kt/V than those who underwent single-room or cohort isolation. During the 24-month follow-up period, 12 patients died. However, none of the deaths occurred during the isolation period, and no differences were observed in patient survival rate according to different isolation strategies.Although 116 participants in 3 HD units were incidentally exposed to MERS-CoV during the 2015 outbreak in Korea, strict patient surveillance and proper isolation practice prevented secondary transmission of the virus. Thus, a renal disaster protocol, which includes proper contact surveillance and isolation practice, must be established in the future to accommodate the needs of HD patients during disasters or outbreaks.

Static intra-access pressure ratio and cardiovascular events in patients undergoing haemodialysis.

Static intra-access pressure ratio (SIAPR) measurement, using haemodialysis machine transducers, is the vascular access surveillance method in patients undergoing haemodialysis. However, little is known about the relationship between the SIAPR and arterial stiffness, and the clinical usefulness of the SIAPR in predicting cardiovascular events. A total of 209 patients undergoing maintenance haemodialysis were evaluated. The SIAPRs ranged from 0.01 to 0.52 (median: 0.23). When the patients were divided into two groups according to their median of SIAPR, the incidence of previous cardiovascular disease, E/E' ratio, and brachial-ankle pulse wave velocity were significantly higher in the patients with SIAPRs of ≤0.23 than in those with SIAPRs of >0.23. Conversely, patients with worse comorbid status had a lower SIAPR than patients without it. In the Kaplan-Meier analysis, the cumulative incidence of cardiovascular events was significantly higher in the patients with SIAPRs of ≤0.23 than in those with SIAPRs of >0.23 (P < 0.001). In the multiple Cox regression analysis, an increase in the SIAPR was associated with a reduced risk for cardiovascular events [hazard ratio: 0.36, 95% confidence interval: 0.21-0.60, P = 0.001]. Therefore, a low SIAPR related with arterial stiffness was a predictor for cardiovascular events.

Peripheral blood transcriptome analysis and development of classification model for diagnosing antibody-mediated rejection vs accommodation in ABO-incompatible kidney transplant.

The major obstacle to successful ABO blood group-incompatible kidney transplantation (ABOi KT) is antibody-mediated rejection (AMR). This study aimed to investigate transcriptional profiles through RNA sequencing and develop a minimally invasive diagnostic tool for discrimination between accommodation and early acute AMR in ABOi KT. Twenty-eight ABOi KT patients were selected: 18 with accommodation and 10 with acute AMR at the 10th day posttransplant protocol biopsy. Complete transcriptomes of their peripheral blood were analyzed by RNA sequencing. Candidate genes were selected by bioinformatics analysis, validated with quantitative polymerase chain reaction, and used to develop a classification model to diagnose accommodation. A total of 1385 genes were differentially expressed in accommodation compared with in AMR with P-adjusted < .05. Functional annotation and gene set enrichment analysis identified several immune-related and immunometabolic pathways. A 5-gene classification model including COX7A2L, CD69, CD14, CFD, and FOXJ3 was developed by logistic regression analysis. The model was further validated with an independent cohort and discriminated between accommodation and AMR with 92.7% sensitivity, 85.7% specificity, and 91.7% accuracy. Our study suggests that a classification model based on peripheral blood transcriptomics may allow minimally invasive diagnosis of acute AMR vs accommodation and subsequent patient-tailored immunosuppression in ABOi KT.

Temporary Renal Artery Clamping With Hemostatic Materials in Diffuse Type of Spontaneous Renal Allograft Rupture: A Case Report.

BACKGROUND: Several surgical strategies have been introduced for spontaneous kidney rupture. Herein, we report on a case in which temporary artery clamping with hemostatic materials was performed. CASE PRESENTATION: A 52-year-old man underwent renal transplant from a living donor (his 20-year-old son). Spontaneous allograft rupture occurred 6 days after transplant. He developed severe abdominal pain, hypotension, and mental changes. His blood hemoglobin level was 3.6 g/dL, which was indicative of severe hemorrhage. Immediate re-exploration revealed a large hematoma in the iliac fossa and that the renal allograft had ruptured, with multiple fracture lines on the entire surface. Because of diffuse surface rupture, surgical suture was not attempted. For manual compressive hemostasis, temporary artery clamping with hemostatic materials was performed. First, we identified the graft artery for temporary clamping, similar to the method in partial nephrectomy. Second, at the time of temporary clamping, the hemostatic matrix was sprayed on the surface of the renal graft. Third, we compressed the whole renal parenchyma with both hands and a dry pad for 5 minutes. After removing the clamp, successful bleeding control was confirmed. Finally, the graft was wrapped with oxidized cellulose. Renal biopsy in the operating room revealed the cause of rupture as acute rejection type IIB. CONCLUSION: Spontaneous renal allograft rupture is a rare but serious complication. When surgical suture is not appropriate for the repair of the ruptured allograft, temporary artery clamping with hemostatic materials can be considered an alternative.

Urate-lowering agents for asymptomatic hyperuricemia in stage 3 - 4 chronic kidney disease: Controversial role of kidney function.

Because the serum uric acid level increases as the glomerular filtration rate (GFR) decreases, hyperuricemia is associated with chronic kidney disease (CKD). Although hyperuricemia is a risk factor for CKD progression, the causal role of uric acid remains controversial in patients with CKD and asymptomatic hyperuricemia. This study included 588 patients with stage 3-4 CKD and asymptomatic hyperuricemia. Using propensity score matching, 165 pairs treated and untreated with pharmacologic urate-lowering therapy were matched. Kaplan-Meier curves were constructed to determine the effect of urate-lowering agents on kidney survival. The prognostic value for kidney survival was ascertained using Cox regression analysis. The GFR changes over time between the patients treated and untreated with urate-lowering agents were assessed using a linear mixed model analysis. The mean age of the matched patients was 63.2 ± 12.7 years, and 52 (15.8%) patients had diabetic nephropathy. The mean estimated GFR (eGFR) and serum uric acid level were 36.7 mL/min/1.73 m2 and 7.8 mg/dL, respectively. During a mean follow-up period of 41.9 months, 87 developed end-stage kidney disease (ESKD). The incidence rates of ESKD were comparable between the patients treated and untreated with urate-lowering agents. The Kaplan-Meier analysis indicated that kidney survival was also comparable between them. In the multivariate analysis, heart failure and low eGFR were the significant prognostic factors for kidney survival. However, pharmacologic urate-lowering therapy was not predictive of kidney survival. The overall GFR decline rate was also comparable between the groups (P = 0.13). The efficacy of pharmacologic urate-lowering therapy in delaying CKD progression remains controversial. Therefore, further randomized controlled trials are needed to confirm its efficacy in attenuating kidney function deterioration in patients with stage 3-4 CKD.

Kidney Stones and Risk of Osteoporotic Fracture in Chronic Kidney Disease.

Osteoporotic fracture associated with calcium dysregulation is more common in patients with kidney stones. However, little is known about the association of kidney stones and bone health status in patients with chronic kidney disease (CKD). This retrospective medical record-based study included 2282 patients with stable stage 3-4 CKD between 2007 and 2017. Of these, 113 patients were diagnosed with kidney stones. Propensity score matching for 226 patients with and without kidney stones showed that osteoporotic fracture occurred more often in patients with kidney stones (33, 29.2%) than in patients without kidney stones (16, 14.2%), resulting in rates of 5.56 and 2.63/100 patient-years, respectively (p < 0.01). In particular, Cox proportional hazard analysis revealed that kidney stones were significantly associated with osteoporotic fracture, even after adjusting for age, sex, body mass index, kidney stones, estimated glomerular filtration rate, excessive alcohol consumption, current smoking, and steroid use in patients with CKD stage 3-4 (hazard ratio, 2.32, 95% CI 1.24-4.34, p = 0.01). This study showed that the presence of kidney stones was a significant predictor for osteoporotic fracture in patients with CKD, suggesting that it should be considered as a clinical risk factor for osteoporotic fracture in them.

Intradialytic exercise improves physical function and reduces intradialytic hypotension and depression in hemodialysis patients.

BACKGROUND/AIMS: As numbers of maintenance hemodialysis patients are growing, debilitating conditions of muscle wasting and atrophy are becoming some of the greatest concerns in end-stage renal disease patients. Exercise training has various potential benefits in terms of prevention of a sustained decline in functional status. This study aimed to evaluate the physical, psychological, laboratory, and dialysis-related effects of intradialytic exercise. METHODS: We enrolled 22 patients from a hemodialysis center for a 6-month non-randomized prospective trial. Combination of aerobic exercise with bicycle ergometer and anaerobic exercise with elastic bands was conducted during hemodialysis. Data including physical fitness test results, dialysis-related measurements, and biochemical laboratory results were collected at baseline, 3, and 6 months. Depression and quality of life were assessed using Beck Depression Inventory and Short Form-36 health survey. RESULTS: After exercise completion, there were significant improvements in back muscle power, forward and backward trunk flexibility, vertical jump, elbow flexion, sit to stand test, and 6-minute walk test (p < 0.05). No significant changes were observed in dry weight, blood pressure, Kt/V, and biochemical variables, except for intradialytic hypotension (p < 0.05). For depression, Beck Depression Inventory showed statistically significant enhancement (p < 0.05). Scores of Short Form-36 health survey did not show significant increase in each domain, except for bodily pain (p < 0.05). CONCLUSION: Combined aerobic and anaerobic exercise training during dialysis was found to be effective on physical health status, intradialytic hypotension, and depression in terms of mental health. Therefore, the findings of the current study may provide an appropriate guidance for encouraging exercise by nephrologists.

Identification of Human B-1 Helper T Cells With a Th1-Like Memory Phenotype and High Integrin CD49d Expression.

Human B-1 cells have been proposed to be CD20+CD27+CD43+CD1c- B cells found in the umbilical cord and adult peripheral blood, but their regulatory mechanisms have not been well elucidated. Previously, we reported that mouse CD49dhigh CD4+ T cells could enhance the secretion of natural antibodies by B-1 cells. In this study, we aimed to investigate the presence and helper functions of the human equivalents of murine CD49dhigh CD4+ T cells. Here, we showed that human CD49dhigh CD4+ T cells found in the peritoneal cavity (PEC), spleen, and peripheral blood can enhance the production of IgM antibodies by B-1 cells. As revealed in mouse, CD49dhigh CD4+ T cells were more abundant in the PEC and showed a higher tendency to form conjugates with B cells than CD49dlow CD4+ T cells. Moreover, CD49dhigh CD4+ T cells showed a Th1-like memory phenotype, characterized by high expression of CD44 and CXCR3; low expression of CD62L and CCR7; rapid production of IFN-γ, tumor necrosis factor-α, and IL-2 upon stimulation with phorbol myristate acetate and ionomycin; and rapid proliferation upon stimulation with anti-CD3 and anti-CD28 antibodies. These cells also expressed high levels of PD-1, ICOS, and CD5, suggesting that they are undergoing chronic stimulation. Remarkably, CD49dhigh CD4+ T cells specifically helped B-1 cells, but not follicular memory B cells (CD27+ CD43-CD1c-) or marginal zone B cells (CD27+CD43-CD1c+), produce IgM and IgG antibodies. In parallel, the titer of human anti-blood group A IgM was positively correlated with the frequency of CD49dhigh CD4+ T cells. In conclusion, we identified human CD49dhigh CD4+ T cells with a Th1-like memory phenotype that secrete Th1 proinflammatory cytokines and help B-1 cells secrete antibodies, thereby aiding in primary defense. We suggest that these CD49dhigh CD4+ T cells are a unique type of B-cell helper T cells distinct from follicular helper T cells.

Safety and efficacy of Rapamune® (Sirolimus) in kidney transplant recipients: results of a prospective post-marketing surveillance study in Korea.

BACKGROUND: Few post-marketing surveillance studies have examined the safety and efficacy of Rapamune® (Sirolimus) in Asian countries. This study aimed to better understand safety and efficacy of Rapamune for kidney transplant recipients in the routine clinical practice setting in Korea. METHODS: This was an open-label, non-comparative, observational, prospective, multi-center, post-marketing surveillance study conducted at 15 Korean transplant centers between 31 August 2009 and 24 September 2015. The subjects were administered Rapamune as part of routine practice. The safety was monitored based on reporting of adverse events (AEs). Efficacy endpoints included acute rejection, graft function, graft survival, and patient survival. RESULTS: Rapamune was most commonly used for late conversion therapy after post-transplant 1 year and was substituted for anti-metabolites (63.6%) or calcineurin inhibitors (28.7%). The median treatment duration of Rapamune was 182 days. Among 209 subjects enrolled, AEs and adverse drug reactions (ADRs) were reported in 54.07% and 43.06% of subjects, respectively, in the safety analysis set. Most of the AEs were expected (96.21%), mild (75.83%), did not result in any action taken with regard to the study drug (72.99%), and resolved by the end of the study (75.36%). The most frequently reported AEs/ADRs were pharyngitis and diarrhea. Most of the serious AEs/ADRs occurred in one or two subjects. Unexpected ADRs of renal artery occlusion and cholangitis were reported by one subject each. The incidence of biopsy-proven acute rejection was 2.87%. At the end of the study, 99.51% of the subjects and their grafts had survived. The mean eGFR was 64.72 ± 19.56 mL/min. CONCLUSIONS: Rapamune had an acceptable safety profile in prevention of kidney allograft rejection in Korea.