Vitamin D and Diabetic Kidney Disease.

Vitamin D is a hormone involved in many physiological processes. Its active form, 1,25(OH)2D3, modulates serum calcium-phosphate homeostasis and skeletal homeostasis. A growing body of evidence has demonstrated the renoprotective effects of vitamin D. Vitamin D modulates endothelial function, is associated with podocyte preservation, regulates the renin-angiotensin-aldosterone system, and has anti-inflammatory effects. Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease worldwide. There are numerous studies supporting vitamin D as a renoprotector, potentially delaying the onset of DKD. This review summarizes the findings of current research on vitamin D and its role in DKD.

Whole-exome sequencing identified mutational profiles of urothelial carcinoma post kidney transplantation.

Kidney transplantation is a lifesaving option for patients with end-stage kidney disease. In Taiwan, urothelial carcinoma (UC) is the most common de novo cancer after kidney transplantation (KT). UC has a greater degree of molecular heterogeneity than do other solid tumors. Few studies have explored genomic alterations in UC after KT. We performed whole-exome sequencing to compare the genetic alterations in UC developed after kidney transplantation (UCKT) and in UC in patients on hemodialysis (UCHD). After mapping and variant calling, 18,733 and 11,093 variants were identified in patients with UCKT and UCHD, respectively. We excluded known single-nucleotide polymorphisms (SNPs) and retained genes that were annotated in the Catalogue of Somatic Mutations in Cancer (COSMIC), in the Integrative Onco Genomic cancer mutations browser (IntOGen), and in the Cancer Genome Atlas (TCGA) database of genes associated with bladder cancer. A total of 14 UCKT-specific genes with SNPs identified in more than two patients were included in further analyses. The single-base substitution (SBS) profile and signatures showed a relative high T > A pattern compared to COMSIC UC mutations. Ingenuity pathway analysis was used to explore the connections among these genes. GNAQ, IKZF1, and NTRK3 were identified as potentially involved in the signaling network of UCKT. The genetic analysis of posttransplant malignancies may elucidate a fundamental aspect of the molecular pathogenesis of UCKT.

Timing of mTORI usage and outcomes in kidney transplant recipients.

The introduction of mammalian target of rapamycin inhibitors (mTORi) as immunosuppressive agents has changed the landscape of calcineurin inhibitor-based immunosuppressive regimens. However, the timing of mTORi conversion and its associated outcomes in kidney transplantation have conflicting results. This study investigated the effect of early or late mTORi post-transplant initiation on major transplant outcomes, including post-transplant malignancy, in kidney transplant recipients in our center. We enrolled 201 kidney transplant recipients with surviving function grafts of >3 months between 1983 and 2016. Patients were divided into three groups: early mTORi (initiated within 6 months of kidney transplantation), late mTORi, (mTORi initiation >6 months after kidney transplantation) and no mTORi. The mean creatinine at conversion was 1.46 ± 0.48 mg/dL and 1.30 ± 0.53 mg/dL for the early and late mTORi groups, respectively. During the study period, 10.5% of mTORi users and 19.2% of mTORi nonusers developed malignancy, mainly urothelial carcinoma. After adjustment for confounding factors, mTORi users were found to have a lower incidence of post-transplant malignancy than did nonusers (adjusted OR: 0.28, P = 0.04). No significant difference was observed between early and late mTORi users. Our results verified the potential advantages of mTORi usage in reducing cancer incidence after kidney transplantation. However, no significant result was found related to the timing of mTORi introduction. Future studies should include a longer observation period with a larger cohort.

Topical tacrolimus and steroids modulate T cells in acute rejection of hand allotransplantation: Two case reports.

Acute rejection is not uncommon after vascularized composite allotransplantation. We reported the effects of adjunctive topical immunosuppressant with topical tacrolimus (Protopic®) and steroid cream (Clobetasol®) in the management of acute rejection in two hand transplantation patients. Case 1 is a 45-year-old male with distal forearm deficit 4 years ago and Case 2 is a 30-year-old male with a proximal forearm deficiency 2 years ago, respectively. Both of them suffered from occupational accident and received hand allotransplantation. Induction was performed with antithymocyte globulins and methylprednisolone. Maintenance therapy consisted of tacrolimus (FK506), mycophenolate mofetil, and prednisone. Both cases experienced acute rejection, which we treated with topical tacrolimus and Clobetasol for 2 weeks, combined with systemic immunosuppressant maintenance therapy without adding pulse-steroid therapy. Clinically, both cases recovered after adjunctive treatments. The skin biopsies showed significantly decreased perivascular lymphocyte infiltration after topical treatment. Immunohistochemical staining showed that CD3+ T-cells and CD20+ B-cells were suppressed in the recovery phase. FoxP3-positive regulatory T cells were increased after treatment. Topical tacrolimus and Clobetasol as an adjunctive treatment with maintenance systemic immunosuppressives may be useful to control acute rejection, which correlated with modulation of lymphocyte activation, especially T cells. The treatment needs further investigation with gaining more comparable data.

Heart Rate Variability Predicts Major Adverse Cardiovascular Events and Hospitalization in Maintenance Hemodialysis Patients.

BACKGROUND/AIMS: Heart rate variability (HRV) has been linked to mortality in maintenance hemodialysis (HD) patients, but it is less clear whether HRV is associated with major adverse cardiovascular events (MACEs) and hospitalization. METHODS: This study enrolled 179 maintenance HD patients. HRV was measured to assess its prognostic significance in relation to MACEs and hospitalization. RESULTS: During the follow-up period of 33.3 ± 6.7 months, 36 (20.1%) patients had a MACE, and 98 (54.7%) experienced hospitalization. In multivariate adjusted Cox regression analysis, low very low frequency (VLF) power (hazard ratio [HR], 0.727; 95% confidence interval [CI], 0.624-0.848; p < 0.001), a history of coronary artery disease, high ultrafiltration rate, the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and the use of beta-blockers were all significantly associated with MACEs. Low VLF power (HR, 0.873; 95% CI, 0.785-0.971; p = 0.012), low serum albumin, low serum creatinine, low Kt/V levels, and high serum calcium-phosphorus product levels significantly predicted hospitalization in maintenance HD patients. CONCLUSIONS: Reduced VLF power is linked to an increased risk of MACEs and hospitalization in maintenance HD patients. Assessing cardiac autonomic function through HRV is of pivotal prognostic significance for this patient population.

Low serum calcium is associated with poor renal outcomes in chronic kidney disease stages 3-4 patients.

BACKGROUND: Mineral disorders are associated with adverse renal outcomes in chronic kidney disease (CKD) patients. Previous studies have associated hypercalcemia and hypocalcemia with mortality; however, the association between serum calcium and renal outcome is not well-described. Whether adding calcium besides phosphorus or in the form of calcium-phosphorus (Ca×P) product into the model of survival analysis could improve the prediction of renal outcomes is not known. METHODS: A prospective cohort of 2144 outpatients with CKD stages 3-4 was evaluated. Cox proportional hazard analysis was performed according to calcium quartiles. RESULTS: The mean calcium level was 9.2±0.7 mg/dL. Low serum calcium (<9.0 mg/dL) was associated with increased risk of requiring renal replacement therapy (RRT) (hazards ratio [HR]:2.12 (95% CI: 1.49-3.02, P<0.05) and rapid renal function progression (odds ratio [OR]: 1.65 (95% CI: 1.19-2.27, P<0.05) compared with high serum calcium (>9.8 mg/dL). Adding calcium into the survival model increased the integrated discrimination improvement by 0.80% (0.12%-1.91%) while calcium-phosphorus product did not improve risk prediction.The combination of high serum phosphorus (>4.2 mg/dL) and low serum calcium (<9.1 mg/dL) was associated with the highest risk of RRT (HR:2.31 (95% CI: 1.45-3.67, P<0.05). CONCLUSION: Low serum calcium is associated with increased risk of RRT and rapid renal function progression in CKD stage 3-4 patients. The integration of serum calcium and phosphorus, but not calcium-phosphorus product should be considered in a predictive model of renal outcome.

NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.

Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan-Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression-free survival, cancer-specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K-AKT-mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT-mTOR pathway. Furthermore, the overexpression of NTRK3 in UM-UC-14 cells promoted AKT-mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT-mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC.

Atypical X-linked agammaglobulinaemia caused by a novel BTK mutation in a selective immunoglobulin M deficiency patient.

BACKGROUND: X-linked agammaglobulinaemia (XLA) is the most common inherited humoural immunodeficiency disorder. Mutations in the gene coding for Bruton's tyrosine kinase (BTK) have been identified as the cause of XLA. Most affected patients exhibit a marked reduction of serum immunoglobulins, mature B cells, and an increased susceptibility to recurrent bacterial infections. However, the diagnosis of XLA can be a challenge in certain patients who have near-normal levels of serum immunoglobulin. Furthermore, reports on XLA with renal involvement are scant. CASE PRESENTATION: We report an atypical XLA patient who presented with selective immunoglobulin M (IgM) immunodeficiency and nephropathy. He was diagnosed with selective IgM immunodeficiency, based on his normal serum immunoglobulin G (IgG) and immunoglobulin A (IgA) levels but undetectable serum IgM level. Intravenous immunoglobulin was initiated due to increased infections and persistent proteinuria but no improvement in proteinuria was found. A lupus-like nephritis was detected in his kidney biopsy and the proteinuria subsided after receiving a mycophenolate mofetil regimen. Although he had a history of recurrent bacterial infections since childhood, XLA was not diagnosed until B-lymphocyte surface antigen studies and a genetic analysis were conducted. CONCLUSIONS: We suggest that B-lymphocyte surface antigen studies and a BTK mutation analysis should be performed in familial patients with selective IgM deficiency to rule out atypical XLA.

Diabetic Kidney Disease in Post-Transplant Diabetes Mellitus: Causes, Treatment and Outcomes.

Kidney transplant recipients are a unique subgroup of chronic kidney disease patients due to their single functioning kidney, immunosuppressive agent usage, and long-term complications related to transplantation. Post-transplant diabetes mellitus (PTDM) has a significant adverse effect on renal outcomes in particular. As transplantations enable people to live longer, cardiovascular morbidity and mortality become more prevalent, and PTDM is a key risk factor for these complications. Although PTDM results from similar risk factors to those of type 2 diabetes, the conditions differ in their pathophysiology and clinical features. Transplantation itself is a risk factor for diabetes due to chronic exposure to immunosuppressive agents. Considering current evidence, this article describes the risk factors, pathogenesis, diagnostic criteria, prevention strategies, and management of PTDM. The therapeutic options are discussed regarding their safety and potential drug-drug interactions with immunosuppressive agents.

Plasma cell-rich related acute rejection in kidney transplant: A case report and review of the literature.

RATIONALE: Plasma cell-rich acute rejection (PCAR), a subtype of T cell-mediated rejection, is a relatively rare type of acute allograft rejection, that is usually associated with a higher rate of graft failure. However, it is difficult to diagnose PCAR precisely. PATIENT CONCERNS: A 45-year-old woman who had received a kidney transplant presented with acute kidney injury and uremic symptoms approximately 1 year after transplantation. DIAGNOSIS: A renal biopsy was performed and pathological examination revealed marked inflammation with abundant plasma cells in areas within interstitial fibrosis and tubular atrophy. The patient was diagnosed with PCAR and chronic active T cell-mediated rejection (CA-TCMR) grade IA. INTERVENTIONS: Immunosuppressants were administered as tacrolimus (2 mg twice daily), mycophenolate mofetil (250 mg twice daily), and prednisolone (15 mg/day) for suspected PCAR. OUTCOMES: The patients showed rapid deterioration in kidney function and reached impending graft failure. LESSONS: PCAR is often associated with poor graft outcome. The high variability in tacrolimus levels could contribute to poor patient outcomes, leaving aggressive immunosuppressive therapy as the remaining choice for PCAR treatment.

Association of glomerular filtration rate slope with timely creation of vascular access in incident hemodialysis.

The factors associated with the timely creation of distal vascular access for hemodialysis initiation are unclear. We aimed to explore the association between the slope of estimated glomerular filtration rate (eGFR) and the successful usage of vascular access upon hemodialysis initiation. This single center retrospective cohort study enrolled chronic kidney disease patients who undertook a multidisciplinary care program from 2003 to 2016. Using eGFR slope as predictor, we evaluated the vascular access created timely upon hemodialysis initiation. Among the 987 patients, vascular access was created at a median eGFR of 5.8 min/ml/1.73 m2, with a median duration of 3.1 months before hemodialysis. The proportions of vascular access created timely, created not timely (vascular access immature), and not created were 68.5%, 8.8%, and 22.7%, respectively. There was a significant negative association of eGFR upon vascular access creation with eGFR slope (r = - 0.182, P < 0.001). The fastest eGFR slope patients (the first quartile or < - 10 min/ml/1.73 m2/year) had the lowest percentage of vascular access created timely. In the multivariable logistic regression analysis, only higher eGFR upon vascular access creation (P = 0.001) and eGFR slope (P = 0.009) were significantly associated with vascular access created timely. The adjusted odds ratios of each quartile of eGFR slopes for vascular access created timely were 0.46 (95% confidence interval 0.27-0.86), 1.30 (0.62, 2.72), 1.00 (reference), and 0.95 (0.48-1.87), respectively. eGFR slope is associated with the timely creation of vascular access for the initiation of hemodialysis in a reverse-J-shaped pattern and may help determine the time of vascular access creation.

Low dose ultraviolet B irradiation at 308 nm with light-emitting diode device effectively increases serum levels of 25(OH)D.

This animal study aimed to elucidate the relationship of low-dose, narrow-band UVB at 308 nm with vitamin D synthesis. C57BL/6 female mice, at 3 weeks-of-age, were randomly divided into the following six groups (n = 6 at each time point of vitamin D measurement), which were: (1) normal diet without UVB irradiation; (2) VDd diet without UVB irradiation; and (3)-(6) VDd diet with 308 nm-UVB irradiation of 12.5, 25, 50, and 100 µω/cm2, respectively. All of the groups needing UVB irradiation received an exposure of 10 min per day, five days per week, and a duration of 3-5 weeks. The mice recovering from severe VDd (plasma total 25-hydroxyvitamin D level increasing from approximately 3 to over 30 ng/mL) only occurred in groups with a UVB irradiation dosage of either 50 or 100 µω/cm2. The optimal, estimated dosage for mice to recover from severe VDd was 355 mJ/cm2 within 3 weeks. Low-dose, narrow-band UVB irradiation at 308 nm is effective in improving VDd in mice. The results obtained, in addition to the especially small side effects of the above UVB irradiation formula, could be further translated to treating VDd-related disorders.

Pyuria, urinary tract infection and renal outcome in patients with chronic kidney disease stage 3-5.

Pyuria is common in chronic kidney disease (CKD), which could be due to either urinary tract infection (UTI) or renal parenchymal inflammation. Only little is known regarding the association of pyuria or UTI with renal outcomes. We investigated 3226 patients with stage 3-5 CKD. Pyuria was defined as ≥ 50 WBC per high-power field (hpf) and was correlated to old age, female, diabetes, hypoalbuminemia, lower eGFR, and higher inflammation status. In Cox regression, patients with more than one episode of pyuria in the first year (11.8%) had increased risks for end-stage renal disease (ESRD) [hazard ratio (95% CI): 1.90 (1.58-2.28); p < 0.001], rapid renal function progression [odds ratio (95% CI): 1.49 (1.13-1.95); p = 0.001], and all-cause mortality [hazard ratio: 1.63 (1.29-2.05); p < 0.001], compared to those without pyuria. In a subgroup analysis, the risk of pyuria for ESRD was modified by CKD stages. We investigated the effects of UTI (urinary symptoms and treated by antibiotics) and pyuria without UTI (urine WBC < 50 to ≥ 10/hpf without any episodes of ≥ 50 WBC/hpf or UTI), while both groups were associated with clinical outcomes. In conclusion, CKD stage 3-5 patients with frequent pyuria or UTI episodes have increased risks of renal outcomes.

Effect of differences in serum creatinine estimation methodologies on estimated glomerular filtration rate.

INTRODUCTION: Serum creatinine is crucial in glomerular filtration rate (GFR) estimation. Various methods of measuring GFR have been developed, which vary in their ability to estimate the prevalence of chronic kidney disease (CKD) and predict consequences associated with CKD. The use of different laboratory devices also results in uncertainty in estimated GFR (eGFR). The purpose of our study was to discuss the effect of differences in laboratory devices on eGFR when performing serum creatinine measurements. METHODS: 163 participants aged 51.22 ± 18.66 years were enrolled during a community health screening programme conducted on 18 June 2011. Samples were sent to four different hospitals using four different devices to check serum creatinine by the Jaffe and enzymatic creatinine methods. RESULTS: Using Roche Cobas Integra 400, Beckman LX20, Hitachi 7180 and Toshiba TBA - c8000, the proportion of the population with eGFR < 60 mL/min/1.73 m2 was 11.04%, 6.75%, 20.25% and 20.86%, respectively. Moreover, 3.68% of the participants had eGFR < 60 mL/min/1.73 m2 in the laboratory when Roche Cobas Integra 400 was used with the enzymatic creatinine method and compensated Jaffe method. CONCLUSION: Although standardisation of serum creatinine measurement has been achieved by using isotope dilution mass spectrometry, differences in measurement devices still cause substantial bias in the overall results. This affects the application of GFR in the estimation of CKD progression and outcomes associated with CKD.

Long-term outcomes of lateral tunneled transposed brachiobasilic arteriovenous fistulas in elderly hemodialysis patient.

BACKGROUND: Arteriovenous fistula is recommended for the general dialysis population, but its use remains controversial in the elderly population. We evaluated the long-term outcomes of lateral tunneled transposed brachiobasilic arteriovenous fistulas in older patients who underwent hemodialysis. METHODS: In this retrospective cohort study, we included patients who received a two-stage transposed brachiobasilic arteriovenous fistula in a medical center from May 2005 to January 2014. The patients were followed up from the fistula placement date until any intervention, death, failure, January 2015, or the end of the sixth year. Death and arteriovenous fistula failure during the observation period were considered as adverse outcomes, and the cause of death was identified. The cumulative patency rate was calculated using the Kaplan-Meier approach to reveal the long-term outcomes of this procedure. RESULTS: Among the 66 patients who underwent surgery, the average age was 65.8 ± 13.5 years and the majority were females (62.1%). After a median follow-up of 20.6 months, 19 patients died, 12 (18.2%) received vascular intervention, and 3 experienced fistula failure. No significant difference was observed in the 6-year cumulative patency rates between younger and older adults (96.3% vs 80.3%, p = 0.58). None of the deaths during the observation period were related to bloodstream infection. CONCLUSION: A two-stage lateral tunneled transposed brachiobasilic arteriovenous fistula can be applied to patients undergoing hemodialysis, regardless of age.

Hematuria and Renal Outcomes in Patients With Diabetic Chronic KidneyDisease.

BACKGROUND: Hematuria may indicate nondiabetic renal disease in diabetic chronic kidney disease (CKD). However, some studies have reported that hematuria is noted in diabetic nephropathy and is associated with albuminuria. Hematuria is a risk factor for end-stage renal disease in glomerulonephritis, but its prognostic value in diabetic CKD is unknown. We investigated the factors associated with hematuria and the prognostic value of hematuria in patients with diabetic CKD. MATERIAL AND METHODS: We included 1958 patients with type 2 diabetes and CKD stages 1-5, and 111 patients underwent renal biopsy. Patients in the biopsied cohort were younger and had more severe proteinuria, compared with those in the total cohort; hematuria was associated with nondiabetic renal disease. RESULTS: In the total cohort, hematuria was observed in 15.0% of the patients and was associated with young age, a lower estimated glomerular filtration rate, proteinuria, high blood pressure and short diabetes duration. Hematuria was significantly associated with an increased risk (hazard ratio 1.39, 95% CI: 1.10-1.76, P < 0.001) of end-stage renal disease, particularly in patients with CKD stages 1-3 or a urine protein-to-creatinine ratio of <1,500mg/g (P for interaction < 0.05). The odds ratio of hematuria for rapid renal progression was 1.81 (95% CI: 1.29-2.53, P < 0.001). CONCLUSIONS: Hematuria is associated with nondiabetic renal disease in biopsied patients with diabetic CKD and is associated with an increased risk of end-stage renal disease in patients with early diabetic CKD.

Diabetic Retinopathy and Clinical Parameters Favoring the Presence of Diabetic Nephropathy could Predict Renal Outcome in Patients with Diabetic Kidney Disease.

Diabetes duration, diabetic retinopathy (DR), and a diagnostic model have been proposed as clinical parameters favoring the presence of diabetic nephropathy (DN) in biopsied patients with diabetic kidney disease. DN, compared with non-diabetic renal disease, had poorer renal outcomes. We tested whether these clinical parameters favoring DN are associated with poorer renal outcomes in non-biopsied patients. In this study, 1330 patients with type 2 diabetes and chronic kidney disease stages 1-4 were included and divided according to diabetes mellitus (DM) duration >8 years, DR, or a diagnostic model for DN. These clinical parameters favoring DN were found in 62-77% of patients and associated with higher levels of proteinuria. In a Cox survival analysis, DR and the diagnostic model favoring DN were associated with an increased risk for end-stage renal disease with adjusted hazard ratios of 1.69 (95% CI: 1.16-2.45, P = 0.006) and 1.66 (95% CI: 1.05-2.61, P = 0.029), respectively. DR was associated with an increased risk for rapid renal disease progression. DM >8 years was not associated with renal outcome. Propensity score-matched analyses also showed similar results. In conclusion, DR and the diagnostic model favoring DN were associated with poorer renal outcomes.

Glycosuria and Renal Outcomes in Patients with Nondiabetic Advanced Chronic Kidney Disease.

Sodium glucose cotransporter 2 inhibitors have shown a potential for renoprotection beyond blood glucose lowering. Glycosuria in nondiabetic patients with chronic kidney disease (CKD) is sometimes noted. Whether glycosuria in CKD implies a channelopathy or proximal tubulopathy is not known. The consequence of glycosuria in CKD is also not studied. We performed a cross-sectional study for the association between glycosuria and urine electrolyte excretion in 208 nondiabetic patients. Fractional excretion (FE) of glucose >4% was 3.4%, 6.3% and 62.5% in CKD stage 3, 4 and 5, respectively. These patients with glycosuria had higher FE sodium, FE potassium, FE uric acid, UPCR, and urine NGAL-creatinine ratio. We conducted a longitudinal study for the consequence of glycosuria, defined by dipstick, in 769 nondiabetic patients with stage 4-5 CKD. Glycosuria was associated with a decreased risk for end-stage renal disease (adjusted hazard ratio: 0.77; CI = 0.62-0.97; p = 0.024) and for rapid renal function decline (adjusted odds ratio: 0.63; CI = 0.43-0.95; p = 0.032); but glycosuria was not associated with all-cause mortality or cardiovascular events. The results were consistent in the propensity-score matched cohort. Glycosuria is associated with increased fractional excretion of electrolytes and is related to favorable renal outcomes in nondiabetic patients with stage 5 CKD.

Hyponatremia is Associated with Fluid Imbalance and Adverse Renal Outcome in Chronic Kidney Disease Patients Treated with Diuretics.

Chronic kidney disease (CKD) is frequently complicated with hyponatremia, probably because of fluid overload or diuretic usage. Hyponatremia in CKD population is associated with increased mortality, but the effect on renal outcome was unknown. We investigated whether hyponatremia is associated with fluid status and is a prognostic indicator for adverse outcomes in a CKD cohort of 4,766 patients with 1,009 diuretic users. We found that diuretic users had worse clinical outcomes compared with diuretic non-users. Hyponatremia (serum sodium <135 mEq/L) was associated with excessive volume and volume depletion, measured as total body water by bioimpedance analysis, in diuretic users, but not in diuretic non-users. Furthermore, in Cox survival analysis, hyponatremia was associated with an increased risk for renal replacement therapy (hazard ratio, 1.45; 95% CI, 1.13-1.85, P < 0.05) in diuretic users, but not in diuretic non-users (P for interaction <0.05); restricted cubic spline model also showed a similar result. Hyponatremia was not associated with all-cause mortality or cardiovascular event whereas hypernatremia (serum sodium >141 mEq/L) was associated with an increased risk for all-cause mortality. Thus, hyponatremia is an indicator of fluid imbalance and also a prognostic factor for renal replacement therapy in CKD patients treated with diuretics.

Novel Vitamin D Receptor Mutations in Hereditary Vitamin D Resistant Rickets in Chinese.

Hereditary 1, 25-dihydroxyvitamin D-resistant rickets (HVDRR), a rare recessive disease, is caused by mutation in the VDR gene encoding the vitamin D receptor leading to the resistance to vitamin D. We described a female toddler with initial presentation of leg tenderness and clinical features of HVDRR including severe rickets, hypocalcemia and hypophosphatemia without alopecia. Genetic analysis revealed novel compound heterozygous mutations of p.M4I and p.H229Q in patient's VDR gene. In cis p.M4I with FOKI-F eliminated both translation start sites of the VDR protein. The p.H229Q VDR exhibited significantly reduced VDR transactivation activity with intact dimerization with RXR. Our report expanded the mutation spectrum of HVDRR, and provided the first case of a benign variant p.M4I plus a common p.M1T polymorphism leading to a pathogenic allele.