Spot Urine Uric Acid to Creatinine Ratio used in the Estimation of Hyperuricosuria in the Young Korean Population

Background: Uric acid levels in urine are measured using urine specimens 24 hours or by uric acid glomerular filtration rate (UAGFR) with spot urine, which additionally requires a blood sample. This study aimed to investigate whether urinary uric acid creatinine ratio (UUACr) obtained by spot urine alone could be recognized as a substitute for UAGFR value, and hyperuricosuria can be screened by UUACr. UUACr is known to vary with age and regional differences. This study focused on the reference value of each value in Korean young populations.Method: We enrolled Korean subjects 1–20 years with normal kidney function, from a single hospital, classified into 5 age groups, 1–5 years, 6–8 years, 9–12 years, 13–15 years, and 16–20 years. We checked spot urine uric acid, creatinine and serum uric acid, creatinine levels on the same day from February 2014 to December 2018. We measured the average of UAGFR and UUACr in each groups. The UUACr cut-off value of the upper 2 standard deviation (SD) of UAGFR were taken.Results: The upper 2 SD of UUACr (mg/mg) and UAGFR (mg/dL) were determined in all age groups. UUACr decreased with grown up (P=0.000), but UAGFR were not statistically different among the groups. UUACr and UAGFR were not significantly different by gender. UUACr and UAGFR were positively correlated; UUACr cut-off value of upper 2 SD UAGFR (0.54 mg/dL) was 0.65 mg/mg in total age.Conclusions: UUACr could potentially be used to screen for hyperuricosuria.

Mitochondrial Dysfunction and Diabetic Nephropathy: Nontraditional Therapeutic Opportunities

Diabetic nephropathy (DN) is a progressive microvascular diabetic complication. Growing evidence shows that persistent mitochondrial dysfunction contributes to the progression of renal diseases, including DN, as it alters mitochondrial homeostasis and, in turn, affects normal kidney function. Pharmacological regulation of mitochondrial networking is a promising therapeutic strategy for preventing and restoring renal function in DN. In this review, we have surveyed recent advances in elucidating the mitochondrial networking and signaling pathways in physiological and pathological contexts. Additionally, we have considered the contributions of nontraditional therapy that ameliorate mitochondrial dysfunction and discussed their molecular mechanism, highlighting the potential value of nontraditional therapies, such as herbal medicine and lifestyle interventions, in therapeutic interventions for DN. The generation of new insights using mitochondrial networking will facilitate further investigations on nontraditional therapies for DN.

Social Isolation Is Associated With Rapid Kidney Function Decline and the Development of Chronic Kidney Diseases in Middle-Aged and Elderly Adults: Findings From the China Health and Retirement Longitudinal Study (CHARLS)

Background: There is limited evidence on the relationship between social isolation and renal outcomes. To address this gap, this study estimated the prospective relationship of social isolation with rapid kidney function decline and the development of chronic kidney disease (CKD) in middle-aged and elderly Chinese with normal kidney function.Methods: We analyzed data from 3,031 participants aged ≥ 45 years with baseline estimated glomerular filtration rates (eGFR) ≥ 60 ml/min/1.73 m2. All data were obtained from the 2011 and 2015 waves of the Chinese Longitudinal Study of Health and Retirement (CHARLS). eGFR was estimated based on a combination of serum creatinine and cystatin C. The primary outcome was rapid decline in renal function, as defined by an eGFR decrease of > 5 ml/min/1.73 m2 per year, while the secondary outcome was the development of CKD, as defined by an eGFR decrease to a level < 60 ml/min/1.73 m2.Results: During the follow-up of 4 years, 258 (8.5%) participants experienced a rapid decline in renal function, while 87 (2.9%) developed CKD. In the fully adjusted model, high social isolation was significantly related to an increased risk of experiencing a rapid decline in renal function (OR 1.805, 95% CI 1.310–2.487) and CKD onset (OR 1.842, 95% CI 1.084–3.129). Among the five components of social isolation, being unmarried, not participating in social activities, and living alone independently predicted declined renal function.Conclusions: Social isolation is significantly associated with the risk of rapid eGFR decline and CKD onset in middle-aged and older adults with normal kidney function in China.

Growth Hormone and IGF1 Actions in Kidney Development and Function

Growth hormone (GH) exerts multiple effects on different organs including the kidneys, either directly or via its main mediator, insulin-like-growth factor-1 (IGF-1). The GH/IGF1 system plays a key role in normal kidney development, glomerular hemodynamic regulation, as well as tubular water, sodium, phosphate, and calcium handling. Transgenic animal models demonstrated that GH excess (and not IGF1) may lead to hyperfiltration, albuminuria, and glomerulosclerosis. GH and IGF-1 play a significant role in the early development of diabetic nephropathy, as well as in compensatory kidney hypertrophy after unilateral nephrectomy. Chronic kidney disease (CKD) and its complications in children are associated with alterations in the GH/IGF1 axis, including growth retardation, related to a GH-resistant state, attributed to impaired kidney postreceptor GH-signaling and chronic inflammation. This may explain the safety of prolonged rhGH-treatment of short stature in CKD.

Preoperative Versus Postoperative Compensation of the Contralateral Normal Kidney in Patients Treated with Radical Nephrectomy for Renal Cell Carcinoma

Background: We sought to identify the factors affecting renal compensatory processes that occur preoperatively as well as postoperatively in patients treated with radical nephrectomy (RNx) for renal cell carcinoma (RCC). Methods: We retrospectively reviewed the records of 906 patients treated with RNx for RCC. We defined the early compensatory process (process 1) as compensatory adaptation of the contralateral normal kidney (CNK) before RNx. We defined the late compensatory process (process 2) as compensatory adaptation of the CNK after RNx. Total compensation was defined as the combination of these two processes. Multivariable logistic regression analyses were used to identify significant factors associated with processes 1, 2, and total compensation. Results: Mean preoperative, 1-week, and 5-year postoperative estimated glomerular filtration rates (eGFR) were 84.5, 57.6, and 63.7 mL/min/1.73 m2, respectively. Female sex (p < 0.001), lower body mass index (BMI) (p < 0.001), absence of hypertension (p = 0.019), lower preoperative eGFR (p < 0.001), larger tumor volume (p < 0.001), and larger CNK volume (p < 0.001) were significantly associated with process 1. Younger age (p = 0.019), higher BMI (p < 0.001), and absence of diabetes mellitus (DM) (p = 0.033) were significantly associated with process 2. Female sex (p < 0.001), younger age (p < 0.001), absence of DM (p = 0.002), lower preoperative eGFR (p < 0.001), and larger tumor (p = 0.001) and CNK volumes (p < 0.001) were significantly associated with total compensation. Conclusions: Different factors affected each compensatory process. Process 1 made a greater contribution to the entire renal compensatory process than process 2.

Design, Synthesis and Bioactivity Evaluation of Novel Chalcone Derivatives Possessing Tryptophan Moiety with Dual Activities of Anti-cancer and Partially Restoring the Proliferation of Normal Kidney Cells Pre-treated with Cisplatin

Background: Chalcone is a broad-spectrum natural product with anti-cancer and anti-inflammatory activities. However, low potency, low selectivity, and serious side effects limit its druggability. L-Tryptophan is an essential precursor molecule of an anti-cancer active substance. Also, the indole moiety inhibits the proliferation of tumor cells by binding to colchicine sites. A decrease in kidney cell activity caused by kidney inflammation is the primary side effect of cancer therapy. Objective: The purpose of this work was to design, synthesize, and perform bioactivity evaluation of novel chalcone derivatives possessing tryptophan moiety with dual activities of anti-cancer and partially restoring the proliferation of normal kidney cells pre-treated with cisplatin. Methods: A series of novel chalcone derivatives possessing tryptophan moiety (5a-5g, 6a-6o) were designed, synthesized, and evaluated for anti-cancer activity against four cancer cell lines (gastric (HGC-27), colon (HCT-116), prostate (PC-3), and lung (A549)), and a human normal cell line (gastric mucosal epithelial (GES-1)). The activity of restoring the proliferation of normal kidney cells pre-treated with cisplatin was evaluated by MTT assay. Cell cycle, apoptosis, and apoptosis proteins (Bax and Bcl-2) were used to evaluate the anti-cancer mechanism of the most potent compound. Moreover, a docking study was performed to explain the high anti-cancer activity of 6n. The expressions of TNF-α, IL-6, and MCP-1 were detected by ELISA. Results: Most of the compounds exhibited high anti-cancer activity against the HGC-27 cell line and exhibited low toxicity against the normal cell line. Based on three rounds of a structure optimization, 6n was discovered as the most potent compound against HGC-27 cells with an IC50 value of 2.02 μM and an SI value of 28.47. Further studies demonstrated that 6n could induce cell cycle arrest at the G2/M phase and the apoptosis of the HGC-27 cell line by reducing the expression of Bcl-2 and improving the expression level of Bax. Molecular docking result displayed 6n bound to the colchicine site. At the same time, 6n also exhibited moderate activity of restoring the proliferation of normal kidney cells pre-treated with cisplatin by reducing the expression of inflammatory substances. Conclusion: Our findings collectively suggested that 6n should be further studied as a potential anti-cancer agent that could partially restore the proliferation of normal kidney cells pre-treated with cisplatin in gastric cancer patients by an anti-inflammatory pathway.

Clinical and genetic characterization of a cohort of proteinuric patients with biallelic CUBN variants

Background Proteinuria is a well-known risk factor for progressive kidney impairment. Recently, C-terminal cubilin (CUBN) variants have been associated with isolated proteinuria without progression of kidney disease. Methods Genetic testing of 347 families with proteinuria of suspected monogenic cause was performed by next-generation sequencing of a custom-designed kidney disease gene panel. Families with CUBN biallelic proteinuria-causing variants were studied at the clinical, genetic, laboratory, and pathologic levels. Results Twelve families (15 patients) bearing homozygous or compound heterozygous proteinuria-causing variants in the C-terminal CUBN gene were identified, representing 3.5% of the total cohort. We identified 14 different sequence variants, five of which were novel. The median age at diagnosis of proteinuria was 4 years (range 9 months to 44 years), and in most cases proteinuria was detected incidentally. Thirteen patients had moderate-severe proteinuria at diagnosis without nephrotic syndrome. These patients showed lack of response to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, normal kidney biopsy, and preservation of normal kidney function over time. The two remaining patients presented a more severe phenotype, likely caused by associated comorbidities. Conclusions Identification of C-terminal pathogenic CUBN variants is diagnostic of an entity characterized by glomerular proteinuria, normal kidney histology, and lack of response to ACEi/ARB treatment. This study adds evidence and increases awareness about albuminuria caused by C-terminal variants in the CUBN gene, which is a benign condition usually diagnosed in childhood with preserved renal function until adulthood.

Osteoporosis after heart transplantation with reference to immunosuppression and renal function

Background Osteoporosis is commonly found in heart transplantation (HT) recipients, and may develop as an adverse effect of the immunosuppressive therapy, as well as be a consequence of factors associated with heart failure prior to HT. Chronic kidney disease (CKD) is furthermore, like osteoporosis, frequently found in the HT patient population, and may also arise as a side-effect of the immunosuppressive therapy. Aims and method We sought to describe the bone mineral density (BMD) evolution, predictors of osteoporosis, and survival, as well as incidence of osteoporosis in relation to CKD up to 10 years after HT. The project was conducted as a retrospective cohort study including patients who underwent HT at an age of at least 20 years between January 1988 and June 2016 at our center. The project was approved by the local ethics board (approval nos. 2010/114, 2011/777, 2014/92). Results Pre-transplant BMD was a negative predictor of osteoporosis during the first post-operative year, with a HR of 0.13 (95% CI 0.063; 0.26; P&lt;0.001) and 0.54 (95% CI 0.34; 0.85; P&lt;0.001) in the lumbar spine and femoral neck, respectively, adjusted for age, gender, BMI, and immunosuppressive therapy. Similarly, pre-transplant BMD was a negative predictor of osteoporosis also up to 10 years after HT, with a HR of 0.19 (95% CI 0.11; 0.32; P&lt;0.001) and 0.55 (95% CI 0.39; 0.78; P=0.001), in the lumbar spine and femoral neck, respectively, adjusted for age, gender, BMI, and immunosuppressive therapy. CKD stage 3 or worse before HT was associated with a greater gain in BMD after HT compared with CKD stage less than 3 or normal kidney function (−2.5% [−5.6; 0.6] versus −6.6% [−8.8;-4.5], P=0.029), and was not associated with osteoporosis (Figure 1). Also, the cumulative incidence of osteoporosis in the lumbar spine after HT was higher in the group with CKD stage less than 3 or normal kidney function. Conclusions The greatest drop in BMD occurs within the first year after HT. Short- and long-term incidence of osteoporosis is positively associated with pre-transplant bone strength, suggesting that early initiation of osteoporosis preventive treatment, pharmacologically and non-pharmacologically, may be beneficial in preventing long- and short-term fracture-related morbidity and morbidity after HT. Moreover, CKD stage 3 or worse before HT was associated with higher lumbar BMD after HT, and was not a predictor of osteoporosis. CKD stage less than 3 or normal kidney function before HT exhibited a greater BMD loss in the lumbar spine. Finally, the change in GFR during the first postoperative year was not associated with long-term BMD loss or osteoporosis. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Anna-Lisa & Sven-Erik Lundgren's Foundation and ALF's Foundations, Lund, Sweden Figure 1