bims-fikidi 2018-05-06 papers

bims-fikidi

Biomed News

on Fibroblast growth factor 23 in chronic kidney disease

Issue of 2018–05–06
37 papers selected by
Regina Goetz, New York University Langone Medical Center

Disorders of Lipid Metabolism in Chronic Kidney Disease.
Associations between single nucleotide polymorphisms in the calcium sensing receptor and chronic kidney disease-mineral and bone disorder in cats.
Albuminuric and non-albuminuric chronic kidney disease in type 1 diabetes: Association with major vascular outcomes risk and all-cause mortality.
The Importance of Sodium Restrictions in Chronic Kidney Disease.
Cardiovascular calcification: The emerging role of micronutrients.
Gadolinium-Based Contrast Agents in Kidney Disease: Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists.
Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.
Age and gender differences in the prevalence and correlates of vitamin D deficiency.
Vancomycin-Associated Acute Kidney Injury with a Steep Rise in Serum Creatinine.
Extreme hypercalcemia in a kidney transplant recipient.
Delayed Ischemic Preconditioning Attenuated Renal Ischemia-Reperfusion Injury by Inhibiting Dendritic Cell Maturation.
Effect of TET2 on the pathogenesis of diabetic nephropathy through activation of transforming growth factor β1 expression via DNA demethylation.
The role of cannabinoid signaling in acute and chronic kidney diseases.
Removal of Procalcitonin and Selected Cytokines during Continuous Veno-Venous Hemodialysis Using High Cutoff Hemofilters in Patients with Sepsis and Acute Kidney Injury.
Metabolite diagnosis of primary hyperoxaluria type 3.
Renal ischemia/reperfusion-induced mitophagy protects against renal dysfunction via Drp1-dependent-pathway.
It is time to revise the kidney allocation system to restore the pediatric advantage.
Disparate levels of beta-catenin activity determine nephron progenitor cell fate.
Kidney Transplantation in HIV-Positive Patients: A Single-Center, 16-Year Experience.
Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms.
Analysis of the high incidence of acute kidney injury associated with acute-on-chronic liver failure.
Protective role of AgRP neuron's PDK1 against salt-induced hypertension.
Effect of pyrolysis temperature on phosphate adsorption characteristics and mechanisms of crawfish char.
Quality of life and depression in haemodialysis patients.
Urinary antimicrobial peptides: Potential novel biomarkers of obstructive uropathy.
Treatment of end-stage renal disease with continuous ambulatory peritoneal dialysis in rural Guatemala.
The impact of exercise and vitamin D supplementation on physical function in community-dwelling elderly individuals: A randomized trial.
Implant success and safety of left atrial appendage occlusion in end stage renal disease patients: Peri-procedural outcomes from an Italian dialysis population.
NGAL attenuates renal ischemia/reperfusion injury through autophagy activation and apoptosis inhibition in rats.
Upregulation of osteopontin expression via the interaction of macrophages and fibroblasts under IL-1b stimulation.
In vivo visualisation of different modes of action of biological DMARDs inhibiting osteoclastic bone resorption.
MDM2 controls NRF2 antioxidant activity in prevention of diabetic kidney disease.
An osteopenic/osteoporotic phenotype delays alveolar bone repair.
Fibroblast growth factor receptor 1 signaling transcriptionally regulates the axon guidance cue slit1.
[Current insights about recurrence of glomerular diseases after renal transplantation].
Genome-wide association studies in kidney transplantation: Advantages and constraints.
Comparison of T1 Mapping and T1rho Values with Conventional Diffusion-weighted Imaging to Assess Fibrosis in a Rat Model of Unilateral Ureteral Obstruction.

Blood Purif. 2018 Apr 27. 46(2): 144-152

Disorders of Lipid Metabolism in Chronic Kidney Disease.

Mustafa C Bulbul, Tuncay Dagel, Baris Afsar, Nuray N Ulusu, Masanarini Kuwabara, Adrian Covic, Mehmet Kanbay.

  Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). One of the most important pathophysiological mechanisms for CVD in patients with CKD is the widespread and possibly accelerated formation of atherosclerotic plaques due to hyperlipidemia, uremic toxins, inflammation, oxidative stress, and endothelial dysfunction. Recent studies showed that the level of oxidized low-density lipoprotein cholesterol increases, and that high--density lipoprotein cholesterol dysfunction occurs as kidney function declines and inflammation becomes more prevalent. In this review, we aimed to discuss the effect of kidney dysfunction, oxidative stress, and inflammation on lipid -profile.

Keywords:  Chronic kidney disease; Hyperlipidemia; Oxidized low-density lipoprotein

DOI:  https://doi.org/10.1159/000488816
Vet J. 2018 05;pii: S1090-0233(18)30047-9. [Epub ahead of print]235 34-41

Associations between single nucleotide polymorphisms in the calcium sensing receptor and chronic kidney disease-mineral and bone disorder in cats.

R F Geddes, R E Jepson, Y Forcada, J Elliott, H M Syme.

  Feline chronic kidney disease (CKD) is associated with high variability in severity of CKD-mineral and bone disorder (CKD-MBD). The calcium sensing receptor (CaSR) regulates circulating parathyroid hormone (PTH) and calcium concentrations. Single nucleotide polymorphisms (SNPs) in the CaSR are associated with severity of secondary renal hyperparathyroidism and total calcium concentrations in human patients receiving haemodialysis. The objective of this study was to explore associations between polymorphisms in the feline CaSR (fCaSR) and biochemical changes observed in CKD-MBD. Client owned cats (≥9years) were retrospectively included. SNP discovery was performed in 20 cats with azotaemic CKD and normal or dysregulated calcium concentrations. Non-pedigree cats (n=192) (125 with azotaemic CKD and 66 healthy), Persians (n=40) and Burmese (n=25) were genotyped for all identified SNPs using KASP. Biochemical parameters from the date of CKD diagnosis or from first visit to the clinic (healthy cats) were used. Associations between genotype and ionized calcium, total calcium, phosphate, PTH and FGF-23 were performed for non-pedigree cats using logistic regression. Sequence alignment against the fCaSR sequence revealed eight novel exonic SNPs. KASP genotyping had high accuracy (99.6%) and a low failure rate (<6%) for all SNPs. Allele frequencies varied between breeds. In non-pedigree cats, one synonymous SNP CaSR:c.1269G>A was associated with logPTH concentration (adjusted for plasma creatinine concentration), with a recessive model having the best fit (G/G vs A/A-G/A, P=0.031). Genetic variation in the fCaSR is unlikely to explain the majority of the variability in presence and severity of CKD-MBD in cats.

Keywords:  CKD-MBD; CaSR; FGF-23; Feline; KASP; PTH; Phosphate

DOI:  https://doi.org/10.1016/j.tvjl.2018.02.010
J Diabetes Complications. 2018 Apr 03. pii: S1056-8727(18)30195-8. [Epub ahead of print]

Albuminuric and non-albuminuric chronic kidney disease in type 1 diabetes: Association with major vascular outcomes risk and all-cause mortality.

Monia Garofolo, Eleonora Russo, Roberto Miccoli, Daniela Lucchesi, Laura Giusti, Veronica Sancho-Bornez, Giuseppe Daniele, Stefano Del Prato, Giuseppe Penno.

   AIMS: Albuminuric and non-albuminuric phenotypes of chronic kidney disease (CKD) may have different cardiovascular risk and survival in type 1 diabetes (T1DM). Herein we estimated risk of major vascular outcomes by the EURODIAB PCS score and determined all-cause mortality rate in 774 T1DM according to CKD phenotypes.
METHODS: We evaluated the distribution of CKD phenotypes [no CKD, stages 1-2, non-albuminuric stage ≥3 (Alb-CKD), albuminuric stage ≥3 (Alb+CKD)], the EURODIAB risk score for major vascular outcomes [low- (LS), intermediate- (IS), and high- (HS) risk] and all-cause mortality over a follow-up of 8.25 ± 2.34 years.
RESULTS: Out of 774 subjects, 692 (89.4%) had no CKD, 53 (6.8%) CKD stages 1-2, 17 (2.2%) Alb-CKD and 12 (1.6%) Alb+CKD; 466 (60.2%) had LS, 205 (26.5%) IS and 103 (13.3%) HS. Distribution of HS was: no CKD, 9.1%; CKD stages 1-2, 34.0%; Alb-CKD, 64.7%; Alb+CKD, 91.7% (P < 0.0001). Mortality increased from no CKD, 3.0%; to stages 1-2, 15.1% (HR 4.504); Alb-CKD, 29.4% (8.573); Alb+CKD, 50.0% (20.683, P < 0.0001). Accounting for age and sex, HRs for mortality compared to no CKD were: CKD stages 1-2, 3.84 (P = 0.001); Alb-CKD, 2.97 (P = 0.046); Alb+CKD, 7.44 (P < 0.0001). Adjusting for sex and the EURODIAB score, HRs for mortality compared to no CKD were: CKD stages 1-2, 2.57 (P = 0.027); Alb-CKD, 2.77 (P = 0.058); Alb+CKD, 4.58 (P = 0.003).
CONCLUSIONS: In our T1DM cohort, one fifth of those with CKDs were non-albuminuric. This phenotype was associated with higher risk of major outcomes and similar rate of mortality as compared to CKD stages 1-2. The greatest risk and highest mortality occur in patients with Alb+CKD.

Keywords:  Albuminuria; All-cause mortality; Cardiovascular risk score; Chronic kidney disease; Glomerular filtration rate; Type 1 diabetes mellitus

DOI:  https://doi.org/10.1016/j.jdiacomp.2018.03.012
J Ren Nutr. 2018 Apr 26. pii: S1051-2276(18)30043-8. [Epub ahead of print]

The Importance of Sodium Restrictions in Chronic Kidney Disease.

Megan Cobb, Dominique Pacitti.

DOI: https://doi.org/10.1053/j.jrn.2018.02.001
Atherosclerosis. 2018 Apr 20. pii: S0021-9150(18)30204-1. [Epub ahead of print]

Cardiovascular calcification: The emerging role of micronutrients.

Antonio Bellasi, Luca Di Lullo, Paolo Raggi.



Keywords:  Aortic valve calcification; Magnesium; Phosphate

DOI:  https://doi.org/10.1016/j.atherosclerosis.2018.04.019
Can Assoc Radiol J. 2018 May;pii: S0846-5371(17)30155-9. [Epub ahead of print]69(2): 136-150

Gadolinium-Based Contrast Agents in Kidney Disease: Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists.

Nicola Schieda, Jason I Blaichman, Andreu F Costa, Rafael Glikstein, Casey Hurrell, Matthew James, Pejman Jabehdar Maralani, Wael Shabana, An Tang, Anne Tsampalieros, Christian van der Pol, Swapnil Hiremath.

  Use of gadolinium-based contrast agents (GBCAs) in renal impairment is controversial, with physician and patient apprehension in acute kidney injury (AKI), chronic kidney disease (CKD), and dialysis because of concerns regarding nephrogenic systemic fibrosis (NSF). The position that GBCAs are absolutely contraindicated in AKI, CKD stage 4 or 5 (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and dialysis-dependent patients is outdated, and may limit access to clinically necessary contrast-enhanced MRI examinations. Following a comprehensive review of the literature and reported NSF cases to date, a committee of radiologists and nephrologists developed clinical practice guidelines to assist physicians in making decisions regarding GBCA administrations. In patients with mild-to-moderate CKD (eGFR ≥30 and <60 mL/min/1.73 m2), administration of standard doses of GBCA is safe and no additional precautions are necessary. In patients with AKI, with severe CKD (eGFR <30 mL/min/1.73 m2), or on dialysis, administration of GBCAs should be considered individually and alternative imaging modalities utilized whenever possible. If GBCAs are necessary, newer GBCAs may be administered with patient consent obtained by a physician (or their delegate), citing an exceedingly low risk (much less than 1%) of developing NSF. Standard GBCA dosing should be used; half or quarter dosing is not recommended and repeat injections should be avoided. Dialysis-dependent patients should receive dialysis; however, initiating dialysis or switching from peritoneal to hemodialysis to reduce the risk of NSF is unproven. Use of a macrocyclic ionic instead of macrocyclic nonionic GBCA or macrocyclic instead of newer linear GBCA to further prevent NSF is unproven. Gadopentetate dimeglumine, gadodiamide, and gadoversetamide remain absolutely contraindicated in patients with AKI, with stage 4 or 5 CKD, or on dialysis. The panel agreed that screening for renal disease is important but less critical when using macrocyclic and newer linear GBCAs. Monitoring for and reporting of potential cases of NSF in patients with AKI or CKD who have received GBCAs is recommended.

Keywords:  Gadolinium; Guideline; Magnetic resonance imaging; NSF; Nephrogenic systemic fibrosis

DOI:  https://doi.org/10.1016/j.carj.2017.11.002
Am J Hum Genet. 2018 May 03. pii: S0002-9297(18)30102-2. [Epub ahead of print]102(5): 832-844

Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.

Genkyst Study Group

  Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

Keywords:  ADPKD; ADPLD; ADTKD; DNAJB11; pathogenic variants; renal cystic disease

DOI:  https://doi.org/10.1016/j.ajhg.2018.03.013
Arch Osteoporos. 2018 Apr 29. 13(1): 49

Age and gender differences in the prevalence and correlates of vitamin D deficiency.

AlJohara M AlQuaiz, Ambreen Kazi, Mona Fouda, Nada Alyousefi.

  Younger adults and males had a higher prevalence of vitamin D deficiency compared to older participants and females. Low intake of milk, central obesity, and lack of use of vitamin D supplements were associated with vitamin D deficiency, highlighting potentially important avenues for preventive intervention.
BACKGROUND: Vitamin D deficiency is a public health concern. This study's objective was to measure the prevalence of vitamin D deficiency and determine its correlates among Saudi adults in Riyadh, Saudi Arabia.
METHODS: A cross-sectional study was conducted with 2835 Saudi males and females aged 30-75 years in 18 different primary health care centers (PHCC) in Riyadh. Detailed interviews on sociodemographic and lifestyle factors and anthropometric measurements were conducted. Serum calcium, phosphorus, parathyroid, alkaline phosphatase, and 25(OH) vitamin D were measured. Multiple logistic regression analyses were conducted.
RESULTS: The mean age (SD) of male and female participants was 43.0 (± 11.7) and 42.8 (± 10.3) years, respectively. Serum 25(OH) vitamin D assays for participants revealed that 72.0% (n = 695) of males and 64.0% (n = 1191) of females had levels < 50 nmol/L (deficiency), whereas 17.3% (n = 166) and 19.4% (n = 362), respectively, had levels of 50-75 nmol/L (insufficiency). Multivariate analyses for males revealed that lack of use of vitamin D supplements [adjusted odds ratio (aOR) = 4.0, 95% CI 1.7, 9.4], younger age [30-40 years aOR = 3.6, 95% CI 1.7, 7.3 and 41-50 years aOR = 4.2, 95% CI 2.0, 8.8], low milk intake [aOR = 1.7, 95% CI 1.0, 2.8], consumption of cola drinks [aOR = 2.0, 95% CI 1.1, 3.9], and central obesity [aOR = 1.8, 95% CI 1.0, 3.4] were associated with low vitamin D. In females, lack of use of vitamin D supplements [aOR = 3.7, 95% CI 2.8, 4.9], younger age [30-40 years aOR = 3.4, 95% CI 2.0, 5.8 and 41-50 years aOR = 2.8, 95% CI 1.6, 4.7], central obesity [aOR = 1.4, 95% CI 1.0, 2.2], and seasonal variation [aOR = 1.6, 95% CI 1.3, 2.1] had higher odds for vitamin D deficiency. Significantly lower levels were observed for men than women for mean serum 25(OH) vitamin D [42.6 (± 24.1) vs. 46.8 (± 30.5)], parathyroid hormone [5.3 (± 2.9) vs. 5.9 (± 2.7)], and phosphorus [1.1 (± 0.2) vs. 1.2 (± 0.2)], respectively; alkaline phosphatase levels [106 (± 32.8) vs. 99 (± 27.8)] [p < 0.01] were significantly higher in males than females.
CONCLUSION: Vitamin D deficiency was highly prevalent, particularly among young adults and those with central obesity. Proper fortification policy, health education, and regular screening PHCCs may help prevent and treat vitamin D deficiency.

Keywords:  Age; Carbonated drinks; Gender differences; Seasonal variation; Supplements; Vitamin D deficiency

DOI:  https://doi.org/10.1007/s11657-018-0461-5
Nephron. 2018 Apr 27. 139(2): 1-12

Vancomycin-Associated Acute Kidney Injury with a Steep Rise in Serum Creatinine.

Juan Carlos Q Velez, Ndidiamaka O Obadan, Amit Kaushal, Mohammed Alzubaidi, Bhavna Bhasin, Sachin H Sachdev, Nithin Karakala, John M Arthur, Ross M Nesbit, Gautam M Phadke.

   BACKGROUND: Vancomycin-associated (VA) acute kidney injury (AKI) is being increasingly recognized. A distinct pattern of rapid rise in serum creatinine (sCr) during VA-AKI has occasionally been observed. However, such scenarios remain underreported.
METHODS: We conducted an online survey at the American Society of Nephrology Communities forum and reviewed publications of VA-AKI via PubMed or Google searching for cases of precipitous AKI (those with rise in sCr ≥1.5 mg/dL/day) attributable to vancomycin.
RESULTS: We identified 12 original cases compiled from 6 different hospitals and 4 published cases (n = 16; 38% women, age 43.5 ± 16 years, weight 108 ± 23 kg, body mass index 35 ± 7 kg/m2) of precipitous AKI observed shortly after large cumulative doses of VA (8.8 ± 5 g). The median steepest 24-h rise in sCr was 2.6 mg/dL (range 1.5-3.5 mg/dL) and the slope of the initial 48-h sCr rise was greater than that of a control AKI (non-VA, n = 48) group (2.03 ± 0.1 vs. 0.62 ± 0.0 mg/dL/day; p < 0.0001). The steep rise in sCr in the VA-AKI was not accompanied by anuria. Overt rhabdomyolysis was absent in all cases. Further, in 3 precipitous VA-AKI cases, simultaneous serum cystatin C values did not rise precipitously, suggesting that the reductions in glomerular filtration rate were overestimated by the sCr increase.
CONCLUSIONS: VA-AKI can manifest with a precipitous rise in sCr shortly after a high cumulative dose of vancomycin. True toxic tubular injury overrepresented by the sCr rise is postulated.

Keywords:  Accelerated; Acute tubular injury; Precipitous; Rapid; Severe; Tubular secretion; Vancomycin nephrotoxicity

DOI:  https://doi.org/10.1159/000487149
CEN Case Rep. 2018 Apr 28.

Extreme hypercalcemia in a kidney transplant recipient.

Erol Demir, Cagla Karaoglan, Gulcin Yegen, Betul Sair, Halil Yazici, Aydin Turkmen, Mehmet Sukru Sever.

  Post-transplant hypercalcemia is a major problem in renal transplant recipients, which may negatively affect both graft and patient survival. In this paper, we present a 66-year-old male kidney transplant recipient, who was admitted to our clinic with symptoms of fever, nausea, vomiting and lethargy. Laboratory data showed good renal function; however, a serum calcium level of 22.1 mg/dL. The patient was treated by isotonic saline together with furosemide and methylprednisolone. Because of treatment resistance, subcutaneous calcitonin and ibandronate were added to the treatment protocol as well. Since all these medications were not effective, hemodialysis with low-calcium (1.25 mmol/L) dialysate was applied for three consecutive days, which resulted in normalization of serum calcium. Several investigations were carried out for diagnosing the underlying etiology. Positron-emission tomography (PET)/CT revealed a strong diffuse uptake of FDG in the bones and spleen. A bone marrow biopsy showed diffuse interstitial infiltration of CD20 + neoplastic B cells and, thus, post transplant lymphoproliferative disease (PTLD) was diagnosed. Tacrolimus was switched to everolimus, mycophenolate mofetil was stopped, while treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) was initiated. Despite all therapeutic interventions, the patient died of septic shock in the intensive care unit on the 10th day of emergency service admission. Importance of hemodialysis as an emergent treatment modality in extreme hypercalcemia, and unfavorable course of PTLD were underlined.

Keywords:  Hemodialysis; Hypercalcemia; Kidney transplantation; Lymphoproliferative disorders

DOI:  https://doi.org/10.1007/s13730-018-0334-1
Cell Physiol Biochem. 2018 Apr 25. 46(5): 1807-1820

Delayed Ischemic Preconditioning Attenuated Renal Ischemia-Reperfusion Injury by Inhibiting Dendritic Cell Maturation.

Ting Zhang, Nana Song, Yi Fang, Jie Teng, XiaLian Xu, Jiachang Hu, Pan Zhang, Rongyi Chen, Zhihui Lu, Xiaofang Yu, Xiaoqiang Ding.

   BACKGROUND/AIMS: Even though delayed ischemic preconditioning (DIPC) has been reported to produce renal protection, the underlying mechanism remains poorly understood. We reported that a 15-minute renal ischemic preconditioning (IPC) 4 days before subsequent ischemia-reperfusion attenuated renal injury Kidney dendritic cells (DCs) are abundant in the renal tubulointerstitium and, depending on their status, can induce immune activation or tolerance. The aim of the present study was to investigate the role of DCs in IPC of the kidney.
METHODS: Mouse kidneys were challenged by transient brief episodes of sublethal ischemia followed by subsequent prolonged ischemia. DC abundance and maturation in the spleen and kidney were measured by flow cytometry and immunohistochemical staining. To confirm the function of mature DCs in the renoprotective effect of IPC on renal ischemia-reperfusion injury the A2 adenosine receptor (A2AR) antagonist SCH58261 was administered to stimulate DC maturation prior to assessment of renal functional and histological injury and the inflammatory reaction.
RESULTS: Compared with sham-operated animals, preconditioned mice had a reduced injury with less CD11c+ cells, lower levels of the pro-inflammatory cytokine IL-17 and reduced expression of the mature DC marker CCR7. Preconditioned mice also produced more of the anti-inflammatory cytokine IL-10. Both renal cells and splenocytes from these mice had more DCs (CD45+/CD11c+/F4/80-), but fewer of these DCs were mature (CD45+/CD11c+/ F4/80-/MHC-II+/CD80+) compared with those from sham-treated animals, suggesting that the immunomodulatory effect of renal ischemic preconditioning is both local and systemic. Additionally, injection of the A2AR antagonist SCH58261 reversed IPC-induced inhibition of DC maturation and mitigated the protective effect of preconditioning, suggesting that DC maturation contributes to immune cell-mediated ischemic preconditioning.
CONCLUSION: Our results show that DIPC of the kidney provides local and systemic immunosuppression by inhibiting DC maturation and hence mediates a renal protective effect.

Keywords:  Acute kidney injury; Delayed Ischemic Preconditioning; Dendritic cells; Ischemia–Reperfusion

DOI:  https://doi.org/10.1159/000489366
Life Sci. 2018 Apr 26. pii: S0024-3205(18)30225-X. [Epub ahead of print]

Effect of TET2 on the pathogenesis of diabetic nephropathy through activation of transforming growth factor β1 expression via DNA demethylation.

Yang Liling, Zhang Qian, Wu Qiong, Wei Yi, Yu Jiawei, Mu Jiao, Zhang Jun, Zeng Wei, Feng Bing.

   AIMS: Transforming growth factor β1 (TGFβ1) plays a pivotal role in the pathogenesis of diabetic nephropathy (DN). However, the mechanism of its expression and activation induced by high glucose (HG) is still unclear. We mainly explored the role of ten-eleven translocation enzyme-2 (TET2) in regulating TGFβ1 expression in the process of DN.
MAIN METHODS: Human mesangial cells (HMCs) and db/db mice were used to analyze the biological effects of hyperglycemia both in vivo and in vitro. Gene expression levels, cell proliferation, protein recruitment levels to TGFβ1 regulatory region, DNA methylation statues and pathological changes in kidney were tested in different groups. Short hairpin RNA(shRNA) and oral inhibitor were used to knock down or inhibit TET2 expression.
KEY FINDINGS: Our study demonstrated that TET2 expression was increased in the renal cortex of db/db mice and in HMCs inducing by HG. We also found that TET2 binding was increased while DNA methylation of CpG islands was reduced in the TGFβ1 regulation region in HG, resulting in the increased expression level of TGFβ1 and cell phenotype transformation. More importantly, clinical research revealed that gradually decreased DNA methylation in the TGFβ1 regulatory region was also present in patients with diabetes and DN.
SIGNIFICANCE: Our work suggests that TET2 plays an important role in the pathogenesis of DN by activating TGFβ1 expression through demethylation of CpG islands in the TGFβ1 regulatory region. This may provide a potential new therapeutic target for DN.

Keywords:  DNA methylation; Diabetic nephropathy; Mesangial cells; Ten-eleven translocation-2 protein; Transforming growth factor beta-1

DOI:  https://doi.org/10.1016/j.lfs.2018.04.044
Kidney Int. 2018 Apr 26. pii: S0085-2538(18)30140-6. [Epub ahead of print]

The role of cannabinoid signaling in acute and chronic kidney diseases.

Federica Barutta, Graziella Bruno, Raffaella Mastrocola, Stefania Bellini, Gabriella Gruden.

  The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes. Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease. This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans. In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people. In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications. Moreover, we give a critical update of synthetic cannabinoid-induced AKI.

Keywords:  acute kidney injury; albuminuria; cannabinoid receptor type 1; cannabinoid receptor type 2; cannabinoids; renal fibrosis

DOI:  https://doi.org/10.1016/j.kint.2018.01.024
Blood Purif. 2018 Apr 27. 46(2): 153-159

Removal of Procalcitonin and Selected Cytokines during Continuous Veno-Venous Hemodialysis Using High Cutoff Hemofilters in Patients with Sepsis and Acute Kidney Injury.

Grzegorz Kade, Sławomir Literacki, Agnieszka Rzeszotarska, Stanisław Niemczyk, Arkadiusz Lubas.

   INTRODUCTION: The purpose of this study was to evaluate the impact of continuous veno-venous hemodialysis (CVVHD) using high cutoff (HCO) hemofilters on the removal of procalcitonin (PCT), and other inflammatory markers in the treatment of patients during septic shock with acute kidney injury (AKI).
MATERIALS AND METHODS: Thirty-six patients with septic shock and AKI were included in the study. Before and after the 24-h HCO-CVVHD, PCT, native C-reactive protein (CRP) and cytokines (interleukin-1β, interleukin-6, interleukin-12, interleukin-17, tumor necrosis factor-α) in serum and effluent were assessed.
RESULTS: After the HCO-CVVHD serum concentrations of PCT, CRP and selected cytokines were significantly lower. The decrease in PCT was bigger than in CRP (p = 0.007). The change in PCT concentration was significantly influenced by PCT and IL-17 clearances (R2 = 0.525; p < 0.001).
CONCLUSION: In contrast to the native CRP, monitoring of PCT during HCO-CVVHD is less useful because it reflects the clearance of this marker and anti-inflammatory effectiveness of the method.

Keywords:  Acute kidney injury; C-reactive protein; Cytokines; High cutoff veno-venous hemodialysis; Procalcitonin; Sepsis

DOI:  https://doi.org/10.1159/000488929
Pediatr Nephrol. 2018 Apr 28.

Metabolite diagnosis of primary hyperoxaluria type 3.

Lawrence Greed, Frank Willis, Lilian Johnstone, Sharon Teo, Ruth Belostotsky, Yaacov Frishberg, James Pitt.

   BACKGROUND: Primary hyperoxaluria type 3 (PH3) is a recently described cause of childhood renal calculi. It results from mutations in the HOGA1 gene and most cases have been diagnosed after clinical ascertainment, exclusion of other genetic hyperoxalurias and mutation testing. Metabolite testing has not been widely applied but holds promise for the rapid screening and diagnosis of patients who are not specifically suspected to have PH3.
CASE-DIAGNOSIS/TREATMENT: Two cases presented with renal calculi. Urine metabolite testing by tandem mass spectrometry was performed as part of the routine diagnostic work-up for this condition. Both had significantly increased levels of the PH3 urine marker 4-hydroxyglutamate and related metabolites. The diagnosis of PH3 was confirmed by the finding of bi-allelic damaging HOGA1 mutations.
CONCLUSIONS: Urine screening by tandem mass spectrometry is a rapid, high-throughput test that can detect PH3 cases that may otherwise not be diagnosed.

Keywords:  Calculi; HOGA1; Oxaluria; Primary hyperoxaluria type 3; Screening

DOI:  https://doi.org/10.1007/s00467-018-3967-6
Exp Cell Res. 2018 Apr 25. pii: S0014-4827(18)30245-3. [Epub ahead of print]

Renal ischemia/reperfusion-induced mitophagy protects against renal dysfunction via Drp1-dependent-pathway.

Nan Li, Hengjin Wang, Chunming Jiang, Miao Zhang.

  Autophagy is upregulated under stress conditions to degrade superfluous proteins and recycle damaged organelles including damaged mitochondria. However, the occurrence of mitochondrial autophagy and its contribution remain to be elucidated during renal ischemia/reperfusion injury (IRI). In this study, mitophagosomes and engulfed mitochondria were frequently observed by electron microscopy after renal IRI vs. control. Meanwhile, the increase of lipidated microtubule associated protein light chain 3 (LC3-II) and decrease of mitochondrial proteins were detected by western blot, suggesting the presence of mitophagy. Drp1 translocated to mitochondria and was phosphorylated at S616 in response to IRI. Interestingly, we found that inhibiting drp1 phosphorylation with mdivi-1 significantly suppressed IRI-induced mitophagy without affecting general autophagy. Furthermore, our results showed that downregulation of mitophagy significantly exacerbated cell apoptosis and markedly aggravated kidney dysfunction induced by IRI. Taken together, these data indicate that mitophagy was activated via Drp1-dependent pathway and such mitophagic clearance of damaged mitochondria protects cells from IRI-induced apoptosis.

Keywords:  Drp1; acute kidney injury; ischemia reperfusion; mitophagy

DOI:  https://doi.org/10.1016/j.yexcr.2018.04.025
Am J Transplant. 2018 Apr 28.

It is time to revise the kidney allocation system to restore the pediatric advantage.

Amy E Gallo, William F Parker, James R Thistlethwaite, Lainie F Ross.

The Organ Procurement and Transplantation Network (OPTN) implemented the kidney allocation system (KAS) based on evaluating and allocating kidneys using a Kidney Donor Profile Index (KDPI). The goals were to make better use of available kidneys and to increase transplant opportunities for difficult-to-match patients. Preserving the pediatric advantage created by "Share 35″ in 2005 was not a priority. Unfortunately, numerous analyses, including ours, demonstrate that the pediatric advantage has deteriorated under KAS. Specifically, we showed young pediatric recipients wait longer on dialysis and have higher rates of delayed graft function (DGF). This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1111/ajt.14898
Dev Biol. 2018 Apr 26. pii: S0012-1606(18)30097-6. [Epub ahead of print]

Disparate levels of beta-catenin activity determine nephron progenitor cell fate.

Harini Ramalingam, Alicia R Fessler, Amrita Das, M Todd Valerius, Jeannine Basta, Lynn Robbins, Aaron C Brown, Leif Oxburgh, Andrew P McMahon, Michael Rauchman, Thomas J Carroll.

Formation of a functional kidney depends on the balance between renewal and differentiation of nephron progenitors. Failure to sustain this balance can lead to kidney failure or stem cell tumors. For nearly 60 years, we have known that signals from an epithelial structure known as the ureteric bud were essential for maintaining this balance. More recently it was discovered that one molecule, Wnt9b, was necessary for both renewal and differentiation of the nephron progenitor cells. How one ligand signaling through one transcription factor promoted two seemingly contradictory cellular processes was unclear. In this study, we show that Wnt9b/beta-catenin signaling alone is sufficient to promote both renewal and differentiation. Moreover, we show that discrete levels of beta-catenin can promote these two disparate fates, with low levels fostering progenitor renewal and high levels driving differentiation. These results provide insight into how Wnt9b regulates distinct target genes that balance nephron progenitor renewal and differentiation.

DOI: https://doi.org/10.1016/j.ydbio.2018.04.020
Am J Kidney Dis. 2018 Apr 25. pii: S0272-6386(18)30546-8. [Epub ahead of print]

Kidney Transplantation in HIV-Positive Patients: A Single-Center, 16-Year Experience.

Gregory E Malat, Suzanne M Boyle, Rahul M Jindal, Stephen Guy, Gary Xiao, Meera N Harhay, Dong H Lee, Karthik M Ranganna, Mysore S Anil Kumar, Alden M Doyle.

  Hahnemann University Hospital has performed 120 kidney transplantations in human immunodeficiency virus (HIV)-positive individuals during the last 16 years. Our patient population represents ∼10% of the entire US population of HIV-positive kidney recipients. In our earlier years of HIV transplantation, we noted increased rejection rates, often leading to graft failure. We have established a multidisciplinary team and over the years have made substantial protocol modifications based on lessons learned. These modifications affected our approach to candidate evaluation, donor selection, perioperative immunosuppression, and posttransplantation monitoring and resulted in excellent posttransplantation outcomes, including 100% patient and graft survival at 1 year and patient and graft survival at 3 years of 100% and 96%, respectively. We present key clinical data, including a granular patient-level analysis of the associations of antiretroviral therapy regimens with long-term survival, cellular and antibody-mediated rejection rates, and the causes of allograft failures. In summary, we provide details on the evolution of our approach to HIV transplantation during the last 16 years, including strategies that may improve outcomes among HIV-positive kidney transplantation candidates throughout the United States.

Keywords:  HIV Organ Policy Equity (HOPE); HIV-positive donor; HIV-positive recipient; Human immunodeficiency virus (HIV); allograft survival; antiretroviral therapy (ART); belatacept; donor selection; end-stage renal disease (ESRD); immunosuppression; kidney transplantation; review

DOI:  https://doi.org/10.1053/j.ajkd.2018.02.352
Am J Hum Genet. 2018 May 03. pii: S0002-9297(18)30103-4. [Epub ahead of print]102(5): 816-831

Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms.

Thomas A Forbes, Sara E Howden, Kynan Lawlor, Belinda Phipson, Jovana Maksimovic, Lorna Hale, Sean Wilson, Catherine Quinlan, Gladys Ho, Katherine Holman, Bruce Bennetts, Joanna Crawford, Peter Trnka, Alicia Oshlack, Chirag Patel, Andrew Mallett, Cas Simons, Melissa H Little.

  Despite the increasing diagnostic rate of genomic sequencing, the genetic basis of more than 50% of heritable kidney disease remains unresolved. Kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of individuals affected by inherited renal disease represent a potential, but unvalidated, platform for the functional validation of novel gene variants and investigation of underlying pathogenetic mechanisms. In this study, trio whole-exome sequencing of a prospectively identified nephronophthisis (NPHP) proband and her parents identified compound-heterozygous variants in IFT140, a gene previously associated with NPHP-related ciliopathies. IFT140 plays a key role in retrograde intraflagellar transport, but the precise downstream cellular mechanisms responsible for disease presentation remain unknown. A one-step reprogramming and gene-editing protocol was used to derive both uncorrected proband iPSCs and isogenic gene-corrected iPSCs, which were differentiated to kidney organoids. Proband organoid tubules demonstrated shortened, club-shaped primary cilia, whereas gene correction rescued this phenotype. Differential expression analysis of epithelial cells isolated from organoids suggested downregulation of genes associated with apicobasal polarity, cell-cell junctions, and dynein motor assembly in proband epithelial cells. Matrigel cyst cultures confirmed a polarization defect in proband versus gene-corrected renal epithelium. As such, this study represents a "proof of concept" for using proband-derived iPSCs to model renal disease and illustrates dysfunctional cellular pathways beyond the primary cilium in the setting of IFT140 mutations, which are established for other NPHP genotypes.

Keywords:  CRISPR/Cas9; IFT140; cilia; functional genomics; gene correction; induced pluripotent stem cells; kidney organoid; nephronophthisis

DOI:  https://doi.org/10.1016/j.ajhg.2018.03.014
Hepatol Int. 2018 Apr 28.

Analysis of the high incidence of acute kidney injury associated with acute-on-chronic liver failure.

Nan Chen, Xiaohong Chen, Xiaoqiang Ding, Jie Teng.

   BACKGROUND: To investigate the incidence, risk, and prognostic factors of acute kidney injury (AKI) in acute-on-chronic liver failure (ACLF) patients.
METHODS: A total of 188 patients were prospectively included and divided into AKI and non-AKI groups. Patients were followed at 1, 3, 7, 14, 28, 60, and 90 days after the onset of AKI. Significant risk factors were screened by univariate and Cox multivariate survival analyses to confirm the independent risk factors for 30- or 90-day mortality and the 90-day renal function recovery rate.
RESULTS: A total of 98 AKI cases (52.1%, [95% CI 44.9-59.3%]) occurred and the risk factors for AKI development in ACLF patients were age > 50 years (p = 0.009) and albumin (Alb) levels < 32 g/L (p = 0.007). The 30- and 90-day mortalities were significantly higher in the AKI than in the non-AKI group (79.6 vs 41.1%, 82.7 vs 56.7%, p < 0.05). AKI highest staging occurring within < 4 days of its onset and spontaneous peritonitis as well as MELD scores > 27 were independent risk factors for 30- and 90-day mortalities of ACLF AKI patients. AKI stage 3 and age > 52 years were independent risk factors for non-renal function recovery in ACLF patients with AKI.
CONCLUSIONS: ACLF patients had a high incidence of AKI, which correlated with 30- and 90-day mortalities.

Keywords:  Acute kidney injury (AKI); Child–Pugh score; KDIGO; Liver failure; MELD score

DOI:  https://doi.org/10.1007/s12072-018-9866-x
Biochem Biophys Res Commun. 2018 Apr 30. pii: S0006-291X(18)30989-6. [Epub ahead of print]

Protective role of AgRP neuron's PDK1 against salt-induced hypertension.

Boyang Zhang, Masanori Nakata, Ming Lu, Jun Nakae, Takashi Okada, Wataru Ogawa, Toshihiko Yada.

  In the hypothalamic arcuate nucleus (ARC), orexigenic agouti-related peptide (AgRP) neurons regulate feeding behavior and energy homeostasis. The 3-phosphoinositide-dependent protein kinase-1 (PDK1) in AgRP neurons serves as a major signaling molecule for leptin and insulin, the hormones regulating feeding behavior, energy homeostasis and circulation. However, it is unclear whether PDK1 in AGRP neurons is also involved in regulation of blood pressure. This study explored it by generating and analyzing AgRP neuron-specific PDK1 knockout (Agrp-Pdk1flox/flox) mice and effect of high salt diet on blood pressure in KO and WT mice was analyzed. Under high salt diet feeding, systolic blood pressure (SBP) of Agrp-Pdk1flox/flox mice was significantly elevated compared to Agrp-Cre mice. When the high salt diet was switched to control low salt diet, SBP of Agrp-Pdk1flox/flox mice returned to the basal level observed in Agrp-Cre mice within 1 week. In Agrp-Pdk1flox/flox mice, urinary noradrenalin excretion and NUCB2 mRNA expression in hypothalamic paraventricular nucleus (PVN) were markedly upregulated. Moreover, silencing of NUCB2 in the PVN counteracted the rises in urinary noradrenalin excretions and SBP. These results demonstrate a novel role of PDK1 in AgRP neurons to counteract the high salt diet-induced hypertension by preventing hyperactivation of PVN nesfatin-1 neurons.

Keywords:  AgRP; Arcuate nucleus; Blood pressure; Foxo1; Nesfatin-1; PDK1; Paraventricular nucleus

DOI:  https://doi.org/10.1016/j.bbrc.2018.04.192
J Colloid Interface Sci. 2018 Apr 21. pii: S0021-9797(18)30463-6. [Epub ahead of print]525 143-151

Effect of pyrolysis temperature on phosphate adsorption characteristics and mechanisms of crawfish char.

Jong-Hwan Park, Jim J Wang, Ran Xiao, Baoyue Zhou, Ronald D Delaune, Dong-Cheol Seo.

  The purpose of this study was to investigate the characteristics of crawfish char (CFC) derived at different pyrolysis temperature and to evaluate its adsorption characteristics on phosphate. Phosphate adsorption by CFC occurred rapidly at the beginning of the reaction, and the time to reach equilibrium was dependent on the pyrolysis temperature. Maximum adsorption capacities of phosphate by CFC at different pyrolysis temperatures were high in order of CFC800 (70.9 mg/g) > CFC600 (56.8 mg/g) > CFC400 (47.2 mg/g) ≫ CFC200 (9.5 mg/g) ≈ uncharred crawfish feedstock (CF) (7.1 mg/g). Spectroscopic analyses using SEM-EDS and FTIR showed that the phosphate present in the CFC itself was associated with carbon, while the phosphate adsorbed on the CFC was closely related to calcium. The adsorption of phosphate by CFC is dominantly affected by pH. Phosphate adsorption of CFC600 primarily occurred at acid and neutral pH which is related to dissolved calcium from surface and phosphate hydrolysis product (H2PO4-), while phosphate adsorption of CFC800 mainly took place at alkaline pH, with precipitation mechanism between PO43- and calcium dissolved from free CaO and Ca(OH)2. Overall, CFC derived at pyrolysis temperatures above 400 °C is effective for waste reduction and phosphate treatment in wastewater.

Keywords:  Adsorption; Calcium; Char; Crawfish waste; Element mapping; Phosphate; Precipitation; Pyrolysis

DOI:  https://doi.org/10.1016/j.jcis.2018.04.078
Psychol Health Med. 2018 Apr 29. 1-10

Quality of life and depression in haemodialysis patients.

Flávio Teles, Ana Letícia Amorim de Albuquerque, Ingrid Karoline Freitas Guedes Lins, Patrícia Carvalho Medrado, André Falcão Pedrosa Costa.

  Chronic kidney disease is associated with a high prevalence of depression, which increases inversely with the glomerular filtration rate. This paper aims to evaluate the factors associated with a low quality of life and depression in patients on haemodialysis. Two hundred patients undergoing haemodialysis answered the Medical Outcomes Study 36 - Item Short - Form Health Survey (SF-36) and Beck Depression Inventory (BDI). Clinical and laboratory variables were analysed and correlated with these two tools. The prevalence of depression was 29%. Anaemia and hypoalbuminemia were independent risk factors for depression. All SF-36 domains showed worse results in patients with depression, and the pain domain presented the highest correlation. Our findings provide evidence that patients on haemodialysis have a low quality of life and a high prevalence of depression. A greater number of comorbidities, an excessive number of medications, diabetes mellitus, anaemia and hypoalbuminemia were associated with a reduced quality of life.

Keywords:  Quality of life; chronic kidney disease; comorbidities; depression

DOI:  https://doi.org/10.1080/13548506.2018.1469779
J Pediatr Urol. 2018 Mar 29. pii: S1477-5131(18)30123-2. [Epub ahead of print]

Urinary antimicrobial peptides: Potential novel biomarkers of obstructive uropathy.

S Gupta, A R Jackson, D G DaJusta, D J McLeod, S A Alpert, V R Jayanthi, K McHugh, A R Schwaderer, B Becknell, C B Ching.

   INTRODUCTION: Antimicrobial peptides (AMPs) have historically been evaluated for their role in protecting against uropathogens. However, there is mounting evidence to support their expression in noninfectious injury, with unclear meaning as to their function. It is possible that AMPs represent urothelial injury. Urinary tract obstruction is known to alter the urothelium; however, AMPs have not been evaluated for expression in this noninfectious injury.
OBJECTIVE: A pilot study to compare urinary AMP expression in children undergoing surgical intervention for ureteropelvic junction obstruction (UPJO) with nonobstructed controls.
STUDY DESIGN: Bladder urine was collected from consenting/assenting pediatric patients with UPJO at intervention. Control bladder urines were obtained from age-matched and sex-matched healthy children without known obstruction or infection. Enzyme-linked immunosorbent assays were run for the following AMPs: β defense 1 (BD-1), neutrophil gelatinase-associated lipocalin (NGAL), cathelicidin (LL-37), hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP), and human α defensin 5 (HD-5); and normalized to urine creatinine. Results were analyzed with Student's t-test or Mann-Whitney U test, when appropriate, and receiver operating characteristic curves. A P-value of <0.05 was considered significant.
RESULTS: Thirty bladder urine samples were obtained from children with UPJO at the time of decompressive intervention. Mean patient age was 4.7 years (range 0.3-18.4); 20 (67%) patients were male. Fifteen bladder urine samples were obtained from age-matched and sex-matched controls. Urinary AMP levels were significantly higher in UPJO patients than controls for BD-1 (P = 0.015), NGAL (P < 0.001), LL-37 (P < 0.001), and HIP/PAP (P = 0.046). Optimal threshold values of these AMPs were determined, with each demonstrating significant odds ratios of predicting urinary obstruction.
DISCUSSION: Certain urinary AMPs are altered even in noninfectious urinary tract pathology. This represents a novel induction of AMP expression, as the current study is the first to report elevations in BD-1 and HIP/PAP in urinary tract obstruction. This suggests other roles for these AMPs outside of their antimicrobial properties, and likely is a reflection of the urothelial and tubular stress resulting from obstructive uropathy.
CONCLUSIONS: Induction of AMPs BD-1, NGAL, LL-37, and HIP/PAP was found to occur in urinary tract obstruction. Further evaluation of AMP expression as a biomarker of uroepithelial injury outside of infection is indicated.

Keywords:  Antimicrobial peptides; UPJ obstruction; Urinary tract; Urologic disease; Urothelium

DOI:  https://doi.org/10.1016/j.jpurol.2018.03.006
BMJ Case Rep. 2018 Apr 28. pii: bcr-2017-223641. [Epub ahead of print]2018

Treatment of end-stage renal disease with continuous ambulatory peritoneal dialysis in rural Guatemala.

Jillian Moore, Pablo Garcia, Peter Rohloff, David Flood.

  A 42-year-old indigenous Maya man presented to a non-profit clinic in rural Guatemala with signs, symptoms and laboratory values consistent with uncontrolled diabetes. Despite appropriate treatment, approximately 18 months after presentation, he was found to have irreversible end-stage renal disease (ESRD) of uncertain aetiology. He was referred to the national public nephrology clinic and subsequently initiated home-based continuous ambulatory peritoneal dialysis. With primary care provided by the non-profit clinic, his clinical status improved on dialysis, but socioeconomic and psychological challenges persisted for the patient and his family. This case shows how care for people with ESRD in low- and middle-income countries requires scaling up renal replacement therapy and ensuring access to primary care, mental healthcare and social work services.

Keywords:  chronic disease / disability nursing; diabetes; dialysis; global health; healthcare improvement and patient safety

DOI:  https://doi.org/10.1136/bcr-2017-223641
J Orthop Sci. 2018 Apr 25. pii: S0949-2658(18)30100-3. [Epub ahead of print]

The impact of exercise and vitamin D supplementation on physical function in community-dwelling elderly individuals: A randomized trial.

Kana Aoki, Mayumi Sakuma, Naoto Endo.

BACKGROUND: We investigated the impact of exercise and vitamin D supplementation on physical function and locomotor dysfunction in community-dwelling elderly individuals.
METHODS: In total, 148 community-dwelling elderly individuals (aged ≥60 years) who were not taking osteoporosis medications participated in a 24-week intervention. The participants were randomly divided into an exercise group, vitamin D group, and exercise and vitamin D group. The participants and outcome-assessing staff were not blinded to group assignment. Exercise comprised three daily sets each of single-leg standing (1 min/leg/set) and squatting (5-6 repetitions/set); vitamin D supplementation was 1000 IU/day. Participants were contacted every 2 weeks to check on their condition and encourage continued participation. The primary outcome was lower limb muscle strength and mass; secondary outcomes were several physical function measurements, serum 25-hydroxyvitamin D levels, and results of a self-assessment questionnaire completed pre- and post-intervention.
RESULTS: We analyzed data from 45, 42, and 43 participants in the exercise, vitamin D, and exercise and vitamin D groups, respectively, who completed the intervention. Locomotive syndrome, which involves reduced mobility due to locomotive organ impairment, was diagnosed in 99 participants (76.2%). Many physical function measurements improved in all groups. Lower limb muscle mass increased significantly in all three groups, with no significant differences between the groups in the degree of change. The average serum 25-hydroxyvitamin D of all vitamin D-supplemented participants increased from 28.1 ng/ml to 47.3 ng/ml after vitamin D supplementation.
CONCLUSIONS: Both exercise and vitamin D supplementation independently improved physical function and increased muscle mass in community-dwelling elderly individuals. Moreover, the combination of exercise and vitamin D supplementation might further enhance these positive effects.
CLINICAL TRIAL REGISTRY: UMIN Clinical Trial, UMIN000028229.

DOI: https://doi.org/10.1016/j.jos.2018.03.011
Int J Cardiol. 2018 Jul 01. pii: S0167-5273(17)36850-X. [Epub ahead of print]262 38-42

Implant success and safety of left atrial appendage occlusion in end stage renal disease patients: Peri-procedural outcomes from an Italian dialysis population.

Simonetta Genovesi, Giorgio Slaviero, Luca Porcu, Gavino Casu, Silvio Bertoli, Antonio Sagone, Federico Pieruzzi, Giovanni Rovaris, Monique Buskermolen, Paolo Danna, Alberto Montoli, Jacopo Oreglia, Gina Contaldo, Patrizio Mazzone.

   AIMS: To estimate the safety and the efficacy of the off label left atrial appendage (LAA) occlusion in chronic dialysis patients with atrial fibrillation (AF). In this preliminary paper, we report the design of the study and the data on peri-procedural complications.
METHODS: This is a prospective cohort study. Primary endpoints are i) incidence of peri-procedural complications, ii) cumulative incidence of two-year thromboembolic events iii) cumulative incidence of two-year bleedings iiii) mortality at two years. Adverse events and death within 30 days of the procedure were recorded.
RESULTS: Fifty patients who underwent LAA occlusion between May 2014 and September 2017 were recruited. Both the mean age of the sample study and the dialysis duration were high [71.8 (9.6) years and 59.4 (78.2) months, respectively]. Most patients (84%) were hypertensive and 62% suffered a previous major bleeding. About half of them presented cardiovascular diseases. CHA2DS2VASCs and HASBLED scores were 4.0 (1.5) and 4.4 (0.9), respectively. Most patients (88%) showed atrial dilatation and 44% left ventricular hypertrophy; 32% had left ventricular ejection fraction <50%. Fifty five percent of patients had permanent AF and 32% paroxysmal AF. All devices were implanted successfully. No deaths or major adverse events were reported during a 30-day follow-up. Three episodes of peri-procedural access site bleeding were reported, requiring no transfusion.
CONCLUSIONS: Our preliminary data suggest the feasibility and safety of LAA occlusion in patients undergoing dialysis. Only the follow-up of these patients over time can provide evidence that LAA occlusion is effective in preventing of thromboembolic events in this very high-risk population.

Keywords:  Atrial fibrillation; Bleeding; Dialysis; Left atrial appendage occlusion; Oral anticoagulant therapy; Thromboembolism

DOI:  https://doi.org/10.1016/j.ijcard.2018.03.083
Chem Biol Interact. 2018 Apr 25. pii: S0009-2797(17)30396-4. [Epub ahead of print]289 40-46

NGAL attenuates renal ischemia/reperfusion injury through autophagy activation and apoptosis inhibition in rats.

Ya-Li Zhang, Shu-Kai Qiao, Rong-Ying Wang, Xiao-Nan Guo.

  Ischemia/reperfusion (I/R) injury is a main cause of acute kidney injury (AKI), and currently lacks effective therapies. This study is to investigate the level of Neutrophil gelatinase-associated lipocalin (NGAL) and autophagy status during renal I/R injury, so as to determine whether the exogenous NGAL protein could exert a protective effect for I/R injury and explore the potential mechanisms. Forty male Wistar rats were randomly divided into the following four groups: Sham, I/R, pre-treated with NGAL before I/R (I/R + pre-N), treated with NGAL after I/R (I/R + post-N). All rats were subjected to clamping the left renal pedicle for 45 min after right nephrectomy, followed by 24 h of reperfusion. Serum creatinine (SCr) and blood urea nitrogen (BUN) were used for renal function, tubular cell apoptosis and autophagy were measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, histological examination and electron microscope, respectively. The tubular cell proliferation was assessed by the protein expression of proliferating cell nuclear antigen (PCNA). Western blotting was used to quantitate the levels of LC3, Beclin-1, Bcl-2 and Bax in kidney tissues. Exogenous NGAL protein intervention significantly improved renal function, reduced tubular cell apoptosis, increased tubular cell proliferation and promoted autophagy activation after renal I/R injury. Further, the efficacy in pre-N was significantly better than post-N. The mechanisms were involved in the regulation of several autophagy and apoptosis-related genes. Our study demonstrated that exogenous NGAL protein play a protective role during I/R injury, which may offer a novel may for prevention and treatment of renal I/R injury.

Keywords:  Apoptosis; Autophagy; Ischemia-reperfusion; Neutrophil gelatinase-associated lipocalin; Proliferation

DOI:  https://doi.org/10.1016/j.cbi.2018.04.018
Cytokine. 2018 Apr 25. pii: S1043-4666(18)30178-9. [Epub ahead of print]110 63-69

Upregulation of osteopontin expression via the interaction of macrophages and fibroblasts under IL-1b stimulation.

Takahiro Shimodaira, Kazuyuki Matsuda, Takaaki Uchibori, Mitsutoshi Sugano, Takeshi Uehara, Takayuki Honda.

   BACKGROUND: Fibrosis is attributed to dysregulation of tissue-remodeling. In remodeling areas, fibroblasts and macrophages actively make contact with each other. Osteopontin (OPN) is a pro-fibrotic molecule, whose expression is upregulated by interleukin (IL)-1β via secretion of its downstream cytokines, such as IL-6. Here, we investigated the effect of interaction between fibroblasts and macrophages under IL-1β stimulation on the expression of OPN.
METHODS: We used human lung fibroblasts and THP-1 macrophages differentiated from THP-1 cells using phorbol 12-myristate 13-acetate. These cells were either cultured alone or co-cultured under IL-1β stimulation. Secretion of OPN and IL-6 were examined by enzyme-linked immunosorbent assay, and mRNA expression was assessed by quantitative real-time PCR. The effects of siRNA against IL-6 or OPN on OPN expression were evaluated.
RESULTS: OPN expression increased when fibroblasts and THP-1 macrophages were co-cultured under IL-1β stimulation. The siRNA against IL-6 in fibroblasts suppressed the upregulation of OPN expression during co-culture, whereas siRNA against IL-6 in THP-1 macrophages did not. The upregulation of expression of OPN mRNA in fibroblasts or THP-1 macrophages when co-cultured under IL-1β stimulation was mediated by IL-6 from fibroblasts. OPN from THP-1 macrophages was involved in the increase of OPN expression in fibroblasts.
CONCLUSIONS: The present study revealed the crosstalk between fibroblasts and THP-1 macrophages under IL-1β stimulation, where IL-6 from fibroblasts, stimulated by IL-1β, upregulated OPN expression in fibroblasts themselves via increase in OPN from THP-1 macrophages. The fibroblasts/macrophages network may induce activation or qualitative changes in both cells, which contributes to inflammation-associated fibrosis.

Keywords:  Fibroblasts; IL-1β; IL-6; Macrophages; Osteopontin

DOI:  https://doi.org/10.1016/j.cyto.2018.04.025
Ann Rheum Dis. 2018 Apr 28. pii: annrheumdis-2017-212880. [Epub ahead of print]

In vivo visualisation of different modes of action of biological DMARDs inhibiting osteoclastic bone resorption.

Yoshinobu Matsuura, Junichi Kikuta, Yuika Kishi, Tetsuo Hasegawa, Daisuke Okuzaki, Toru Hirano, Masafumi Minoshima, Kazuya Kikuchi, Atsushi Kumanogoh, Masaru Ishii.

   OBJECTIVES: Osteoclasts play critical roles in inflammatory bone destruction. Precursor cell migration, cell differentiation, and functional cell activation are all in play. Biological disease-modifying antirheumatic drugs (DMARDs) have been shown to significantly inhibit both bone erosion as well as synovitis, although how such agents reduce osteoclastic bone destructionin vivo has not been fully explained. Here, we used an intravital time-lapse imaging technique to directly visualise mature osteoclasts and their precursors, and explored how different biological DMARDs acted in vivo.
METHODS: Lipopolysaccharide (LPS) was injected into the calvarial periosteum of fluorescent reporter mice to induce inflammatory bone destruction. Time-lapse imaging was performed via intravital multiphoton microscopy 5 days after LPS injection. Biological DMARDs, including monoclonal antibodies (mAbs) against the interleukin (IL) 6 receptor (IL-6R) and tumour necrosis factor α (TNFα), or cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-Ig, were intraperitoneally administered at the time of LPS injection. We determined CD80/86 expression levels in mature osteoclasts and their precursors by flow cytometry, quantitative PCR and immunohistochemistry.
RESULTS: Of the biologicals tested, anti-IL-6R and anti-TNFα mAbs affected mature osteoclasts and switched bone-resorbing osteoclasts to non-resorbing cells. CTLA4-Ig had no action on mature osteoclasts but mobilised osteoclast precursors, eliminating their firm attachment to bone surfaces. In agreement with these results, CD80/86 (the target molecules of CTLA4-Ig) were prominently expressed only in osteoclast precursor cells, being suppressed during osteoclast maturation.
CONCLUSIONS: Intravital imaging revealed that various biological DMARDs acted at specific therapeutic time points during osteoclastic bone destruction, with different efficacies. These results enable us to grasp the real modes of action of drugs, optimising the usage of drug regimens.

Keywords:  dmards (biologic); inflammation; pharmacokinetics

DOI:  https://doi.org/10.1136/annrheumdis-2017-212880
Biochim Biophys Acta. 2018 Apr 25. pii: S0167-4889(18)30074-0. [Epub ahead of print]

MDM2 controls NRF2 antioxidant activity in prevention of diabetic kidney disease.

Weiying Guo, Dan Tian, Ye Jia, Wenlin Huang, Mengnan Jiang, Junnan Wang, Weixia Sun, Hao Wu.

  Oxidative stress and P53 contribute to the pathogenesis of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system, is negatively regulated by P53 and prevents DKD. Recent findings revealed an important role of mouse double minute 2 (MDM2) in protection against DKD. However, the mechanism remained unclear. We hypothesized that MDM2 enhances NRF2 antioxidant signaling in DKD given that MDM2 is a key negative regulator of P53. The MDM2 inhibitor nutlin3a elevated renal P53, inhibited NRF2 signaling and induced oxidative stress, inflammation, fibrosis, DKD-like renal pathology and albuminuria in the wild-type (WT) non-diabetic mice. These effects exhibited more prominently in nutlin3a-treated WT diabetic mice. Interestingly, nutlin3a failed to induce greater renal injuries in the Nrf2 knockout (KO) mice under both the diabetic and non-diabetic conditions, indicating that NRF2 predominantly mediates MDM2's action. On the contrary, P53 inhibition by pifithrin-α activated renal NRF2 signaling and the expression of Mdm2, and attenuated DKD in the WT diabetic mice, but not in the Nrf2 KO diabetic mice. In high glucose-treated mouse mesangial cells, P53 gene silencing completely abolished nutlin3a's inhibitory effect on NRF2 signaling. The present study demonstrates for the first time that MDM2 controls renal NRF2 antioxidant activity in DKD via inhibition of P53, providing MDM2 activation and P53 inhibition as novel strategies in the management of DKD.

Keywords:  Diabetes; Diabetic nephropathy; Nrf2; Oxidative stress; P53

DOI:  https://doi.org/10.1016/j.bbamcr.2018.04.011
Bone. 2018 Apr 25. pii: S8756-3282(18)30173-X. [Epub ahead of print]

An osteopenic/osteoporotic phenotype delays alveolar bone repair.

Chih-Hao Chen, Liao Wang, U Serdar Tulu, Masaki Arioka, Melika Maghazeh Moghim, Benjamin Salmon, Chien-Tzung Chen, Waldemar Hoffmann, Jessica Gilgenbach, John B Brunski, Jill A Helms.

  Aging is associated with a function decline in tissue homeostasis and tissue repair. Aging is also associated with an increased incidence in osteopenia and osteoporosis, but whether these low bone mass diseases are a risk factor for delayed bone healing still remains controversial. Addressing this question is of direct clinical relevance for dental patients, since most implants are performed in older patients who are at risk of developing low bone mass conditions. The objective of this study was to assess how an osteopenic/osteoporotic phenotype affected the rate of new alveolar bone formation. Using an ovariectomized (OVX) rat model, the rates of tooth extraction socket and osteotomy healing were compared with age-matched controls. Imaging, along with molecular, cellular, and histologic analyses, demonstrated that OVX produced an overt osteoporotic phenotype in long bones, but only a subtle phenotype in alveolar bone. Nonetheless, the OVX group demonstrated significantly slower alveolar bone healing in both the extraction socket, and in the osteotomy produced in a healed extraction site. Most notably, osteotomy site preparation created a dramatically wider zone of dying and dead osteocytes in the OVX group, which was coupled with more extensive bone remodeling and a delay in the differentiation of osteoblasts. Collectively, these analyses demonstrate that the emergence of an osteoporotic phenotype delays new alveolar bone formation.

Keywords:  Alveolar bone; Computer models; Osteotomy; Ovariectomy; Rats; Tooth extraction

DOI:  https://doi.org/10.1016/j.bone.2018.04.019
Cell Mol Life Sci. 2018 Apr 28.

Fibroblast growth factor receptor 1 signaling transcriptionally regulates the axon guidance cue slit1.

Jung-Lynn Jonathan Yang, Gabriel E Bertolesi, Carrie L Hehr, Jillian Johnston, Sarah McFarlane.

  Axons sense molecular cues in their environment to arrive at their post-synaptic targets. While many of the molecular cues have been identified, the mechanisms that regulate their spatiotemporal expression remain elusive. We examined here the transcriptional regulation of the guidance gene slit1 both in vitro and in vivo by specific fibroblast growth factor receptors (Fgfrs). We identified an Fgf-responsive 2.3 kb slit1 promoter sequence that recapitulates spatiotemporal endogenous expression in the neural tube and eye of Xenopus embryos. We found that signaling through Fgfr1 is the main regulator of slit1 expression both in vitro in A6 kidney epithelial cells, and in the Xenopus forebrain, even when other Fgfr subtypes are present in cells. These data argue that a specific signaling pathway downstream of Fgfr1 controls in a cell-autonomous manner slit1 forebrain expression and are novel in identifying a specific growth factor receptor for in vivo control of the expression of a key embryonic axon guidance cue.

Keywords:  Axon guidance; Forebrain; Promoter; Retinal ganglion cell; Signal transduction; Xenopus

DOI:  https://doi.org/10.1007/s00018-018-2824-x
Nephrol Ther. 2018 Apr 26. pii: S1769-7255(18)30069-5. [Epub ahead of print]

[Current insights about recurrence of glomerular diseases after renal transplantation].

Tomek Kofman, Julie Oniszczuk, Philippe Lang, Philippe Grimbert, Vincent Audard.

  Recurrence of glomerular disease after renal transplantation is a frequent cause of graft loss. Incidence, risk factors and outcome of recurrence are widely due to the underlying glomerular disease. Graft biopsy analysis is required to confirm the definitive diagnosis of recurrence and to start an appropriate therapy that, in some cases, remains challenging to prevent graft failure. Increased use of protocol biopsy and recent advances in our understanding of the pathogenesis of some glomerular diseases with the identification of some relevant biomarkers provide a unique opportunity to initiate kidney-protective therapy at early stages of recurrence on the graft. This review summarizes our current knowledge on the management of many recurrent primary and secondary glomerulonephritis after kidney transplantation.

Keywords:  Biopsie rénale; Glomerular disease; Graft loss; Maladies glomérulaires; Perte du greffon; Prognosis; Pronostic; Recurrence; Renal biopsy; Récidive

DOI:  https://doi.org/10.1016/j.nephro.2018.03.001
Transpl Immunol. 2018 Apr 25. pii: S0966-3274(18)30048-0. [Epub ahead of print]

Genome-wide association studies in kidney transplantation: Advantages and constraints.

Jianxin Yang, Frans H J Claas, Michael Eikmans.

  Since the discovery of the human leukocyte antigen (HLA) system, the role of HLA molecules in the field of transplantation has been appreciated: better matching leads to better graft function. Since then, the association of other genetic polymorphisms with clinical outcome has been investigated in many studies. Genome-wide association studies (GWAS) represent a powerful tool to identify causal genetic variants, by simultaneously analyzing millions of single nucleotide polymorphisms scattered across the genome. GWAS in transplantation may indeed be useful to reveal novel markers that may potentially be involved in the mechanism of allograft rejection and graft failure. However, the relevance of GWAS for risk stratification or donor selection for an individual patient is limited as is already reflected by the fact that many parameters, significant in one study, cannot be confirmed in another one.

Keywords:  Genome-wide association studies; Kidney transplantation

DOI:  https://doi.org/10.1016/j.trim.2018.04.004
Acad Radiol. 2018 Apr 25. pii: S1076-6332(18)30136-3. [Epub ahead of print]

Comparison of T1 Mapping and T1rho Values with Conventional Diffusion-weighted Imaging to Assess Fibrosis in a Rat Model of Unilateral Ureteral Obstruction.

Genwen Hu, Wen Liang, Mingxiang Wu, Caiyong Lai, Yingjie Mei, Yufa Li, Jianmin Xu, Liangping Luo, Xianyue Quan.

   RATIONALE AND OBJECTIVES: The aim of this study was to investigate the potential of magnetic resonance imaging (MRI) T1 mapping and T1 relaxation time in the rotating frame (T1rho) for assessment of renal fibrosis in a rat model of unilateral ureteral obstruction (UUO).
MATERIALS AND METHODS: UUO was created in 36 rats. Six rats were scanned at each of the six time points (on days 0, 1, 3, 5, 10, and 15 after UUO). The contralateral kidneys were examined as controls. Hematoxylin-eosin, Masson's trichrome, and alpha-smooth muscle actin (α-SMA) antibody staining assays were performed. MRI data obtained with a 3.0T scanner were analyzed with α-SMA expression and Masson's staining.
RESULTS: The T1 relaxation times and T1rho values increased, and the mean apparent diffusion coefficient (ADC) values decreased with time after UUO. Simple regression analysis indicated that the mean ADCs, T1 relaxation times, and T1rho values had strong correlations with the α-SMA expression levels (R2 = 0.34, R2 = 0.66, R2 = 0.71, respectively; P <.001) and positive Masson's staining (R2 = 0.38, R2 = 0.67, R2 = 0.65, respectively; P <.001).
CONCLUSIONS: The T1 mapping and T1rho parameters had better correlations with α-SMA expression and Masson's staining than ADC values.

Keywords:  T1 mapping; T1rho; renal fibrosis; unilateral ureteral obstruction

DOI:  https://doi.org/10.1016/j.acra.2018.03.023