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Background Pain affects 60% of the autosomal dominant polycystic kidney disease (ADPKD) population. Despite being an early and debilitating symptom, it is poorly characterized and management is suboptimal. This study aimed to develop an ADPKD-specific pain assessment tool (APAT) to facilitate pain research. Methods Following a systematic review of PATs used in ADPKD studies and against international recommendations for pain trials, our multi-disciplinary team of clinical experts and patients constructed an ADPKD-pain conceptual framework of key pain evaluation themes. We compiled a new APAT covering domains prioritized within our framework using components of questionnaires validated in other chronic pain disorders. The APAT was administered longitudinally within a randomized high-water intake trial (NCT02933268) to ascertain feasibility and provide pilot data on ADPKD pain. Results Thirty-nine ADPKD participants with chronic kidney disease Stages 1–4 provided 129 APAT responses. Each participant completed a median of 3 (range 1–10) assessments. Respondents' mean ± standard deviation age was 47 ± 13 years; 59% (23) were female; and 69% (27) had enlarged kidneys with median time from diagnosis 14.2 (interquartile range 7.0–25.9) years. Pain (52%) and associated analgesic use (29%) were common. Pain severity was associated with increasing age [odds ratio (OR) = 1.07, P = 0.009], female gender (OR = 4.34, P = 0.018), estimated glomerular filtration rate <60 mL/min/1.73 m2 (OR = 5.45, P = 0.021) and hypertension (OR = 12.11, P = 0.007), but not with kidney size (P = 0.23). The APAT achieved good internal consistency (Cronbach's alpha coefficient = 0.91) and test–retest reliability (domain intra-class correlation coefficients ranging from 0.62 to 0.90). Conclusions The APAT demonstrated good acceptability and reliability, and following further validation in a larger cohort could represent an invaluable tool for future ADPKD pain studies. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant polycystic kidney disease (ADPKD) affects 12.5 million worldwide. Vasopressin drives cysts growth and in animal models can be suppressed through high water intake. A randomized controlled trial of 'high' versus 'standard' water intake in ADPKD is essential to determine if this intervention is beneficial. We conducted an ADPKD patient survey to gain an understanding of current fluid intake practices and the design challenges of a randomized water intake trial. Methods: In collaboration with the PKD Charity, we developed and distributed an online survey to ADPKD patients over age 16 years and not on renal replacement therapy. Results: Of the 2377 invited, 89 ADPKD patients completed the Survey of current water Intake practices in autosomal dominant Polycystic kidney disease (SIPs) online questionnaire. Most were female (65, 73%) and white (84, 94%), with a median age group of 45-49 years. The risk of contamination between treatment arms was highlighted by the survey as the majority (70, 79%) routinely discussed ADPKD management with family despite only 17% sharing the same household. More participants reported drinking beyond thirst (65, 73%) than those actually indicating a daily fluid intake of>2 L (54, 61%). This discrepancy emphasizes inaccuracies of fluid intake estimates and the requirement for objective methods of measuring water intake. Overall, only 51% believed high water intake was beneficial, while 91% were willing to participate in research evaluating this. Conclusion: ADPKD poses unique design challenges to a randomized water intake trial. However, the trial is likely to be supported by the ADPKD community and could impact significantly on PKD management and associated healthcare costs. [ABSTRACT FROM AUTHOR]

Exosomes derived from all nephron segments are present in human urine, where their functionality is incompletely understood. Most studies have focused on biomarker discovery rather than exosome function. Through sequencing we identified the miRNA repertoire of urinary exosomes from healthy volunteers; 276 mature miRNAs and 345 pre-miRNAs were identified (43%/7% of reads). Among the most abundant were members of the miR-10, miR-30 and let-7 families. Targets for the identified miRNAs were predicted using five different databases; genes encoding membrane transporters and their regulators were enriched, highlighting the possibility that these miRNAs could modulate key renal tubular functions in a paracrine manner. As proof of concept, cultured renal epithelial cells were exposed to urinary exosomes and cellular exosomal uptake was confirmed; thereafter, reduced levels of the potassium channel ROMK and kinases SGK1 and WNK1 were observed in a human collecting duct cell line, while SPAK was unaltered. In proximal tubular cells, mRNA levels of the amino acid transporter gene SLC38A2 were diminished and reflected in a significant decrement of its encoded protein SNAT2. Protein levels of the kinase SGK1 did not change. Thus we demonstrated a novel potential function for miRNA in urinary exosomes. [ABSTRACT FROM AUTHOR]

Anion exchanger 1 (AE1) mediates Cl−/HCO3− exchange in erythrocytes and kidney intercalated cells where it functions to maintain normal bodily acid-base homeostasis. AE1's C-terminal tail (AE1C) contains multiple potential membrane targeting/retention determinants, including a predicted PDZ binding motif, which are critical for its normal membrane residency. Here we identify PDLIM5 as a direct binding partner for AE1 in human kidney, via PDLIM5's PDZ domain and the PDZ binding motif in AE1C. Kidney AE1 (kAE1), PDLIM5 and integrin-linked kinase (ILK) form a multiprotein complex in which PDLIM5 provides a bridge between ILK and AE1C. Depletion of PDLIM5 resulted in significant reduction in kAE1 at the cell membrane, whereas over-expression of kAE1 was accompanied by increased PDLIM5 levels, underscoring the functional importance of PDLIM5 for proper kAE1 membrane residency, as a crucial linker between kAE1 and actin cytoskeleton-associated proteins in polarized cells. [ABSTRACT FROM AUTHOR]

Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.

Peroxiredoxin 6 (PRDX6) is one of the six members of the PRDX family, which have peroxidase and antioxidant activity. PRDX6 is unique, containing only one conserved cysteine residue (C47) rather than the two found in other PRDXs. A yeast two-hybrid screen found PRDX6 to be a potential binding partner of the C-terminal tail of anion exchanger 1 (AE1), a Cl(-)/HCO(3)(-) exchanger basolaterally expressed in renal α-intercalated cells. PRDX6 immunostaining in human kidney was both cytoplasmic and peripheral and colocalized with AE1. Analysis of native protein showed that it was largely monomeric, whereas expressed tagged protein was more dimeric. Two methionine oxidation sites were identified. In vitro and ex vivo pull-downs and immunoprecipitation assays confirmed interaction with AE1, but mutation of the conserved cysteine resulted in loss of interaction. Prdx6 knockout mice had a baseline acidosis with a major respiratory component and greater AE1 expression than wild-type animals. After an oral acid challenge, PRDX6 expression increased in wild-type mice, with preservation of AE1. However, AE1 expression was significantly decreased in knockout animals. Kidneys from acidified mice showed widespread proximal tubular vacuolation in wild-type but not knockout animals. Knockdown of PRDX6 by siRNA in mammalian cells reduced both total and cell membrane AE1 levels. Thus, PRDX6-AE1 interaction contributes to the maintenance of AE1 during cellular stress such as during metabolic acidosis., (Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)