Use of a donor kidney with known autosomal dominant polycystic kidney disease in a highly sensitised paediatric recipient.

We report the use of an autosomal-dominant polycystic kidney disease (ADPKD) donor kidney in a paediatric recipient. A 14-year-old boy on haemodialysis for 4 years following loss of a first kidney transplant, highly sensitised, and with limited vascular options for ongoing dialysis access, was offered a deceased brain death donor transplant from a mid-30s donor with known ADPKD but normal kidney function and negligible proteinuria. After extensive discussion with the patient and family, discussing all alternative options and review of available literature, the kidney was accepted and implanted. Graft function was immediate. An early post-transplant creatinine rise was attributed to possible antibody-mediated rejection, treated with plasmapheresis and rituximab. Ten months post-transplant, the patient remains dialysis-free with stable function. Extended criteria kidneys are already considered for highly sensitised or long-waiting dialysis patients. Though the literature is limited, kidneys from patients with ADPKD could be considered within extended criteria offers on a case-by-case basis.

Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation.

The sodium-chloride cotransporter (NCC) in the distal convoluted tubule contributes importantly to sodium balance and blood pressure (BP) regulation. NCC phosphorylation determines transport activity and has a diurnal rhythm influenced by glucocorticoids. Disturbing this rhythm induces "nondipping" BP, an abnormality that increases cardiovascular risk. The receptor through which glucocorticoids regulate NCC is not known. In this study, we found that acute administration of corticosterone to male C57BL6 mice doubled NCC phosphorylation without affecting total NCC abundance in both adrenalectomized and adrenal-intact mice. Corticosterone also increased the whole kidney expression of canonical clock genes: period circadian protein homolog 1 (Per1), Per2, cryptochrome 1, and aryl hydrocarbon receptor nuclear translocator-like protein 1. In adrenal-intact mice, chronic blockade of glucocorticoid receptor (GR) with RU486 did not change total NCC but prevented corticosterone-induced NCC phosphorylation and activation of clock genes. Blockade of mineralocorticoid receptor (MR) with spironolactone reduced the total pool of NCC but did not affect stimulation by corticosterone. The diurnal rhythm of NCC phosphorylation, measured at 6-h intervals, was blunted by chronic GR blockade, and a similar dampening of diurnal variation was seen in GR heterozygous null mice. These effects on NCC phosphorylation did not reflect altered rhythmicity of plasma corticosterone or serum and glucocorticoid-induced kinase 1 activity. Both mineralocorticoids and glucocorticoids emerge as regulators of NCC, acting via distinct receptor pathways. MR activation provides maintenance of the NCC protein pool; GR activation dynamically regulates NCC phosphorylation and establishes the diurnal rhythm of NCC activity. This study has implications for circadian BP homeostasis, particularly in individuals with abnormal glucocorticoid signaling as is found in chronic stress and corticosteroid therapy.

Patient satisfaction and outcomes of partial wrist denervation in inflammatory arthritis.

INTRODUCTION: Inflammatory arthritis frequently affects the wrist, resulting in pain and disability. This study aims to investigate the long-term outcome of patients who underwent posterior interosseous nerve (PIN) denervation for inflammatory arthritis of the wrist. METHOD: xForty consecutive wrists (36 patients) treated with PIN denervation were identified (mean follow-up 47 months; mean age 62.6 years, 77.5% female). Pain and function scores were objectively measured using the patient-rated wrist-evaluation (PRWE) questionnaires. Data was compared for pre-operation and post-operation (early and long term). The Student's t test was used to compare differences between groups for continuous data, whilst the sign test was utilised for pairwise comparisons. The p value was set at 0.05 for all comparisons. RESULTS: Three patients died during the course of this study from causes unrelated to wrist surgery, resulting in 93% follow-up. PRWE questionnaires demonstrated a significant improvement following PIN denervation (median pain pre-op 42 vs post-op 16 (p < 0.001); median function pre-op 82 vs post-op 41 (p < 0.001), respectively). There were no differences identified between early and long-term post-operative scores. Four cases (10%) had persistent, ulnar-based pain and required secondary salvage wrist arthrodesis. However, 95% of patients remained "very satisfied" or "satisfied" after surgery. CONCLUSIONS: This study highlights the effectiveness of PIN denervation as a simple alternative to wrist arthrodesis due to long-term improvement in pain and preservation of function. We recommend this procedure in the presence of a positive diagnostic PIN infiltration test to avoid wrist arthrodesis for as long as possible. In patients with predominantly ulnar-based wrist pain, the outcome is less predictable and this subgroup of patients should be counselled about the possibility of subsequent salvage wrist fusion. Key Points • One of the largest study cohorts which report on the outcome of the wrist PIN denervation procedure with over 2-year follow-up • Clinical outcomes of success are enhanced with the use of validated, objective patient-reported outcome measures relating to overall satisfaction, pain relief and function. • Long-term outcomes are compared to pre-operative and immediate post-operative outcome scores, demonstrating the benefits of PIN denervation and the longevity it provides.

Urinary Extracellular Vesicle Protein Profiling and Endogenous Lithium Clearance Support Excessive Renal Sodium Wasting and Water Reabsorption in Thiazide-Induced Hyponatremia.

INTRODUCTION: Thiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC). METHODS: Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry. RESULTS: Analysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients. CONCLUSION: Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before thiazide initiation.

Glucocorticoids Induce Nondipping Blood Pressure by Activating the Thiazide-Sensitive Cotransporter.

Blood pressure (BP) normally dips during sleep, and nondipping increases cardiovascular risk. Hydrochlorothiazide restores the dipping BP profile in nondipping patients, suggesting that the NaCl cotransporter, NCC, is an important determinant of daily BP variation. NCC activity in cells is regulated by the circadian transcription factor per1. In vivo, circadian genes are entrained via the hypothalamic-pituitary-adrenal axis. Here, we test whether abnormalities in the day:night variation of circulating glucocorticoid influence NCC activity and BP control. C57BL6/J mice were culled at the peak (1:00 AM) and trough (1:00 PM) of BP. We found no day:night variation in NCC mRNA or protein but NCC phosphorylation on threonine(53) (pNCC), required for NCC activation, was higher when mice were awake, as was excretion of NCC in urinary exosomes. Peak NCC activity correlated with peak expression of per2 and bmal1 (clock genes) and sgk1 and tsc22d3 (glucocorticoid-responsive kinases). Adrenalectomy reduced NCC abundance and blunted the daily variation in pNCC levels without affecting variation in clock gene transcription. Chronic corticosterone infusion increased bmal1, per1, sgk1, and tsc22d3 expression during the inactive phase. Inactive phase pNCC was also elevated by corticosterone, and a nondipping BP profile was induced. Hydrochlorothiazide restored rhythmicity of BP in corticosterone-treated mice without affecting BP in controls. Glucocorticoids influence the day:night variation in NCC activity via kinases that control phosphorylation. Abnormal glucocorticoid rhythms impair NCC and induce nondipping. Night-time dosing of thiazides may be particularly beneficial in patients with modest glucocorticoid excess.