Kidney Research UK Research Articles

Skin and Kidney Contribute to Salt‐Sensitive Hypertension in the SAME rat

Loss of Hsd11b2 causes the syndrome of apparent mineralocorticoid excess (SAME) and salt‐sensitive hypertension, which has been demonstrated in the SAME rat 1. We aimed to determine how salt‐sensitive hypertension developed in young SAME rats.Hsd11b2−/− rats were hypertensive (158 versus 119mmHg controls; measured under anaesthesia) and plasma volume contracted (haematocrit 0.49 versus 0.42 control) by 5 weeks of age and showed profound hypokalemia (2mM plasma K+ versus 4.5mM control) the latter being evident from 15 days of age.Adult kidney RNA‐seq analysis suggested a coordinate down‐regulation of electrolyte and water transporters, while a‐ENaC (Scnn1a; 1.66‐fold), the flow‐induced BK channel (Kcnma1; 2.65‐fold) and the HKA2 channel (Atp12a; 4.29‐fold) were significantly up‐regulated. Young Hsd11b2−/− animals exhibited polydipsia and polyuria from weaning age (~20 days old) and, as with adults, they excreted a higher proportion of ingested Na+ (56%) through the kidney, compared to controls (38%), suggesting that the coordinate changes in nephron transporters are already in place around weaning age.Notably, we observed increased skin electrolytes in neonatal animals, (by drying and ashing pelts and determining electrolytes using atomic absorption spectroscopy). Neonatal Hsd11b2−/− animals retained higher [Na+] in their pelts than the controls.Our data suggest that increased Na+ intake [from mothers’ milk] results in increased Na+ storage in skin at the expense of K+. The ensuing hypokalemia primes the developing nephron to deliver increased Na+ and water to the connecting tubule and cortical collecting duct by weaning age. Glucocorticoid‐induced Na+ uptake in the kidney, and reduced Na+ storage capacity in the pelt, both then contribute to progressive salt‐sensitive hypertension.Support or Funding InformationBritish Heart Foundation Centre of Research Excellence Award (RE/08/001/23904); Kidney Research UK project grant

Contactin-1 Antibodies Link Autoimmune Neuropathies to Nephrotic Syndrome

Background: There is an established association between acquired inflammatory demyelinating neuropathies and nephrotic syndrome, but a common immunopathological mechanism has yet to be determined. Antibodies to known glomerular podocyte antigens occur in up to 90% of patients with nephrotic syndrome due to idiopathic membranous glomerulonephritis (MGN), the majority targeting the phospholipase A2 receptor (PLA2R). In patients with immune-mediated neuropathies, antibodies targeting molecules of the node of Ranvier, such as contactin-1 (CNTN1), are increasingly recognised. Methods: In this study, sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, were tested for CNTN1 antibodies. Topographical binding patterns were determined using teased nerve fibres and live myelinated nerve co-cultures. CNTN1 expression in human kidney was characterised by immunohistochemistry, western blotting and PCR. Findings: A total of 16 patients with an immune-mediated neuropathy and MGN were seropositive for IgG4 anti-CNTN1 antibodies. The onset and resolution of both disorders had a close temporal relationship. The majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Four further patients with isolated MGN were also positive for the same antibodies at lower titres. CNTN1 protein was detected within glomerular deposits in biopsies from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. Interpretation: These data provide evidence that CNTN1 antibodies precipitate both autoimmune neuropathy and MGN. The temporal correlation of these disorders, as well as the presence of CNTN1 protein and antibodies in both peripheral nerve and diseased glomeruli, supports a common antibody-mediated pathological process, and defines a new antigenic target in MGN. CNTN1 antibodies have diagnostic and therapeutic relevance, and may additionally serve as a means of monitoring disease activity in both conditions. Funding Statement: Medical Research Council (MRC), GBS/CIDP Foundation International, MRC and Kidney Research UK. Declaration of Interests: SR runs a not-for-profit diagnostic testing service for nodal/paranodal antibodies. He has received a speaker’s honorarium and/or travel expenses from Fresenius Medical Care, Excemed, Alnylam and argenx. AR has received honoraria from Sarepta, Roche and Sanofi Aventis, is a member of MND Association Clinical Advisory Board, and was a member of NICE MND Guideline Development Group. ASC receives funding from NIHR University College London Hospitals Biomedical research centre. AM is a clinical fellow with grant reference number MR/P001777/1. SPi is was funded by a grant from the Karolinska Institutet during the course of the study. All other authors have nothing to declare. Ethics Approval Statement: Research Ethics Committee approval number 14/SC/0280

Kidney disease and pregnancy

Pregnancy can be a joyous yet stressful event, even at the best of times. The addition of kidney dysfunction during this time can introduce the risk of potentially life-threatening complications to both mother and child. However, thanks to new research, funded by Kidney Research UK, ways are being developed to diagnose acute kidney injury (AKI) earlier, helping to identify those at risk and predicting the extent of kidney function decline in pregnant women with chronic kidney disease (CKD).

Scientists reveal how a faulty gene leads to kidney disease

Research funded by Kidney Research UK has provided new insights into why a faulty gene involved in nephrotic syndrome leads to disease in some patients. The findings could pave the way for new ways to prevent or treat the condition, by revealing new targets to intervene in the process. Around 1 in 50,000 children are diagnosed with nephrotic syndrome each year.

General and Abdominal Adiposity and Mortality in Mexico City: A Prospective Study of 150000 Adults.

Some reports suggest that body mass index (BMI) is not strongly associated with mortality in Hispanic populations. To assess the causal relevance of adiposity to mortality in Mexican adults, avoiding reverse causality biases. Prospective study. 2 Mexico City districts. 159755 adults aged 35 years and older at recruitment, followed for up to 14 years. Participants with a hemoglobin A1c level of 7% or greater, diabetes, or other chronic diseases were excluded. BMI, waist-to-hip ratio, waist circumference, and cause-specific mortality. Cox regression, adjusted for confounders, yielded mortality hazard ratios (HRs) after at least 5 years of follow-up and before age 75 years. Among 115400 participants aged 35 to <75 years at recruitment, mean BMI was 28.0 kg/m2 (SD, 4.1 kg/m2) in men and 29.6 kg/m2 (SD, 5.1 kg/m2) in women. The association of BMI at recruitment with all-cause mortality was J-shaped, with the minimum at 25 to <27.5 kg/m2. Above 25 kg/m2, each 5-kg/m2 increase in BMI was associated with a 30% increase in all-cause mortality (HR, 1.30 [95% CI, 1.24 to 1.36]). This association was stronger at ages 40 to <60 years (HR, 1.40 [CI, 1.30 to 1.49]) than at ages 60 to <75 years (HR, 1.24 [CI, 1.17 to 1.31]) but was not materially affected by sex, smoking, or other confounders. The associations of mortality with BMI and waist-to-hip ratio were similarly strong, and each was weakened only slightly by adjustment for the other. Waist circumference was strongly related to mortality and remained so even after adjustment for BMI and hip circumference. Analyses were limited to mortality. General, and particularly abdominal, adiposity were strongly associated with mortality in this Mexican population. Mexican Health Ministry, Mexican National Council of Science and Technology, Wellcome Trust, Medical Research Council, and Kidney Research UK.

Shared Hemodialysis Care: Increasing Patient Involvement in Center-Based Dialysis.

Reann’s story“When I first heard that I could share doing some of my own hemodialysis, I was scared and thought I could never do that! Despite my initial fear, I have learned how to needle. I found this rewarding and now I am in control. I have a lot less issues with my fistula now and I can get

Development of a new class of drugs to treat autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a disease that affects over 60 000 people in the UK alone, and around 12 million people worldwide. In this article, Maria Thompson describes the development of a new class of drugs aimed at treating ADPKD, which has been funded in part by Kidney Research UK

Disparities in kidney health across the UK

Kidney Research UK has published a report into kidney health inequalities in the UK, which shows how particular groups of people are at greater risk of developing kidney disease. Rosie Loft explains how the report shows that these groups face worse outcomes from kidney disease and sets out the research needed to address these challenges

Single Cell Ablation in the Zebrafish Kidney using SPIM and a Bessel Beam

Selective plane illumination microscopy (SPIM) uses low‐powered laser light to rapidly and precisely capture high‐resolution images of cells within live organisms, revealing fine details of the cell structure. By combining a bespoke SPIM/Bessel beam in combination with appropriate fluorescent cell‐specific reporters, individual cells can be located and targeted for ablation via apoptosis.Incorporation of fluorescent reporters such as LifeAct‐red fluorescent protein (RFP) or the photosensitizing protein, KillerRed (KR), into the genome of the optically clear zebrafish larvae, allows specifically labelled cells to be visualized and/or optically ablated deep within developing organs and in real‐time. We have used this technology to visualize and target a) cells of the renin lineage (CoRLs)1 and b) podocytes, within the live Zebrafish kidney. Transgenic fish expressing KR under the control of the renin and podocin promoters were established and used independently for imaging/ablation experiments. Using a Bessel beam in combination with SPIM to precisely activate KR allows relatively low laser power to be employed resulting in 100% viability of the fish following laser treatment. Low energy laser ablation allows the cell injury/ablation to be imaged and assessed over an extensive time period (hours).Support or Funding InformationBHF Center of Research Excellence Award; Kidney Research UK award; EPSRC/MRC DT (Optima) AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acute SGLT2 Inhibition and the Pressure Natriuresis Response in Rats with Type 1 Diabetes

Increasing blood pressure (BP) induces natriuresis due to downregulation of sodium transport in the proximal tubule. This pressure natriuresis (PN) response influences long‐term BP. Type‐1 diabetic (T1DM) patients show enhanced tubular sodium reabsorption and high BP. We have found that tubular sodium reabsorption is not modulated by BP in T1DM rats. The molecular mechanism of impaired PN is unknown but the sodium‐glucose cotransporter SGLT2 is a plausible candidate and inhibitors acutely induce diuresis in T1DM rats. This study tested the hypothesis that SGLT2 inhibition with dapagliflozin would improve the acute PN response in T1DM rats.T1DM was induced in male Sprague‐Dawley rats by streptozotocin (30–45mg/kg IP; plasma glucose 13.3–&gt;35mmol). After 3 weeks rats were anaesthetised with Inactin (120mg/kg, IP). The jugular vein was cannulated and isotonic saline (containing FITC‐inulin and p‐amino hippurate for measurement of glomerular filtration rate (GFR) and renal plasma flow (RPF)) was infused. Rats were randomly allocated to receive either dapagliflozin (50mg/kg; n=7) or saline vehicle (n=7) and after an equilibration period and baseline urine collection, BP was increased by sequential arterial ligation of first the coeliac and mesenteric arteries and then the distal aorta and the natriuretic response was measured. Experiments were performed under a single blind and rats were euthanised by an overdose of anaesthetic. Data are mean +SD and comparisons were made by 2‐way ANOVA. GFR and RPF were not different between treatment groups and were unaffected by the experimentally‐induced rise in BP, consistent with autoregulation. In vehicle‐treated rats, incremental rises in BP increased urine flow rate from a baseline of 6 ± 3 to a peak of 51 ± 28μl/min/gkw (P&lt;0.01), sodium excretion from 1.7 ± 0.5 to 16.7 ± 1.4 μmol/min/gkw (P&lt;0.01) and fractional sodium excretion from 0.2 ± 7.6 to 5.4 ± 4.5% (P&lt;0.01). The dapaglifozin‐treated rats responded to increasing pressure with a diuresis and natriuresis but the peak absolute (3.8 ± 4.1μmol/min/gkw; P=0.010) and fractional (15.2 ± 8.0%; P=0.018) sodium excretion were significantly lower than in the vehicle‐ group. Dapagliflozin increased urinary glucose excretion from 0.1 ± 0.2 to 0.4 ± 0.2μmol/min/gkw: glucose excretion was not modified by increasing BP in either group. Although dapagliflozin increased urine flow and glucose excretion at steady‐state BP, it did not enhance the acute PN response in T1DM rats. Thus, impaired PN in T1DM does not reflect increased SGLT2 activity.Support or Funding InformationBritish Heart Foundation studentship FS/16/54/32730 &amp; Kidney Research UK Project Grant RP2/2014This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Corticosteroid Regulation of ENaC‐Mediated Na+ Transport in a Cellular Model of the Cortical Collecting Duct

Na+ absorption in the distal nephron is under strict hormonal control, perhaps most notably by the mineralocorticoid aldosterone. The specificity of aldosterone action is conferred by the enzyme 11β‐hydroxysteroid dehydrogenase 2 (11βHSD2) which is thought to protect the mineralocorticoid receptor (MR) from illicit occupancy by glucocorticoids, which circulate freely at ~100 fold greater concentration. In vivo studies challenge this model e.g. mice haploinsufficient for 11βHSD2 exhibit salt‐sensitive hypertension associated with downregulated ENaC‐mediated Na+ absorption1. This downregulation can be reversed by glucocorticoid receptor (GR), but not MR, blockade, strongly indicating a role for the GR. The present study has therefore utilised a cellular model of the collecting duct to interrogate the molecular pathways enabling corticosteroids to regulate ENaC activity.ENaC‐mediated Na+ transport was quantified across monolayers of mCCDcl1 cells via electrometric measurements of amiloride‐sensitive current (Iami). SGK1 abundance and activity were monitored by Western blot analysis.Time course experiments revealed that both aldosterone (3nM) and the synthetic glucocorticoid dexamethasone (100nM) stimulated Iami within 1h. Whilst aldosterone‐induced Iami peaked at 3–6h before returning to baseline, dexamethasone‐induced Iami remained stimulated after 24h. Increasing concentrations of the endogenous glucocorticoid corticosterone (0.01–100nM) did not alter Iami, indicative of functional 11βHSD2. At concentrations ≥1μM however, Iami was stimulated indicating the capacity of the enzyme had been surpassed. Inhibition of 11βHSD2 with carbenoxolone (CBX) unmasked a concentration‐dependent stimulation of Iami by corticosterone appearing at 1nM. Changes in Iami correlated with increased abundance and activity of the serum and glucocorticoid‐induced kinase 1 (SGK1). Aldosterone also stimulated Iami, as well as SGK1 abundance and activity, in a concentration‐dependent manner but was unaffected by pre‐treatment with CBX confirming that aldosterone is not a substrate for 11βHSD2. To determine the steroid receptors involved in mediating the effects of corticosteroids, Iami was measured following pharmacological inhibition of the MR using the non‐steroidal compound PF‐03882845 or of the GR using mifepristone. Application of aldosterone (3nM), dexamethasone (100nM) or corticosterone (100nM, in the presence of CBX) for 3h, stimulated Iami by 2.8‐, 3.9‐ and 3.6‐fold, respectively. Both aldosterone‐ and corticosterone‐induced Iami were inhibited predominantly (&gt;65%) by MR antagonism, but were also inhibited by GR antagonism, ~55% and ~20%, respectively. In contrast, dexamethasone‐induced Iami was inhibited predominantly by GR antagonism, with only a small component inhibited by MR blockade.Whilst stimulation of ENaC‐mediated Na+ transport by aldosterone and corticosterone, unlike dexamethasone, is predominantly mediated by MR, these data indicate that the GR may play a permissive role in mediating the Na+ retaining effects of endogenous corticosteroids in the distal nephron.Support or Funding InformationFunded by a Kidney Research UK Intermediate Fellowhship.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis

BackgroundIntravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited.MethodsIn a multicenter, open-label trial with blinded end-point evaluation, we randomly assigned adults undergoing maintenance hemodialysis to receive either high-dose iron sucrose, administered intravenously in a proactive fashion (400 mg monthly, unless the ferritin concentration was >700 μg per liter or the transferrin saturation was ≥40%), or low-dose iron sucrose, administered intravenously in a reactive fashion (0 to 400 mg monthly, with a ferritin concentration of <200 μg per liter or a transferrin saturation of <20% being a trigger for iron administration). The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death, assessed in a time-to-first-event analysis. These end points were also analyzed as recurrent events. Other secondary end points included death, infection rate, and dose of an erythropoiesis-stimulating agent. Noninferiority of the high-dose group to the low-dose group would be established if the upper boundary of the 95% confidence interval for the hazard ratio for the primary end point did not cross 1.25.ResultsA total of 2141 patients underwent randomization (1093 patients to the high-dose group and 1048 to the low-dose group). The median follow-up was 2.1 years. Patients in the high-dose group received a median monthly iron dose of 264 mg (interquartile range [25th to 75th percentile], 200 to 336), as compared with 145 mg (interquartile range, 100 to 190) in the low-dose group. The median monthly dose of an erythropoiesis-stimulating agent was 29,757 IU in the high-dose group and 38,805 IU in the low-dose group (median difference, −7539 IU; 95% confidence interval [CI], −9485 to −5582). A total of 320 patients (29.3%) in the high-dose group had a primary end-point event, as compared with 338 (32.3%) in the low-dose group (hazard ratio, 0.85; 95% CI, 0.73 to 1.00; P<0.001 for noninferiority; P=0.04 for superiority). In an analysis that used a recurrent-events approach, there were 429 events in the high-dose group and 507 in the low-dose group (rate ratio, 0.77; 95% CI, 0.66 to 0.92). The infection rate was the same in the two groups.ConclusionsAmong patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was superior to a low-dose regimen administered reactively and resulted in lower doses of erythropoiesis-stimulating agent being administered. (Funded by Kidney Research UK; PIVOTAL EudraCT number, 2013-002267-25.)

Gene editing to halt kidney disease: a research breakthrough

A groundbreaking piece of research, undertaken by scientists from Newcastle University and funded by Kidney Research UK, used a technique called exon-skipping to bypass the mutation that caues kidn...

Supporting research: the Allied Health Professional Fellowship

Research into kidney disease is vital to improve treatments and quality of life. Kidney Research UK has, therefore, set up a fellowship scheme, providing funding for allied health professionals wis...

BOWMAN'S CAPSULE CORRECTED: UNDISCOVERED VASCULAR CHAMBERS IN THE RENAL GLOMERULUS

The structure of the kidney glomerulus, known since Bowman's description in 18571, is of arterial afferent capillaries leading to exchange capillaries and an efferent arteriole. While investigating the three dimensional structure of the glomerulus we discovered that this description is incorrect in adult human glomeruli. Serial section reconstruction of glomeruli perfused‐fixed under physiological colloid osmotic and hydrostatic pressures showed that afferent and efferent arterioles lead into previously undescribed ellipsoid, wide vascular chambers (VCs). From the afferent vascular chamber (AVC), 5–7 long, non‐branching, conduit vessels lead to the glomerular edge where branching occurs. Using multiphoton microscopy, a signal consistent with banded (fibrilar) collagen was seen in second harmonic generation mode in unfixed glomeruli in a region consistent with vascular chamber walls imaged by two photon fluorescence. Electron microscopy confirmed that a layer of banded collagen surrounds VC walls. Approximately thirteen highly branched, first order vessels (E1) converge on the efferent VC (EVC), which drains into the efferent arteriole. Complex vortical flow modelling predicted that the AVC acts as a plenum manifold, distributing and balancing blood flow/pressure to conduit vessels supplying blood to different glomerular lobules. These previously undescribed adaptations of glomerular vascular structure in humans could regulate haemodynamic pressure and flow in glomeruli, and their disturbance provide a new mechanism to explain kidney diseases.Support or Funding InformationThe Richard Bright Research Trust, Kidney Research UK (2014–2015) and the Medical Research Council G10002073 and MR/K020366/1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

High Versus Ad Libitum Water Intake in Patients with Autosomal Dominant Polycystic Kidney Disease (DRINK): An Open Label, Randomised Controlled Phase 2 Trial

Background: Vasopressin promotes cyst growth in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Vasopressin receptor antagonists slow disease progression, but their use is limited by side effects and cost. High water intake suppresses vasopressin production and may provide a viable alternative to pharmacological receptor blockade. We aimed to assess the feasibility of a definitive randomised high water intake trial in ADPKD. Methods: We conducted a phase 2, single-centre open-label randomised controlled trial (NCT02933268). Adults aged 16 years and older with ADPKD and an eGFR20ml/min/1.73m2 were randomly assigned to prescribed high water intake (HW) targeting a urine osmolality of 270mOsm/kg, or ad libitum (AW) intake. The co-primary outcomes were the proportion of participants achieving target urine osmolality and the rate of recruitment. Secondary outcomes included separation between treatment arms, changes in GFR, copeptin, and safety. Findings: 42 participants with a median baseline eGFR 75.8 (IQR 46.5-107.5) ml/min/1.73m2 and urine osmolality 352 (IQR 202-452) mOsm/Kg were enrolled over 12 months and randomised to HW (n=21) or AW (n=21). After 8 weeks, 67% in the HW compared to 24% in the AW group had a urine osmolality of 270mOsm/kg, p=0.001. The median week-8 urine osmolality was significantly higher in the AW compared to HW group (379 IQR 235-503 v 194 IQR 190-438 mOsm/kg, p=0.01). There was no difference in median week 8 plasma copeptin (AW=4.1, IQR 2.9-11.2 vs HW=3.6, IQR 2.7-5.7, p=0.25) and no evidence of acute effects of increased hydration on measured or estimated GFR. Interpretation: It is possible to recruit to and achieve separation between trial arms in urine osmolality in a randomised trial. A definitive trial assessing the effect of high water intake on kidney function in ADPKD is feasible. Clinical Trial Number: NCT02933268 Funding Statement: The study is funded by the British Renal Society and Kidney Care UK (formerly British Kidney Patient Association) grant programme, the PKD Charity, the Addenbrooke’s Charitable Trust and Kidney Research UK. Declaration of Interests: None declared Ethics Approval Statement: DRINK was approved by the East of England Essex Research Committee (16/EE/0026) and the study was overseen by the trial steering committee.

Fellows Day 2017 and the Kidney Research UK alumni programme

The 2017 Kidney Research UK Fellows Day presented an opportunity for members of its alumni programme to to come together share their latest research. Maria Thompson and Louise Crathorne summarise the most exciting talks and presentations given at the event in Swansea this September, and explain what they mean for the future of kidney care.

Paediatric kidney study offers new hope to children on dialysis

Kidney Research UK and Kids Kidney Research have merged. In this article, Maria Thompson and Allison Parkinson discuss how the extra funding this provides will help improve the lives of paediatric patients on dialysis in the UK, starting with a 3-year research project on how haemodiafiltration may enhance quality of life for children on this renal replacement therapy.

NURTURE: breaking ground with a unique new kidney biobank

Kidney Research UK is in the process of setting up a unique kidney biobank, collecting biological samples from 14 sites in England, Scotland and Wales. In this article, Angela Lumsdon provides an overview of how the biobank will operate, from sample collection to processing, and explains how the associated data collected can help improve kidney care provision in the future.

The ACE project: a collaboration to support pre-dialysis patients

Kidney Research UK and The Heart of England Foundation Trust have come together with an initiative to help support pre-dialysis patients. Neerja Jain, Sarah Williams and Angela Lumsdon explain the Acceptance, Choice and Empowerment (ACE) project: a peer educator-based community initiative that aims to improve choice and quality of life.