Publications by authors named "Christopher G Winearls"

36 Publications

Intravenous Iron Dosing and Infection Risk in Patients on Hemodialysis: A Prespecified Secondary Analysis of the PIVOTAL Trial.

J Am Soc Nephrol 2020 05 6;31(5):1118-1127. Epub 2020 Apr 6.

Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.

Background: Experimental and observational studies have raised concerns that giving intravenous (IV) iron to patients, such as individuals receiving maintenance hemodialysis, might increase the risk of infections. The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial randomized 2141 patients undergoing maintenance hemodialysis for ESKD to a high-dose or a low-dose IV iron regimen, with a primary composite outcome of all-cause death, heart attack, stroke, or hospitalization for heart failure. Comparison of infection rates between the two groups was a prespecified secondary analysis.

Methods: Secondary end points included any infection, hospitalization for infection, and death from infection; we calculated cumulative event rates for these end points. We also interrogated the interaction between iron dose and vascular access (fistula versus catheter).

Results: We found no significant difference between the high-dose IV iron group compared with the lose-dose group in event rates for all infections (46.5% versus 45.5%, respectively, which represented incidences of 63.3 versus 69.4 per 100 patient years, respectively); rates of hospitalization for infection (29.6% versus 29.3%, respectively) also did not differ. We did find a significant association between risk of a first cardiovascular event and any infection in the previous 30 days. Compared with patients undergoing dialysis with an arteriovenous fistula, those doing so a catheter had a higher incidence of having any infection, hospitalization for infection, or fatal infection, but IV iron dosing had no effect on these outcomes.

Conclusions: The high-dose and low-dose IV iron groups exhibited identical infection rates. Risk of a first cardiovascular event strongly associated with a recent infection.
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http://dx.doi.org/10.1681/ASN.2019090972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217408PMC
May 2020

High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial.

Lancet Haematol 2019 Apr 11;6(4):e217-e228. Epub 2019 Mar 11.

Centre for Clinical Haematology, University of Birmingham, Birmingham, UK.

Background: In multiple myeloma, severe acute kidney injury due to myeloma cast nephropathy is caused by pathogenic free light chain immunoglobulin in serum. High cutoff haemodialysis (HCO-HD) can remove large quantities of free light chain immunoglobulin from serum, but its effect on clinical outcomes is uncertain. We therefore aimed to assess whether HCO-HD could increase the frequency of renal recovery in patients with de novo multiple myeloma, severe acute kidney injury, and myeloma cast nephropathy relative to treatment with standard high-flux haemodialysis (HF-HD).

Methods: In this open-label, phase 2, multicentre, randomised controlled trial (EuLITE), we recruited patients with newly diagnosed multiple myeloma, biopsy-confirmed cast nephropathy, and acute kidney injury that required dialysis from renal services in 16 hospitals in the UK and Germany. Patients were randomly assigned (1:1) by random number generation to receive intensive HCO-HD (in sessions lasting 6-8 h) or standard HF-HD and they were stratified by age and centre. Patients and the medical staff treating them were not masked to treatment allocation. Patients received bortezomib, doxorubicin, and dexamethasone chemotherapy, and were then followed up for 2 years. The primary outcome was independence from dialysis at 90 days after random allocation to groups, which was assessed in an intention-to-treat population. The trial has completed follow-up, and is registered at the ISRCTN registry, number ISRCTN45967602.

Findings: Between June 7, 2008, and Sept 18, 2013, we recruited 90 patients, of whom 43 (48%) were randomly assigned to receive HCO-HD and 47 (52%) were randomly assigned to receive HF-HD. All 90 patients were included in the analysis of the primary outcome. One (2%) patient from the HF-HD group withdrew consent before receiving treatment. During treatment, nine (21%) patients from the HCO-HD group and two (4%) patients in the HF-HD group discontinued trial treatment. After 90 days, 24 (56%) patients in the HCO-HD group and 24 (51%) patients in the HF-HD group were independent from dialysis (relative risk 1·09, 95% CI 0·74-1·61; p=0·81). During the 2-year follow-up, 98 serious adverse events were reported in the HCO-HD group and 82 serious adverse events were reported in the HF-HD group. The most common serious adverse events were infections and adverse events related to the cardiovascular and thrombotic and musculoskeletal systems. During the first 90 days, 26 infections were reported in the HCO-HD group and 13 infections were reported in the HF-HD group, including 14 lung infections in the HCO-HD group and three lung infections in the HF-HD group.

Interpretation: In this phase 2 study, HCO-HD did not improve clinical outcomes for patients with de novo multiple myeloma and myeloma cast nephropathy who required haemodialysis for acute kidney injury and who received a bortezomib-based chemotherapy regimen relative to those receiving HF-HD. These results do not support proceeding to a phase 3 study for HCO-HD in these patients.

Funding: Gambro, Janssen, and Binding Site.
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http://dx.doi.org/10.1016/S2352-3026(19)30014-6DOI Listing
April 2019

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis.

N Engl J Med 2019 01 26;380(5):447-458. Epub 2018 Oct 26.

From the Department of Renal Medicine, King's College Hospital (I.C.M., C.W.), and University College London (D.C.W.), London, Hull and East Yorkshire Hospitals NHS Trust and Hull York Medical School, Hull (S.B.), Lister Hospital, Stevenage (K.F.), and University of Hertfordshire, Hertfordshire (K.F.), the Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford (P.A.K.), the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (H.M., I.F.), University of Glasgow, Glasgow, Freeman Hospital, Newcastle upon Tyne (C.R.V.T.), and the Oxford Kidney Unit, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford (C.G.W.) - all in the United Kingdom; and the Division of Cardiology and Metabolism, Department of Cardiology, Berlin-Brandenburg Center for Regenerative Therapies, German Center for Cardiovascular Research partner site Berlin, Charité Universitätsmedizin Berlin, Berlin (S.D.A.).

Background: Intravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited.

Methods: In 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.

Results: A 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.

Conclusions: Among 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 .).
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http://dx.doi.org/10.1056/NEJMoa1810742DOI Listing
January 2019

Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data.

Am J Nephrol 2018 10;48(4):260-268. Epub 2018 Oct 10.

Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.

Background: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown.

Methods: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin < 400 µg/L and transferrin saturation (TSAT) levels < 30% receiving erythropoiesis-stimulating agents (ESA) were eligible. Enrolled patients were randomized to a proactive, high-dose IV iron arm (iron sucrose 400 mg/month unless ferritin > 700 µg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 µg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2-4 years.

Results: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry.

Conclusions: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice.

Trial Registration: EudraCT number: 2013-002267-25.
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http://dx.doi.org/10.1159/000493551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262676PMC
January 2020

Declining comorbidity-adjusted mortality rates in English patients receiving maintenance renal replacement therapy.

Kidney Int 2018 05 12;93(5):1165-1174. Epub 2018 Feb 12.

Medical Research Council Population Health Research Unit, Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK; Oxford Kidney Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Electronic address:

We aimed to compare long-term mortality trends in end-stage renal disease versus general population controls after accounting for differences in age, sex and comorbidity. Cohorts of 45,000 patients starting maintenance renal replacement therapy (RRT) and 5.3 million hospital controls were identified from two large electronic hospital inpatient data sets: the Oxford Record Linkage Study (1965-1999) and all-England Hospital Episode Statistics (2000-2011). All-cause and cause-specific three-year mortality rates for both populations were calculated using Poisson regression and standardized to the age, sex, and comorbidity structure of an average 1970-2008 RRT population. The median age at initiation of RRT in 1970-1990 was 49 years, increasing to 61 years by 2006-2008. Over that period, there were increases in the prevalence of vascular disease (from 10.0 to 25.2%) and diabetes (from 6.7 to 33.9%). After accounting for age, sex and comorbidity differences, standardized three-year all-cause mortality rates in treated patients with end-stage renal disease between 1970 and 2011 fell by about one-half (relative decline 51%, 95% confidence interval 41-60%) steeper than the one-third decline (34%, 31-36%) observed in the general population. Declines in three-year mortality rates were evident among those who received a kidney transplant and those who remained on dialysis, and among those with and without diabetes. These data suggest that the full extent of mortality rate declines among RRT patients since 1970 is only apparent when changes in comorbidity over time are taken into account, and that mortality rates in RRT patients appear to have declined faster than in the general population.
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http://dx.doi.org/10.1016/j.kint.2017.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912929PMC
May 2018

Biliary Tract and Liver Complications in Polycystic Kidney Disease.

J Am Soc Nephrol 2017 Sep 2;28(9):2738-2748. Epub 2017 May 2.

Clinical Trial Service Unit and Epidemiological Studies Unit, and

Polycystic liver disease is a well described manifestation of autosomal dominant polycystic kidney disease (ADPKD). Biliary tract complications are less well recognized. We report a 50-year single-center experience of 1007 patients, which raised a hypothesis that ADPKD is associated with biliary tract disease. We tested this hypothesis using all England Hospital Episode Statistics data (1998-2012), within which we identified 23,454 people with ADPKD and 6,412,754 hospital controls. Hospitalization rates for biliary tract disease, serious liver complications, and a range of other known ADPKD manifestations were adjusted for potential confounders. Compared with non-ADPKD hospital controls, those with ADPKD had higher rates of admission for biliary tract disease (rate ratio [RR], 2.24; 95% confidence interval [95% CI], 2.16 to 2.33) and serious liver complications (RR, 4.67; 95% CI, 4.35 to 5.02). In analyses restricted to those on maintenance dialysis or with a kidney transplant, RRs attenuated substantially, but ADPKD remained associated with biliary tract disease (RR, 1.19; 95% CI, 1.08 to 1.31) and perhaps with serious liver complications (RR, 1.15; 95% CI, 0.98 to 1.33). The ADPKD versus non-ADPKD RRs for biliary tract disease were larger for men than women (heterogeneity <0.001), but RRs for serious liver complications appeared higher in women (heterogeneity <0.001). Absolute excess risk of biliary tract disease associated with ADPKD was larger than that for serious liver disease, cerebral aneurysms, and inguinal hernias but less than that for urinary tract infections. Overall, biliary tract disease seems to be a distinct and important extrarenal complication of ADPKD.
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http://dx.doi.org/10.1681/ASN.2017010084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576944PMC
September 2017

A proposal for standardized grading of chronic changes in native kidney biopsy specimens.

Kidney Int 2017 04;91(4):787-789

Chronic changes represent an important component of native kidney biopsy evaluation and have a major bearing on predicting prognosis and guiding treatment. We propose here a uniform, semiquantitative approach to assessing such changes, which include glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis, and we report these findings as an overall chronicity grade.
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http://dx.doi.org/10.1016/j.kint.2017.01.002DOI Listing
April 2017

Long-term effects of lithium on renal function.

Lancet 2015 Nov 13;386(10007):1942-1943. Epub 2015 Nov 13.

Oxford Kidney Unit, Oxford University Hospitals, Old Road, Headington, Oxford OX3 7LE, UK.

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http://dx.doi.org/10.1016/S0140-6736(15)00831-4DOI Listing
November 2015

Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN.

J Am Soc Nephrol 2016 May 13;27(5):1278-87. Epub 2015 Nov 13.

Mayo Clinic, Rochester, Minnesota.

Renal pathologists and nephrologists met on February 20, 2015 to establish an etiology/pathogenesis-based system for classification and diagnosis of GN, with a major aim of standardizing the kidney biopsy report of GN. On the basis of etiology/pathogenesis, GN is classified into the following five pathogenic types, each with specific disease entities: immune-complex GN, pauci-immune GN, antiglomerular basement membrane GN, monoclonal Ig GN, and C3 glomerulopathy. The pathogenesis-based classification forms the basis of the kidney biopsy report. To standardize the report, the diagnosis consists of a primary diagnosis and a secondary diagnosis. The primary diagnosis should include the disease entity/pathogenic type (if disease entity is not known) followed in order by pattern of injury (mixed patterns may be present); score/grade/class for disease entities, such as IgA nephropathy, lupus nephritis, and ANCA GN; and additional features as detailed herein. A pattern diagnosis as the sole primary diagnosis is not recommended. Secondary diagnoses should be reported separately and include coexisting lesions that do not form the primary diagnosis. Guidelines for the report format, light microscopy, immunofluorescence microscopy, electron microscopy, and ancillary studies are also provided. In summary, this consensus report emphasizes a pathogenesis-based classification of GN and provides guidelines for the standardized reporting of GN.
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http://dx.doi.org/10.1681/ASN.2015060612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849835PMC
May 2016

Donor transmission of Cryptococcus neoformans presenting late after renal transplantation.

Clin Kidney J 2013 Apr;6(2):224-7

The Oxford Kidney Unit , Oxford University Hospitals NHS Trust , Oxford OX3 7LE , UK.

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http://dx.doi.org/10.1093/ckj/sft006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432446PMC
April 2013

Does prophylactic anticoagulation reduce the risk of femoral tunneled dialysis catheter-related complications.

J Vasc Access 2013 Apr-Jun;14(2):135-42. Epub 2012 Nov 14.

Oxford Kidney Unit, Churchill Hospital, Oxford University Hospitals NHS Trust, Headington, Oxford, UK.

Purpose: To determine the incidence and predictors of femoral tunneled dialysis catheter (TDC)-related complications and whether prophylactic anticoagulation is associated with reduced catheter-related deep vein thrombosis (CRT) or prolonged patency.

Methods: A retrospective review of femoral TDCs inserted for maintenance hemodialysis in patients from two dialysis units that have used two different strategies to reduce thrombotic complications. One center routinely considered all femoral TDCs for prophylactic anticoagulation, whilst the other restricted anticoagulation to TDCs that had required repeated treatment with urokinase locks to maintain patency. Survival analyses were performed to establish complication rates, identify predictors of complications and assess the effect of prophylactic anticoagulation use.

Results: Of the 194 femoral TDCs identified, 178 (92%) were associated with at least one complication. Approximately three quarters did not provide adequate small solute clearance; one half were not in use by three months; one quarter had at least one catheter-related infection (2.3 per 1000 catheter days); and one in ten developed a CRT (1.1 per 1000 catheter days). Prophylactic anticoagulation was not associated with significant improvements in rates of catheter occlusion, CRT, catheter-related infection or dialysis adequacy. A previous ipsilateral femoral TDC was identified as a statistically significant predictor of a CRT (adjusted hazard ratio 3.7 [95% confidence interval 1.4-9.8]; P=.007).

Conclusions: Femoral TDCs are associated with poor patency rates and high complication rates; reusing femoral veins for TDCs should be avoided where possible, and this study provides no evidence to support routine prophylactic anticoagulation in all patients with femoral TDCs.
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http://dx.doi.org/10.5301/jva.5000117DOI Listing
March 2014

Myeloma kidney: improving clinical outcomes?

Adv Chronic Kidney Dis 2012 Sep;19(5):342-51

Oxford Kidney Unit, Churchill Hospital, Oxford, United Kingdom.

Renal impairment is a common complication of multiple myeloma, affecting 20% to 40% of new cases (depending on the definition). Most cases are mild and easily reversible, but it may manifest as severe acute renal injury requiring dialysis. Renal impairment is associated with a large tumor mass and consequently confers a poor prognosis. The prognosis of myeloma has improved with the introduction of novel agents and autologous stem cell transplantation. These improvements appear to apply equally to patients with renal impairment, although the risk of complication is usually higher in this group of patients. In addition to improved overall survival, there is some evidence that novel therapies have improved the renal prognosis. Treatment with high-dose dexamethasone and bortezomib can rapidly reduce light chain production and provide an opportunity for renal recovery. Although trials of plasma exchange (to remove the nephrotoxic light chain) have shown a disappointing lack of benefit, high cutoff dialysis removes larger quantities of light chain; therefore, trials are underway to investigate whether this can improve the renal prognosis independently of chemotherapy. Outcomes in patients with myeloma kidney do appear to be improving, but more trials are needed (some of which are in progress). There is cause for optimism for physicians and for patients suffering from this condition.
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http://dx.doi.org/10.1053/j.ackd.2012.03.001DOI Listing
September 2012

Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing.

J Am Soc Nephrol 2012 May 1;23(5):915-33. Epub 2012 Mar 1.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.

Mutations in two large multi-exon genes, PKD1 and PKD2, cause autosomal dominant polycystic kidney disease (ADPKD). The duplication of PKD1 exons 1-32 as six pseudogenes on chromosome 16, the high level of allelic heterogeneity, and the cost of Sanger sequencing complicate mutation analysis, which can aid diagnostics of ADPKD. We developed and validated a strategy to analyze both the PKD1 and PKD2 genes using next-generation sequencing by pooling long-range PCR amplicons and multiplexing bar-coded libraries. We used this approach to characterize a cohort of 230 patients with ADPKD. This process detected definitely and likely pathogenic variants in 115 (63%) of 183 patients with typical ADPKD. In addition, we identified atypical mutations, a gene conversion, and one missed mutation resulting from allele dropout, and we characterized the pattern of deep intronic variation for both genes. In summary, this strategy involving next-generation sequencing is a model for future genetic characterization of large ADPKD populations.
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http://dx.doi.org/10.1681/ASN.2011101032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338301PMC
May 2012

Survival after starting renal replacement treatment in patients with autosomal dominant polycystic kidney disease: a single-centre 40-year study.

Nephron Clin Pract 2012 23;120(1):c42-7. Epub 2011 Dec 23.

Oxford Kidney Unit, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.

Background/aims: Adult polycystic kidney disease (ADPKD) has a predictable natural history and the relative lack of co-morbidity allows a relatively unconfounded assessment of survival. We examined whether survival on renal replacement treatment (RRT) has improved over the last four decades compared to that in the general population.

Methods: We conducted a retrospective cohort study of all patients with ADPKD who received RRT between 1971 and 2000 at the Oxford Kidney Unit. The main exposure was period of start of treatment (1971-1985 vs. 1986-2000) and the key outcome was overall survival. Standard Cox regression techniques were used to assess the association between these baseline variables and survival.

Results: Age at start of RRT (HR per 1 year 1.08; 95% CI 1.06-1.10) and presence of a functioning transplant (HR 0.22; 95% CI 0.16-0.31) were associated with improved survival in unadjusted analyses. After adjustment for age the period of treatment also became a significant predictor of overall survival (HR 0.67; 95% CI 0.47-0.97).

Conclusions: Survival on RRT appears to have improved and exceeds that observed in the general population, such that RRT now provides almost two-thirds of the life expectancy of the general population, compared to about half in earlier decades.
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http://dx.doi.org/10.1159/000334429DOI Listing
September 2012

An observational cohort study of extended dosing (once every 2 weeks or once monthly) regimens with darbepoetin alfa in patients with chronic kidney disease not on dialysis: the EXTEND study.

Nephrol Dial Transplant 2012 Jun 2;27(6):2303-11. Epub 2011 Dec 2.

Klinik für Nephrologie und Dialyseverfahren, Klinikum Lüdenscheid, Lüdenscheid, Germany.

Background: Darbepoetin alfa (DA) has been shown to be an effective treatment of anaemia in patients with chronic kidney disease (CKD) not on dialysis (NoD). EXTEND is an observational study assessing the effectiveness of DA administered once biweekly (Q2W) or monthly (QM) in a general CKD-NoD population.

Methods: Adult CKD-NoD patients starting DA Q2W/QM treatment in June 2006 or later were eligible. Retrospective and/or prospective data including haemoglobin levels and erythropoiesis-stimulating agent (ESA) dosing were collected for 6 months before and 12 months after DA initiation. Mean Hb levels were calculated every 3 months, and ESA dose was converted to a geometric mean weekly DA equivalent dose and summarized monthly.

Results: Data from 4278 patients showed that patients receiving ESA treatment before DA Q2W/QM initiation had a mean (95% confidence interval) Hb level of 11.9 g/dL (11.8-12.0 g/dL) at initiation and 11.6 g/dL (11.6-11.7 g/dL) at Months 10-12, with mean ESA dose of 22 μg/week (21-23 μg/week) prior to initiation, 16 μg/week (15-16 μg/week) at initiation and 16 μg/week (15-16 μg/week) at Month 12. In ESA-naive patients, Hb levels increased from 10.3 g/dL (10.2-10.3 g/dL) at initiation to 11.7 g/dL at Months 4-6 and were maintained at a mean level of 11.7 g/dL (11.7-11.8 g/dL) at Months 10-12, with mean ESA dose of 16 μg/week (16-17 μg/week) at initiation and 16 μg/week (16-17 μg/week) at Month 12. In the 85% of patients receiving DA at extended intervals (Q2W or less frequently) at Month 12, 12 patients (0.3%) experienced DA-related adverse reactions.

Conclusion: DA Q2W/QM was an effective treatment of anaemia in the general CKD-NoD patient population and a dose increase was not required in patients switching from a previous ESA regimen.
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http://dx.doi.org/10.1093/ndt/gfr677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3363980PMC
June 2012

Classification of chronic kidney disease in the elderly: pitfalls and errors.

Nephron Clin Pract 2011 10;119 Suppl 1:c2-4. Epub 2011 Aug 10.

Oxford Kidney Unit, The Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK.

The average glomerular filtration rate (GFR) is lower in the elderly than in the young and is usually a consequence of biological ageing, the rate of which varies between individuals. In some subjects, the decline is aggravated by concomitant vascular disease. The prevalence of significant kidney disease in the elderly has been overestimated - largely by rendering a diagnosis of chronic kidney disease by reference to estimates of GFR which are found in the young. A stable low GFR in the elderly, provided it is physiologically sufficient to meet homeostatic demands, is not a disease per se and seldom progresses to true kidney failure. However, it can be a risk factor for acute kidney injury drug misdosing, and possibly cardiovascular disease, so it should be noted.
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http://dx.doi.org/10.1159/000328013DOI Listing
December 2011

Simultaneous necrotizing glomerulonephritis and Hodgkin's lymphoma: a case report and review of the literature.

Nephrol Dial Transplant 2011 Oct 21;26(10):3403-8. Epub 2011 Jul 21.

Oxford Kidney Unit, Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK.

Glomerulonephritis occurs in 1% of Hodgkin's lymphoma patients. In the even rarer setting of rapidly progressive glomerulonephritis, lymphoma may go unrecognized. We describe a case of necrotizing glomerulonephritis in which treatment with cyclophosphamide and steroids led to resolution of lymphadenopathy. Two years later, recrudescent lymphadenopathy was shown to be Hodgkin's lymphoma, but renal disease did not recur.
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http://dx.doi.org/10.1093/ndt/gfr394DOI Listing
October 2011

Late presentation of patients with end-stage renal disease for renal replacement therapy--is it always avoidable?

Nephrol Dial Transplant 2011 Nov 31;26(11):3646-51. Epub 2011 Mar 31.

Richard Bright Renal Unit, Southmead Hospital, Bristol, UK.

Background: Twenty-five to 30% of new renal replacement therapy (RRT) patients present late to renal services. The proportion in whom this is avoidable, and whether awareness of chronic kidney disease (CKD) has reduced its incidence is not known.

Methods: Adult patients starting RRT (2003-2008) in a single unit were grouped according to the time interval between first presentation to the unit and start of RRT: <90 days (late presenters); 90-364 days; ≥ 365 days. 'Late presenters' were classified as follows: acute kidney injury--patients who had acute but irreversible renal failure; 'avoidable' late referrals, if they had known pre-existing CKD and 'unavoidable' late referrals, if they had unpredictable rapid progression of their CKD or had no prior contact with health care. Mortality risk associated with late presentation was explored using multivariable Cox regression.

Results: Late presentation was common (24.3%) but late referrals accounted for only 7.4% and 3.9% were avoidable. The incidence of late referrals decreased from 9.2% in 2003-2005 to 5.5% in 2006-2008 (trend P = 0.07). Late presentation was associated with increased mortality after adjusting for comorbidity, transplantation and permanent vascular access, and the majority of late presenters died due to malignancy or withdrawal of RRT.

Conclusions: The lower incidence of late referrals and the falling trend could be due to implementation of automated estimated glomerular filtration rate reporting and the increased awareness of CKD in primary care. Future prospective studies are needed to examine the extent to which frailty contributes to this mortality risk.
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http://dx.doi.org/10.1093/ndt/gfr164DOI Listing
November 2011

Association of long-term administration of the survivin mRNA-targeted antisense oligonucleotide LY2181308 with reversible kidney injury in a patient with metastatic melanoma.

Am J Kidney Dis 2011 Feb 21;57(2):300-3. Epub 2010 Dec 21.

Churchill Hospital, Oxford, UK.

A 57-year-old man with metastatic melanoma was treated with the survivin inhibitor and antisense oligonucleotide LY2181308 as part of a First-in-Human Dose trial. After 18 months of treatment, he developed kidney injury and the treatment was discontinued. At 9 months and before the development of kidney injury, LY2181308 concentrations were 8- to 10-fold higher relative to median predicted values, but within the targeted exposure considered to be safe. However, at 17 months, 28 days after stopping LY2181308 therapy, LY2181308 concentration exceeded the predicted range by 38-fold. His decreased kidney function was slow to improve after stopping treatment. A kidney biopsy showed signs of acute tubular injury with regeneration. Complete recovery of kidney function occurred 6 months after treatment was stopped. The relationship between high exposures and slow LY2181308 clearance with the gradual improvement in kidney function after stopping the antisense treatment suggests that the oligonucleotide was related to the kidney injury. Based on this case report, kidney function should be monitored frequently in patients receiving long-term treatment with antisense oligonucleotides that specifically target survivin, particularly when they receive concomitant angiotensin-converting enzyme inhibitors or nonsteroidal anti-inflammatory drugs.
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http://dx.doi.org/10.1053/j.ajkd.2010.09.024DOI Listing
February 2011

Genetic variation of DKK3 may modify renal disease severity in ADPKD.

J Am Soc Nephrol 2010 Sep 8;21(9):1510-20. Epub 2010 Jul 8.

Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.

Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/beta-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations.
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http://dx.doi.org/10.1681/ASN.2010030237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013521PMC
September 2010

Screening strategies for CKD.

Nephrol Dial Transplant 2010 Sep 21;25(9):3126-7; author reply 3127-9. Epub 2010 Jun 21.

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http://dx.doi.org/10.1093/ndt/gfq335DOI Listing
September 2010

Presentation and survival of patients with severe acute kidney injury and multiple myeloma: a 20-year experience from a single centre.

Nephrol Dial Transplant 2010 Feb 19;25(2):419-26. Epub 2009 Sep 19.

Oxford Kidney Unit, Churchill Hospital, Oxford, UK.

Background: Myeloma is the second most common haematological malignancy and is a cause of severe acute kidney injury (serum creatinine >or=500 micromol/L) that has long been associated with a poor prognosis, although previous series have been small.

Methods: We have therefore documented the natural history of all 107 patients referred to a large regional renal unit over a 20-year period and investigated factors associated with survival over a long period of time using Cox regression methods.

Results: Three factors were found to be significantly and independently associated with survival: use of chemotherapy [hazard ratio (HR) 0.21, 95% CI: 0.08-0.46, P < 0.001], serum albumin (HR 0.49, 95% CI: 0.29-0.82, P = 0.02 for >or=35 g/L versus <35 g/L) and dialysis independence (HR 0.43, 95% CI: 0.24-0.76, P = 0.005). However, survival was not found to be better for patients presenting in the second decade compared to the first (HR 0.88, 95% CI: 0.52-1.50, P = 0.65).

Conclusions: This analysis highlights the need for clinical trials of novel chemotherapy regimens in this complicated group of patients. Furthermore, whether strategies to restore or preserve dialysis-independent renal function provide additional benefit to effective chemotherapy also requires further investigation. The advent of efficacious low toxicity chemotherapy (such as thalidomide and bortezomib) and new dialysis techniques to remove free light chains may radically alter the outcome of this group of patients.
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http://dx.doi.org/10.1093/ndt/gfp488DOI Listing
February 2010

eGFR: Readjusting its rating.

Clin J Am Soc Nephrol 2009 May;4(5):867-9

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http://dx.doi.org/10.2215/CJN.01830309DOI Listing
May 2009

Dissecting and refining the staging of chronic kidney disease.

Kidney Int 2009 May 25;75(10):1009-14. Epub 2009 Feb 25.

Oxford Kidney Unit, The Churchill, Oxford Radcliffe Hospitals NHS Trust, University of Oxford, Headington, Oxford, UK.

The current Kidney Disease Outcomes Quality Initiative (KDOQI) staging system of chronic kidney disease (CKD) is simple but too rigid to accommodate variations in renal function observed in the general population. The formula most commonly used to estimate renal function is not validated in subjects without a priori evidence of renal disease. Their combined use results in inappropriate diagnosis of CKD and improbable estimates of prevalence rates. Although this initiative has raised the profile of kidney disease, the exaggeration of the scope of the problem could distract nephrologists from their specialist role. The nephrology community needs a revised staging system for CKD that allows accurate, effective, and timely communication with patients, primary care doctors, public health physicians, and policy makers. Its single most important function will be to identify those patients who will benefit from targeted screening and effective and safe interventions. We offer for discussion a modified definition and staging system of CKD based on the presence of unequivocal, irreversible structural kidney disease, the presence or degree of impairment of kidney function, and the consequences thereof.
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http://dx.doi.org/10.1038/ki.2009.49DOI Listing
May 2009

Reassuring results with regard to the effect of donor nephrectomy on cardiovascular outcomes.

Nat Clin Pract Nephrol 2009 Mar 20;5(3):126-7. Epub 2009 Jan 20.

University of Oxford, Clinical Trial Service Unit, Oxford, UK.

This article discusses the conclusions of a retrospective cohort study reported by Garg et al. on behalf of the Donor Nephrectomy Outcomes Research (DONOR) Network. This study compared the incidence of cardiovascular events in a cohort of kidney donors with that in a matched control population, to establish whether living kidney donation is associated with increased cardiovascular risk. Garg et al. found that living kidney donors had a very low risk of death or cardiovascular events that was not significantly different to that of the control population (2.0 vs 2.7 events per 1,000 person-years; hazard ratio 0.7, 95% CI 0.4-1.2). During follow-up, hypertension was diagnosed more frequently among donors than controls, but this finding might reflect the close monitoring of donors. Although the study provides reassuring information for counseling potential kidney donors, the sample of patients was not sufficiently large to resolve uncertainties over the influence of reduced kidney function on the risk of cardiovascular disease.
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http://dx.doi.org/10.1038/ncpneph1035DOI Listing
March 2009

Chronic kidney disease in Taiwan.

Lancet 2008 Dec;372(9654):1949-50; author reply 1950-1

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http://dx.doi.org/10.1016/S0140-6736(08)61835-8DOI Listing
December 2008

Routine reporting of estimated glomerular filtration rate: not ready for prime time.

Nat Clin Pract Nephrol 2008 Aug 1;4(8):422-3. Epub 2008 Jul 1.

David Geffen School of Medicine at UCLA, Los Angeles, CA , USA.

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http://dx.doi.org/10.1038/ncpneph0860DOI Listing
August 2008

In the wake of progress--ethical problems of renal failure treated by dialysis.

Clin Med (Lond) 2006 Jan-Feb;6(1):76-80

Oxford Kidney Unit, Churchill Hospital.

The ability of dialysis in the 1960s to prolong the lives of patients with terminal renal failure created a running and changing debate in bioethics. The first issue was the selection of suitable individuals to be treated in the limited facilities available. Progress in technology was ahead of any medical or ethical consensus. The costs of treatment soon exceeded the will or means of health funders to pay, creating a system of covert rationing and fiscal fudges with which physicians reluctantly colluded. Evidence, epidemiology and public opinion eventually prevailed and the UK now provides a satisfactory, if imperfect, programme of renal replacement therapy (RRT) for most patients with end-stage renal failure who can benefit. The ethical challenges in developed countries are now different and relate to end of life decisions. In poorer countries the issues are starker as treatment has to be rationed or provided only for those who can afford it.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954439PMC
http://dx.doi.org/10.7861/clinmedicine.6-1-76DOI Listing
August 2007
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