Publications by authors named "Paul Cockwell"

147 Publications

Acute kidney injury is more common in men than women after accounting for socioeconomic status, ethnicity, alcohol intake and smoking history.

Biol Sex Differ 2021 Apr 8;12(1):30. Epub 2021 Apr 8.

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2GW, UK.

Background: The association of several comorbidities, including diabetes mellitus, hypertension, cardiovascular disease, heart failure and chronic kidney or liver disease, with acute kidney injury (AKI) is well established. Evidence on the effect of sex and socioeconomic factors are scarce. This study was designed to examine the association of sex and socioeconomic factors with AKI and AKI-related mortality and further to evaluate the additional relationship with other possible risk factors for AKI occurrence.

Methods: We included 3534 patients (1878 males with mean age 61.1 ± 17.7 and 1656 females 1656 with mean age 60.3 ± 20.0 years) admitted to Queen Elizabeth or Heartlands Hospitals, Birmingham, between October 2013 and January 2016. Patients were prospectively followed-up for a median 47.70 [IQR, 18.20] months. Study-endpoints were incidence of AKI, based on KDIGO-AKI Guidelines, and all-cause mortality. Data acquisition was automated, and information on mortality was collected from the Hospital Episode Statistics and Office of National Statistics. Socioeconomic status was evaluated with the Index of Multiple Deprivation (IMD).

Results: Incidence of AKI was higher in men compared to women (11.3% vs 7.1%; P < 0.001). Model regression analysis revealed significant association of male sex with higher AKI risk (OR, 1.659; 95% CI, 1.311-2.099; P < 0.001); this association remained significant after adjustment for age, eGFR, IMD, smoking, alcohol consumption, ethnicity, existing comorbidities and treatment (OR, 1.599; 95% CI, 1.215-2.103; P = 0.001). All-cause mortality was higher in patients with compared to those without AKI. Males with AKI had higher mortality rates in the first 6-month and 1-year periods after the index AKI event. The association of male sex with mortality was independent of socioeconomic factors but was not statistically significant after adjustment for existing comorbidities.

Conclusions: Men are at higher risk of AKI and this association is independent from existing risk factors for AKI. The association between male sex and AKI-related mortality was not independent from existing comorbidities. A better understanding of factors associated with AKI may help accurately identify high-risk patients.
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http://dx.doi.org/10.1186/s13293-021-00373-4DOI Listing
April 2021

Kidney injury and disease in patients with haematological malignancies.

Nat Rev Nephrol 2021 Mar 30. Epub 2021 Mar 30.

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

Acute kidney injury (AKI) is common in patients with cancer, especially in those with haematological malignancies. Kidney injury might be a direct consequence of the underlying haematological condition. For example, in the case of lymphoma infiltration or extramedullary haematopoiesis, it might be caused by a tumour product; in the case of cast nephropathy it might be due to the presence of monoclonal immunoglobulin; or it might result from tumour complications, such as hypercalcaemia. Kidney injury might also be caused by cancer treatment, as many chemotherapeutic agents are nephrotoxic. High-intensity treatments, such as high-dose chemotherapy followed by haematopoietic stem cell transplantation, not only increase the risk of infection but can also cause AKI through various mechanisms, including viral nephropathies, engraftment syndrome and sinusoidal obstruction syndrome. Some conditions, such as thrombotic microangiopathy, might also result directly from the haematological condition or the treatment. Novel immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cell therapy, can also be nephrotoxic. As new therapies for haematological malignancies with increased anti-tumour efficacy and reduced toxicity are developed, the number of patients receiving these treatments will increase. Clinicians must gain a good understanding of the different mechanisms of kidney injury associated with cancer to better care for these patients.
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http://dx.doi.org/10.1038/s41581-021-00405-7DOI Listing
March 2021

Imbalanced turnover of collagen type III is associated with disease progression and mortality in high-risk chronic kidney disease patients.

Clin Kidney J 2021 Feb 14;14(2):593-601. Epub 2020 Jan 14.

College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Background: Tubulointerstitial fibrosis is a major pathological feature in chronic kidney disease (CKD) and collagen type III (COL3) is a major component of the renal fibrotic scar. We hypothesized that a dysregulated turnover of COL3 is an important determinant of CKD progression. We assessed the relationship between fragments reflecting active formation (PRO-C3) and degradation (C3M) of COL3 and CKD disease progression and mortality in a prospective cohort of CKD patients.

Methods: We measured PRO-C3 and C3M in urine (uPRO-C3 and uC3M) and serum (sPRO-C3 and sC3M) of 500 patients from the Renal Impairment in Secondary Care study. Disease progression was defined as a decline in estimated glomerular filtration rate >30% or the start of renal replacement therapy within 12 and 30 months.

Results: Levels of uC3M/creatinine decreased, whereas levels of uPRO-C3/creatinine and sPRO-C3 increased with increasing CKD stage. uC3M/creatinine was inversely and independently associated with disease progression by 12 months {odds ratio [OR] 0.39 [95% confidence interval (CI) 0.18-0.83]; P = 0.01 per doubling of uC3M/creatinine} with development of end-stage renal disease [hazard ratio (HR) 0.70 (95% CI 0.50-0.97); P = 0.03 per doubling of uC3M/creatinine]. sPRO-C3 at baseline was independently associated with increased mortality [HR 1.93 (95% CI 1.21-3.1); P = 0.006 per doubling of sPRO-C3] and disease progression by 30 months [OR 2.16 (95% CI 1.21-3.84); P = 0.009 per doubling of sPRO-C3].

Conclusions: Dynamic products of COL3 formation and degradation were independently associated with CKD progression and mortality and may represent an opportunity to link pathological processes with targeted treatments against fibrosis.
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http://dx.doi.org/10.1093/ckj/sfz174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886548PMC
February 2021

The urgent need to vaccinate dialysis patients against severe acute respiratory syndrome coronavirus 2: a call to action.

Kidney Int 2021 04 12;99(4):791-793. Epub 2021 Feb 12.

Division of Medicine, George Institute for Global Health India, University of New South Wales, New Delhi, India; Division of Medicine, School of Public Health, Imperial College, London, UK; Division of Medicine, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India.

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http://dx.doi.org/10.1016/j.kint.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879104PMC
April 2021

The effect of admission and pre-admission serum creatinine as baseline to assess incidence and outcomes of acute kidney injury in acute medical admissions.

Nephrol Dial Transplant 2021 Jan 17. Epub 2021 Jan 17.

Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, Birmingham, UK.

Background: Acute kidney injury (AKI) in hospital-admitted patients is a common complication associated with increased mortality. The diagnosis of AKI relies on the ascertainment of peak increase in serum creatinine (SCr). This study evaluated the incidence of AKI using the increase from mean 7-365 days pre-admission (AKIpre) and admission (AKIadm) SCr levels, and examined the associations of AKI and changes in SCr levels with all-cause mortality.

Methods: A total of 2436 patients admitted to a tertiary hospital were recruited and followed-up for a median of 47.70 (interquartile range 18.20) months. AKI incidence and severity were defined according to the Kidney Disease: Improving Global Outcomes-AKI Guidelines. Follow-up data were collected from the Hospital Episode Statistics and Office of National Statistics. Mortality was evaluated during a short- (30 days), mid- (1 year) and long-term (4 years) period.

Results: No difference in the AKI rates using AKIpre and AKIadm (12.5% versus 12.2%; P = 0.695) or in the AKI severity (P = 0.261) was evident. Agreement between the two definitions was modest (Kappa-statistic = 0.596, P < 0.001). Patients with AKIpre or AKIadm had increased all-cause mortality compared with those without AKI during all follow-up periods. In fully adjusted regression analysis, AKIpre [hazard ratio (HR) = 2.226, 95% confidence interval (CI) 1.140-4.347; P = 0.027] and AKIadm (HR = 2.105, 95% CI 1.090-4.064; P = 0.027) remained associated with 30-day mortality. Results for the 1- and 4-year periods were similar. Increases of >4.00 μmol/L and >6.06% from pre-admission or >6.00 μmol/L and >17.24% from admission SCr levels presented increased mortality risk during follow-up.

Conclusions: Use of admission or pre-admission SCr provides similar incidence rates, but they diagnose different sets of patients. Even minor increases in SCr, below those required for the classification of AKI, were associated with increased mortality. These findings can help the clinicians to identify patients at higher risk for adverse outcomes.
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http://dx.doi.org/10.1093/ndt/gfaa333DOI Listing
January 2021

Oxidative stress links periodontal inflammation and renal function.

J Clin Periodontol 2021 Mar 28;48(3):357-367. Epub 2021 Jan 28.

Periodontal Research Group, School of Dentistry, University of Birmingham and Birmingham Community Healthcare Trust, Birmingham, UK.

Aims: Patients with chronic kidney disease (CKD) are also susceptible to periodontitis. The causal link between periodontitis and CKD may be mediated via systemic inflammation/oxidative stress. Using structural equation modelling (SEM), this cross-sectional study aimed to explore the causal relationship between periodontal inflammation (PI) and renal function.

Materials And Methods: Baseline data on 770 patients with stage 3-5 (pre-dialysis) CKD from an ongoing cohort study were used. Detailed, bioclinical data on PI and renal function, as well as potential confounders and mediators of the relationship between the two, were collected. SEMs of increasing complexity were created to test the causal assumption that PI affects renal function and vice versa.

Results: Structural equation modelling confirmed the assumption that PI and renal function are causally linked, mediated by systemic oxidative stress. The magnitude of this effect was such that a 10% increase in PI resulted in a 3.0% decrease in renal function and a 10% decrease in renal function resulted in a 25% increase in PI.

Conclusions: Periodontal inflammation represents an occult source of oxidative stress in patients with CKD. Further clinical studies are needed to confirm whether periodontal therapy, as a non-pharmacological approach to reducing systemic inflammatory/oxidative stress burden, can improve outcomes in CKD.
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http://dx.doi.org/10.1111/jcpe.13414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986430PMC
March 2021

Renal outcome in patients with newly diagnosed multiple myeloma: results from the UK NCRI Myeloma XI trial.

Blood Adv 2020 11;4(22):5836-5845

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

Renal injury is a common complication of multiple myeloma (MM) and is associated with adverse outcome. Despite this, the natural history of renal injury in patients with MM remains uncertain especially in the context of intensive therapy and novel therapies. To address the lack of data, we evaluated the renal function of 2334 patients from the UK National Cancer Research Institute Myeloma XI trial at baseline and at 12 months to assess renal function over time and the factors associated with change. Patients who had severe acute kidney injury or a requirement for dialysis were excluded. At 12 months of the 1450 evaluable patients planned for autologous transplantation; 204 (14%) patients had a decline in estimated glomerular filtration rate (eGFR) ≥25% from baseline, 341 (23.5%) had an improvement and 905 (62%) had no significant change in eGFR. Renal outcome at 12 months for the 884 evaluable patients who were not planned for transplant was similar. Improved renal function was more likely if patients were <70 years old, male, had an average eGFR <60 mL per minute per 1.73 m2 and a higher baseline free light chain level >1000 mg/L, and/or a free light chain response of >90%. It did not correlate with monoclonal-protein response, transplantation, or use of a bortezomib-based regimen. We show that with current therapies the proportion of patients who have a significant decline in renal function in the first 12 months is small. The greatest relative improvement in eGFR is seen in patients with high free light chain at baseline and a high light chain response. This trial was registered at http://www.isrctn.com as #49407852.
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http://dx.doi.org/10.1182/bloodadvances.2020002872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686889PMC
November 2020

Development of an electronic patient-reported outcome measure (ePROM) system to aid the management of patients with advanced chronic kidney disease.

J Patient Rep Outcomes 2020 Jul 8;4(1):55. Epub 2020 Jul 8.

University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

Background: Effective management of patients with chronic kidney disease (CKD) relies on timely detection of clinical deterioration towards end stage kidney failure. We aimed to design an electronic Patient-Reported Outcome Measure (ePROM) system, which would allow patients with advanced CKD (pre-dialysis) to: (i) remotely self-report their symptoms using a simple and secure online platform; (ii) share the data with the clinical team in real-time via the electronic patient record to help optimise care. We adopted a staged development process which included: a systematic review of PROMs used in CKD; formation of a co-design team; prototype system design/development, user acceptance testing and refinement; finalisation of the system for testing in a pilot/feasibility trial.

Results: A co-design team was convened, including patients with lived experience of CKD; clinical team members; IT/Informatics experts; academics; and Birmingham Clinical Trials Unit representatives. A prototype system was developed and iterative changes made before finalisation during a series of operational meetings. The system allows patients to remotely self-report their symptoms; provides tailored self-management advice; allows monitoring of real-time patient ePROM data; sends automated notifications to the patient/clinical team in the advent of a severe symptom report; and incorporates longitudinal ePROM symptom data into the electronic patient record. Feasibility of the system will be evaluated as part of the National Institute for Health Research funded RePROM (Renal electronic Patient-Reported Outcome Measure) pilot trial (ISRCTN12669006).

Conclusions: Routine ePROM collection with real-time feedback has the potential to improve outcomes and reduce health service costs. We have successfully developed a trial-ready ePROM system for advanced CKD, the feasibility of which is currently being explored in a pilot trial. Assuming feasibility is demonstrated, formal evaluation of efficacy will take place in a future multi-centre randomised controlled trial.
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http://dx.doi.org/10.1186/s41687-020-00223-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343684PMC
July 2020

Optimal management of acute kidney injury in critically ill patients with invasive fungal infections being treated with liposomal amphotericin B.

BMJ Case Rep 2020 May 12;13(5). Epub 2020 May 12.

Department of Nephrology, Queen Elizabeth Hospital Birmingham, Birmingham, UK

Critically ill patients are at risk of developing both acute kidney injury (AKI) and invasive fungal infections (IFIs). Prompt and efficient treatment of the IFI is essential for the survival of the patient. This article examines three distinct clinical situations where liposomal amphotericin B, a broad-spectrum antifungal agent, was successfully used in the setting of AKI. The first was infection in a 63-year-old man with bleeding oesophageal varices related to advanced liver disease. The second was gastrointestinal mucormycosis in a 74-year-old man who developed a small bowel obstruction following an autologous stem cell transplant for mantle cell lymphoma. The third was a infection in a 32-year-old woman on immunosuppression for a bilateral lung transplant for cystic fibrosis. In all three cases, liposomal amphotericin B was required for urgent management of the patient's IFI. We discuss the rationale for treatment with a potentially nephrotoxic agent in this setting.
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http://dx.doi.org/10.1136/bcr-2019-233072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228453PMC
May 2020

The impact of chronic kidney disease on developed countries from a health economics perspective: A systematic scoping review.

PLoS One 2020 24;15(3):e0230512. Epub 2020 Mar 24.

Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.

Chronic kidney disease (CKD) affects over 10% of the global population and poses significant challenges for societies and health care systems worldwide. To illustrate these challenges and inform cost-effectiveness analyses, we undertook a comprehensive systematic scoping review that explored costs, health-related quality of life (HRQoL) and life expectancy (LE) amongst individuals with CKD. Costs were examined from a health system and societal perspective, and HRQoL was assessed from a societal and patient perspective. Papers published in English from 2015 onward found through a systematic search strategy formed the basis of the review. All costs were adjusted for inflation and expressed in US$ after correcting for purchasing power parity. From the health system perspective, progression from CKD stages 1-2 to CKD stages 3a-3b was associated with a 1.1-1.7 fold increase in per patient mean annual health care cost. The progression from CKD stage 3 to CKD stages 4-5 was associated with a 1.3-4.2 fold increase in costs, with the highest costs associated with end-stage renal disease at $20,110 to $100,593 per patient. Mean EuroQol-5D index scores ranged from 0.80 to 0.86 for CKD stages 1-3, and decreased to 0.73-0.79 for CKD stages 4-5. For treatment with renal replacement therapy, transplant recipients incurred lower costs and demonstrated higher HRQoL scores with longer LE compared to dialysis patients. The study has provided a comprehensive updated overview of the burden associated with different CKD stages and renal replacement therapy modalities across developed countries. These data will be useful for the assessment of new renal services/therapies in terms of cost-effectiveness.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230512PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092970PMC
June 2020

Post-transplant Monoclonal Gammopathy of Renal Significance: A Case Series.

Transplant Proc 2020 Apr 3;52(3):857-864. Epub 2020 Mar 3.

Department of Renal Medicine, University Hospitals Birmingham, Birmingham, United Kingdom.

Monoclonal gammopathy of renal significance (MGRS) is a new concept with evolving evidence for treatment. MGRS in the transplant kidney is a rare cause of renal transplant dysfunction that can lead to graft loss. Most cases of post-transplant MGRS are due to recurrent disease. Clone-specific chemotherapy is required to target the underlying clone, and this may improve graft survival; however, this can be challenging, as most patients are elderly with age-related comorbidities and may have complications associated with increasing immunosuppression. Here, we report 3 cases of renal allograft MGRS, and each case highlights different challenges in the diagnosis and management of this condition.
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http://dx.doi.org/10.1016/j.transproceed.2019.12.040DOI Listing
April 2020

Serum free light chain level at diagnosis in myeloma cast nephropathy-a multicentre study.

Blood Cancer J 2020 03 3;10(3):28. Epub 2020 Mar 3.

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

Myeloma cast nephropathy (MCN) is a common cause of severe renal impairment in multiple myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002-2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107-114600). Serum creatinine was 535 μmol/L (range 168-2993) and eGFR 7 ml/min/1.73 m (range 1-34). Six patients (5.8%) had an FLC level <1500 mg/L, which is the International Myeloma Working Group threshold for MCN and two patients were below the International Kidney and Monoclonal Gammopathy working group threshold of 500 mg/L; one was hypercalcaemic, and one had high-normal serum calcium level and had received a non-steroidal anti-inflammatory agent. Sixty-nine (67%) patients required haemodialysis treatment of whom 36 (52.1%) recovered independent renal function. Sixty-six (64%) patients died with a median OS of 2.5 years (95% CI 1.8-3.3). A landmark analysis revealed that independence from dialysis was associated with improved survival at 3-months (P = 0.003), 6-months (P = 0.035) and 9-months (P = 0.014); there was no survival benefit observed beyond 12 months (P = 0.146). Serum FLC level at diagnosis was neither associated with renal function recovery nor with OS. This is the largest reported cohort of patients with biopsy-confirmed MCN and prospectively measured serum FLC levels. These results indicate that a serum monoclonal FLC > 500 mg/L should be considered the threshold level associated with the development of MCN.
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http://dx.doi.org/10.1038/s41408-020-0295-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054310PMC
March 2020

Association between non-malignant monoclonal gammopathy and adverse outcomes in chronic kidney disease: A cohort study.

PLoS Med 2020 02 28;17(2):e1003050. Epub 2020 Feb 28.

University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

Background: In studies including the general population, the presence of non-malignant monoclonal gammopathy (MG) can be causally associated with kidney damage and shorter survival. We assessed whether the presence of an MG is associated with a higher risk of kidney failure or death in individuals with chronic kidney disease (CKD).

Methods And Findings: Data were used from 3 prospective cohorts of individuals with CKD (not on dialysis or with a kidney transplant): (1) Renal Impairment in Secondary Care (RIISC, Queen Elizabeth Hospital and Heartlands Hospital, Birmingham, UK, N = 878), (2) Salford Kidney Study (SKS, Salford Royal Hospital, Salford, UK, N = 861), and (3) Renal Risk in Derby (RRID, Derby, UK, N = 1,739). Participants were excluded if they had multiple myeloma or any other B cell lymphoproliferative disorder with end-organ damage. Median age was 71.0 years, 50.6% were male, median estimated glomerular filtration rate was 42.3 ml/min/1.73 m2, and median urine albumin-to-creatinine ratio was 3.4 mg/mmol. All non-malignant MG was identified in the baseline serum of participants of RIISC. Further, light chain MG (LC-MG) was identified and studied in participants of RIISC, SKS, and RRID. Participants were followed up for kidney failure (defined as the initiation of dialysis or kidney transplantation) and death. Associations with the risk of kidney failure were estimated by competing-risks regression (handling death as a competing risk), and associations with death were estimated by Cox proportional hazards regression. In total, 102 (11.6%) of the 878 RIISC participants had an MG. During a median follow-up time of 74.0 months, there were 327 kidney failure events and 202 deaths. The presence of MG was not associated with risk of kidney failure (univariable subhazard ratio [SHR] 0.97 [95% CI 0.68 to 1.38], P = 0.85; multivariable SHR 1.16 [95% CI 0.80 to 1.69], P = 0.43), and although there was a higher risk of death in univariable analysis (hazard ratio [HR] 2.13 [95% CI 1.49 to 3.02], P < 0.001), this was not significant in multivariable analysis (HR 1.37 [95% CI 0.93 to 2.00], P = 0.11). Fifty-five (1.6%) of the 3,478 participants from all 3 studies had LC-MG. During a median follow-up time of 62.5 months, 564 of the 3,478 participants progressed to kidney failure, and 803 died. LC-MG was not associated with risk of kidney failure (univariable SHR 1.07 [95% CI 0.58 to 1.96], P = 0.82; multivariable SHR 1.42 [95% CI 0.78 to 2.57], P = 0.26). There was a higher risk of death in those with LC-MG in the univariable model (HR 2.51 [95% CI 1.59 to 3.96], P < 0.001), but not in the multivariable model (HR 1.49 [95% CI 0.93 to 2.39], P = 0.10). An important limitation of this work was that only LC-MG, rather than any MG, could be identified in participants from SKS and RRID.

Conclusions: The prevalence of MG was higher in this CKD cohort than that reported in the general population. However, the presence of an MG was not independently associated with a significantly higher risk of kidney failure or, unlike in the general population, risk of death.
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http://dx.doi.org/10.1371/journal.pmed.1003050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048272PMC
February 2020

Acute kidney injury calculated using admission serum creatinine underestimates 30-day and 1-year mortality after acute stroke.

Clin Kidney J 2020 Feb 10;13(1):46-54. Epub 2019 May 10.

Department of Nephrology, University Hospitals Birmingham, Birmingham, UK.

Background: Acute kidney injury (AKI) diagnosis requires ascertainment of change from a known baseline. Although pre-admission serum creatinine (SCr) is recommended, to date, all studies of AKI in acute stroke have used the first SCr on admission.

Methods: All patients admitted with an acute stroke to an emergency hospital were recruited. We compared use of pre-admission SCr with admission SCr to diagnose AKI. Regression analyses were used to identify risk factors for 30-day and 1-year mortality, respectively.

Results: A total of 1354 patients were recruited from December 2012 to September 2015. Incidence of AKI was 18.7 and 19.9% using pre-admission SCr and admission SCr, respectively. Diagnosis of AKI was associated with significantly increased 30-day and 1-year mortality. Diagnosis of AKI using pre-admission SCr had a stronger relationship with both 30-day and 1-year mortality. In 443 patients with a pre-admission SCr and at least two SCr during admission, AKI diagnosed using pre-admission SCr had a stronger relationship than AKI diagnosed using admission SCr with 30-day mortality [odds ratio (OR) = 2.64; 95% confidence interval (CI) 1.36-5.12; P = 0.004 versus OR = 2.10; 95% CI 1.09-4.03; P = 0.026] and 1-year mortality [hazard ratio (HR) = 1.90, 95% CI 1.32-2.76; P = 0.001 versus HR = 1.47; 95% CI 1.01-2.15; P = 0.046] in fully adjusted models.

Conclusions: AKI after stroke is common and is associated with increased 30-day and 1-year mortality. Using first SCr on admission gives a comparable AKI incidence to pre-admission SCr, but underestimates 30-day and 1-year mortality risk.
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http://dx.doi.org/10.1093/ckj/sfz049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025354PMC
February 2020

The global burden of chronic kidney disease.

Lancet 2020 02 13;395(10225):662-664. Epub 2020 Feb 13.

University Hospital of the West Indies and University of West Indies, Kingston, Jamaica.

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http://dx.doi.org/10.1016/S0140-6736(19)32977-0DOI Listing
February 2020

Distribution of plasma oxidised phosphatidylcholines in chronic kidney disease and periodontitis as a co-morbidity.

Free Radic Biol Med 2020 01 20;146:130-138. Epub 2019 Oct 20.

Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, B4 7ET, UK. Electronic address:

Individuals with chronic kidney disease (CKD) and periodontitis as a co-morbidity have a higher mortality rate than individuals with CKD and no periodontitis. The inflammatory burden associated with both diseases contributes to an increased risk of cardiovascular and all-cause mortality. We previously demonstrated that periodontitis is associated with increasing circulating markers of inflammation and oxidative stress. We propose that inflammatory oxidised phosphocholines may contribute to the increased risk of cardiovascular disease in patients with CKD. However, the analysis of oxidised phospholipids has been limited by a lack of authentic standards for absolute quantification. Here, we have developed a comprehensive quantification liquid chromatography-mass spectrometry-based multiple reaction monitoring method for oxidised phospholipids (including some without available authentic species) that enables us to simultaneously measure twelve oxidised phosphatidylcholine species with high levels of sensitivity and specificity. The standard curves for commercial standards 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphatidylcholine (PGPC); 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphatidylcholine (PONPC), 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphatidylcholine (PAzPC) and 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphatidylcholine (POVPC), were linear with a correlation coefficient greater than 0.99 for all analytes. The method is reproducible, with intra- and inter-day precision <15%, and accuracy within ±5% of nominal values for all analytes. This method has been successfully applied to investigate oxidised phosphatidylcholine in plasma from CKD patients with and without chronic periodontitis and the data that was obtained has been compared to plasma from healthy controls. Comparative analysis demonstrates altered chain fragmented phosphatidylcholine profiles in the plasma samples of patients with CKD and periodontitis as a co-morbidity compared to healthy controls.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.10.012DOI Listing
January 2020

A collaborative, individual-level analysis compared longitudinal outcomes across the International Network of Chronic Kidney Disease (iNETCKD) cohorts.

Kidney Int 2019 11 30;96(5):1217-1233. Epub 2019 Aug 30.

Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Rates of chronic kidney disease (CKD) progression, end stage kidney disease (ESKD), all-cause mortality, and cardiovascular (CVD) events among individuals with CKD vary widely across countries. Well-characterized demographic, comorbidity, and laboratory markers captured for prospective cohorts may explain, in part, such differences. To investigate whether core characteristics of individuals with CKD explain differences in rates of outcomes, we conducted an individual-level analysis of eight studies that are part of iNET-CKD, an international network of CKD cohort studies. Overall, the rate of CKD progression was 40 events/1000 person-year (95% confidence interval 39 - 41), 28 (27 - 29) for ESKD, 41 (40 - 42) for death, and 29 (28 - 30) for CVD events. However, standardized rates were highly heterogeneous across studies (over 92.5%). Interactions by study group on the association between baseline characteristics and outcomes were then identified. For example, the adjusted hazard ratio for CKD progression was 0.44 (95% confidence interval 0.35 - 0.56) for women vs. men among the Japanese (CKD-JAC), while it was 0.66 (0.59 - 0.75) among the Uruguayan (NRHP). The adjusted hazard ratio for ESKD was 2.02 (95% CI 1.88 - 2.17) per 10 units lower baseline eGFR among Americans (CRIC), while it was 3.01 (2.57 - 3.53) among Canadians (CanPREDDICT) (significant interaction for comparisons across all studies). The risks of CKD progression, ESKD, death, and CVD vary across countries even after accounting for the distributions of age, sex, comorbidities, and laboratory markers. Thus, our findings support the need for a better understanding of specific factors in different populations that explain this variation.
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http://dx.doi.org/10.1016/j.kint.2019.07.024DOI Listing
November 2019

In Reply to 'A Psychiatrist's View on Patient-Reported Outcomes in Patients Undergoing Hemodialysis'.

Am J Kidney Dis 2019 11 19;74(5):711-712. Epub 2019 Sep 19.

Centre for Patient Reported Outcomes Research, University of Birmingham, and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

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http://dx.doi.org/10.1053/j.ajkd.2019.07.009DOI Listing
November 2019

Cross-sectional observation study to investigate the impact of risk-based stratification on care pathways for patients with chronic kidney disease: protocol paper.

BMJ Open 2019 06 9;9(6):e027315. Epub 2019 Jun 9.

Centre for Patient Reported Outcomes Research and Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

Introduction: Chronic kidney disease (CKD) management in the UK is usually primary care based, with National Institute for Health and Care Excellence (NICE) guidelines defining criteria for referral to secondary care nephrology services. Estimated glomerular filtration rate (eGFR) is commonly used to guide timing of referrals and preparation of patients approaching renal replacement therapy. However, eGFR lacks sensitivity for progression to end-stage renal failure; as a consequence, the international guideline group, Kidney Disease: Improving Global Outcomes has recommended the use of a risk calculator. The validated Kidney Failure Risk Equation may enable increased precision for the management of patients with CKD; however, there is little evidence to date for the implication of its use in routine clinical practice. This study will aim to determine the impact of the Kidney Failure Risk Equation on the redesignation of patients with CKD in the UK for referral to secondary care, compared with NICE CKD guidance.

Method And Analysis: This is a cross-sectional population-based observational study using The Health Improvement Network database to identify the impact of risk-based designation for referral into secondary care for patients with CKD in the UK. Adult patients registered in primary care and active in the database within the period 1 January 2016 to 31 March 2017 with confirmed CKD will be analysed. The proportion of patients who meet defined risk thresholds will be cross-referenced with the current NICE guideline recommendations for referral into secondary care along with an evaluation of urinary albumin-creatinine ratio monitoring.

Ethics And Dissemination: Approval was granted by The Health Improvement Network Scientific Review Committee (Reference number: 18THIN061). Study outcomes will inform national and international guidelines including the next version of the NICE CKD guideline. Dissemination of findings will also be through publication in a peer-reviewed journal, presentation at conferences and inclusion in the core resources of the Think Kidneys programme.
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http://dx.doi.org/10.1136/bmjopen-2018-027315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561412PMC
June 2019

Biological variation of measured and estimated glomerular filtration rate in patients with chronic kidney disease.

Kidney Int 2019 08 7;96(2):429-435. Epub 2019 Mar 7.

Clinical Biochemistry, East Kent Hospitals University NHS Foundation Trust, Canterbury, Kent, UK. Electronic address:

When assessing changes in glomerular filtration rate (GFR) it is important to differentiate pathological change from intrinsic biological and analytical variation. GFR is measured using complex reference methods (e.g., iohexol clearance). In clinical practice measurement of creatinine and cystatin C are used in the Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equations to provide estimated GFR. Here we studied the biological variability of measured and estimated GFR in twenty nephrology outpatients (10 male, 10 female; median age 71, range 50-80 years) with moderate CKD (GFR 30-59 ml/min per 1.73 m). Patients underwent weekly GFR measurement by iohexol clearance over four consecutive weeks. Simultaneously, GFR was estimated using the MDRD, CKD-EPI, CKD-EPI and CKD-EPI equations. Within-subject biological variation expressed as a percentage [95% confidence interval] for the MDRD (5.0% [4.3-6.1]), CKD-EPI (5.3% [4.5-6.4]), CKD-EPI (5.3% [4.5-6.5]), and CKD-EPI (5.0% [4.3-6.2]) equations were broadly equivalent. The within-subject biological variation for MDRD and CKD- EPI estimated GFR were each significantly lower than that of the measured GFR (6.7% [5.6-8.2]). Reference change values, the point at which a true change in a biomarker in an individual can be inferred to have occurred with 95% probability were calculated. By the MDRD equation, positive and negative reference change values were 15.1% and 13.1% respectively. If an individual's baseline MDRD estimated GFR (ml/min per 1.73 m) was 59, significant increases or decreases would be to values over 68 or under 51 respectively. Within-subject variability of estimated GFR was lower than measured GFR. Reference change values can be used to understand GFR changes in clinical practice. Thus, estimates of GFR are at least as reliable as measured GFR for monitoring patients over time.
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http://dx.doi.org/10.1016/j.kint.2019.02.021DOI Listing
August 2019

The Use of Patient-Reported Outcomes in Patients Treated With Maintenance Hemodialysis: A Perspective.

Am J Kidney Dis 2019 09 25;74(3):399-406. Epub 2019 Apr 25.

Centre for Patient Reported Outcomes Research, University of Birmingham, Birmingham, United Kingdom; Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, United Kingdom; NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, United Kingdom.

There is increasing interest in the integration of patient-reported outcomes (PROs) into health care research and clinical practice for the benefit of patients with end-stage kidney disease receiving hemodialysis. In a research setting, PROs can be used as a patient-centered primary or secondary outcome in clinical studies. In routine care, PRO data may be used to support service delivery through benchmarking and audit or inform and enhance the care of the individual patient by improving patient-clinician communication. Despite evidence demonstrating the potential benefits of PROs and prioritization of these outcomes by patients, their use in kidney disease remains limited. Although there are significant methodological and operational challenges for the widespread integration of PROs, there is now consensus that this area should be at the forefront of clinical research and implementation science. We discuss the current use of PROs for patients with end-stage kidney disease receiving hemodialysis and identify a roadmap for increasing the evidence base and introducing PROs into mainstream clinical practice.
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http://dx.doi.org/10.1053/j.ajkd.2019.01.035DOI Listing
September 2019

Patient and Clinician Perspectives on Electronic Patient-Reported Outcome Measures in the Management of Advanced CKD: A Qualitative Study.

Am J Kidney Dis 2019 08 16;74(2):167-178. Epub 2019 Apr 16.

Centre for Patient Reported Outcomes Research, University of Birmingham, Edgbaston, Birmingham, United Kingdom; Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham, United Kingdom.

Rationale & Objective: Chronic kidney disease (CKD) can substantially affect patients' health-related quality of life. Electronic patient-reported outcome measures (ePROMs) may capture symptoms and health-related quality of life and assist in the management of CKD. This study explored patient and clinician views on the use of a renal ePROM system.

Study Design: Qualitative study.

Setting & Participants: 12 patients with stage 4 or 5 CKD (non-dialysis dependent); 22 clinicians (6 CKD community nurses, 1 clinical psychologist, 10 nephrologists, 3 specialist registrars, and 2 renal surgeons) in the United Kingdom.

Analytical Approach: Semi-structured interviews and focus group discussion during which patients received paper versions of the Kidney Disease Quality of Life-36 and the Integrated Patient Outcome Scale-Renal to exemplify the type of content that could be included in an ePROM. Thematic analysis of interview transcripts.

Results: 4 themes were identified: (1) general opinions of PROMs, (2) potential benefits and applications of an ePROM system, (3) practical considerations for the implementation of ePROMs, and (4) concerns, barriers, and facilitators. Patients were willing to complete ePROMs on a regular basis as part of their care despite clinician concerns about patient burden. Patients assessed the questionnaires favorably. Clinicians suggested that the extent of adoption of renal ePROM systems in routine clinical settings should be based on evidence of significant impact on patient outcomes. Clinicians were concerned that an ePROM system may raise patient expectations to unrealistic levels and expose clinicians to the risk for litigation. Patients and clinicians identified potential benefits and highlighted issues and concerns that need to be addressed to ensure the successful implementation of the renal ePROM system.

Limitations: Transferability of the findings may be limited because only English-speaking participants were recruited to the study.

Conclusions: A renal ePROM system may play a supportive role in the routine clinical management of patients with advanced CKD if the concerns of clinicians and patients can be sufficiently addressed.
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http://dx.doi.org/10.1053/j.ajkd.2019.02.011DOI Listing
August 2019

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

The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group.

Nat Rev Nephrol 2019 01;15(1):45-59

Division of Nephrology, Hematology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.
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http://dx.doi.org/10.1038/s41581-018-0077-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136169PMC
January 2019

Cardiovascular, thromboembolic and renal outcomes in IgA vasculitis (Henoch-Schönlein purpura): a retrospective cohort study using routinely collected primary care data.

Ann Rheum Dis 2019 02 28;78(2):261-269. Epub 2018 Nov 28.

Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

Background: IgA vasculitis (IgAV, Henoch-Schönlein purpura) is a small-vessel vasculitis most common in children but also occurring in adults. Case series have suggested that IgAV may be associated with cardiovascular disease and venous thromboembolism, but this has not been evaluated in population-based studies. Renal disease and hypertension are possible complications of the disease with unknown incidence.

Methods: Using a large UK primary care database, we conducted an open retrospective matched cohort study of cardiovascular, venous thrombotic and renal outcomes in adult-onset and childhood-onset IgAV. Control participants were selected at a 2:1 ratio, matched for age and sex. Adjusted HRs (aHRs) were calculated using Cox proportional hazards models.

Results: 2828 patients with adult-onset IgAV and 10 405 patients with childhood-onset IgAV were compared with age-matched and sex-matched controls. There was significantly increased risk of hypertension (adult-onset aHR 1.42, 95% CI 1.19 to 1.70, p < 0.001; childhood-onset aHR 1.52, 95% CI 1.22 to 1.89, p < 0.001) and stage G3-G5 chronic kidney disease (adult-onset aHR 1.54, 95% CI 1.23 to 1.93, p < 0.001; childhood-onset aHR 1.89, 95% CI 1.16 to 3.07, p=0.010). There was no evidence of association with ischaemic heart disease, cerebrovascular disease or venous thromboembolism. All-cause mortality was increased in the adult-onset IgAV cohort compared with controls (aHR 1.27, 95% CI 1.07 to 1.50, p=0.006).

Conclusions: Patients with IgAV are at increased risk of hypertension and chronic kidney disease (CKD) compared with individuals without IgAV; analysis restricted to adult-onset IgAV patients showed increased mortality. Appropriate surveillance and risk factor modification could improve long-term outcomes in these patients.
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http://dx.doi.org/10.1136/annrheumdis-2018-214142DOI Listing
February 2019

Chronic kidney disease, health-related quality of life and their associated economic burden among a nationally representative sample of community dwelling adults in England.

PLoS One 2018 26;13(11):e0207960. Epub 2018 Nov 26.

Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom.

Chronic kidney disease (CKD) affects up to 15% of the adult population and is strongly associated with other non-communicable chronic diseases including diabetes. However, there is limited information on a population basis of the relationship between CKD and health-related quality of life (HRQoL) and the consequent economic cost. We investigated this relationship in a representative sample in England using the 2010 Health Survey for England. Multivariable Tobit models were used to examine the relationship between HRQoL and CKD severity. HRQoL was converted to quality adjusted life year (QALY) measures by combining decrements in quality of life with reductions in life expectancy associated with increased disease severity. QALYs were adjusted for discounting and monetised using the UK threshold for reimbursement of £30,000. The QALYs were then used in conjunction with forecasted prevalence to estimate the HRQoL burden associated with CKD among individuals with diabetes up to 2025. Individuals with more severe CKD had lower HRQoL compared to those with better kidney function. Compared to those with normal/low normal kidney function and stage 1 CKD, those with stage 2, stage 3 with albuminuria and stage 4/5 CKD experienced a decrement of 0.11, 0.18 and 0.28 in their utility index, respectively. Applying the UK reimbursement threshold for a QALY, the monetised lifetime burden of reduced HRQoL due to stage 2, stage 3 with albuminuria and stage 4/5 CKD were £103,734; £83,399; £125,335 in males and £143,582; £70,288; £203,804 in females, respectively. Utilizing the predicted prevalence of CKD among individuals with diabetes mellitus, the economic burden of CKD per million of individuals with diabetes is forecasted at approximately £11.4 billion in 2025. In conclusion, CKD has a strong adverse impact on HRQoL in multiple domains. The estimated economic burden of CKD among individuals with diabetes mellitus in the UK is projected to rise markedly over time.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207960PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258125PMC
May 2019