The effect of primary renal disease upon outcomes after renal transplant.

BACKGROUND: This study investigated whether nature of primary renal disease affects clinical outcomes after renal transplantation at a single center in the United Kingdom. METHODS: This was a retrospective cohort study of 961 renal transplant recipients followed up at a large renal center from 2000 to 2020. Separation of diseases responsible for end-stage kidney disease included glomerulonephritis, diabetic kidney disease, hypertensive nephropathy, autosomal dominant polycystic kidney disease, unknown cause, other causes and chronic pyelonephritis. Outcome data included graft loss, cardiovascular events, malignancy, post-transplant diabetes mellitus and death, analyzed according to primary disease type. RESULTS: The mean age at transplantation was 47.3 years. During a mean follow-up of 7.6 years, 18% of the overall cohort died corresponding to an annualised mortality rate of 2.3%. Death with a functioning graft occurred at a rate of 2.1% per annum, with the highest incidence observed in in patients with diabetic kidney disease (4.1%/year). Post-transplant cardiovascular events occurred in 21% of recipients (2.8% per year), again highest in recipients with diabetic kidney disease (5.1%/year) and hypertensive nephropathy (4.5%/year). Post-transplant diabetes mellitus manifested in 19% of the cohort at an annualized rate of2.1% while cancer incidence stood at 9% with an annualized rate of 1.1% . Graft loss occurred in 6.8% of recipients at the rate of1.2% per year with chronic allograft injury, acute rejection and recurrent glomerulonephritis being the predominant causative factors. Median + IQR dialysis-free survival of the whole cohort was 16.2 (9.9 - > 20) years, being shortest for diabetic kidney disease (11.0 years) and greatest for autosomal dominant polycystic kidney disease (18.2 years) .The collective mean decline in eGFR over time was -1.14ml/min/year. Recipients with Pre-transplant diabetic kidney disease exhibited the fastest rate of decline(-2.1ml/min/year) a statistically significant difference in comparison to the other native kidney diseases with Autosomal dominant polycystic kidney disease exhibiting the lowest rate of decline(-0.05ml/min/year) CONCLUSION: Primary renal disease can influence the outcome after renal transplantation, with patients with prior diabetic kidney disease having the poorest outcome in terms of dialysis-free survival and loss of transplant function. Autosomal polycystic kidney disease, other cause and unknown cause had the best outcomes compared to other primary renal disease groups.

Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study.

AIMS: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). METHODS AND RESULTS: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. CONCLUSION: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.

Maintaining Renin-Angiotensin-Aldosterone System Inhibitor Treatment with Patiromer in Hyperkalaemic Chronic Kidney Disease Patients: Comparison of a Propensity-Matched Real-World Population with AMETHYST-DN.

INTRODUCTION: Guideline-directed renin-angiotensin-aldosterone system inhibitor (RAASi) therapy is rarely achieved in clinical settings, often due to hyperkalaemia. We assessed the potassium binder, patiromer, on continuation of RAASi therapy in hyperkalaemic patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) in the AMETHYST-DN trial, propensity score-matched to a real-world cohort not receiving patiromer (Salford Kidney Study). METHODS: The phase 2, open-label AMETHYST-DN trial (NCT01371747) randomized 304 adults with CKD on RAASi, T2DM, hyperkalaemia (serum potassium [sK+] >5.0 mEq/L), and hypertension to receive patiromer, 8.4-33.6 g/day for 12 months. Patients underwent propensity score matching for systolic blood pressure (BP), heart failure status, and estimated glomerular filtration rate (eGFR), with 321 patients with CKD, T2DM, hyperkalaemia, and on RAASi from a prospective CKD cohort (Salford Kidney Study). Changes in RAASi utilization, sK+, BP, proteinuria, and eGFR during 12-month follow-up were assessed by Mann-Whitney U or χ2 tests. RESULTS: Matching produced 135:135 patients with no significant differences in age, sex, systolic BP, sK+, eGFR, or heart failure status, although differences in diastolic BP remained (p < 0.001). After 12 months, 100% of AMETHYST-DN patients receiving patiromer remained on RAASi therapy, whereas 38.5% of the Salford Kidney Cohort discontinued RAASi (p < 0.001); hyperkalaemia contributed in 16% of patients (42% of RAASi discontinuations). Significantly greater reductions in sK+ and BP, but not proteinuria or eGFR, were observed in AMETHYST-DN, compared with Salford Kidney Study patients (p < 0.05). CONCLUSIONS: These results demonstrate the benefit of patiromer for sK+ management to enable RAASi use while revealing beneficial effects on BP.

Using Prior Knowledge on Systems Through PBPK to Gain Further Insight into Routine Clinical Data on Trough Concentrations: The Case of Tacrolimus in Chronic Kidney Disease.

BACKGROUND: Routine therapeutic drug monitoring (TDM) relies heavily on measuring trough drug concentrations. Trough concentrations are affected not only by drug bioavailability and clearance, but also by various patient and disease factors and the volume of distribution. This often makes interpreting differences in drug exposure from trough data challenging. This study aimed to combine the advantages of top-down analysis of therapeutic drug monitoring data with bottom-up physiologically-based pharmacokinetic (PBPK) modeling to investigate the effect of declining renal function in chronic kidney disease (CKD) on the nonrenal intrinsic metabolic clearance ( CLint ) of tacrolimus as a case example. METHODS: Data on biochemistry, demographics, and kidney function, along with 1167 tacrolimus trough concentrations for 40 renal transplant patients, were collected from the Salford Royal Hospital's database. A reduced PBPK model was developed to estimate CLint for each patient. Personalized unbound fractions, blood-to-plasma ratios, and drug affinities for various tissues were used as priors to estimate the apparent volume of distribution. Kidney function based on the estimated glomerular filtration rate ( eGFR ) was assessed as a covariate for CLint using the stochastic approximation of expectation and maximization method. RESULTS: At baseline, the median (interquartile range) eGFR was 45 (34.5-55.5) mL/min/1.73 m 2 . A significant but weak correlation was observed between tacrolimus CLint and eGFR (r = 0.2, P < 0.001). The CLint declined gradually (up to 36%) with CKD progression. Tacrolimus CLint did not differ significantly between stable and failing transplant patients. CONCLUSIONS: Kidney function deterioration in CKD can affect nonrenal CLint for drugs that undergo extensive hepatic metabolism, such as tacrolimus, with critical implications in clinical practice. This study demonstrates the advantages of combining prior system information (via PBPK) to investigate covariate effects in sparse real-world datasets.

Peritoneal dialysis-associated peritonitis presenting with Ralstonia pickettii infection: A novel series of three cases during the COVID-19 pandemic.

Peritoneal dialysis (PD)-associated peritonitis secondary to Ralstonia infection is very rare. Ralstonia pickettii is an organism that can grow in contaminated saline, water, chlorhexidine, and other medical products used in laboratories and the clinical setting. Infective endocarditis, prosthetic joint, and severe chest infections are previously reported with R. pickettii infection. We report a novel series of three cases diagnosed with PD-associated peritonitis caused by R. pickettii, where the cases appeared consecutively to our unit during a span of 4 weeks. During the COVID-19 pandemic, there were increased uses of non-sterile gloves by clinical staff as a form of personal protective equipment throughout patient interaction and PD exchange, as recommended by local hospital policy for all staff attending to patient care. A multidisciplinary team root cause analysis of our cases suggested non-sterile gloves being the likely source of environmental contamination, leading to PD-associated peritonitis caused by R. pickettii in this scenario.

Risk factors for infective endocarditis in patients receiving hemodialysis: A propensity score matched cohort study.

In patients receiving hemodialysis, infective endocarditis (IE) may present in a similar way to other causes of bacteremia, which may delay early diagnosis and can lead to worse outcomes. In this study, we aimed to identify the risk factors for IE in hemodialysis patients with bacteremia. This study was conducted on all patients diagnosed with IE and receiving hemodialysis between 2005 and 2018 in Salford Royal Hospital. Patients with IE were propensity score matched with similar hemodialysis patients with episodes of bacteremia between 2011 and 2015 (non-IE bacteremic (NIEB)). Logistic regression analysis was used to predict the risk factors associated with infective endocarditis. There were 35 cases of IE, and these were propensity matched with 70 NIEB cases. The median age of the patients was 65 years with a predominance of males (60%). The IE group had higher peak C-reactive protein compared to the NIEB group (median, 253 mg/L vs. 152, p = 0.001). Patients with IE had a longer duration of prior dialysis catheter use than NIEB patients (150 vs. 28.5 days: p = 0.004). IE patients had a much higher 30-day mortality rate (37.1% vs. 17.1%, p = 0.023). Logistic regression analysis showed previous valvular heart disease (OR: 29.7; p < 0.001), and a higher baseline C-reactive protein (OR: 1.01; p = 0.001) as significant predictors for infective endocarditis. Bacteremia in patients receiving hemodialysis through a catheter access should be actively investigated with a high index of suspicion for infective endocarditis, particularly in those with known valvular heart disease and a higher baseline C-reactive protein.

The epidemiology of primary FSGS including cluster analysis over a 20-year period.

INTRODUCTION: Focal segmental glomerulosclerosis (FSGS) is one of the leading causes of nephrotic syndrome in adults. This epidemiological study describes a renal centre's 20-year experience of primary FSGS. METHODS: Patients were identified with a diagnosis of primary FSGS after exclusion of known secondary causes. In this retrospective observational study, data was collected for baseline demographics, immunosuppression and outcomes. A two-step cluster analysis was used to identify natural groupings within the dataset. RESULTS: The total cohort was made up of 87 patients. Those who received immunosuppression had lower median serum albumin than those who did not- 23g/L vs 40g/L (p<0.001) and higher median urine protein creatinine ratios (uPCR)- 795mg/mmol vs 318mg/mmol (p <0.001). They were more likely to achieve complete remission (62% vs 40%, p=0.041), but relapsed more 48.6% vs 22% (p=0.027). Overall 5 year mortality was 10.3% and 5 year progression to RRT was seen in 17.2%. Complete remission was observed in 49.4%. The 2-step cluster analysis separated the cohort into 3 clusters: cluster 1 (n=26) with 'nephrotic-range proteinuria'; cluster 2 (n=43) with 'non-nephrotic-range proteinuria'; and cluster 3 (n=18) with nephrotic syndrome. Immunosuppression use was comparable in clusters 1 and 3, but lower in cluster 2 (77.8% and 69.2% vs 11.6%, p<0.001). Rates of complete remission were greatest in clusters 1 and 3 vs cluster 2: 57.7% and 66.7% vs 37.2%. CONCLUSION: People who received immunosuppression had lower serum albumin and achieved remission more frequently, but were also prone to relapse. Our cluster analysis highlighted 3 FSGS phenotypes: a nephrotic cluster that clearly require immunosuppression; a cohort with preserved serum albumin and non-nephrotic range proteinuria who will benefit from supportive care; and lastly a cluster with heavy proteinuria but serum albumin > 30g/L. This group may still have immune mediated disease and thus could potentially benefit from immunosuppression. TRIAL REGISTRATION: This study protocol was reviewed and approved by the 'Research and Innovation committee of the Northern Care Alliance NHS Group', study approval number (Ref: ID 22HIP54).

Does previous stroke modify the relationship between inflammatory biomarkers and clinical endpoints in CKD patients?

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for stroke. Stroke is also an independent risk factor for worse CKD outcomes and inflammation may contribute to this bidirectional relationship. This study aims to investigate inflammatory biomarkers in patients with non-dialysis CKD (ND-CKD) with and without stroke. METHODS: A propensity matched sample from > 3000 Salford Kidney Study (SKS) patients, differentiated by previous stroke at study recruitment, had stored plasma analyzed for interleukin- 6 (IL-6), Von Willebrand Factor (VWF) and C-reactive protein (CRP). Multivariable cox regression analysis investigated associations between inflammation and death, end-stage renal disease (ESRD) and future non-fatal cardiovascular events (NFCVE). RESULTS: A total of 157 previous stroke patients were compared against 162 non-stroke patients. There were no significant differences in inflammatory biomarkers between the two groups. Previous stroke was associated with greater mortality risk, hazard ratio (HR) (95% CI) was 1.45 (1.07-1.97). Higher inflammatory biomarker concentrations were independently associated with death but not ESRD or NFCVE in the total population. For each 1 standard deviation (SD) increase in log IL-6, VWF and CRP, the HR for all-cause mortality were 1.35 (1.10-1.70), 1.26 (1.05-1.51) and 1.34 (1.12-1.61), respectively. CRP retained its independent association (HR 1.47 (1.15-1.87)) with death in the stroke population. CONCLUSION: Previous stroke is an important determinant of mortality. However, the adverse combination of stroke and ND-CKD does not seem to be driven by higher levels of inflammation detected after the stroke event. Biomarkers of inflammation were associated with worse outcome in both stroke and non-stroke ND-CKD patients. TRIAL REGISTRATION: 15/NW/0818 .

Adverse outcomes associated with rapid linear and non-linear patterns of chronic kidney disease progression.

BACKGROUND: Patients with rapidly declining renal function face the dual threat of end-stage renal disease (ESRD) and mortality prior to ESRD. What is less well characterised is whether the pattern of the renal trajectory, linear or non-linear, unmasks subgroups of rapidly progressing patients that face adverse outcomes in a differential manner. METHODS: An individual eGFR slope was applied to all outpatient estimated glomerular filtration rate (eGFR) values for each patient in the Salford Kidney Study from 2002 to 2018 who had at least 2 years follow-up, ≥4 eGFR values and baseline eGFR 15 to < 60 ml/min/1.73m2. Rapid progression was defined as an annual eGFR slope of ≤ - 3 ml/min/1.73m2/yr and patients were categorised as linear or non-linear progressors based on the nature of their eGFR-time graphs. A Fine-Gray competing risk hazard model was used to determine factors associated with progression to ESRD and with mortality prior to ESRD. Cumulative incidence function curves highlighted differences in outcomes between linear and non-linear patients. RESULTS: There were 211 rapidly deteriorating patients with linear eGFR trajectories and 61 rapid non-linear patients in the study cohort. Factors associated with ESRD included younger age, male gender, lower baseline eGFR and higher serum phosphate, whilst older age, history of myocardial infarction and anaemia predicted mortality prior to ESRD. Over a median follow-up of 3.7 years, linear progressors reached ESRD sooner whilst those with non-linear progression faced significantly higher rates of mortality prior to ESRD. CONCLUSIONS: Patients with rapid eGFR decline have high rates of adverse outcomes that are differentially expressed in those progressing linearly and non-linearly as a result of differing phenotypic profiles. Consequently, addressing individual risk factor profiles is important to deliver optimal personalised patient care.

A randomised controlled trial to examine the effects of cinacalcet on bone and cardiovascular parameters in haemodialysis patients with advanced secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism may lead to increased cardiovascular risk. The use of cinacalcet may improve bone and cardiovascular health with improved parathormone (PTH) and phosphate control. METHODS: This is an open-label prospective randomised controlled trial to compare progression of cardiovascular and chronic kidney disease mineral and bone disorder (CKD-MBD) parameters. Patients were randomised to receive cinacalcet alongside standard therapy or standard therapy alone. Thirty-six haemodialysis patients who had > 90 days on dialysis, iPTH > 300 pg/mL, calcium > 2.1 mmol/L and age 18-75 years were included. Following randomization, all 36 patients underwent an intensive 12-week period of bone disease management aiming for iPTH 150-300 pg/mL. The primary outcome was change in vascular calcification using CT agatston score. Secondary outcomes included pulse wave velocity (PWV), left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), augmentation index (Aix) and bone measurements. The above measurements were obtained at baseline and 12 months. RESULTS: There was no evidence of a group difference in the progression of calcification (median change (IQR) cinacalcet: 488 (0 to1539); standard therapy: 563 (50 to 1214)). In a post hoc analysis combining groups there was a mean (SD) phosphate reduction of 0.3 mmol/L (0.7) and median (IQR) iPTH reduction of 380 pg/mL (- 754, 120). Regression of LVMI and CIMT was seen (P = 0.03 and P = 0.001) and was significantly associated with change of phosphate on multi-factorial analyses. CONCLUSIONS: With a policy of intense CKD-MBD parameter control, no significant benefit in bone and cardiovascular markers was seen with the addition of cinacalcet to standard therapy over one year. Tight control of hyperphosphataemia and secondary hyperparathyroidism may lead to a reduction in LVMI and CIMT but this needs further investigation. Although the sample size was small, meticulous trial supervision resulted in very few protocol deviations with therapy.

Longitudinal change in c-terminal fibroblast growth factor 23 and outcomes in patients with advanced chronic kidney disease.

BACKGROUND: Fibroblast growth factor23 (FGF23) is elevated in CKD and has been associated with outcomes such as death, cardiovascular (CV) events and progression to Renal Replacement therapy (RRT). The majority of studies have been unable to account for change in FGF23 over time and those which have demonstrate conflicting results. We performed a survival analysis looking at change in c-terminal FGF23 (cFGF23) over time to assess the relative contribution of cFGF23 to these outcomes. METHODS: We measured cFGF23 on plasma samples from 388 patients with CKD 3-5 who had serial measurements of cFGF23, with a mean of 4.2 samples per individual. We used linear regression analysis to assess the annual rate of change in cFGF23 and assessed the relationship between time-varying cFGF23 and the outcomes in a cox-regression analysis. RESULTS: Across our population, median baseline eGFR was 32.3mls/min/1.73m2, median baseline cFGF23 was 162 relative units/ml (RU/ml) (IQR 101-244 RU/mL). Over 70 months (IQR 53-97) median follow-up, 76 (19.6%) patients progressed to RRT, 86 (22.2%) died, and 52 (13.4%) suffered a major non-fatal CV event. On multivariate analysis, longitudinal change in cFGF23 was significantly associated with risk for death and progression to RRT but not non-fatal cardiovascular events. CONCLUSION: In our study, increasing cFGF23 was significantly associated with risk for death and RRT.

Investigating the utility of COVID-19 antibody testing in end-stage renal disease patients receiving haemodialysis: a cohort study in the United Kingdom.

BACKGROUND: End-stage renal disease (ESRD) patients receiving haemodialysis (HD) are a vulnerable group of patients with increased mortality from COVID-19. Despite improved understanding, the duration of host immunity following COVID-19 infection and role of serological testing alone or in addition to real-time reverse transcription polymerase chain reaction (rRT-PCR) testing in the HD population is not fully understood, which this study aimed to investigate. METHODS: There were two parts to this study. Between 15th March 2020 to 15th July 2020, patients receiving HD who tested positive on rRT-PCR for SARS-CoV-2 were recruited into the COVID-19 arm, whilst asymptomatic patients without a previous diagnosis of COVID-19 were recruited to the epidemiological arm of the Salford Kidney Study (SKS). All patients underwent monthly testing for anti-SARS-CoV-2 antibodies as per routine clinical practice since August 2020. The aims were twofold: firstly, to determine seroprevalence and COVID-19 exposure in the epidemiological arm; secondly, to assess duration of the antibody response in the COVID-19 arm. Baseline characteristics were reviewed between groups. Statistical analysis was performed using SPSS. Mann-Whitney U and Chi-squared tests were used for testing significance of difference between groups. RESULTS: In our total HD population of 411 patients, 32 were PCR-positive for COVID-19. Of the remaining patients, 237 were recruited into the SKS study, of whom 12 (5.1%) had detectable anti-SARS-CoV-2 antibodies. Of the 32 PCR-positive patients, 27 (84.4%) were symptomatic and 25 patients admitted to hospital due to their symptoms. Of the 22 patients in COVID-19 arm that underwent testing for anti-SARS-CoV-2 IgG antibodies beyond 7 months, all had detectable antibodies. A higher proportion of the patients with COVID-19 were frail compared to patients without a diagnosis of COVID-19 (64.3% vs 34.1%, p = 0.003). Other characteristics were similar between the groups. Over a median follow up of 7 months, a higher number of deaths were recorded in patients with a diagnosis of COVID-19 compared to those without (18.7% vs 5.9%, p = 0.003). CONCLUSIONS: Serological testing in the HD population is a valuable tool to determine seroprevalence, monitor exposure, and guide improvements for infection prevention and control (IPC) measures to help prevent local outbreaks. This study revealed HD patients mount a humoral response detectable until at least 7 months after COVID-19 infection and provides hope of similar protection with the vaccines recently approved.

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

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.

Older age and frailty are the chief predictors of mortality in COVID-19 patients admitted to an acute medical unit in a secondary care setting- a cohort study.

BACKGROUND: There is a need for more observational studies across different clinical settings to better understand the epidemiology of the novel COVID-19 infection. Evidence on clinical characteristics of COVID-19 infection is scarce in secondary care settings in Western populations. METHODS: We describe the clinical characteristics of all consecutive COVID-19 positive patients (n = 215) admitted to the acute medical unit at Fairfield General Hospital (secondary care setting) between 23 March 2020 and 30 April 2020 based on the outcome at discharge (group 1: alive or group 2: deceased). We investigated the risk factors that were associated with mortality using binary logistic regression analysis. Kaplan-Meir (KM) curves were generated by following the outcome in all patients until 12 May 2020. RESULTS: The median age of our cohort was 74 years with a predominance of Caucasians (87.4%) and males (62%). Of the 215 patients, 86 (40%) died. A higher proportion of patients who died were frail (group 2: 63 vs group 1: 37%, p < 0.001), with a higher prevalence of cardiovascular disease (group 2: 58 vs group 1: 33%, p < 0.001) and respiratory diseases (group 2: 38 vs group 1: 25%, p = 0.03). In the multivariate logistic regression models, older age (odds ratio (OR) 1.03; p = 0.03), frailty (OR 5.1; p < 0.001) and lower estimated glomerular filtration rate (eGFR) on admission (OR 0.98; p = 0.01) were significant predictors of inpatient mortality. KM curves showed a significantly shorter survival time in the frail older patients. CONCLUSION: Older age and frailty are chief risk factors associated with mortality in COVID-19 patients hospitalised to an acute medical unit at secondary care level. A holistic approach by incorporating these factors is warranted in the management of patients with COVID-19 infection.

Pain management in patients with end-stage renal disease and calciphylaxis- a survey of clinical practices among physicians.

BACKGROUND: Calciphylaxis is a rare condition usually seen in patients with end-stage renal disease. Pain is a hallmark of this condition and can be extremely difficult to control. Anecdotal data suggests that pain management in calciphylaxis is challenging with variable approaches across the United Kingdom (UK) and internationally. A knowledge and practice survey was conducted to establish current practice in the management of pain in patients with calciphylaxis, in the UK. Based on the results and clinical experience the authors suggest a clinical practice guideline. METHODS: An online questionnaire was circulated among physicians (renal and palliative care) involved in the management of pain in calciphylaxis. The questionnaire included a mix of open-ended questions and questions with drop down options. RESULTS: One hundred and six clinicians responded to the survey of which 60 (57%) respondents were from palliative medicine; the remaining 46 (43%) were from renal medicine. 31 (30%) respondents across both specialties had not encountered any patients with a diagnosis of calciphylaxis (renal-2, palliative care-29). A referral to the palliative care team was undertaken by 18% of renal physicians, 32% referred to the pain team and 50% referred to both. Only 3% of the palliative medicine respondents indicated that they had received a referral from the renal team at the time of diagnosis. Opioids were the preferred initial drug of choice for the management of all types of pain. Paracetamol was universally selected as the preferred first-choice adjuvant agent for management of all types of pain. The importance of advance care planning was highlighted with 72% undertaking advanced care planning discussions often or most of the time. CONCLUSION: There was wide variation in the current practice of pain management in patients with calciphylaxis, with variation between renal specialists and palliative care specialists. Referral to specialists in pain management is not universal despite the severe nature of the pain experienced by patients with calciphylaxis. The data generated has facilitated the development of a clinical practice guideline to support complex pain management in a group of patients with multiple comorbidities.

Predictive factors of rapid linear renal progression and mortality in patients with chronic kidney disease.

BACKGROUND: Risk factors predictive of rapid linear chronic kidney disease (CKD) progression and its associations with end-stage renal disease (ESRD) and mortality requires further exploration, particularly as patients with linear estimated glomerular filtration rate (eGFR) trajectory represent a clear paradigm for understanding true CKD progression. METHODS: A linear regression slope was applied to all outpatient eGFR values for patients in the Salford Kidney Study who had ≥2 years follow-up, ≥4 eGFR values and baseline CKD stages 3a-4. An eGFR slope (ΔeGFR) of ≤ - 4 ml/min/1.73m2/yr defined rapid progressors, whereas - 0.5 to + 0.5 ml/min/1.73m2/yr defined stable patients. Binary logistic regression was utilised to explore variables associated with rapid progression and Cox proportional hazards model to determine predictors for mortality prior to ESRD. RESULTS: There were 157 rapid progressors (median ΔeGFR - 5.93 ml/min/1.73m2/yr) and 179 stable patients (median ΔeGFR - 0.03 ml/min/1.73m2/yr). Over 5 years, rapid progressors had an annual rate of mortality or ESRD of 47 per 100 patients compared with 6 per 100 stable patients. Factors associated with rapid progression included younger age, female gender, higher diastolic pressure, higher total cholesterol:high density lipoprotein ratio, lower albumin, lower haemoglobin and a urine protein:creatinine ratio of > 50 g/mol. The latter three factors were also predictive of mortality prior to ESRD, along with older age, smoking, peripheral vascular disease and heart failure. CONCLUSIONS: There is a heterogenous interplay of risk factors associated with rapid linear CKD progression and mortality in patients with CKD. Furthermore, rapid progressors have high rates of adverse outcomes and require close specialist monitoring.

Associations of urological malignancies with renal progression and mortality in advanced chronic kidney disease: a propensity-matched cohort study.

BACKGROUND: Urological malignancy (UM) in patients with chronic kidney disease (CKD) is an added burden to their overall morbidity and mortality. UM is itself a common cause of CKD. Understanding the associations of UM with outcomes in advanced CKD can help in optimisation of the management of these patients. This study investigates the distribution and association of urological malignancy with outcomes (renal progression and mortality) in patients with advanced non-dialysis dependent CKD. METHODS: The study was conducted in 2637 of 3115 patients recruited in the Salford Kidney Study between the years 2002 and 2016. A comparative analysis was performed between 160 patients with UM (at baseline and incident) and 2477 patients with no malignancy. Cox-regression models and Kaplan-Meir estimates were used to explore the association between the presence of UM with mortality and renal outcome. Linear regression analysis was used to calculate the rate of progression of CKD in the groups. A 1:3 propensity score matched cohort of 640 patients was generated and utilised in the above analyses. RESULTS: 4.4% had a history of UM at baseline with the annual incident rate being 0.37%. The site of malignancy was the kidney in 40% with comparable numbers for prostatic malignancy (39%). 70% (111/160) of UM patients had a medical cause as their primary diagnosis for CKD. Over a median follow up of 4 years, 34% (905) patients died. In the matched sample, the proportion of deaths was similar between the groups (UM 44% versus no malignancy 48%, p = 0.36). 30% reached end-stage renal disease (ESRD) with no difference between the groups. In the Cox-regression model, UM did not prove to be a risk factor associated with either all-cause mortality (HR:1.03; CI: 0.79-1.35; p = 0.81) or reaching ESRD (HR:1.12; CI: 0.80-1.58; p = 0.49). The rate of decline in estimated glomerular filtration rate (eGFR) was similar between the groups (- 1.05 vs - 1.25 mL/min/1.73m2/year, p = 0.31). CONCLUSIONS: There was no correlation observed between UM and all-cause mortality or ESRD. Medical causes of CKD have a significant influence on the outcomes in patients with UM, whereas the UM did not. Hence, a coordinated approach with early liaison between the urology and nephrology teams is needed in the management of UM patients with CKD.

Non-alcoholic fatty liver disease and clinical outcomes in chronic kidney disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor associated with cardiovascular disease (CVD) and incidence of chronic kidney disease (CKD). NAFLD is threatening to become a major public health problem in association with the metabolic syndrome. The association of NAFLD with outcomes in patients with advanced CKD has not been evaluated. In this study, the prevalence of NAFLD and its impact on cardiovascular and renal outcomes and mortality were determined in a large secondary care CKD cohort. METHODS: The study was conducted on 1148 CKD patients within a cohort of 3061 CKD patients, who had undergone ultrasound imaging of the liver over a 15-year period. A propensity-matched population from within the cohort was also included. Cox regression analysis was used to study the association of NAFLD with cardiovascular events, end-stage renal disease and mortality and linear regression analysis for CKD progression. RESULTS: The prevalence of NAFLD was 17.9%. The median duration of follow-up after scanning was 5.4 years, with a median estimated glomerular filtration rate (eGFR) of 33.5 mL/min/1.73 m2 in this population. NAFLD proved to be a strong independent risk factor for cardiovascular events [hazard ratio (HR) 2.03; 95% confidence interval (CI) 1.33-3.13; P < 0.01] but it was not associated with all-cause mortality (HR 0.79; 95% CI 0.58-1.08; P = 0.14) or CKD progression (P = 0.09 for rate of decline of eGFR slope). Patients with CKD are known to have high cardiovascular risk; the propensity-matched analysis showed that NAFLD increased this cardiovascular risk (HR 2.00; CI 1.10-3.66; P < 0.05). CONCLUSIONS: NAFLD has a strong independent association with cardiovascular events, even in an advanced CKD cohort with high comorbidity. The implication is that routine screening for NAFLD may be warranted in CKD populations to enable targeted interventions for CVD prevention in higher risk patients.

Cancer patterns and association with mortality and renal outcomes in non-dialysis dependent chronic kidney disease: a matched cohort study.

BACKGROUND: Cancer in patients with chronic kidney disease (CKD) is an added burden to their overall morbidity and mortality. Cancer can be a cause or an effect of CKD. In CKD patients, a better understanding of cancer distribution and associations can aid in the proper planning of renal replacement therapy (RRT) and in the choice of chemotherapeutic agents, many of which are precluded in more advanced CKD. This study aims to investigate the distribution and the association of cancer with mortality, renal progression and RRT assignment in a non-dialysis dependent CKD cohort, few studies have investigated this in the past. METHODS: The study was carried out on 2952 patients registered in the Salford Kidney Study (SKS) between October 2002 and December 2016. A comparative analysis was performed between 339 patients with a history of cancer (previous and current) and 2613 patients without cancer at recruitment. A propensity score matched cohort of 337 patients was derived from each group and used for analysis. Cox-regression models and Kaplan-Meier estimates were used to compare the association of cancer with mortality and end-stage renal disease (ESRD) outcomes. Linear regression analysis was applied to generate the annual rate of decline in estimated glomerular filtration rate (delta eGFR). RESULTS: Of our cohort, 13.3% had a history of cancer at recruitment and the annual rate of de novo cancers in the non-cancer patients was 1.6%. Urogenital cancers including kidney and bladder, and prostate and testicle in males, ovary and uterus in females, were the most prevalent cancers (46%), as expected from the anatomical or physiological roles of these organs and relationship to nephrology. Over a median follow-up of 48 months, 1084 (36.7%) of patients died. All-cause mortality was higher in the previous and current cancer group (49.6% vs 35%, p < 0.001), primarily because of cancer-specific mortality. Multivariate Cox regression analysis showed a strong association of cancer with all-cause mortality (HR:1.41; 95%CI: 1.12-1.78; p = 0.004). There was no difference between the groups regarding reaching end-stage renal disease (26% in both groups) or the rate of decline in eGFR (- 0.97 for cancer vs - 0.93 mL/min/year for non-cancer, p = 0.93). RRT uptake was similar between the groups (17.2% vs 19.3%, p = 0.49). CONCLUSIONS: Cancer status proved to be an added burden and an independent risk factor for all-cause mortality but not for renal progression. CKD patients with a previous or current history of cancer should be assessed on a case by case basis in planning for renal replacement therapy options, and the presence of cancer should not be a limitation for RRT provision including transplantation.

Impact of prior stroke on major clinical outcome in chronic kidney disease: the Salford kidney cohort study.

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for stroke in the general population. The impact of prior stroke on major clinical outcomes in CKD populations is poorly characterised. METHODS: The Salford Kidney Study is a UK prospective cohort of more than 3000 patients recruited since 2002 and followed until March 2018. Multivariable Cox regression examined associations of stroke at two time points; cohort inception, and at dialysis initiation, with risks of death, non-fatal cardiovascular events (NFCVE) and end stage renal disease (ESRD). RESULTS: 277 (9.1%) of 3060 patients suffered a prior stroke and this was associated with mortality, ESRD and future NFCVE after cardiovascular risk factor adjustments. Median survival for prior stroke patients was 40 months vs 77 months in patients without a stroke. Prior stroke was independently associated with mortality (HR 1.20 95%CI 1.0-1.43, p = 0.05). Of 579 patients who reached ESRD and commenced dialysis, a prior stroke (N = 48) was independently associated with mortality. Median survival for the prior stroke group was 29 months compared with 50 months for the non-stroke group. Only 70 and 75% of patients who had suffered an ischaemic stroke were prescribed antiplatelets or statins respectively. CONCLUSIONS: A diagnosis of stroke is strongly and independently associated with several adverse clinical outcomes for patients with CKD. Prior stroke profoundly alters cardiovascular risk in CKD patients. Greater attention to primary and secondary preventive strategies is warranted which may improve these outcomes.