Kidney Transplant-Associated Viral Infection Rates and Outcomes in a Single-Centre Cohort.

BACKGROUND: Opportunistic infections remain a significant cause of morbidity and mortality after kidney transplantation. This retrospective cohort study aimed to assess the incidence and predictors of post-transplant DNA virus infections (CMV, EBV, BKV and JCV infections) in kidney transplant recipients (KTR) at a single tertiary centre and evaluate their impact on graft outcomes. METHODS: KTR transplanted between 2000 and 2021 were evaluated. Multivariate logistic regression analysis and Cox proportional hazard analyses were used to identify factors associated with DNA virus infections and their impact on allograft outcomes respectively. A sub-analysis of individual viral infections was also conducted to describe the pattern, timing, interventions, and outcomes of individual infections. RESULTS: Data from 962 recipients were evaluated (Mean age 47.3 ± 15 years, 62% male, 81% white). 30% of recipients (288/962) had infection(s) by one or more of the DNA viruses. Individually, CMV, EBV, BKV and JCV viruses were diagnosed in 13.8%. 11.3%, 8.9% and 4.4% of recipients respectively. Factors associated with increased risk of post-transplant DNA virus infection included recipient female gender, higher number of HLA mismatch, lower baseline estimated glomerular filtration rate (eGFR), CMV seropositive donor, maintenance with cyclosporin (rather than tacrolimus) and higher number of maintenance immunosuppressive medications. The slope of eGFR decline was steeper in recipients with a history of DNA virus infection irrespective of the virus type. Further, GFR declined faster with an increasing number of different viral infections. Death-censored graft loss adjusted for age, gender, total HLA mismatch, baseline eGFR and acute rejection was significantly higher in recipients with a history of DNA virus infection than those without infection (adjusted hazard ratio (aHR, 1.74, 95% CI, 1.08-2.80)). In contrast, dialysis-free survival did not differ between the two groups of recipients (aHR, 1.13, 95% CI, 0.88-1.47). CONCLUSION: Post-transplant DNA viral infection is associated with a higher risk of allograft loss. Careful management of immunosuppression and close surveillance of at-risk recipients may improve graft outcomes.

Outcomes in dialysis versus conservative care for older patients: A prospective cohort analysis of stage 5 Chronic Kidney Disease.

BACKGROUND: The benefits of dialysis in older people with ESKD are not clear. We prospectively evaluated whether dialysis has survival advantage compared to conservative care (CC) in older people who were medically suitable for dialysis therapy. METHODS: This was a prospective observational study of CKD patients aged ≥75 years when eGFR first reached ≤15ml/min/1.73m2. Hazard ratios (HR) for death were compared between patients who chose dialysis versus conservative care (CC) from when first seen in pre-dialysis clinic (eGFR ≤15ml/min/1.73m2), and when initiation of dialysis was first considered (eGFR ≤10ml/min/1.73m2). Patients with co-morbidities likely to significantly reduce life expectancy such as advanced heart failure, advanced dementia, and malignancy, were excluded. RESULTS: There were 204 patients (123 dialysis, 81 CC). 115 went on to record eGFR of ≤10ml/min/1.73m2 (73 dialysis, 42 CC). The median survival from eGFR first ≤15ml/min/1.73m2 for the dialysis and CC groups were 42 (33-50) months and 31 (21-41) months. The adjusted hazard ratio (HR) for death in the dialysis group compared to CC was 0.61 (0.41-0.61, p = 0.01). The median survival from eGFR first ≤10ml/min/1.73m2 for dialysis and CC group were 36 (25-47) months and 12 (0-5) months. The adjusted HR for death in the dialysis group compared to CC was 0.36 (0.21-0.62, p <0.001). CONCLUSION: Dialysis confers a survival benefit in older patients medically suitable for dialysis. This study is novel in being both prospective and in excluding patients with co-morbidities which may limit suitability for dialysis and life expectancy. A future focus on quality of life is needed to establish the true benefits of dialysis in older people.

Comparing the impact of older age on outcome in chronic kidney disease of different etiologies: a prospective cohort study.

BACKGROUND: In older patients with chronic kidney disease (CKD), the risk of progression to end stage renal disease and cardiovascular death both differ compared to younger patients. This likely reflects differences in case mix and co-morbid burdens. We sought to establish the extent to which age itself is an independent biomarker of adverse outcome in CKD. METHODS: This was an analysis of the Salford Kidney Study, a prospective, longitudinal, observational study of 2,667 patients with eGFR < 60 ml/min/1.73 m2. Patients were divided into four age groups (< 55, 55-65, 65-75 and > 75 years). Within group adjusted hazard ratios for death in older compared to younger patients were calculated for different primary renal diseases. A competing risk model of death and renal replacement therapy (RRT) as outcomes was performed. RESULTS: The median age of the cohort was 67.1 years [interquartile range (IQR): 55.6-75.3] and median eGFR 30.8 ml/min/1.73 m2 (IQR: 20.6-43.2). Follow up was 3.5 ± 2.9 years. Overall, the adjusted HR for death in patients aged > 75 years compared to those < 55 years was 4.4 (95% CI 3.4-5.9), p < 0.001. The HR for death differed between primary renal diseases and CKD stages. In diabetic nephropathy, the HR was 3.0 (1.8-5.3, p < 0.001), in glomerulonephritis the HR was 12.2 (5.6-25.5, p < 0.001). The cumulative incidence of RRT was < 0.1 at 10 years for patients > 75 years, compared with 0.50 in those < 55 years. Death was more likely at 20 months in those aged 75 years or older (0.17) than at 10 years in those aged < 55 years (0.10). CONCLUSION: This study demonstrates that the risk associated with older age shows significant variability between primary renal diseases. This is whilst acknowledging that observational studies carry the risk of hidden bias not adjusted for in the statistical model.

Estimating renal function in old people: an in-depth review.

Estimates of glomerular filtration rate (eGFR) should provide accurate measure of an individual's kidney function because important clinical decisions such as timing of renal replacement therapy and drug dosing may be dependent on eGFR. Formulae from which eGFR is derived are generally based on serum creatinine measurement, such as Cockcroft-Gault, MDRD and CKD-EPI. More recently, calculation of eGFR using other laboratory biomarkers such as cystatin C has emerged with apparent greater accuracy. In old people, there is age-related physiological change in the kidney, which could lead to reduced GFR. Likewise, physiological changes in body composition that occur with the ageing process impede the use of a single creatinine-based calculation of eGFR across all adult age groups. Studies have shown differences in the prevalence of CKD based on the type of equation used to estimate GFR. This review discusses the evolution of eGFR calculations and the relative accuracy of such equations in older population.

Effect of a Quality Improvement Program to Improve Guideline Adherence and Attainment of Clinical Standards in Dialysis Care: Report of Outcomes in Year 1.

BACKGROUND: Best practice in dialysis is synthesised in clear international guidelines. However, a large gap remains between the international guidelines and the actual delivery of care. In this paper, we report outcomes for the first year of a multifaceted dialysis improvement programme in our network. METHODS: One year collaborative involving 3 haemodialysis units and a peritoneal dialysis (PD) programme involving 299 dialysis patients. Each unit addressed a different indicator (unit A - catheter-related bloodstream infection [CRBSI], unit B - pre-dialysis blood pressure [BP], unit C - dialysis dose, unit D - anaemia) with a shared aim to match the top 10% in the UK. Tailored multifaceted approaches include a modified collaborative methodology with an aim, framework, driver diagram, learning sessions, facilitated meetings, plan-do-study-act cycles and continuous measurement. Analysis of outcomes, costings, erythropoietin stimulating agent and iron use, and safety culture attributes. RESULTS: Unit A reduced CRBSI from 2.65 to 0.5 per 1,000 catheter days (p = 0.02). Unit B improved attainment of target BP from 37.5 to 67.2% (p = 0.003). Unit C improved attainment of target urea reduction ratio from 75.8 to 91.4% (p = 0.04). PD unit D improved attainment of target haemoglobin from 45.5 to 62.7% (p = 0.01), with no significant change in the indicators in a non-intervention unit. Safety culture attributes improved. Costs associated with admission for fluid overload and infection, erythropoietin, iron and thrombokinase use decreased 36% (£415,620-£264,143). CONCLUSIONS: Units that took part in this collaborative improved guideline adherence compared both to their own pre-intervention performance and a non-intervention unit. Such multifaceted interventions are a useful methodology to improve dialysis care.

The Associations of Blood Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin with Progression from CKD to ESRD.

BACKGROUND AND OBJECTIVES: Elevated levels of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are associated with negative outcomes in CKD. Our study aimed to explore the prognostic accuracy of blood levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for progression to ESRD, major adverse cardiovascular events, and death in a large cohort of adult patients with all-cause nondialysis-dependent CKD stages 3-5. We considered whether these factors improve prediction in relation to traditional biomarkers and clinical parameters. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were measured on baseline plasma samples from 1982 patients who were recruited to the Chronic Renal Insufficiency Standards Implementation Study between the start of June of 2002 and the start of June of 2013. Associations with study end points were assessed using Cox regression models, receiver operator characteristic curve analyses, and reclassification statistics. RESULTS: Over a median follow-up of 29.5 months (interquartile range, 14.9-53.5), 21.6% of patients progressed to ESRD, 27% died, and 6.6% suffered a major adverse cardiovascular event. Higher blood levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were independently associated with a greater risk for ESRD (hazard ratio, 1.25; 95% confidence interval, 1.10 to 1.43; P<0.001 and hazard ratio, 1.35; 95% confidence interval, 1.14 to 1.59; P≤0.001, respectively, per 1 SD higher biomarker concentration). There was no association with risk for cardiovascular events or death. The addition of biomarkers to our baseline risk model of traditional clinical characteristics and laboratory parameters did not significantly improve model discrimination or risk reclassification. CONCLUSIONS: In patients with moderate to severe CKD, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin blood levels are independent risk factors for progression to ESRD. Additional studies are needed to establish the utility and cost-effectiveness of these novel biomarkers in the clinical setting.

OLDER PEOPLE WITH CHRONIC KIDNEY DISEASE: DEFINITION, AND INFLUENCE OF BIOMARKERS AND MEDICATIONS UPON CARDIOVASCULAR AND RENAL OUTCOMES.

BACKGROUND: Chronic kidney disease (CKD) is a global problem. With an ageing population the burden on the health services has increased due to the growing number of older people with CKD. This group of individuals is far different to the younger CKD population and their risk of cardiovascular death is far greater than the risk of progressing to end stage kidney disease (ESKD). OBJECTIVE: In this review we explore the role of certain biomarkers and medications in predicting the risk of progression to ESKD and death in old people with CKD. METHODS: An electronic literature search of EMBASE and MEDLINE databases was performed using Healthcare Databases Advanced Search (HDAS) in December 2014. RESULTS: Albuminuria is a key biomarker in predicting the risk of death and progression to ESKD. Cystatin C appears to be superior in predicting the risk of cardiovascular and non-cardiovascular death compared to GFR or creatinine. Several inflammatory biomarkers can be used to predict the risk of death and progression to CKD but measuring and monitoring them in routine clinical practice will be expensive and impractical. The effects of long-term RAAS inhibition in older people are not well established. Older people especially those with CKD receive suboptimal secondary preventive measures. Due to multiple comorbidities older people with CKD are usually receiving a number of medications. This can potentially lead to significant adverse drug events (ADE) due to drug interactions. CONCLUSION: Novel non-traditional risk factors like albuminuria, Cystatin C and inflammatory biomarkers play an important role in predicting their risk of death and progression to ESKD. The efficacy and safety of medications in older people with CKD is not well established and requires more extensive, focused study.

Body mass index has no effect on rate of progression of chronic kidney disease in non-diabetic subjects.

BACKGROUND: Chronic kidney disease (CKD) is increasingly prevalent worldwide. Furthermore, obesity is now a global problem with major health implications. There is a clear association between obesity and the development of CKD but it is not known whether obesity is a risk factor for the progression of pre-existing kidney disease. We examined the relationship between the body mass index (BMI) and the rate of progression of CKD in non-diabetic adults. METHODS: The Chronic Renal Insufficiency Standards Implementation Study (CRISIS) is a prospective observational study in a predominantly white population in Greater Manchester. From the CRISIS database, we assessed rate of progression of CKD in 499 adults attending the hospital. Baseline measurements including BMI were obtained and estimated glomerular filtration rate (eGFR) was monitored. The rate of deterioration of eGFR was derived over time, defined as ΔeGFR (mL/min/1.73 m2/year) and assessed using univariate analysis of variance. RESULTS: In the groups as a whole, no relationship between BMI and ΔeGFR was shown. Dividing the subjects into obese (BMI≥30) and non-obese (BMI<30) groups and further breakdown into CKD stages 3, 4 and 5, also showed no relationship between BMI and ΔeGFR. Univariate analysis of variance was used. CONCLUSIONS: Neither BMI as a continuous variable nor obesity (BMI≥30) as a categorical variable was associated with an increased rate of progression of existing CKD in this predominantly white population.

The use of eGFR and ACR to predict decline in renal function in people with diabetes.

BACKGROUND: There have been few attempts to estimate progression of kidney disease in people with diabetes in a single large population with predictive modelling. The aim of this study was to investigate the rate of progression of chronic kidney disease in people with diabetes according to their estimated glomerular filtration rate (eGFR) and presence of albuminuria. METHODS: Data were collected on all people with diabetes in Salford, UK, where an eGFR could be calculated using the four-variable MDRD formula and urinary albumin-creatinine ratio (uACR) was available. All data between 2001 and 2007 were used in the model. Classification of albuminuria status was based on the average of their first two uACR measurements. A longitudinal mixed effect dynamic regression model was fitted to the data. Parameters were estimated by maximum likelihood. RESULTS: For the analysis of the population, average progression of eGFR, uACR and drug prescribing were available in 3431 people. The regression model showed that in people with diabetes and macroalbuminuria, eGFR declined at 5.7% per annum, while the eGFR of those with microalbuminuria or without albuminuria declined at 1.5% and 0.3% per annum, respectively, independently of age (P < 0.0001). CONCLUSIONS: The longitudinal effect of time on eGFR showed that people with diabetes and macroalbuminuria have an estimated 19 times more rapid decline in renal function compared with those without albuminuria. This study demonstrates that the progression of kidney disease in diabetic people without albuminuria is relatively benign compared with those with albuminuria.

Factors associated with kidney disease progression and mortality in a referred CKD population.

BACKGROUND: Knowing how kidney disease progresses is important for decision making in patients with chronic kidney disease (CKD) and for designing clinical services. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We examined renal function trajectories in CRISIS (Chronic Renal Insufficiency Standards Implementation Study), in which 1,325 patients with CKD stages 3-5 and mean age of 65.1 years were followed up prospectively for a median of 26 months after referral to a regional nephrology center in the United Kingdom. By protocol, estimated glomerular filtration rate was determined every 12 months. PREDICTORS: CKD stage defined as estimated glomerular filtration rate ≥ 45 (stage 3a), 30-44 (3b), 15-29 (4), and < 15 (5) mL/min/1.73 m². OUTCOMES: Onset of renal replacement therapy (RRT), death, the composite end point of RRT or death, or decreasing CKD stage. RESULTS: During a median follow-up of 26 months, 13% reached the end point of RRT (5.1 events/100 patient-years), 20% died (9.6 deaths/100 patient-years), and 33% reached the combined end point of RRT or death (14.7 events/100 patient-years). For stage 3a, baseline prevalence and annual probabilities of decreasing CKD stage, RRT, and death were 18.0%, 0.41, 0.01, and 0.02, respectively. Corresponding values for stage 3b were 32.5%, 0.22, < 0.01, and 0.06; for stage 4, 36.5%, 0.17, 0.03, and 0.10; and for stage 5, 13.2%, zero (by definition), 0.31, and 0.08, respectively. Markov model projections suggested a steady decrease for proportions with stages 3a, 3b, and 4; a steady increase for death and RRT; and a biphasic pattern for (non-RRT) stage 5, with a plateau in the first 2 years followed by a steady decrease. LIMITATIONS: Single-center observational study. CONCLUSION: This study suggests that death and RRT are the dominant outcomes in patients referred for management of CKD and that most patients spend comparatively little time in late stages without RRT.

Serum phosphate and mortality in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective longitudinal study examined whether phosphate level was associated with death in a referred population. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets. RESULTS: Mean (SD) eGFR was 32 (15) ml/min per 1.73 m(2), age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality. CONCLUSIONS: In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival.

Circulating methylarginine levels and the decline in renal function in patients with chronic kidney disease are modulated by DDAH1 polymorphisms.

In patients with chronic kidney disease, high plasma levels of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, are thought to contribute to decline in renal function. Here we took a candidate gene approach to determine any causal role of asymmetric dimethylarginine in the progression of chronic kidney disease. The impact of single-nucleotide polymorphisms in the genes encoding the two isoforms of the asymmetric dimethylarginine-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), on enzyme expression, plasma asymmetric dimethylarginine levels, and longitudinal changes in estimated glomerular filtration rate were determined in various patient groups. There was evidence suggesting that the rs17384213 DDAH1 GG genotype was associated with increased expression of its mRNA in kidney allografts. Healthy subjects carrying the rs17384213 G allele had lower plasma asymmetric dimethylarginine, and a similar borderline association was found in patients with chronic kidney disease. This allele, however, was independently associated with a steeper decline in renal function in two separate cohorts of patients with chronic kidney disease. We conclude that polymorphisms in DDAH1 alter the rate of decline of glomerular filtration rate in subjects with chronic kidney disease. Our findings show that DDAH1 modulates plasma asymmetric dimethylarginine and contributes to the decline in renal function. However, it appears that increases in circulating methylarginine did not mediate progressive kidney injury.

The effects of statins on the progression of atherosclerotic renovascular disease.

BACKGROUND/AIMS: The aim was to examine the influence of statin therapy on the natural history of atherosclerotic renal artery stenosis (RAS). METHODS: Our hospital atherosclerotic renovascular disease (ARVD) database was analysed for patients who underwent repeat renal angiography during clinical follow-up. Patients with >or=1 RAS lesion and >or=4 months between baseline and repeat renal angiography were analysed. 79 patients were included. Baseline renal arterial anatomy was classified as normal, 50% RAS or renal artery occlusion. RESULTS: Mean follow-up time between angiograms was 27.8 +/- 22.3 (4.0-101.9) months. Progression of RAS occurred in 28 (23%) vessels, regression in 14 (12%) and no significant change in 79 (65%). Multivariate regression analysis showed that baseline proteinuria >0.6 g/day increased the risk of progressive disease (relative risk, RR, 3.8; 95% confidence interval, CI, 1.2-12.1), treatment with statin reduced the risk of progression (RR 0.28; 95% CI 0.10-0.77). 14 renal arteries from 12 patients showed RAS regression with a greater proportion on statin [statin treatment 10 (83%) versus no statin treatment 2 (17%), p = 0.001]. Change in estimated glomerular filtration rate (eGFR) per year was not different between statin- and no-statin-treated groups. CONCLUSIONS: Progression or development of RAS was significantly less likely to occur with statin therapy. Delta eGFR did not correlate with progression of RAS, reflecting the importance of intrarenal injury in the aetiology of renal dysfunction. Our results suggest statin therapy can alter the natural history of ARVD.

The unrecognized prevalence of chronic kidney disease in diabetes.

BACKGROUND: Diabetes mellitus and chronic kidney disease (CKD) are common and exhibit synergistic associations with premature mortality. Current diabetes guidelines in the UK recommend annual urinary albumin and serum creatinine determinations to screen for diabetic kidney disease. The aim of this study was to estimate the burden of CKD in patients with diabetes and examine the ability of serum creatinine and albuminuria to detect clinically meaningful CKD compared with estimated glomerular filtration rate (eGFR). METHODS: All adults known to have diabetes in primary and secondary care in Salford, UK, alive with independent renal function on 1 January 2004 were included in this observational study (n=7596). Demographic and laboratory parameters were obtained from the Electronic Patient Record. eGFR was determined using the 4-variable modification of diet in renal disease (MDRD) formula. Clinically meaningful CKD was defined as an eGFR <60 ml/min/1.73 m(2). RESULTS: Creatinine and albuminuria were measured in the preceding 2 years in 82.3 and 55.2% of subjects, respectively. In patients with CKD, normoalbuminuria was present in 48.8%, and serum creatinine was normal (or=120 micromol/l) had a sensitivity and specificity of 45.3 and 100%, respectively, to identify CKD. The combination of abnormal creatinine and albuminuria had an improved performance but still failed to detect a large number with CKD (sensitivity 82.4%, specificity 75.4%). Serum creatinine failed to identify CKD more often in females (OR 8.22, CI 6.56-10.29). CONCLUSIONS: Undiagnosed CKD is common in diabetes. Current screening strategies, based on creatinine or albuminuria, fail to identify a considerable number of subjects with CKD. Incorporating eGFR into screening for CKD would identify individuals earlier in the natural history of the disease and enable early effective treatment to delay progression of CKD.