Faster Chronic Kidney Disease Progression Research Articles

#5302 REVISITING THE PATHOGENIC ROLE OF THE SLC8A1 GENE IN A FAMILY WITH A NOVEL TERMINAL GROSS DELETION IN THE UMOD GENE

Abstract Background and Aims Autosomal dominant tubulointerstitial kidney disease (ADTKD) - the third most common genetic disorder in adults with CKD - comprises a heterogeneous group of rare, hereditary kidney diseases characterized by family history of progressive chronic kidney disease (CKD) with bland urine sediment, absence of significant proteinuria and normal or small-sized kidneys. Biopsy findings are nonspecific and the gold standard for definitive diagnosis is identification of a pathogenic variant in the genes UMOD, MUC1, HNF1β, REN or SEC61A1. Method Case report. Results The proband was a 27-year-old white male referred for CKD, KDIGO stage 3a. His medical history was relevant for nocturnal enuresis until age 10; arterial hypertension diagnosed at age 19; and asymptomatic hyperuricemia, disproportional to the level of renal function impairment. Urinalysis was negative for protein, red blood cells or leucocytes and magnetic resonance imaging showed normal sized kidneys with bilateral cysts in the medulla and the corticomedullary junction. The family pedigree (Figure 1) illustrates that hyperuricemic nephropathy and CKD segregated in this family with an autosomal dominant pattern of inheritance. A custom NGS-based gene panel allowed to identify in the proband (IV-2) and his affected brother (IV-1): (i) a previously unreported large deletion in the UMOD gene, encompassing the entire exon 11, classified as “likely pathogenic”; ii) an ultra-rare nonsense SLC8A1 allele — c.16C>T p.(Arg6*), classified as “variant of uncertain clinical significance (VUS)”; (iii) an ultra-rare missense variant in the gene encoding polycystin-1 (PKD1) — c.9170T>C p.(Val3057Ala), classified as VUS. Since the latter was inherited from their healthy mother (III-1) it was considered a benign variation, similar to the more common p.Val3057Met variant affecting the same codon. Other affected family member (III-5) was heterozygous for the UMOD exon 11 deletion, which was excluded in two healthy relatives (III-1, III-4), establishing the primary diagnosis of ADTKD-UMOD. It is noteworthy that the only two gross UMOD deletions associated with ADTKD affected evolutionarily conserved residues in exon 4 [1]. The presence of the SLC8A1 p.(Arg6*) allele in patients IV-1 and IV-2, who had early clinical presentations, together with its absence in patient III-5, who had a significantly later clinical onset than her older brother (III-2), suggests that it exerted a pathogenic or disease modifier role in this family, in accordance with the predicted protein truncating effect. Indeed, genome-wide linkage analysis in 5 multiplex families with ADTKD identified involvement of chromosome 2p22.1-p21; SLC8A1 was the most likely gene but no pathogenic variants could be identified; copy number variants might have been missed [2]. Unfortunately, in our family study, we could not identify any subject segregating only the SLC8A1 p.(Arg6*) allele, which would have been indispensable to demonstrate its pathogenicity. Conclusion Herein, we report a family with hyperuricemic nephropathy where genetic testing identified a novel, likely pathogenic UMOD variant. The mechanisms underlying the pathogenicity of exon 11 deletion require further study. Additionally, the co-segregation of an ultra-rare nonsense SLC8A1 variant in some individuals was associated with earlier onset and faster progression of CKD, suggesting once again a role for SLC8A1 in the pathogenesis of ADTKD.

Reducing Dietary Acid With Fruit and Vegetables Versus Oral Alkali in People With Chronic Kidney Disease (ReDACKD): A Clinical Research Protocol.

Individuals with chronic kidney disease (CKD) can develop metabolic acidosis which, in turn, is associated with faster progression of CKD and an increased need for dialysis. Oral sodium bicarbonate (the current standard of care therapy for metabolic acidosis) is poorly tolerated leading to low adherence. Base-producing or alkalizing Fruit and vegetables have potential as an alternative treatment for metabolic acidosis as they have been shown to reduce acid load arising from the diet. This trial will evaluate the feasibility of providing base-producing fruit and vegetables as a dietary treatment for metabolic acidosis, compared with oral sodium bicarbonate. A 2-arm, open-label, dual-center, randomized controlled feasibility trial. Two Canadian sites: a nephrology clinic in Winnipeg, Manitoba, and a nephrology clinic in Halifax, Nova Scotia. Adult participants with G3-G5 CKD and metabolic acidosis. Participants will undergo baseline measurements and attend 5 study visits over 12 months at which they will have a measurement of feasibility criteria as well as blood pressure, blood and urine biochemistry, 5-repetition chair stand test (STS5), and questionnaires to assess quality of life and symptoms. Furthermore, participants fill out Automated Self-Administered 24-hour recalls (ASA-24) in the beginning, middle, and end of trial. A total of 40 eligible participants will be randomized 1:1 to either base-producing fruit and vegetables (experimental) group or sodium bicarbonate (control) group, beginning from a daily dose of 1500 mg. Using self-administered dietary assessments, lack of supervision over the consumption of study treatments and the possible disappointment of the control group for not receiving fruit and vegetables would be considered as limitations for this study. However, we are planning to undertake proper practices to overcome the possible limitations. These practices are discussed throughout the article in detail. This study will generate data on base-producing fruit and vegetables consumption as a dietary treatment for metabolic acidosis in CKD. The data will be used to design a future multi-center trial looking at slowing CKD progression in people with metabolic acidosis. This study is registered on clinicaltrials.gov with the identifier NCT05113641.

MO086: Sex Differences in Ambulatory Blood Pressure Trajectories and Blood Pressure Variability in Hemodialysis Patients

Abstract BACKGROUND AND AIMS Ambulatory blood pressure (BP) control is worse in men than in women with chronic kidney disease (CKD), and this may partially explain the faster CKD progression in men. The aim of this study is to investigate possible sex-differences in ambulatory BP levels, BP trajectories and BP variability (BPV) in hemodialysis patients. METHOD 129 male and 91 female hemodialysis patients that underwent 48-h ABPM with Mobil-O-Graph-NG were included in this analysis. Ambulatory BP levels over the 2-day interdialytic interval (including two daytime and two nighttime periods) were recorded. We calculated the standard deviation (SD), weighted SD (wSD), coefficient of variation (CV) and average real variability (ARV) of BP with validated formulas. RESULTS Age, dialysis vintage, antihypertensive treatment and history of major comorbidities did not differ between men and women. Pre-dialysis SBP levels did not differ between men and women (145.1 ± 22.7 versus 145.9 ± 25.7 mmHg, P = 0.808), but DBP was marginally higher in men (87.6 ± 14.0 versus 84.0 ± 13.7 mmHg, P =0.055). About 48-h SBP/DBP (137.2 ± 17.4/81.9 ± 12.1 mmHg versus 132.2 ± 19.2/75.9 ± 11.7 mmHg, P = 0.045/<0.001) as well as DBP during the first and SBP/DBP during the second 24-h period were significantly higher in men than in women. Similarly, daytime SBP/DBP was significantly higher in men (138.3 ± 17.5/83.2 ± 12.3 mmHg versus 131.9 ± 19.4/76.4 ± 11.5 mmHg, P = 0.011/<0.001). No significant between-group differences were detected for nighttime SBP. All SBP variability indices were similar between men and women; DBP-SD, DBP-wSD and DBP-ARV were higher in men (44-h DBP-ARV 9.4 ± 1.8 versus 8.6 ± 1.9, P = 0.002). No significant differences were revealed in the dipping pattern between men and women. CONCLUSION Ambulatory BP levels and trajectories, as well as DBP variability indices are higher in men than women hemodialysis patients. This worse ambulatory BP profile in male compared to female patients may impact on the incidence of cardiovascular events.

Safety and Efficacy of DOACs in Patients with Advanced and End-Stage Renal Disease.

The prevalence of chronic kidney disease (CKD) is increasing due to the aging of the population and multiplication of risk factors, such as hypertension, arteriosclerosis and obesity. Impaired renal function increases both the risk of bleeding and thrombosis. There are two groups of orally administered drugs to prevent thromboembolic events in patients with CKD who require anticoagulation: vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). Although VKAs remain the first-line treatment in patients with advanced CKD, treatment with VKAs is challenging due to difficulties in maintaining the appropriate anticoagulation level, tendency to accelerate vascular calcification and faster progression of CKD in patients treated with VKAs. On the other hand, the pleiotropic effect of DOACs, including vascular protection and anti-inflammatory properties along with comparable efficacy and safety of treatment with DOACs, compared to VKAs observed in preliminary reports encourages the use of DOACs in patients with CKD. This review summarizes the available data on the efficacy and safety of DOACs in patients with CKD and provides recommendations regarding the choice of the optimal drug and dosage depending on the CKD stage.

Hyperuricaemia, gout and allopurinol in the CKD Queensland registry

IntroductionThere is scant data on the role of hyperuricaemia, gout and allopurinol treatment in chronic kidney disease (CKD). Therefore, our aim is to investigate the possible associations between hyperuricaemia, gout, prescription of allopurinol and renal outcomes in patients with CKD.MethodsThe retrospective cohort study involved 1123 Royal Brisbane and Women’s Hospital (RBWH) patients, enrolled in the CKD.QLD registry from May 2011 to August 2017. Patients were divided into two uric acid categories, with uric acid ≤ 0.36 mmol/L and > 0.36 mmol/L. Association of delta estimated glomerular filtration rate (eGFR) with gout, allopurinol treatment and hyperuricaemia were analysed.ResultsPatients with an entry urate > 0.36 mmol/L were older, had higher body mass index (BMI) and worse baseline kidney function. Proportion of patients with gout, hyperuricaemia and allopurinol treatment increased with advanced CKD stages. Age-adjusted analysis revealed a significant association between serum urate level and delta eGFR, with no significant association between gout, treatment with allopurinol and delta eGFR. Furthermore, neither gout nor the prescription of allopurinol had a significant effect on the time to renal death (composite end point of kidney replacement therapy or death).ConclusionHyperuricaemia seemed to be independently associated with faster CKD progression or renal death. This was not observed with gout or prescription of allopurinol. Furthermore, allopurinol was not associated with decreased incidence of cardiovascular events. These data suggest that hyperuricaemia is likely the effect and not the cause of CKD or CKD progression.Graphic abstract

Low expression of HIV genes in podocytes accelerates the progression of diabetic kidney disease in mice

With the widespread use combination antiretroviral therapy, there has been a dramatic decrease in HIV-associated nephropathy. However, although the patients living with HIV have low or undetectable viral load, the prevalence of chronic kidney disease (CKD) in this population remains high. Additionally, improved survival is associated with aging-related comorbidities such as diabetes and cardiovascular disease. A faster progression of CKD is associated with concurrent HIV infection and diabetes than with HIV infection or diabetes alone. To explore the potential pathogenic mechanisms that synergistically drive CKD progression by diabetes and HIV infection, we generated a new mouse model with a relatively low expression of HIV-1 proviral genes specifically in podocytes (pod-HIV mice) to better mimic the setting of kidney injury in patients living with HIV. While no apparent kidney phenotypes were observed at baseline in pod-HIV mice, the induction of mild diabetic kidney disease with streptozotocin led to significant worsening of albuminuria, glomerular injury, podocyte loss, and kidney dysfunction as compared to the mice with diabetes alone. Mechanistically, diabetes and HIV-1 synergistically increased the glomerular expression of microRNA-34a (miR-34a), thereby reducing the expression of Sirtuin-1 (SIRT1) deacetylase. These changes were also associated with increased acetylation and activation of p53 and p65 NF-κB and with enhanced expression of senescence and inflammatory markers. The treatment of diabetic pod-HIV mice with the specific Sirtuin-1 agonist BF175 significantly attenuated albuminuria and glomerulopathy. Thus, our study highlights the reduction in Sirtuin-1 as a major basis of CKD progression in diabetic patients living with HIV and suggests Sirtuin-1 agonists as a potential therapy.

Alfa-1-microglobulina: valor pronóstico en la enfermedad renal crónica

Objectivesα1-microglobulin (α1M) is a tubular protein used for detecting acute lesions of proximal tubules. This study evaluated the use of urine α1M excretion as a marker of chronic kidney disease (CKD) progression and life survival. Design and methodsIn all 163 patients were recruited (90 men), mean age 61.6±16.4 years. Urinary α1M was evaluated using an immunonephelometric assay. Patients were divided into 2 groups according to urinary α1M excretion (cut-off value: 32.85mg/24h). ResultsEnd stage renal disease-free survival was 94.2% at 5 years for patients with lower α1M. For patients in the highest percentile, renal function survival was 72.7% (P=.011). Life survival was 94.4% for patients with α1M in the lower percentiles. For patients in the upper percentile, live survival was 54.2% (P=.001). The Cox regression analysis showed an independent association of CKD progression with high α1M excretion (P=.043). Conclusionsα1M urinary excretion was associated with faster CKD progression and higher mortality. Further studies are needed to determine whether the association between α1M urinary excretion and excess mortality risk represents a causal link.

MO026TREATMENT WITH ACTIVE VITAMIN D DOES NOT IMPROVE LEFT VENTRICULAR HYPERTROPHY BUT FURTHER INCREASES FGF23 AND ACCELERATES CKD PROGRESSION IN CHILDREN

Abstract Background and Aims Elevated FGF23, activation of the renin-angiotensin-aldosterone system (RAAS), and vitamin D and Klotho deficiency promote left ventricular hypertrophy (LVH) and LV fibrosis in chronic kidney disease (CKD). Whether treatment with active vitamin D affects uremic cardiomyopathy and/or FGF23/Klotho system in CKD is unclear. Method 5/6 nephrectomized (5/6Nx) rats, as a well-established model of CKD, were dose-dependently treated with calcitriol for 10 weeks and the cardiac phenotype, including local RAAS activation, was investigated compared to untreated 5/6Nx and sham-operated rats. Additionally, 38 children with eGFR ≤ 30 ml/min/1.73 m2 selected from the Cardiovascular Comorbidity in Children with CKD (4C) study were enrolled in a case-control study. Nineteen children were started on active vitamin D treatment with either calcitriol or calcidiol (average dosage 0.4 μg/day), and 19 CKD children with non-active vitamin D treatment matched for age, eGFR, serum calcium, parathyroid hormone, and phosphate served as controls. LV mass index (LVMI), LVH prevalence (LVMI >95th percentile), intact (iFGF23) and C-terminal FGF23 (cFGF23), and soluble Klotho (sKlotho) were assessed at baseline and after nine months. Results In 5/6Nx rats, FGF23 synthesis in bone and heart was enhanced compared to sham-operated rats, and calcitriol further stimulated its expression in bone only. Renal Klotho expression was reduced in 5/6 rats and almost normalized after calcitriol treatment. 5/6Nx induced cardiomyocyte growth and LV fibrosis, and calcitriol treatment significantly ameliorated both. Cardiac RAAS genes, such as angiotensinogen, renin, angiotensin-converting-enzyme, and angiotensin II receptor type I, were significantly upregulated in 5/6Nx rats compared to sham-operated animals, and normalized by calcitriol treatment. In the 4C study cohort, median plasma cFGF23 and iFGF23 were significantly elevated in both groups, whereas sKlotho was not altered compared to healthy children. Forty-seven percent and 42% of active vitamin D-treated patients and controls, respectively, received blood pressure (BP) medications, however diastolic BP was slightly but significantly enhanced in both groups compared to healthy children. Mean LVMI and LVH prevalence of 47% in active vitamin D-treated patients and controls did not differ at baseline. After nine months, median cFGF23 and iFGF23 were significantly increased in active vitamin D-treated patients compared to controls. sKlotho levels were decreased in the active vitamin D-treated group compared to baseline but not in controls. A significant decline in median eGFR was observed in active vitamin D group but not in controls. Likewise, the median eGFR change during the observation period was higher in the active vitamin D group compared to controls. Median LVMI as well as frequency of LVH did not change significantly during vitamin D treatment, nor in controls. Consequently, final median LVMI as well as percentage of patients with LVH did not significantly differ between groups. Conclusion Calcitriol treatment in 5/6Nx rats improves cardiac hypertrophy and fibrosis, reduces uremia-induced cardiac RAAS gene expression, and improves renal Klotho expression. By contrast, treatment with active vitamin D does not decrease the prevalence of LVH in children with advanced CKD compared to matched controls. This may be due to further enhancement of FGF23 levels, faster progression of CKD associated with reduced Klotho in active vitamin D-treated patients and/or concomitant treatment with RAAS inhibitors. The latter may blunt the favorable effects of calcitriol on the activated RAAS.

Alcohol Consumption and Progression of Chronic Kidney Disease: Results From the Korean Cohort Study for Outcome in Patients with Chronic Kidney Disease

ObjectiveTo assess the association of alcohol consumption with chronic kidney disease (CKD) progression in patients with CKD. Patients and MethodsThe KoreaN cohort study for Outcome in patients with CKD (KNOW-CKD) is a prospective observational study that included detailed questionnaires regarding alcohol consumption. The 1883 individuals with CKD were enrolled from April 1, 2011, through February 28, 2016, and followed until May 31, 2017. Using a questionnaire, alcohol consumption pattern was classified according to the amount of alcohol per occasion (none, moderate, or binge) or drinking frequency (none, occasional, or regular). The primary endpoint was a composite of 50% or greater decline in estimated glomerular filtration rate (eGFR) from the baseline level or end-stage renal disease. ResultsDuring a follow-up of 5555 person-years (median, 2.95 years), the primary outcome occurred in 419 patients. Unadjusted cause-specific hazards model showed that the risk of the primary outcome was lower in drinkers than in non-drinkers. However, a fully adjusted model including eGFR and proteinuria yielded a reverse association. Compared with non-drinking, regular and occasional binge drinking were associated with a 2.2-fold (95% CI, 1.38-3.46) and a 2.0-fold (95% CI, 1.33-2.98) higher risk of CKD progression, respectively. This association was particularly evident in patients who had decreased kidney function and proteinuria. There was a significant interaction between alcohol consumption and eGFR for CKD progression. The slopes of eGFR decline were steeper in binge drinkers among patients with eGFR less than 60 mL/min/1.73 m2. ConclusionsHeavy alcohol consumption was associated with faster progression of CKD.

SAT-175 TRAJECTORIES OF KIDNEY FUNCTION AND THEIR PREDICTORS: FINDINGS FROM THE CHRONIC RENAL INSUFFICIENCY COHORT (CRIC) STUDY

Change in kidney function is not uniform across patients with chronic kidney disease (CKD). Kidney function trajectories and their predictors are poorly characterized and likely differ by diabetes status. The Chronic Renal Insufficiency Cohort (CRIC) Study is an on-going, multi-center, prospective cohort study of men and women with moderate to advanced CKD implemented in seven centers across the United States. Data from 3,939 CRIC participants (51% with diabetes and 44% non-Hispanic black) over the first five years of follow-up was used to determine groupings based on estimated glomerular filtration rate (eGFR) trajectories from group-based trajectory models using Stata version 14.2. Predictors of kidney function trajectories were selected from among 30 established and novel sociodemographic, clinical and biochemical factors from study baseline. Final models were generated after step-wise selection using multinomial logistic regression models for those with and without diabetes, separately. Three cubic kidney function trajectory groupings best fit the longitudinal pattern of eGFR change among CRIC participants with and without diabetes (Figure). The stable trajectories centered around 72 mL/min/1.73m2 for those without diabetes, around 62 mL/min/1.73m2 for those with diabetes, and included 21.1% and 14.9% of those participants, respectively. The middle trajectories included 42.3% of those without diabetes and 42.6% with diabetes, and reflected, on average, less than a one mL/min/1.73m2 decline per year. The steepest trajectories included 36.6% and 42.5% of those without and with diabetes, respectively. Predictors of steeper eGFR trajectories included established risk factors such as baseline eGFR and albuminuria for both diabetics and non-diabetics. Novel risk factors included NTproBNP and PTH regardless of diabetes status, smoking among non-diabetics, and serum bicarbonate, CX3CL1 (an inflammatory chemokine) and NGAL among those with diabetes. Between 15-20% of those with and without diabetes appear to have stable kidney function over five years of follow-up, while the remainder of diabetics have slightly steeper kidney function trajectories, on average, compared to those without diabetes in the CRIC Study. Shared predictors of steeper eGFR trajectories across diabetes status included a cardiac marker and a marker of mineral metabolism. Among diabetics, inflammatory and kidney injury markers are also significantly associated with faster CKD progression.

Management of Hypertension in CAKUT: Protective Factor for CKD.

Patients with congenital kidney and urinary tract abnormalities (CAKUT) will often develop end-stage renal disease at some point and the need for renal replacement therapy is associated with high rates of morbidity and mortality. Hence, efforts to slow the progression of the disease are essential. Hypertension has been proven to be an independent risk factor for faster decline of glomerular filtration rate in renal patients, but studies involving only children with CAKUT are scarce. We performed a literature review to explore the association of hypertension with faster chronic kidney disease progression in children with CAKUT and also treatment options in this condition. A recent study reported an annual decline in GFR of 1.8 ml/min/1.73 m2 among hypertensive patients with non-glomerular CKD, compared with 0.8 ml/min/1.73 m2 in normotensive children. A multicenter prospective cohort in Brazil showed that a 1-unit increase in systolic blood pressure Z-score was associated with a 1.5-fold higher risk of disease progression. Since renin-angiotensin-aldosterone system activation is the most important mechanism of hypertension in these children, the first-line therapy involves the use of inhibitors of this axis, including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers type I, which also promote an anti-fibrotic effect. Recent studies have shown a good safety profile for use in patients with chronic kidney disease and also in those with solitary kidneys. Hypertension is an independent risk factor for kidney disease progression and should be promptly managed for renal protection, especially among patients with CAKUT, the primary cause of chronic kidney disease in the pediatric population.

Neuropeptide Y and chronic kidney disease progression: a cohort study.

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that has been implicated in various disorders including obesity, gastrointestinal and cardiovascular diseases. We investigated the relationship between circulating NPY and the progression of the glomerular filtration rate (GFR) and proteinuria and the risk for a combined renal endpoint (>30% GFR loss, dialysis/transplantation) in two European chronic kidney disease (CKD) cohorts including follow-up of 753 and 576 patients for 36 and 57 months, respectively. Average plasma NPY was 104 ± 32pmol/L in the first CKD cohort and 119 ± 41pmol/L in the second one. In separate analyses of the two cohorts, NPY associated with the progression of the estimated GFR (eGFR) and proteinuria over time in both unadjusted and adjusted {eGFR: -3.60 mL/min/1.73m2 [95% confidence interval (CI): -4.46 to - 2.74] P < 0.001 and -0.83 mL/min/1.73m2 (-1.41 to - 0.25, P = 0.005); proteinuria: 0.18 g/24 h (0.11-0.25) P < 0.001 and 0.07 g/24 h (0.005-0.14) P = 0.033} analyses by the mixed linear model. Accordingly, in a combined analysis of the two cohorts accounting for the competitive risk of death (Fine and Gray model), NPY predicted (P = 0.005) the renal endpoint [sub-distribution hazard ratio (SHR): 1.09; 95% CI: 1.03-1.16; P = 0.005] and the SHR in the first cohort (1.14, 95% CI: 1.04-1.25) did not differ (P = 0.25) from that in the second cohort (1.06, 95% CI: 0.98-1.15). NPY associates with proteinuria and faster CKD progression as well as with a higher risk of kidney failure. These findings suggest that the sympathetic system and/or properties intrinsic to the NPY molecule may play a role in CKD progression.

The CHA2DS2-VASc score strongly correlates with glomerular filtration rate and predicts renal function decline over time in elderly patients with atrial fibrillation and chronic kidney disease

BackgroundThe decline of renal function affects stroke risk in patients with atrial fibrillation (AF). Here, we aim to study the predictive value of the CHA2DS2-VASc score, a stroke-risk stratification model in AF, for renal function and renal decline in patients with AF and chronic kidney disease (CKD). MethodsTwo electronic health record cohorts with AF and CKD stage III/IV were evaluated (Cohort #1 (IMS-DA, Germany): 18,539 patients with 125,149 estimated glomerular filtration rate (eGFR) measurements; Cohort #2 (IMS-THIN, United Kingdom): 18,240 patients with 133,676 eGFR measurements). The eGFR trajectories were analysed with multi-level mixed-effects regression and joint models for longitudinal and survival data. ResultsIn IMS-DA, the mean baseline eGFR was 52.0ml/min/1.73m2, and declined by 1.03ml/min/1.73m2/year (95%CI: 0.86–1.19, p<0.0001). In IMS-THIN, the mean baseline eGFR was 48.0ml/min/1.73m2, and declined by 0.44ml/min/1.73m2/year (95%CI: 0.37–0.51, p<0.0001).In both datasets, higher CHA2DS2-VASc scores (median: 4 points) were strongly associated with both lower baseline eGFR (p<0.0001) and faster progression of CKD (p=0.002). Mean baseline eGFR values were higher in patients with a CHA2DS2-VASc score of 0 compared to patients with a score of 8 points. Conversely, the annual declines in eGFR were lower in patients with a score of 0 compared to patients with a score of 8 points in both databases. ConclusionThe CHA2DS2-VASc score can identify AF patient subgroups with lower baseline eGFR and a higher risk of CKD progression, which has important implications for the management of anticoagulation in these patients.

Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort.

Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies. Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point. Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b = -0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD. CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.

Apolipoprotein L1: from obscurity to consistency to controversy

Apolipoprotein L1 (APOL1) is associated with increased incidence of chronic kidney disease (CKD) and end-stage renal disease, and with faster progression of CKD, in African Americans. APOL1 is expressed in intra- and extrarenal vascular tissue, making it a candidate to explain the increased incidence of cardiovascular disease in CKD. This Commentary discusses the disparate results from three studies showing that APOL1 renal risk genotypes are either harmful, neutral, or protective in the context of cardiovascular disease.

Warfarin Therapy That Results in an International Normalization Ratio above the Therapeutic Range Is Associated with Accelerated Progression of Chronic Kidney Disease

Background/Aims: We had previously reported that acute kidney injury (AKI) in warfarin-treated chronic kidney disease (CKD) patients may occur shortly after an acute increase in the International Normalization Ratio (INR) >3.0 with formation of occlusive red blood casts. Recovery from this warfarin-associated AKI is poor. Here we investigated whether excessive warfarin therapy could accelerate the progression of CKD. Methods: We analyzed serum creatinine (SC) and INR in 103 consecutive CKD patients on warfarin therapy in our Nephrology program from 2005 to the present. Results: Forty-nine patients experienced at least 1 episode of INR >3.0. Of these, 18 patients (37%, Group 1) developed an unexplained increase in SC ≧0.3 mg/dl coincident with INR >3.0 (mean SC increase 0.61 ± 0.44 mg/dl); 31 patients (63%, Group 2) showed stable SC (mean SC change 0.04 ± 0.19 mg/dl). Subsequent CKD progression was accelerated in Group 1, but not in Group 2. The 2 groups were not different with respect to demographics, comorbidities, blood pressure, or therapies. However, African Americans were overrepresented in Group 1 (p = 0.035). Conclusions: Overanticoagulation is associated with faster progression of CKD in a high percentage of patients. Our results indicate the need for prospective trials. Nevertheless, we suggest that our findings are sufficiently compelling at this point to justi- fy extra caution in warfarin-treated CKD patients to avoid overanticoagulation.

Differences in progression of CKD and mortality amongst Caucasian, Oriental Asian and South Asian CKD patients

Ethnic differences in chronic kidney disease (CKD) progression are not well characterized but are of interest across and within countries. We followed up a large CKD cohort of patients of three different ethnic origins [Caucasian, Oriental Asian (OA) and South Asian (SA)] from time of nephrology referral in a universal health care system. Key outcomes were time to death and/or renal replacement therapy (RRT) and rate of decline in estimated GFR (eGFR). The effects of known predictors (blood pressure, proteinuria, age, sex, diabetes, cardiovascular disease and medications) and of other laboratory abnormalities were assessed using multivariate modelling techniques, including both Cox proportional hazards and competing risk approach. The cohort comprised 3444 patients (2626 Caucasians, 397 OA and 421 SA). All-cause mortality rates are higher in Caucasians than SA or OA [hazard ratio (HR) 0.693 and 0.803, P < 0.05]. OA and SA have higher risks of progressing to RRT (HR 1.281 and 1.349, P < 0.05) and lower risks of death before RRT (HR 0.718 and 0.520, P < 0.05) compared to Caucasians after adjustment for usual risk factors. However, when adjusted for additional laboratory abnormalities, differences did not persist for progression, but did for survival advantage of Asians. The median rate of decline in eGFR (in millilitres per minute per 1.73m(2)) was significantly slower in Caucasians (-2.11) than in OA (-2.93) or SA (-3.56), P = 0.027. Asians appear to have faster CKD progression and lower mortality rates compared to Caucasians. This effect is not explained by the usual variables, but rates of progression may be related to differences in severity of laboratory abnormalities at different CKD stages. Further research is needed to understand the implications of these findings.

Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population

Fibroblast growth factor-23 (FGF23) is a hormonal regulator of circulating phosphate and vitamin D levels. Serum FGF23 is elevated in chronic kidney disease (CKD) and is a prognostic marker of poor outcomes, such as faster CKD progression and increased mortality in hemodialysis patients. Despite the high prevalence of cardiovascular disease in CKD, the relation between circulating FGF23 and cardiovascular risk factors, both in CKD and in the community, has not been studied in detail. We evaluated the relation between FGF23, left ventricular mass index (LVMI), hypertrophy (LVH) and LV geometry, employing the community-based PIVUS cohort. In total, 795 Swedish men and women aged 70 were included of which 164 had an age-adjusted diminished renal function (estimated glomerular filtration rate < 60 mL/min/1.73 m 2). FGF23 was positively associated with LVMI ( β = 0.11, CI 0.01–0.18), with increased odds for the presence of LVH (OR 1.28, CI 1.09–1.51) and for concentric hypertrophy (OR 1.45, CI 1.19–1.77) in the whole population. All associations were stronger in subjects with eGFR < 60 mL/min/1.73 m 2 ( β = 0.30, CI 0.15–0.46 for LVMI; OR 1.86, CI 1.30–2.67 for the presence of LVH; OR 1.83, CI 1.17–2.85 and OR 1.87, CI 1.08–3.22 for concentric and eccentric hypertrophy, respectively). The results were essentially unaltered in multivariate models. In summary, elevated serum FGF23 levels, even within the normal range, are associated with increased LVMI and increased risk for the presence of LVH in elderly subjects. Additional longitudinal studies that evaluate the predictive power of FGF23 and whether FGF23 has additional clinical applications are needed.

Outcomes Associated with Race in Males with Nondialysis-Dependent Chronic Kidney Disease

Blacks are over-represented among dialysis patients, but they have better survival rates than whites. It is unclear if the over-representation of blacks on dialysis is due to faster loss of kidney function or greater survival (or both) in predialysis stages of chronic kidney disease (CKD). We compared predialysis mortality, incidence of end stage renal disease (ESRD), and slopes of estimated GFR (eGFR) in 298 black versus 945 white male patients with moderate and advanced nondialysis-dependent CKD (NDD-CKD) from a single medical center. Mortality and ESRD incidence were compared in parametric survival models, and slopes of eGFR were assessed in mixed-effects models. Blacks had lower crude mortality and higher crude ESRD incidence. The lower mortality in blacks was explained by differences in case mix, especially a lower prevalence of cardiovascular disease, and the higher incidence of ESRD was explained by differences in case mix and baseline kidney function. The slopes of eGFR were similar in blacks and whites. Lower mortality in black versus white patients is also observed in NDD-CKD and can be accounted for by differences in clinical characteristics. Higher mortality of black patients in earlier stages of CKD may result in the selection of a subgroup with fewer comorbidities and better survival in later stages of CKD. The higher crude ESRD rate in blacks appears to result from lower mortality in late stages of CKD, not faster progression of CKD.