Pro: Should we correct vitamin D deficiency/insufficiency in chronic kidney disease patients with inactive forms of vitamin D or just treat them with active vitamin D forms?

Evidence for the usefulness of using vitamin D to treat 'renal bone disease' is now nearly six decades old. In regular clinical practice, however, it is more like three decades, at most, that we have routinely been using vitamin D to try to prevent, or reverse, the impact of hyperparathyroidism on the skeleton of patients with chronic kidney disease (CKD). The practice has been in the main to use high doses of synthetic vitamin D compounds, not naturally occurring ones. However, the pharmacological impacts of the different vitamin D species and of their different modes, and styles of administration cannot be assumed to be uniform across the spectrum. It is disappointingly true to say that even in 2016 there is a remarkable paucity of evidence concerning the clinical benefits of vitamin D supplementation to treat vitamin D insufficiency in patients with stage 3b-5 CKD. This is even more so if we consider the non-dialysis population. While there are a number of studies that report the impact of vitamin D supplementation on serum vitamin D concentrations (unsurprisingly, usually reporting an increase), and some variable evidence of parathyroid hormone concentration suppression, there has been much less focus on hard or semi-rigid clinical end point analysis (e.g. fractures, hospitalizations and overall mortality). Now, in 2016, with the practice pattern changes of first widespread clinical use of vitamin D and second widespread supplementation of cholecalciferol or ergocalciferol by patients (alone, or as multivitamins), it is now, in my view, next to impossible to run a placebo-controlled trial over a decent period of time, especially one which involved clinically meaningful (fractures, hospitalisation, parathyroidectomy, death) end-points. In this challenging situation, we need to ask what it is we are trying to achieve here, and how best to balance potential benefits with potential harm.

Relationship of FGF23 to indexed left ventricular mass in children with non-dialysis stages of chronic kidney disease.

BACKGROUND: The aim of this study was to evaluate the association of serum intact fibroblast growth factor 23 (FGF23) concentrations with indexed left ventricular mass in children with non-dialysis stages 3-5 of chronic kidney disease (CKD). METHODS: The study cohort comprised 83 children (51 boys; mean age 12.1 ± 3.2 years) with a mean estimated glomerular filtration rate (eGFR) of 32.3 ± 14.6 ml/min/1.73 m(2) who underwent clinic and ambulatory blood pressure measurement (ABPM), echocardiography and evaluation of biochemical markers of CKD-associated mineral bone disease. RESULTS: The mean left ventricular mass index (LVMI) was 35.9 ± 8.5 g/m(2.7) (± standard deviation), with 30 (36.1 %) children showing left ventricular hypertrophy (LVH), all eccentric, as defined using age-specific criteria. For all subjects, the mean FGF23 concentration was 142.2 ± 204.4 ng/l and the normalised distribution following log transformation was 1.94 ± 0.39. There was significant univariate correlation of LVMI with GFR, body mass index (BMI) z-score and calcium intake, but not with 24-h systolic ABPM z-score, log intact parathyroid hormone or log FGF23. On multivariate analysis following adjustment for confounders, only elemental calcium content (g/kg/day) estimated from prescribed calcium-based phosphate binder dose (ß = 154.9, p < 0.001) and BMI z-score (ß = 2.397, p = 0.003) maintained a significant positive relationship with LVMI (model r (2) = 0.225). CONCLUSIONS: We observed no significant relationship of FGF23 with LVMI. Larger studies in children are needed to clarify the roles of calcium-containing phosphate binders and FGF23 with LV mass and their roles in the evolution of the development of adverse cardiovascular outcomes.

Vitamin D analogues to target residual proteinuria: potential impact on cardiorenal outcomes.

Residual proteinuria, the amount of proteinuria that remains during optimally dosed renin-angiotensin-aldosterone system (RAAS) blockade, is an independent risk factor for progressive renal function loss and cardiovascular complications in chronic kidney disease (CKD) patients. Dual RAAS blockade may reduce residual proteinuria but without translating into improved cardiorenal outcomes at least in diabetic nephropathy; rather, dual RAAS blockade may increase the risk of adverse events. These findings have challenged the concept of residual proteinuria as an absolute treatment target. Therefore, new strategies must be explored to address whether by further reduction of residual proteinuria using interventions not primarily targeting the RAAS benefit in terms of cardiorenal risk reduction would accrue. Both clinical and experimental intervention studies have demonstrated that vitamin D can reduce residual proteinuria through both RAAS-dependent and RAAS-independent pathways. Future research should prospectively explore vitamin D treatment as an adjunct to RAAS blockade in an interventional trial exploring clinically relevant cardiorenal end points.

Statins in chronic kidney disease and kidney transplantation.

HMG-CoA reductase inhibitors (statins) have been shown to improve cardiovascular (CV) outcomes in the general population as well as in patients with cardiovascular disease (CVD). Statins' beneficial effects have been attributed to both cholesterol-lowering and cholesterol-independent "pleiotropic" properties. By their pleiotropic effects statins have been shown to reduce inflammation, alleviate oxidative stress, modify the immunologic responses, improve endothelial function and suppress platelet aggregation. Patients with chronic kidney disease (CKD) exhibit an enormous increase in CVD rates even from early CKD stages. As considerable differences exist in dyslipidemia characteristics and the pathogenesis of CVD in CKD, statins' CV benefits in CKD patients (including those with a kidney graft) should not be considered unequivocal. Indeed, accumulating clinical evidence suggests that statins exert diverse effects on dialysis and non-dialysis CKD patients. Therefore, it seems that statins improve CV outcomes in non-dialysis patients whereas exert little (if any) benefit in the dialysis population. It has also been proposed that dyslipidemia might play a causative role or even accelerate renal injury. Moreover, ample experimental evidence suggests that statins ameliorate renal damage. However, a high quality randomized controlled trial (RCT) and metaanalyses do not support a beneficial role of statins in renal outcomes in terms of proteinuria reduction or retardation of glomerular filtration rate (GFR) decline.

Active vitamin D treatment for reduction of residual proteinuria: a systematic review.

Despite renin-angiotensin-aldosterone system blockade, which retards progression of CKD by reducing proteinuria, many patients with CKD have residual proteinuria, an independent risk factor for disease progression. We aimed to address whether active vitamin D analogs reduce residual proteinuria. We systematically searched for trials published between 1950 and September of 2012 in the Medline, Embase, and Cochrane Library databases. All randomized controlled trials of vitamin D analogs in patients with CKD that reported an effect on proteinuria with sample size≥50 were selected. Mean differences of proteinuria change over time and odds ratios for reaching ≥15% proteinuria decrease from baseline to last measurement were synthesized under a random effects model. From 907 citations retrieved, six studies (four studies with paricalcitol and two studies with calcitriol) providing data for 688 patients were included in the meta-analysis. Most patients (84%) used an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker throughout the study. Active vitamin D analogs reduced proteinuria (weighted mean difference from baseline to last measurement was -16% [95% CI, -13% to -18%]) compared with controls (+6% [95% CI, 0% to +12%]; P<0.001). Proteinuria reduction was achieved more commonly in patients treated with an active vitamin D analog (204/390 patients) than control patients (86/298 patients; OR, 2.72 [95% CI, 1.82 to 4.07]; P<0.001). Thus, active vitamin D analogs may further reduce proteinuria in CKD patients in addition to current regimens. Future studies should address whether vitamin D therapy also retards progressive renal functional decline.

Bone alkaline phosphatase in CKD-mineral bone disorder.

Overall and cardiovascular mortality in patients with chronic kidney disease (CKD) is greatly increased, without obvious current effective treatments. Mineral and bone disorder (MBD) is a common manifestation of CKD and contributes to the high risk of fracture and cardiovascular mortality in these patients. Traditionally, clinical management of CKD-MBD focused on attenuation of secondary hyperparathyroidism due to impaired renal activation of vitamin D and phosphate retention, although recently, adynamic forms of renal bone disease have become more prevalent. Definitive diagnosis was based on histologic (histomorphometric) analysis of bone biopsy material supported by radiologic changes and changes in levels of surrogate laboratory markers. Of these various markers, parathyroid hormone (PTH) has been considered to be the most sensitive and currently is the most frequently used; however, the many pitfalls of measuring PTH in patients with CKD increasingly are appreciated. We propose an alternative or complementary approach using bone alkaline phosphatase (ALP), which is directly related to bone turnover, reflects bone histomorphometry, and predicts outcomes in hemodialysis patients. Here, we consider the overall merits of bone ALP as a marker of bone turnover in adults with CKD-MBD, examine published bone histomorphometric data comparing bone ALP to PTH, and discuss possible pathogenic mechanisms by which bone ALP may be linked to outcomes in patients with CKD.

PTH--a particularly tricky hormone: why measure it at all in kidney patients?

Plasma parathyroid hormone (PTH) concentrations are commonly measured in the context of CKD, as PTH concentration elevation is typical in this clinical context. Much has been inferred from this raised PTH concentration tendency, both about the state of skeletal integrity and health and also about the potential clinical outcomes for patients. However, we feel that reliance on PTH concentrations alone is a dangerous substitute for the search for, and use of, more precise and reliable biomarkers. In this article, we rehearse these arguments, bringing together patient-level and analytical considerations for the first time.

Dyslipidemia, statins, and CKD patients' outcomes - review of the evidence in the post-sharp era.

Hyperlipidemia in the general population is strongly associated with an increased incidence of major adverse cardiovascular (CV) events (MACE). It is well established that HMG-CoA reductase inhibitors (statins) reduce CV and all-cause mortality in the general population, as well as in patients with CV disease (CVD). However, such a finding has not been definitively confirmed in patients with chronic kidney disease (CKD). Given that CV risk gradually increases with increasing stages of CKD (and is even higher in dialysis patients), it is of major relevance and importance to identify whether CKD patients might also benefit from alteration of lipid fractions, and how this might best be achieved. Bearing in mind that animal model and preclinical evidence suggests dyslipidemia might also be a factor promoting worsening renal function, it could legitimately be asked whether treating it may also therefore have a nephroprotective effect.

Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights.

Antibody-mediated pure red cell aplasia is a very rare but devastating condition affecting patients receiving treatment with erythropoiesis-stimulating agents. New cases continue to emerge, generally in clusters, consistent with an 'environmental' trigger to its pathogenesis. Defining the causes of antibody-mediated pure red cell aplasia is clearly of importance for patients with chronic kidney disease, but any developments in this area may also have relevance to other disease areas as therapeutic delivery of endogenous proteins rapidly increases. This review focuses on the current knowledge regarding the etiology of antibody-mediated pure red cell aplasia and the current approach to therapy.

Mineral metabolism and vitamin D in chronic kidney disease--more questions than answers.

Patients with chronic kidney disease (CKD) are at increased risk of total and cardiovascular morbidity and mortality. The underlying pathophysiology of this association remains largely unexplained and there is currently no clear interventional pathway. Emphasis has been placed on measuring serum levels of calcium, phosphate and parathyroid hormone (PTH) to monitor disease progression, driven by the assumption that achieving values within the 'normal' range will translate into improved outcomes. Retrospective studies have provided a body of evidence that abnormal levels of mineral biomarkers, and phosphate in particular, are associated with clinical events. Disturbances in vitamin D metabolism are also likely to contribute to the pathophysiology of CKD. Designing studies that yield useful information has proved to be difficult, partly owing to conceptual and financial limitations, but also because of the tight interdependency of calcium, phosphate and PTH, and the potential impact of vitamin D on these mineral metabolites. An intervention that perturbs any one of these factors is likely to exert effects on the others, making isolation of the individual variables almost impossible. However, some therapies in current use have the potential to act as probes to answer questions relating to the association between mineral biomarkers and outcomes in CKD.

Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guidelines: a European Renal Best Practice (ERBP) commentary statement.

Under the auspices of the European Renal Best Practice, a group of European nephrologists, not serving on the Kidney Disease Improving Global Outcomes (KDIGO) working group, but with significant clinical and research interests and expertise in these areas, was invited to examine and critique the Chronic Kidney Disease-Mineral and Bone Disorder KDIGO document published in August 2009. The final form of this paper in Nephrology Dialysis Transplantation, as a commentary, not as a position statement, reflects the fact that we have had no more evidence to review, discuss and debate available to us than was available to the KDIGO working group. However, we have felt that we were able to comment on specific areas where we feel that further clinical guidance would be helpful, thereby going beyond the KDIGO position as reflected in their document. This present paper, we hope, will be of most use to the practising kidney specialist and those allied to the clinical team.

Sodium thiosulfate: new hope for the treatment of calciphylaxis.

Calciphylaxis/calcific uremic arteriolopathy is rare but an important cause of morbidity and mortality in patients with chronic and end-stage kidney disease with increasing prevalence. Intravenous sodium thiosulfate (STS) has rapidly emerged from a seldom used therapy for the treatment of calciphylaxis/calcific uremic arteriolopathy to a treatment that is being increasingly utilized globally due to multiple positive outcomes shared in the form of case reports and reviews during the past 6 years. Its role as a rather potent antioxidant has uniquely been associated with a prompt decrease in pain and its slower chelating properties are associated with regression of subcutaneous calcifications. Excessive reactive oxygen species (ROS) activate nuclear transcription factor, NF(kappa)B and downstream cytokines resulting in inflammation, which may result in dysregulated hepatic protein synthesis. Indeed, inflammation activates acute-phase reactant synthesis, while concurrently inhibiting synthesis of fetuin-A (an inhibitor of extraosseous calcification) and the antioxidant albumin. Additionally, ROS may decrease locally synthesized matrix GLA proteins and this combination may contribute to increased vascular and subcutaneous calcification. STS used alone or in combination with other novel emerging therapies may result in the improved clinical outcomes in this challenging clinical condition.