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.

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.

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.

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.

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.

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.

Current management of secondary hyperparathyroidism: a multicenter observational study (COSMOS).

STUDY AIMS: To survey bone mineral disturbances in the hemodialysis (HD) population in Europe and current clinical practice in Europe for the prevention, diagnosis and treatment of secondary hyperparathyroidism (SHPT) in HD patients. PRIMARY OBJECTIVES: First, to estimate the prevalence of Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline achievement in a representative sample of European hemodialysis subjects. As part of this objective, we will investigate the prevalence of achievement by type of dialysis, type of center and time on dialysis (less than or greater than 1 year). Among new dialysis subjects (less than 1 year), we will evaluate prevalence of K/DOQI target achievement until the end of the study. The study will run for 3 years. Second, to estimate the association of bone mineral markers (parathyroid hormone [PTH], calcium [Ca], serum phosphorus [P] and calcium phosphate product [CaxP]) classified by achievement of K/DOQI targets with mortality and overall cardiovascular hospitalization. Third, to characterize the longitudinal changes in bone mineral markers. As part of this objective, we will describe the patterns and predictors of bone mineral markers and achievement, with K/DOQI targets, using repeated measurements on individuals over time. SECONDARY OBJECTIVES: First, To estimate the association of bone mineral markers (PTH, Ca, P and CaxP) classified by achievement of K/DOQI targets with specific cardiovascular outcomes, parathyroidectomy, manifest bone disease (including incidence of symptomatic bone fractures), hospitalizations and vascular access. Second, to evaluate the additional value of albumin and hemoglobin levels in conjunction with bone mineral markers in the prediction of mortality and clinical events.

Current dilemmas in inhibiting the renin-angiotensin system: do not forget real life.

For a long time, the inhibition of the renin-angiotensin-aldosterone (RAA) axis has been considered a must in almost all patients with progressive chronic kidney disease (CKD), with the aim of reducing the rate of progression to end-stage renal disease (ESRD). However, recent data from a meta-analysis, including the ALLHAT study, and a study in Canadian diabetic patients questioned the usefulness of angiotensin converting enzyme (ACE) inhibition in delaying the onset of dialysis. Publication of these data led to an intensive recent debate among reputed nephrologists, with numerous pros and cons regarding the pharmacological influence of CKD progression. The authors of the present review critically discuss the arguments and counterarguments of this challenging debate. Finally, a cautious view for the practicing nephrologist is expressed, highlighting the difference between study patients and real-life patients, and the possible overlooked aspects of recent renal protection studies (the importance of central blood pressure, of ambulatory blood pressure monitoring and possible, the impact of angiotensin converting inhibitors on stroke), are presented.

Posttransplantation anemia in adult renal allograft recipients: prevalence and predictors.

BACKGROUND: Management of anemia is an important factor in the care of patients with chronic kidney disease as the anemic state can confer significant morbidity and mortality. Posttransplantation anemia (PTA) has received comparatively less attention in the literature, and the prevalence and predictors of PTA vary between different studies. The purpose of this study was to investigate a large posttransplant population from 3 centres in the UK to elucidate the point prevalence of PTA, its determinants and the use of erythropoiesis stimulating agents (ESA) in these patients. METHODS: All adult patients with functioning renal transplants and attending renal transplant outpatients at Guy's, King's College, or St. Helier Hospitals, London, as of 31/12/2004 who had a valid hemoglobin in the previous 3 months, and who were more than 3 months postengraftment, were identified. Patients' notes and electronic patient records were obtained and a detailed cross-sectional clinical and biochemical database was constructed. The data were analyzed for the point prevalence of PTA, the prevalence of ESA use and for determinants of hemoglobin. The WHO criteria were used to define anemia and all patients on treatment with an ESA was classified as anemic irrespective of hemoglobin. RESULTS: A total of 1,511 (947 male) patients were studied. Mean age was 48.1+/-13.7 years with no difference between the sexes. Mean time posttransplantation was 8.5+/-7.2 years and mean estimated MDRD GFR was 47.6+/-18.9 ml/min with a higher GFR in males (49.9+/-19.0 v 43.8+/-18.0 mL/min, P<0.0001). Mean hemoglobin in the studied population was 12.9+/-1.6 g/dl with a significantly higher level among males than females (mean 13.3+/-1.6 v 12.3+/-1.4 g/dl, P<0.0001). The prevalence of anemia was 45.6% with a prevalence of 44.1% among males and 48.1% amongst females. Severe anemia was present in 50 subjects (3.3% of the total cohort). One hundred and forty-five patients (9.6% of the entire cohort) were being treated with an ESA. Of these subjects, 41 did not meet WHO criteria for the definition of anemia. After multiple regression analyses, age, female sex, renal function and to a lesser extent serum ferritin and therapy with angiotensin converting enzyme inhibitors/angiotensin II receptor blockers (both negatively associated) were predictive of hemoglobin. CONCLUSIONS: The prevalence of anemia posttransplantation was high while comparatively few patients were being treated with erythropoiesis stimulating agents. The strongest predictors of hemoglobin in this cohort of patients were age, female sex and allograft function. Medical therapy with MMF and sirolimus was associated with a high prevalence of anemia but this was likely to be the result of poorer graft function in these subjects who mostly had chronic allograft nephropathy. A large interventional prospective study with valid control groups is now needed to assess the long-term contributions of clinical and biochemical factors of renal function and to elucidate the effects of therapy on outcome.

Serial echocardiographic changes in patients on hemodialysis: an evaluation of guideline implementation.

BACKGROUND: Few studies have addressed the description of serial changes in left ventricular mass (LVM) and relevant risk factors. All these studies were initiated before the implementation of EBPG or K/DOQI guidelines. The aims of our study were to prospectively describe trends in left ventricular (LV) structure and function, evaluate risk factors for progression of LVM derived from serial echocardiographic measurements starting January 2003, 6 months after full implementation of EBPG in our unit. METHODS: One hundred seventy-six patients were enrolled at baseline, between 1 January 2003 and 1 October 2004; 33 patients were excluded from analysis due to poor echocardiographic window, 14 patients died and 26 were transplanted or transferred during the follow-up period of minimum 12 months. One hundred and three patients were included in the final analysis (mean age 51 years, mean follow-up 24.1 +/- 14.4 months). Echocardiography was performed at inclusion and at the end of study. Biochemical, blood pressure (BP) and medication data were collected and the means of monthly values were used. RESULTS: At baseline, 86.4% of the patients had left ventricular hypertrophy (LVH) (56.3% concentric hypertrophy, 30.1% eccentric hypertrophy, 6.8% concentric remodeling and only 6.8% normal LV geometry), 25.6% had systolic dy-sfunction and 50.5% had abnormal LV volume index (LVVI). Similar data were recorded at follow-up (82.5%, 44.7%, 37.9%, 7.7%, 9.7%, and 19.5%, respectively). Baseline left ventricular mass index (LVMI) significantly correlated with hemoglobin (Hb) and total protein level. LVMI at follow-up correlated to Hb, SBP, PP, mean level of serum phosphate, calcium x phosphate product and cholesterol. Independent predictors for LVMI (multiple regressions) were anemia and mineral metabolism markers. In our population, 62.1% of the patients had a regression of LVMI, with a mean decrease in LVMI of 12 g/m 2 (1.7 +/- 11.7 g/m 2 /month) over more than 12 months of guideline implementation. Regressors had a significant improvement of anemia, serum phosphate level and calcium x phosphate product (p<0.05). CONCLUSION: Our study suggests that a holistic interventional approach, targeting various pathogenic mechanisms, as per guidelines, can elicit at least a partial regression in LV structural and functional abnormalities in hemodialysis patients.

The epidemics of cardiovascular disease in elderly patients with chronic kidney disease--two facets of the same problem.

There is increasing evidence that even mild renal dysfunction is a novel potent cardiovascular risk factor in the general elderly population. With more severe renal impairment, cardiovascular risk increases proportionately. This issue deserves attention, as chronic kidney disease (CKD) is predominantly a disease of the elderly, and the mean age of end-stage renal disease patients entering dialysis is growing constantly. In the dialysis population, when clinically significant cardiovascular disease (CVD) (particularly congestive heart failure) is present, survival is worse. Thus, every effort should be made to identify and treat cardiovascular risk factor in the early stages of CKD. However, elderly renal patients receive less proper cardiovascular therapy compared to non-renal subjects of the same age. This review deals briefly with the most significant data published in the last decade on CVD in elderly with CKD.

Bleeding post coronary artery bypass surgery. Clopidogrel--cure or culprit?

BACKGROUND: Clopidogrel, in addition to aspirin, has become a common treatment of acute coronary syndrome and for stent thrombosis prevention, when given before percutaneous transluminal coronary angioplasty. However, some patients turn out to have surgical coronary artery disease and are sent for coronary artery bypass grafting (CABG) where the irreversible effect of aspirin and clopidogrel on platelet function becomes a concern. This study was conducted to evaluate the role of preoperative use of clopidogrel in bleeding complications after CABG. MATERIAL AND METHODS: A total of 462 patients who underwent CABG between 2001 and 2003 were studied as a retrospective cohort. Comparison was made between patients who had taken clopidogrel within 7 days of surgery (n=162), and those who were not exposed to clopidogrel (n=300). Chest tube output and bleeding index (a modified TIMI criteria), were the primary outcomes measured. RESULTS: Our data showed that patients taking clopidogrel within 7 days of surgery have a higher bleeding index than those who were not exposed to the drug (p = 0.024). Similarly, chest tube output was significantly higher in those who were exposed to clopidogrel within 7 days compared to those not taking clopidogrel (p = 0.01). To further dissect this relationship, we divided our population into three categories. We found that patients taking clopidogrel within 3 days prior to CABG (immediate exposure) have a higher bleeding index and TIMI major bleeding than either patients taking the drug between 3 and 7 days (recent exposure) or patients not exposed to clopidogrel at all (p = 0.009 and 0.03 respectively for inter-groups comparison). The same was true for chest tube output (p = 0.05 and 0.01 respectively). CONCLUSION: Clopidogrel increased the risk of post-CABG bleeding if taken within three days prior to surgery but not if taken before that.

Dynamics of the circadian blood pressure profiles after renal transplantation.

BACKGROUND: Abnormalities of diurnal blood pressure (BP) rhythm ("nondipping") are well-described in dialysis patients, and have prognostic importance. It is controversial whether successful renal transplantation (RTx) improves diurnal BP rhythm. To date, no study has attempted to define and model the evolution of diurnal BP rhythm profiles from dialysis to engraftment, focusing on the immediate (4-6 weeks) and medium-term (>1 year) postengraftment periods. METHODS: To test if kidney transplantation normalizes the BP profile, ambulatory blood pressure monitoring (ABPM) was performed in 20 living related transplants (age, 30.3+/-5.1 years; 11 males, on dialysis for 25.6 months) 1 month preRTx and repeated 1 month and >1 year (ABPM3) after successful RTx. Dipping was defined as a sleep-to-awake ratio>0.92 (for systolic BP) and >0.90 (for diastolic BP). RESULTS: PreRTx only 15% patients were dippers. At 1 month postRTx (creatinine clearance, 65.8 ml/min), all patients were complete nondippers. However, after >1 year postRTx (creatinine clearance, 70.4 ml/min), 40% were now dippers. Most importantly, overall, 30% of the patients improved significantly their circadian rhythm (35.3% of the initial preRTx nondippers). Despite successful renal transplantation, 55% patients maintained unchanged their nondipping profile throughout all three ABPM recordings. The only determinants of "long-term" postRTx circadian rhythm are the contemporary level of the renal function and the baseline, dialysis dipping profile: SBP3 sleep-to-awake ratio is related with serum creatinine3 (r=0.58, P=0.001), creatinine clearance (r=-0.41, P=0.036) and SBP1 sleep-to-awake ratio (r=0.48, P=0.034); similarly DBP3 sleep-to-awake ratio is related with serum creatinine3 (r=0.63, P=0.001), creatinine clearance (r=-0.471, P=0.036) and SBP1 sleep-to-awake ratio (r=0.53, P=0.016). In all, 57% of the variance in dipping status can be attributed and explained by the contribution of renal function and initial circadian variability. CONCLUSIONS: Half of the nondipper dialysis patients maintain a permanently abnormal circadian rhythm, despite successful RTx. In the short term, RTx is associated with a highly abnormal diurnal profile, exclusively related to ciclosporin dose and levels. However, in the longer term, renal transplantation leads to a significant improvement of the circadian blood pressure profile, influenced by the renal function level and by the pretransplantation dipping profile.

Arterial stiffness in renal patients: an update.

According to recent data, arterial stiffness is a major independent risk factor for cardiovascular morbidity and mortality in both the general and renal populations. Because of several factors (vascular calcifications among them), large arteries are stiffer in patients with chronic kidney disease compared with the nonrenal population, contributing to the enormous cardiovascular mortality in renal patients. This review briefly analyzes methods for determination of arterial stiffness, focusing on 2 parameters, pulse wave velocity and the augmentation index, particularly useful in assessing arterial compliance in renal patients. Effects of different methods of renal replacement therapy on arterial wall properties also are discussed. Finally, the most promising novel and/or potential therapies regarding reduction of arterial stiffness in renal patients are reviewed.