Lawrence P. McMahon

KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease

To the Editor: We have read the letter to the editor by Jerzy Przedlacki1 and the response from the authors2 of the Kidney Disease-Improving Global Outcomes (KDIGO) clinical practice guidelines for bisphosphonate (BP) treatment in chronic kidney disease (CKD), and would like to share our concerns regarding the use of BP treatment of CKD. The kidney is the organ that excretes many drugs, and any change in renal function will affect the pharmacology of these drugs. Existing or residual renal function of the patient will have to be taken into account while prescribing drugs. This is just as important for the patient with CKD 4 or 5, including those with CKD 5 already on peritoneal dialysis or hemodialysis, who may still have residual renal function. Nephrotoxic drugs including nonsteroidal anti-inflammatory drugs can very readily destroy whatever residual renal function patients may still have. Residual renal function is important to preserve as it contributes to less patient morbidity and mortality3 in the dialysis patient. Recently, there have been adverse reports of a certain BP that works by inhibiting osteoclast-mediated bone resorption, thereby slowing the breakdown of bone to reduce the risk of fractures. As of 14 August 2009, there have been 139 post-marketing reports of renal impairment following its use as an infusion worldwide. Many of these occur in patients with pre-existing medical conditions or risk factors (elderly, renal impairment, and/or concurrent dehydration), or in those on nonsteroidal anti-inflammatory drugs or other concurrent exposure to other nephrotoxic agents. There have also been cases requiring dialysis, and occasional fatal outcomes have been reported in patients with pre-existing renal impairment and concomitant risk factors.4, 5, 6, 7

Effects of Early and Late Intervention with Epoetin α on Left Ventricular Mass among Patients with Chronic Kidney Disease (Stage 3 or 4): Results of a Randomized Clinical Trial

It is not known whether prevention of anemia among patients with chronic kidney disease would affect the development or progression of left ventricular (LV) hypertrophy. A randomized controlled trial was performed with 155 patients with chronic kidney disease (creatinine clearance, 15 to 50 ml/min), with entry hemoglobin concentrations ([Hb]) of 110 to 120 g/L (female patients) or 110 to 130 g/L (male patients). Patients were monitored for 2 yr or until they required dialysis; the patients were randomized to receive epoetin alpha as necessary to maintain [Hb] between 120 and 130 g/L (group A) or between 90 and 100 g/L (group B). [Hb] increased for group A (from 112 +/- 9 to 121 +/- 14 g/L, mean +/- SD) and decreased for group B (from 112 +/- 8 to 108 +/- 13 g/L) (P < 0.001, group A versus group B). On an intent-to-treat analysis, the changes in LV mass index for the groups during the 2-yr period were not significantly different (2.5 +/- 20 g/m(2) for group A versus 4.5 +/- 20 g/m(2) for group B, P = NS). There was no significant difference between the groups in 2-yr mean unadjusted systolic BP (141 +/- 14 versus 138 +/- 13 mmHg) or diastolic BP (80 +/- 6 versus 79 +/- 7 mmHg). The decline in renal function in 2 yr, as assessed with nuclear estimations of GFR, also did not differ significantly between the groups (8 +/- 9 versus 6 +/- 8 ml/min per 1.73 m(2)). In conclusion, maintenance of [Hb] above 120 g/L, compared with 90 to 100 g/L, had similar effects on the LV mass index and did not clearly affect the development or progression of LV hypertrophy. The maintenance of [Hb] above 100 g/L for many patients in group B might have been attributable to the relative preservation of renal function.

Biological Variability of Plasma Intact and C-Terminal FGF23 Measurements

CONTEXT FGF23 measurement may have a role in the management of patients with chronic kidney disease (CKD). OBJECTIVE Our objective was to study the biological variability of plasma intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) concentrations. DESIGN Plasma samples were taken from 12 healthy adults at multiple time points on 2 consecutive days to assess diurnal variability of FGF23 concentrations. Early-morning fasting and nonfasting samples were also taken over a 6-wk period to estimate components of biological variation. Samples from 170 volunteers were used to define reference intervals. FGF23 concentrations were measured by commercial ELISA. Western blotting was used to analyze FGF23 species from the plasma of healthy adults and patients with predialysis CKD and those undergoing dialysis. PARTICIPANTS AND SETTING A total of 180 healthy adults and 18 adults with stage 3-5D CKD participated in this study at a hospital research unit. MAIN OUTCOME MEASURE Estimates were made of the biological variability of plasma FGF23 concentrations. RESULTS iFGF23, but not cFGF23, showed significant diurnal variation. cFGF23 had a significantly lower intra-individual variation than iFGF23 (8.3 vs. 18.3%) but higher inter-individual variation than iFGF23 (28.9 vs. 19.2%). Fourteen samples would be needed to estimate an individuals homeostatic set point (within 10%) for iFGF23 compared with only three samples for cFGF23. Using Western blotting, C-terminal FGF23 fragments were detected in the plasma of individuals with normal renal function and at all stages of renal disease. The percent cFGF23 was significantly higher in those without renal impairment (P < 0.001) and was positively correlated with plasma phosphate concentration in those with normal renal function. CONCLUSIONS The high intra-individual biological variability of iFGF23 may limit its clinical use as a diagnostic or management tool. Risk-related thresholds may be more appropriate for clinical decision making based on cFGF23 measurements than conventional reference intervals. FGF23 cleavage pathways may be an important natural regulatory mechanism for phosphate control.

The impact of stopping inhibitors of the renin–angiotensin system in patients with advanced chronic kidney disease

Background. Inhibition of the renin-angiotensin-aldosterone system (RAAS) has shown to slow chronic kidney disease (CKD) progression. This is most notable at the earlier stages of diabetic and proteinuric nephropathies. Objective. Here, we observed the impact of discontinuation of angiotensin converting enzyme inhibitors (ACEi)/ angiotensin receptors blockers (ARB) in patients with advanced kidney disease. Methods. 52 patients (21 females and 31 males) with advanced CKD (stages 4 and 5), who attended our low clearance clinic (LCC) in preparation for renal replacement therapy (RRT). Mean age was 73.3 ± 1.8 years with an estimated glomerular filtration rate (eGFR) of 16.38 ± 1 ml/ min/1.73 m 2 . Baseline urine protein:creatinine ratio (PCR) was 77 ± 20 mg/mmol. 46% suffered from diabetes mellitus. Patients were followed for at least 12 months before and after ACEi/ARB were stopped. Results. 12 months after discontinuation of ACEi/ARB eGFR increased significantly to 26.6 ± 2.2 ml/min/ 1.73 m 2 (p = 0.0001). 61.5% of patients had more than a 25% increase in eGFR, whilst 36.5% had an increase exceeding 50%. There was a significant decline in the eGFR slope -0.39 ± 0.07 in the 12 months preceding discontinuation. The negative slope was reversed +0.48 ± 0.1 (p = 0.0001). Mean arterial blood pressure (MAP) increased from 90 ± 1.8 mmHg to 94 ± 1.3 mmHg (p = 0.02), however ≥50% of patients remained within target. Overall proteinuria was not affected (PCR before = 77 ± 20 and after = 121.6 ± 33.6 mg/mmol). Conclusion. Discontinuation of ACEi/ARB has undoubtedly delayed the onset of RRT in the majority of those studied. This observation may justify a rethink of our approach to the inhibition of the RAAS in patients with advanced CKD who are nearing the start of RRT.

Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.

Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD.

BACKGROUND Vascular stiffening occurs in normal ageing and is accelerated in chronic kidney disease (CKD). Vascular calcification contributes to this stiffening and to the high incidence of vascular morbidity and mortality in this population. A network of inhibitors work in concert to reduce mineralization risk in extra-osseous tissue. Fetuin-A is an important systemic inhibitor of ectopic calcification. A fraction of the total circulating fetuin-A interacts with mineral ions to form stable colloidal complexes, calciprotein particles (CPP), preventing deposition. We sought to assess whether CPP fetuin-A levels were associated with procalcific factors and aortic stiffness in a cohort of patients with Stages 3 and 4 CKD. METHODS We measured fetuin-A CPP levels, serum inflammatory markers [C-reactive protein (CRP), interleukin-6, tumour necrosis factor-α], oxidized low-density lipoprotein (oxLDL), bone morphogenetic protein-2 (BMP-2) and -7 (BMP-7) and aortic pulse wave velocity (APWV) in a cohort of 200 CKD patients. Serum measurements were also made in 78 healthy controls. CPP fetuin-A phosphorylation was characterized by phosphate-affinity gel chromatography. RESULTS Fetuin-A-containing CPPs were only detectable in the serum of CKD patients. Inflammatory markers, oxLDL and BMP-2 levels were all significantly higher in the CKD than control subjects. CPP fetuin-A levels were independently associated with serum phosphate, high-sensitivity C-reactive protein, oxLDL, BMP-2/7 ratio and inversely with estimated glomerular filtration rate (model R(2) = 0.51). After adjusting for confounders, CPP fetuin-A levels were independently associated with APWV. Only phosphorylated fetuin-A was present in serum CPP. CONCLUSION Increased CPP fetuin-A levels reflect an increasingly procalcific milieu and are associated with increased aortic stiffness in patients with pre-dialysis CKD.

Serum Calcification Propensity Predicts All-Cause Mortality in Predialysis CKD

Medial arterial calcification is accelerated in patients with CKD and strongly associated with increased arterial rigidity and cardiovascular mortality. Recently, a novel in vitro blood test that provides an overall measure of calcification propensity by monitoring the maturation time (T50) of calciprotein particles in serum was described. We used this test to measure serum T50 in a prospective cohort of 184 patients with stages 3 and 4 CKD, with a median of 5.3 years of follow-up. At baseline, the major determinants of serum calcification propensity included higher serum phosphate, ionized calcium, increased bone osteoclastic activity, and lower free fetuin-A, plasma pyrophosphate, and albumin concentrations, which accounted for 49% of the variation in this parameter. Increased serum calcification propensity at baseline independently associated with aortic pulse wave velocity in the complete cohort and progressive aortic stiffening over 30 months in a subgroup of 93 patients. After adjustment for demographic, renal, cardiovascular, and biochemical covariates, including serum phosphate, risk of death among patients in the lowest T50 tertile was more than two times the risk among patients in the highest T50 tertile (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1 to 5.4; P=0.04). This effect was lost, however, after additional adjustment for aortic stiffness, suggesting a shared causal pathway. Longitudinally, serum calcification propensity measurements remained temporally stable (intraclass correlation=0.81). These results suggest that serum T50 may be helpful as a biomarker in designing methods to improve defenses against vascular calcification.

Development, Prevention, and Potential Reversal of Left Ventricular Hypertrophy in Chronic Kidney Disease

Although a high prevalence of left ventricular (LV) hypertrophy is recognized with increasing severity of chronic kidney disease (CKD), previously neither its progression nor its potential for prevention or reversal has been addressed adequately in this population group. A nested analysis of a 2-yr study involving 155 patients with stage 3/4 CKD, examining effects of hemoglobin change (range, 90 to 130 g/L) on LV mass in patients with (n = 46; 30%) and without (n = 105; 70%) initial LV hypertrophy, is reported. At baseline, the group with LV hypertrophy was older (P < 0.01), had higher BP (P < 0.01), had greater LV wall and cavity dimensions (P < 0.001), and had more prevalent use of antihypertensive agents (P < 0.001) but a lower hemoglobin concentration (P < 0.05) and GFR (P < 0.01). A total of 117 patients were available for assessment at 2 yr. Importantly, 57 (68%) with initial normal LV indices showed no appreciable change with time; however, 27 (32%) developed LV hypertrophy, with growth in both wall and cavity dimensions (P < 0.001). In contrast, 23 (50%) of those with initial LV hypertrophy maintained elevated LV indices, whereas 10 (22%) regressed, through wall but not cavity reduction, to within normal LV indices. Predisposing factors to maintaining or achieving normal LV mass dimensions included relative youth (P < 0.05), a lower pulse pressure (P < 0.05), and a higher GFR (P < 0.05) but not hemoglobin concentration or parathyroid hormone levels. These findings suggest that even at a relatively advanced stage of renal dysfunction, control of BP and volume, together with regulated metabolic and clinical indices, may contribute to the prevention or even reversal of LV hypertrophy in a substantial proportion of patients.

Fetuin-A-Containing Calciprotein Particles Reduce Mineral Stress in the Macrophage

The formation of fetuin-A-containing calciprotein particles (CPP) may facilitate the clearance of calcium phosphate nanocrystals from the extracellular fluid. These crystals may otherwise seed extra-osseous mineralization. Fetuin-A is a partially phosphorylated glycoprotein that plays a critical role in stabilizing these particles, inhibiting crystal growth and aggregation. CPP removal is thought to be predominantly mediated by cells of the reticuloendothelial system via type I and type II class A scavenger receptor (SR-AI/II). Naked calcium phosphate crystals are known to stimulate macrophages and other cell types in vitro, but little is known of the effect of CPP on these cells. We report here, for the first time, that CPP induce expression and secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β in murine RAW 264.7 macrophages. Importantly, however, CPP induced significantly lower cytokine secretion than hydroxyapatite (HAP) crystals of equivalent size and calcium content. Furthermore, CPP only had a modest effect on macrophage viability and apoptosis, even at very high levels, compared to HAP crystals, which were strongly pro-apoptotic at much lower levels. Fetuin-A phosphorylation was found to modulate the effect of CPP on cytokine secretion and apoptosis, but not uptake via SR-AI/II. Prolonged exposure of macrophages to CPP was found to result in up-regulated expression of SR-AI/II. CPP formation may help protect against some of the pro-inflammatory and harmful effects of calcium phosphate nanocrystals, perhaps representing a natural defense system for calcium mineral stress. However, in pathological states where production exceeds clearance capacity, these particles may still stimulate pro-inflammatory and pro-apoptotic cascades in macrophages, which may be important in the pathogenesis of vascular calcification.

The SOMANZ Guidelines for the Management of Hypertensive Disorders of Pregnancy 2014

Accurate blood pressure measurement is important. Attention should be paid to: • Correct posture • Cuff size • DeviceMercury sphygmomanometers remain the gold standard Self-initiated and automated blood pressure monitors may have wide intra-individual error, and their accuracy may be further compromised in preeclamptic women. Aneroid sphygmomanometers may be used but require regular recalibration to ensure accurate measurements. ABPM may help identify women with white coat hypertension.