Cardiovascular MRI with ferumoxytol.

The practice of contrast-enhanced magnetic resonance angiography (CEMRA) has changed significantly in the span of a decade. Concerns regarding gadolinium (Gd)-associated nephrogenic systemic fibrosis in those with severely impaired renal function spurred developments in low-dose CEMRA and non-contrast MRA as well as efforts to seek alternative MR contrast agents. Originally developed for MR imaging use, ferumoxytol (an ultra-small superparamagnetic iron oxide nanoparticle), is currently approved by the US Food and Drug Administration for the treatment of iron deficiency anaemia in adults with renal disease. Since its clinical availability in 2009, there has been rising interest in the scientific and clinical use of ferumoxytol as an MR contrast agent. The unique physicochemical and pharmacokinetic properties of ferumoxytol, including its long intravascular half-life and high r1 relaxivity, support a spectrum of MRI applications beyond the scope of Gd-based contrast agents. Moreover, whereas Gd is not found in biological systems, iron is essential for normal metabolism, and nutritional iron deficiency poses major public health challenges worldwide. Once the carbohydrate shell of ferumoxytol is degraded, the elemental iron at its core is incorporated into the reticuloendothelial system. These considerations position ferumoxytol as a potential game changer in the field of CEMRA and MRI. In this paper, we aim to summarise our experience with the cardiovascular applications of ferumoxytol and provide a brief synopsis of ongoing investigations on ferumoxytol-enhanced MR applications.

[FGF23 and Klotho: the new cornerstones of phosphate/calcium metabolism]. / FGF23 et Klotho : les nouveaux incontournables du métabolisme phosphocalcique.

Since its first description as a phosphaturic agent in the early 2000s, fibroblast growth factor 23 (FGF23) has rapidly become the third key player of phosphate/calcium metabolism after PTH and vitamin D. FGF23 is a protein synthesized by osteocytes that acts mainly as a phosphaturic factor and a suppressor of 1α hydroxylase activity in the kidney. It inhibits the expression of type IIa and IIc sodium-phosphate cotransporters on the apical membrane of proximal tubular cells, thus leading to inhibition of phosphate reabsorption. Moreover, it also inhibits 1α hydroxylase activity. These two renal pathways account together for the hypophosphatemic effect of FGF23, but FGF23 has also been recently described as an inhibiting factor for PTH synthesis. Its exact role in bone remains to be defined. A transmembrane protein, Klotho, is an essential cofactor for FGF23 biological activity, but it can also act by itself for calcium and PTH regulation. This paper gives an overview of these recent data of phosphate/calcium physiology, as well as a description of clinical conditions associated with FGF23 deregulation (genetic diseases and chronic kidney disease). As a conclusion, future therapeutic consequences of the FGF23/Klotho axis are discussed.

A new era in phosphate binder therapy: what are the options?

Dietary restriction of phosphorus and current dialysis prescription are unable to maintain phosphorus levels within the recommended range (2.7-5.5 mg/dl) in patients with advanced chronic kidney disease (CKD). Therefore, phosphate binders that limit the absorption of dietary phosphorus are commonly prescribed for this patient group. The first phosphate binders were introduced more than 30 years ago and included aluminum salts; however, although effective binders, the use of these agents was subsequently restricted because of concerns over aluminum accumulation in the central nervous system, bone, and hematopoietic cells. In subsequent years, calcium salts, namely calcium carbonate and calcium acetate, became the most widely used phosphate binders; however, increasing evidence now suggests that prolonged use of these agents increases the total body calcium load, induces adynamic bone, and potentially increases the risk of cardiovascular and soft tissue calcification. Sevelamer is the first phosphate-binding agent that is non-absorbed, calcium-free, and metal-free. To date, this agent has been shown to effectively control serum phosphorus levels in patients with CKD. It may also attenuate coronary and aortic calcification and has a number of other beneficial effects on lipid metabolism and inflammation among others. Lanthanum carbonate is another new agent that is reported to provide similar phosphate control to calcium-based phosphate binders but concerns that the long-term administration of such compound may lead to tissue accumulation may limit its use.

Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.

Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.

Non-invasive assessments of cardiovascular disease in patients with renal failure.

Vascular calcification is common in patients with chronic renal failure, and it may contribute to the very high mortality rate from cardiovascular causes in the end-stage renal disease population. Vascular calcification in chronic renal failure can arise from the calcification of the intimal layer of arteries as a result of atherosclerosis or from medial wall calcification due largely to alterations in mineral metabolism. Although several reports indicate that coronary artery calcification, as measured by electron-beam computed tomography, is quite common in patients with end-stage renal disease who are treated with dialysis, the clinical significance of these findings remain uncertain. In the general population, electron-beam computed tomography evidence of coronary calcification serves as a useful index of atherosclerotic burden and has value as a predictor of adverse coronary events. The relationship between coronary artery calcification and atherosclerotic cardiovascular disease has not been adequately studied, however, in patients with end-stage renal disease, and calcification scores in this population may reflect both intimal and medial wall calcification. Assessments using coronary angiography are needed to determine the diagnostic value of electron-beam computed tomography as a predictor of atherosclerotic cardiovascular disease in patients with chronic renal failure. Nevertheless, electron-beam computed tomography makes it possible to detect the presence and monitor the progression of coronary calcification in those undergoing long-term dialysis. The technique may provide important information about the impact of new therapeutic strategies aimed at reducing the risks of vascular calcification in those with chronic renal failure.

Validation of PD Adequest 2.0 for pediatric dialysis patients.

Kinetic modeling has proven to be a valuable tool for peritoneal dialysis (PD) prescription in adult PD patients. The clinical application of this procedure has rarely been studied in children. We therefore evaluated the PD Adequest 2.0 for Windows program (Baxter Healthcare Co., Deerfield, IL) as a prescription aid for the management of pediatric PD patients by comparing the measured and predicted PD clearances, total drain volumes, and net ultrafiltration in 34 children (15 males) (mean age 10.9 +/- 6.0 years) receiving long-term PD. In each case, a 4-h peritoneal equilibration test was conducted with a standardized test exchange volume of 1,100 ml/m2 BSA. A total of 43 24-h dialysate (plus urine in 12) collections were analyzed. The levels of agreement between measured and predicted values for weekly peritoneal and total urea Kt/V, weekly peritoneal and total creatinine clearance, daily drain volume, net ultrafiltration and daily peritoneal urea and creatinine mass removal were assessed with correlation coefficients (re) and Bland-Altman limits of agreement. The study revealed that there is a basic level of agreement between measured and modeled values for solute removal and total drain volume, with correlation coefficients ranging from 0.75 to 0.98. In contrast, the rc for net ultrafiltration was only 0.34. The majority (75%) of patients had modeled urea and creatinine clearances that were within 20% of their measured values. These data suggest that the PD Adequest 2.0 for Windows program can predict urea and creatinine clearances with reasonable accuracy in pediatric PD patients, making it a valuable resource in prescription management.

Surgical aspects of dialysis in newborns and infants weighing less than ten kilograms.

PURPOSE: Renal failure occurs in children with moderate frequency. Surgical aspects of establishing and maintaining dialysis access in small infants are exceptionally challenging. The purpose of this review is to evaluate the authors' experience with dialysis access for infants less than 10 kg, particularly with respect to the surgical care required. METHODS: A retrospective review was conducted between 1991 and 1999 of all pediatric dialysis patients weighing 10 kg or less (n = 29). Age at start of dialysis, duration of dialysis, modes of dialysis, and complications specific to peritoneal (PD) and hemodialysis (HD) were examined. RESULTS: The mean age at start of dialysis was 10.4 months and continued for an average duration of 16.3 months. Seventy-two percent of all patients required both modes of dialysis. HD and PD duration averaged 7.8 and 10.5 months, respectively. Catheter durability was 3.1 and 4.5 months per catheter for HD and PD, respectively. There was no significant difference in complications when comparing HD and PD. Patients who weighed 5 to 10 kg had significantly longer PD catheter durability than patients 0 to 5 kg (P = .001). Forty-one percent of patients terminated dialysis after transplantation, whereas 24% died awaiting transplantation. CONCLUSION: Despite a large number of operations required, infants less than 10 kg can be bridged successfully, by surgical intervention and subsequent dialysis, to transplantation.

Implications of intermittent calcitriol therapy on growth and secondary hyperparathyroidism.

Secondary hyperparathyroidism is the most common skeletal lesion in pediatric patients undergoing maintenance dialysis. The present review summarizes a prospective randomized study that evaluated the biochemical and skeletal responses to intermittent calcitriol therapy in 33 pediatric patients on peritoneal dialysis with secondary hyperparathyroidism. Also, the effect of intermittent calcitriol therapy on linear growth was evaluated in 16 of 33 patients who had completed the clinical trial. Serum parathyroid hormone levels decreased by 62% from 648+/-125 pg/ml in patients treated with intermittent intraperitoneal (IP) calcitriol, and values remained unchanged from pre-treatment levels of 670+/-97 pg/ml with oral calcitriol therapy. Overall serum total and ionized calcium levels were higher in patients treated with IP calcitriol during the study. In contrast to these biochemical findings, the skeletal lesions of secondary hyperparathyroidism improved after 12 months of treatment in both groups and adynamic bone occurred in 33% of the patients. Z-scores for height decreased from -1.80 /-0.3 to -2.00+/-0.3, P<0.01, after 12 months of intermittent calcitriol therapy. Such findings suggest that an intermittent schedule of calcitriol administration adversely affects chondrocyte activity within epiphyseal cartilage in pre-pubertal children with end-stage renal disease.

Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.

BACKGROUND: Cardiovascular disease is common in older adults with end-stage renal disease who are undergoing regular dialysis, but little is known about the prevalence and extent of cardiovascular disease in children and young adults with end-stage renal disease. METHODS: We used electron-beam computed tomography (CT) to screen for coronary-artery calcification in 39 young patients with end-stage renal disease who were undergoing dialysis (mean [+/-SD] age, 19+/-7 years; range, 7 to 30) and 60 normal subjects 20 to 30 years of age. In those with evidence of calcification on CT scanning, we determined its extent. The results were correlated with the patients' clinical characteristics, serum calcium and phosphorus concentrations, and other biochemical variables. RESULTS: None of the 23 patients who were younger than 20 years of age had evidence of coronary-artery calcification, but it was present in 14 of the 16 patients who were 20 to 30 years old. Among those with calcification, the mean calcification score was 1157+/-1996, and the median score was 297. By contrast, only 3 of the 60 normal subjects had calcification. As compared with the patients without coronary-artery calcification, those with calcification were older (26+/-3 vs. 15+/-5 years, P<0.001) and had been undergoing dialysis for a longer period (14+/-5 vs. 4+/-4 years, P< 0.001). The mean serum phosphorus concentration, the mean calcium-phosphorus ion product in serum, and the daily intake of calcium were higher among the patients with coronary-artery calcification. Among 10 patients with calcification who underwent follow-up CT scanning, the calcification score nearly doubled (from 125+/-104 to 249+/-216, P=0.02) over a mean period of 20+/-3 months. CONCLUSIONS: Coronary-artery calcification is common and progressive in young adults with end-stage renal disease who are undergoing dialysis.

Impaired growth, delayed ossification, and reduced osteoclastic activity in the growth plate of calcium-supplemented rats with renal failure.

Linear growth is reduced in prepubertal children with adynamic renal osteodystrophy, suggesting that the proliferation and/or differentiation of epiphyseal growth plate chondrocytes is abnormal in this disorder. To examine this issue, in situ hybridization and histochemistry were used to measure selected markers of endochondral bone formation and bone resorption in the proximal tibia of subtotally nephrectomized rats fed a high calcium diet to induce biochemical changes consistent with adynamic osteodystrophy. Blood ionized calcium concentrations were higher and serum PTH levels were lower in nephrectomized, calcium-supplemented rats than in either intact or nephrectomized control animals. Linear growth and tibial length were reduced, but messenger RNA levels for type II collagen, type X collagen, and the PTH/PTHrP receptor did not differ from control values in nephrectomized rats given supplemental calcium. In contrast, both the width of epiphyseal cartilage and the height of the zone of hypertrophic chondrocytes were greater in calcium-supplemented nephrectomized rats. These morphological changes were associated with decreases in histochemical staining for tartrate-resistant acid phosphatase and lower levels of messenger RNA expression for the matrix metalloproteinase MMP-9/gelatinase B immediately adjacent to the epiphyseal growth plate. Diminished chondroclastic/osteoclastic activity alters growth plate morphology and adversely affects linear bone growth in calcium-supplemented, nephrectomized rats.

Vitamin D receptor as a candidate tumor-suppressor gene in severe hyperparathyroidism of uremia.

Most chronic renal failure patients with severe refractory hyperparathyroidism harbor at least one monoclonal parathyroid tumor, but the specific acquired genetic defects that confer this clonal selective advantage remain poorly understood. Somatic inactivation of the vitamin D receptor (VDR) gene could contribute to clonal outgrowth, because a parathyroid cell containing this lesion would have an impaired response to the antiproliferative influence of 1,25-dihydroxyvitamin D3. Furthermore, diminished expression of VDR protein has been described in uremia-associated parathyroid tumors. Therefore, to assess VDR gene inactivation's potential pathogenetic role in this disease, we rigorously analyzed the VDR gene in 59 parathyroid tumors surgically resected from uremic patients. First, Southern blotting and/or PCR analyses of 29 tumor samples from 14 genetically informative patients revealed no allelic losses at the VDR locus. Next, direct DNA sequencing of all VDR splice junctions, associated intronic sequences, and virtually the entire VDR-coding region for all 59 tumors revealed no acquired mutations. Last, 37 tumor DNA samples were subjected to comparative genomic hybridization, and no chromosomal losses in the VDR region (12cen-q12) were observed. These observations suggest that inactivating defects within the VDR gene do not commonly contribute to the primary pathogenesis of severe refractory hyperparathyroidism in uremia.

Altered diurnal regulation of blood ionized calcium and serum parathyroid hormone concentrations during parenteral nutrition.

BACKGROUND: Little is known about parathyroid gland function in patients receiving total parenteral nutrition (TPN). OBJECTIVE: Our objective was to determine whether parathyroid gland function is abnormal in TPN recipients. DESIGN: Six patients with a mean (+/-1 SD) age of 45.5 +/- 8.0 y who had been receiving TPN for 18.7 +/- 2. 8 y underwent bone biopsy, bone mass measurements with dual-energy X-ray absorptiometry, and dynamic tests of parathyroid gland function. Diurnal variations in blood ionized calcium (iCa(2+)) and serum parathyroid hormone (PTH) concentrations were also assessed. Results were compared with those of healthy volunteers. RESULTS: Bone mass and bone formation were subnormal in all patients. Basal serum PTH concentrations were moderately higher in the TPN recipients than in healthy volunteers, and values obtained every 30 min over 24 h were significantly higher (P < 0.001) in TPN recipients (5.0 +/- 0.9 pmol/L) than in healthy volunteers (2.6 +/- 0.6 pmol/L). The percentage increase in serum PTH during citrate-induced hypocalcemia was lower in the TPN recipients, consistent with secondary hyperparathyroidism. Evening infusions of calcium-containing TPN eliminated the nocturnal rise in serum PTH, increased the amplitude of change for iCa(2+) and PTH over 24 h, increased the orderliness of change for iCa(2+) and PTH as measured by approximate entropy (ApEn), and enhanced the synchrony of change between iCa(2+) and PTH. Treatment for 10 d with calcium-free TPN restored the nocturnal rise in serum PTH and increased ApEn for PTH. ApEn for iCa(2+) remained low, suggesting that a component of nutrient solutions, but not calcium per se, enhances the regularity of PTH release in TPN recipients. CONCLUSION: Parathyroid gland function is abnormal in long-term TPN recipients, which may contribute to disturbances in bone metabolism.

A novel immunoradiometric assay detects full-length human PTH but not amino-terminally truncated fragments: implications for PTH measurements in renal failure.

In 8 adolescents with end-stage renal disease (ESRD), basal PTH concentrations measured with a novel immunoradiometric assay (IRMA) (Scantibodies Laboratory, Inc.; S-IRMA) were invariably lower than those estimated with an established assay (Nichols Institute; N-IRMA) (263 +/- 228 versus 645 +/- 442 pg/ml, respectively; p<0.00001). During in vivo dynamic testing, set points for calcium-regulated PTH release were indistinguishable for both IRMAs (1.21 +/- 0.05 versus 1.22 +/- 0.06). However, maximal PTH concentrations were significantly lower when measured by S-IRMA then by N-IRMA (557 +/- 448 and 1114 +/- 606 pg/ml, respectively); minimum PTH concentrations were 41 +/- 65 pg/ml (5.0 +/- 4.2% of maximum) and 189 +/- 137 pg/ml (13.6 +/- 7.2% of maximum), respectively. Correlation between PTH and blood ionized calcium indicated that PTH measured by S-IRMA decreased more readily than the concentrations determined by N-IRMA. The N-IRMA showed indistinguishable cross-reactivity with hPTH(1-84) and hPTH(7-84), while the S-IRMA detected only the full-length peptide. Furthermore, the radiolabeled detection antibody of the N-IRMA interacted equivalently with hPTH(1-34) and hPTH(2-34), while the S-IRMA showed crossreactivity only with hPTH(1-34). These differences in assay specificity could explain the observed differences in ESRD, and suggest that PTH concentrations estimated by the S-IRMA reflect more accurately the amount of biologically active PTH in the circulation. Since low concentrations of PTH are frequently associated with adynamic bone disease, our findings may have significant implications for the treatment of renal osteodystrophy with calcium and/or biologically active vitamin D analogs.

[Children with chronic renal failure: evaluation of the nutritional status and management]. / L'enfant insuffisant rénal chronique: évaluation de l'état nutritionnel et prise en charge.

Since malnutrition is a well recognized problem in children with chronic renal failure, nutritional management of these children is essential. This review describes methods for nutritional assessment and suggests guidelines for providing maximal dietary support in children with chronic renal insufficiency. Optimal nutritional management includes an adequate caloric and protein intake, a restriction of phosphorus intake and an appropriate intake of electrolytes and vitamins.

Growth retardation in children with chronic renal failure.

Growth retardation is a major obstacle to full rehabilitation of children with chronic renal failure (CRF). Several factors have been identified as contributors to impaired linear growth and they include protein and calorie malnutrition, metabolic acidosis, growth hormone resistance, anemia, and renal osteodystrophy. Although therapeutic interventions such as the use of recombinant human growth hormone, recombinant human erythropoietin, and calcitriol have made substantial contributions, the optimal therapeutic strategy remains to be defined. Indeed, growth failure persists in a substantial proportion of children with renal failure and those treated with maintenance dialysis. In addition, the increasing prevalence of adynamic lesions of renal osteodystrophy and its effect on growth have raised concern about the continued generalized use of calcitriol in children with CRF. Recent studies have shown the critical roles of parathyroid hormone-related protein (PTHrP) and the PTH/PTHrP receptor in the regulation of endochondral bone formation. The PTH/PTHrP receptor mRNA expression has been shown to be down-regulated in kidney and growth plate cartilage of animals with renal failure. Differences in the severity of secondary hyperparathyroidism influence not only growth plate morphology but also the expression of selected markers of chondrocyte proliferation and differentiation in these animals. Such findings suggest potential molecular mechanisms by which cartilage and bone development may be disrupted in children with CRF, thereby contributing to diminished linear growth.

Longitudinal evaluation of transport kinetics in children receiving peritoneal dialysis.

Functional stability of the peritoneal membrane is necessary for maintenance of peritoneal dialysis (PD) as a therapeutic option. Few studies have investigated this issue in children. We evaluated the peritoneal membrane solute transport capacity longitudinally in 26 children (mean age 11.0+/-5.5 years) receiving long-term PD. Each patient underwent a standardized peritoneal equilibration test on two occasions (mean interval between studies 19.8+/-5.9 months) to determine solute dialysate to plasma (D/P) ratios, dialysate glucose to initial dialysate glucose (D/D(0)) ratios, and mass transfer area coefficients (MTAC). The correlation of transport capacity with peritonitis history was also assessed. No significant change in MTAC, D/P, or D/D(0) values were found when comparing original and follow-up data of the group overall. However, transport of creatinine and glucose was significantly (P<0.05) greater in the peritonitis group compared with the group without peritonitis, and differences in the change over time between the peritonitis groups was significant for MTAC creatinine (P=0.035) and D/D(0) glucose (P=0.020). In summary, this experience demonstrates functional stability of the peritoneal membrane in pediatric patients receiving PD. However, follow-up assessments of peritoneal solute kinetics may be necessary in patients with a history of peritonitis in order to permit early identification of those who may be at risk for ultrafiltration failure and sclerosing peritonitis.