Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective.

BACKGROUND: Nephropathic cystinosis (NC) is a rare lysosomal disease, leading to early kidney failure and extra-renal comorbidities. Its prognosis strongly relies on early diagnosis and treatment by cysteamine. Developing economies (DEing) face many challenges when treating patients for rare and chronic diseases. The aim here is to evaluate the access to investigations and treatment in DEing, and to assess for potential inequalities with Developed Economies (DEed). METHODS: In this international cross-sectional study, a questionnaire on access, price and reimbursement of genetic, biological analyses, and treatment was sent to nephrology centers worldwide during 2022. RESULTS: A total of 109 centers responded, coming from 49 countries and managing 741 patients: 43 centers from 30 DEing and Economies in transition (TrE), and 66 from 19 DEed. In 2022, genetics availability was 63% in DEing and 100% in DEed, whereas intra leukocytes cystine levels (IL-CL) were available for 30% of DEing patients, and 94% of DEed patients, both increasing over the last decade, as has access to immediate release cysteamine and to cysteamine eye drops in DEing. However, delayed released cysteamine can be delivered to only 7% vs. 74% of patients from DEing and DEed, respectively, and is still poorly reimbursed in DEing. CONCLUSIONS: Over the last decade, access to investigations (namely genetics and IL-CL) and to cysteamine have improved in DEing and TrE. However, discrepancies remain with DEed: access to delayed released cysteamine is limited, and reimbursement is still profoundly insufficient, therefore limiting their current use.

Genetic assessment in primary hyperoxaluria: why it matters.

Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial diagnostic tool for patients with PH to define the disease type. Patients with PH type 1 (PH1) have a worse prognosis than those with other PH types, despite the same extent of oxalate excretion. The relation between genotype and clinical phenotype in PH1 is extremely heterogeneous with respect to age of first symptoms and development of kidney failure. Some mutations are significantly linked to pyridoxine-sensitivity in PH1, such as homozygosity for p.G170R and p.F152I combined with a common polymorphism. Although patients with these mutations display on average better outcomes, they may also present with CKD stage 5 in infancy. In vitro studies suggest pyridoxine-sensitivity for some other mutations, but confirmatory clinical data are lacking (p.G47R, p.G161R, p.I56N/major allele) or scarce (p.I244T). These studies also suggest that other vitamin B6 derivatives than pyridoxine may be more effective and should be a focus for clinical testing. PH patients displaying the same mutation, even within one family, may have completely different clinical outcomes. This discordance may be caused by environmental or genetic factors that are unrelated to the effect of the causative mutation(s). No relation between genotype and clinical or biochemical phenotypes have been found so far in PH types 2 and 3. This manuscript reviews the current knowledge on the genetic background of the three types of primary hyperoxaluria and its impact on clinical management, including prenatal diagnosis.

Assessment of mineral and bone biomarkers highlights a high frequency of hypercalciuria in asymptomatic healthy teenagers.

AIM: Assessment of mineral metabolism is complex in paediatrics. METHODS: We assessed the evolution of the main mineral and bone biomarkers (total/bone alkaline phosphatase ALP/BAP, ß-crosslaps, osteocalcin, sclerostin, C-terminal and intact FGF23) in 100 healthy teenagers (10-18 years, 50 boys). RESULTS: At a mean age of 13.7 ± 2.2 years, phosphatemia, tubular phosphate reabsorption, ALP and BAP significantly decreased along puberty in both genders, whilst parathyroid hormone (PTH), 25-vitamin D (25D), FGF23, plasma calcium and urinary calcium were not modified. In girls, osteocalcin, ß-crosslaps and sclerostin significantly decreased at the end of puberty. Calciuria above the crystallisation threshold (>3.8 mmol/L) and urinary calcium/creatinine ratio >0.7 mmol/mmol were found in 39% and 6% of subjects, respectively. Multivariable analyses showed that renal function and PTH were significant predictors of calciuria and urinary calcium/creatinine, whilst 25D remained a predictor only of urinary calcium/creatinine ratio. CONCLUSION: Using the most recent assays, this study provides data for mineral/bone biomarkers across puberty and highlights the risk of hyper-calciuria in apparent asymptomatic healthy teenagers, not related to calcium intake but rather to 25D. Future studies are required to dissect the underlying mechanisms increasing calciuria and prevent nephrolithiasis as early as during childhood.

Longitudinal Bone Mineralization Assessment in Children Treated With Long-Term Parenteral Nutrition for Severe Intestinal Failure.

BACKGROUND: Metabolic bone disease is common in children receiving home parenteral nutrition (HPN) for intestinal failure (IF). Long-term evolution of bone mass in pediatric IF is poorly documented. The aims of this study were (1) to determine the prevalence of low bone mass (LBM) in children receiving HPN for IF, (2) to evaluate the evolution of total bone mineral content (TBMC) during HPN with dual-energy x-ray absorptiometry (DXA), and (3) to identify related factors. METHODS: All children referred in our HPN center from 2004 to 2014 were eligible. Inclusion criteria were HPN dependence due to noninflammatory IF, at least 2 TBMC assessments, and HPN duration of at least 2 years at last DXA. TBMC was expressed in z score for ideal weight for height (WFH). LBM was defined by a TBMC WFH z score ≤-2 standard deviations (SD). RESULTS: A total of 175 DXAs for 31 children were performed, mean of 5.6 ± 2.9 assessments per child. The median time between first and last DXA recorded was 6.2 years (0.7-16.6). At the first DXA, 14 children (45%) had a LBM. TBMC increased by +0.1 ± 0.04 SD per year of HPN (P = .012). The risk of LBM decreased with an odds ratio of 0.9 per year of HPN (95% confidence interval, 0.92-0.99; P = .018). Lean mass z score and calcium parenteral intakes were related to the TBMC improvement. CONCLUSION: LBM is common in pediatric IF, but bone status could improve during HPN in these children.

French law: what about a reasoned reimbursement of serum vitamin D assays?

The number of serum 25-hydroxyvitamin D (25OHD) assays has increased tenfold in France in less than 10 years, sometimes for invalidated reasons. In 2013, the French National Authority for Health (Haute autorité de santé, or HAS) limited the indications for serum 25OHD measurements to rickets/osteomalacia, older adults with recurrent falls, monitoring of kidney transplant in adults, and surgical treatment of obesity in adults. Our aim here was to note that other indications for serum 25OHD measurements are supported by previous literature and by a number of national and international recommendations, in particular the following: any situation of bone fragility, any chronic renal failure <45 mL/min/1.73m2, any situation of malabsorption, clinical signs consistent with vitamin D deficiency or vitamin D overload, and calcium phosphorus evaluation. We suggest that the measurement of serum 25OHD concentration should remain reimbursed as part of these extended indications.

Bone assessment in children with chronic kidney disease: data from two new bone imaging techniques in a single-center pilot study.

Bone damage in children with chronic kidney disease (CKD) is a challenge for pediatric nephrologists. Areal measurements of bone mineral density (BMD) by dual x-ray absorptiometry (DXA) have been routinely performed to assess bone mass but recent international guidelines have concluded that DXA was of less value in CKD. The aim of this study is to evaluate bone quality in CKD children using new bone imaging techniques in a pilot cross-sectional single-center study. We performed bone imaging (high-resolution peripheral quantitative computed tomography, HR-pQCT, XtremeCT, Scanco Medical AG, Switzerland), to assess compartmental volumetric BMD and trabecular microarchitecture in 22 CKD children and 19 controls. In seven younger patients (i.e., under 10 years of age), we performed bone texture analysis (BMA, D3A Medical Systems, France) in comparison to 15 healthy prepubertal controls. Among older children, CKD patients had significantly lower height and body weight without significant impairment of BMD and microarchitecture than healthy controls. In univariate analysis, there were significant correlations between cortical BMD and glomerular filtration rate (r= -0.46), age (r=0.60) and body mass index (r=0.67). In younger children, bone texture parameters were not different between patients and controls. Our results did not show significant differences between healthy controls and CKD children for compartmental bone densities and microarchitecture, but the small sample size and the heterogeneity of the CKD group require caution in the interpretation. Novel bone imaging techniques seem feasible in children, and further longitudinal studies are required to thoroughly explore long-term cardiovascular and bone consequences of phosphate-calcium metabolism deregulation during CKD.

Assessment of bone microarchitecture in chronic kidney disease: a comparison of 2D bone texture analysis and high-resolution peripheral quantitative computed tomography at the radius and tibia.

Bone microarchitecture can be studied noninvasively using high-resolution peripheral quantitative computed tomography (HR-pQCT). However, this technique is not widely available, so more simple techniques may be useful. BMA is a new 2D high-resolution digital X-ray device, allowing for bone texture analysis with a fractal parameter (H(mean)). The aims of this study were (1) to evaluate the reproducibility of BMA at two novel sites (radius and tibia) in addition to the conventional site (calcaneus), (2) to compare the results obtained with BMA at all of those sites, and (3) to study the relationship between H(mean) and trabecular microarchitecture measured with an in vivo 3D device (HR-pQCT) at the distal tibia and radius. BMA measurements were performed at three sites (calcaneus, distal tibia, and radius) in 14 healthy volunteers to measure the short-term reproducibility and in a group of 77 patients with chronic kidney disease to compare BMA results to HR-pQCT results. The coefficient of variation of H(mean) was 1.2, 2.1, and 4.7% at the calcaneus, radius, and tibia, respectively. We found significant associations between trabecular volumetric bone mineral density and microarchitectural variables measured by HR-pQCT and H(mean) at the three sites (e.g., Pearson correlation between radial trabecular number and radial H(mean) r = 0.472, P < 0.001). This study demonstrated a significant but moderate relationship between 2D bone texture and 3D trabecular microarchitecture. BMA is a new reproducible technique with few technical constraints. Thus, it may represent an interesting tool for evaluating bone structure, in association with biological parameters and DXA.

Assessment of hand bone loss in rheumatoid arthritis by high-resolution peripheral quantitative CT.

OBJECTIVES: A new high-resolution peripheral quantitative CT (HR-pQCT) system allows for in vivo assessment of bone microarchitecture and volumetric bone mineral density (vBMD) with an 82 microm isotropic resolution. With this device, the microarchitecture impairment was evaluated in patients with rheumatoid arthritis (RA) in comparison with healthy controls and measured the erosion volume at metacarpal heads (MCPs). METHODS: In this cross-sectional study, the reproducibility was first assessed by 3 HR-pQCT exams with repositioning in 14 patients with late RA and 14 healthy subjects. Then, HR-pQCT parameters were measured in a group of 93 patients with RA and 31 healthy controls. Two RA subgroups were distinguished: early RA (disease duration < or =2 years) (n=36) and late RA (n=57) and compared them to healthy controls. RESULTS: The precision of the HR-pQCT volumetric measurements as assessed with coefficient of variation ranged from 0.7% to 1.8% in patients with late RA and from 0.6% to 1.4% in healthy subjects at MCPs. Total and trabecular vBMD and trabecular thickness were significantly decreased in patients with RA compared to healthy subjects and were significantly correlated to disease activity. The erosion volume was highly correlated to a semiquantitative assessment using the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) scoring system applied to the HR-pQCT slices. CONCLUSIONS: This study demonstrated the good reproducibility of the HR-pQCT volumetric measurements at MCPs and confirmed the involvement of trabecular compartment in periarticular osteopoenia. Thus, HR-pQCT appears interesting to simultaneously assess differences in bone volumetric density, microarchitecture and erosions.