Mónica Furlano

Lanthanum carbonate for the control of hyperphosphatemia in chronic renal failure patients: a new oral powder formulation – safety, efficacy, and patient adherence

Chronic kidney disease (CKD) is associated with very high mortality rates, mainly of cardiovascular origin. The retention of phosphate (P) and increased fibroblast growth factor-23 levels are common, even at early stages of CKD, due to disturbances in normal P homeostasis. Later, hyperphosphatemia appears, which has also been strongly associated with high mortality rates linked to P-mediated cardiovascular and procalcifying effects. Treatment guidelines for these patients continue to be poorly implemented, at least partially due to the lack of adherence to a P-restricted diet and P-binder therapy. Calcium-free P binders, such as lanthanum carbonate, have been associated with a decreased progression of vascular calcification, rendering them an important therapeutic alternative for these high cardiovascular risk CKD patients. Lanthanum carbonate has typically been available as chewable tablets, and the new presentation as an oral powder may provide a useful alternative in the therapeutic armamentarium. This powder is a tasteless, odorless, and colorless semisolid compound miscible with food. In a recent study in healthy individuals, the safety and efficacy of this novel form were evaluated, and it was concluded that it is well tolerated and pharmacodynamically equivalent to the chewable form. In the long run, individualization of preferences and treatments seems an achievable goal prior to final demonstration of improvements in hard outcomes in wide clinical trials in CKD patients.

A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases

Molecular diagnosis of inherited kidney diseases remains a challenge due to their expanding phenotypic spectra as well as the constantly growing list of disease-causing genes. Here we develop a comprehensive approach for genetic diagnosis of inherited cystic and glomerular nephropathies. Targeted next generation sequencing of 140 genes causative of or associated with cystic or glomerular nephropathies was performed in 421 patients, a validation cohort of 116 patients with previously known mutations, and a diagnostic cohort of 207 patients with suspected inherited cystic disease and 98 patients with glomerular disease. In the validation cohort, a sensitivity of 99% was achieved. In the diagnostic cohort, causative mutations were found in 78% of patients with cystic disease and 62% of patients with glomerular disease, mostly familial cases, including copy number variants. Results depict the distribution of different cystic and glomerular inherited diseases showing the most likely diagnosis according to perinatal, pediatric and adult disease onset. Of all the genetically diagnosed patients, 15% were referred with an unspecified clinical diagnosis and in 2% genetic testing changed the clinical diagnosis. Therefore, in 17% of cases our genetic analysis was crucial to establish the correct diagnosis. Complex inheritance patterns in autosomal dominant polycystic kidney disease and Alport syndrome were suspected in seven and six patients, respectively. Thus, our kidney-disease gene panel is a comprehensive, noninvasive, and cost-effective tool for genetic diagnosis of cystic and glomerular inherited kidney diseases. This allows etiologic diagnosis in three-quarters of patients and is especially valuable in patients with unspecific or atypical phenotypes.

Autosomal Dominant Polycystic Kidney Disease: Clinical Assessment of Rapid Progression

Background: Autosomal dominant polycystic kidney disease (ADPKD) causes the development of renal cysts and leads to a decline in renal function. Limited guidance exists in clinical practice on the use of tolvaptan. A decision algorithm from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Working Groups of Inherited Kidney Disorders and European Renal Best Practice (WGIKD/ERBP) has been proposed to identify candidates for tolvaptan treatment; however, this algorithm has not been assessed in clinical practice. Methods: Eighteen-month cross-sectional, unicenter, observational study assessing 305 consecutive ADPKD patients. The ERA-EDTA WGIKD/ERBP algorithm with a stepwise approach was used to assess rapid progression (RP). Subsequently, expanded criteria based on the REPRISE trial were applied to evaluate the impact of extended age (≤55 years) and estimated glomerular filtration rate (eGFR; ≥25 mL/min/1.73 m2). Results: Historical eGFR decline, indicative of RP, was fulfilled in 26% of 73 patients who were candidates for RP assessment, mostly aged 31–55 years. Further tests including ultrasound and MRI measurements of kidney volume plus genetic testing enabled the evaluation of the remaining patients. Overall, 15.7% of patients met the criteria for rapid or likely RP using the algorithm, and the percentage increased to 27% when extending age and eGFR. Conclusions: The ERA-EDTA WGIKD/ERBP algorithm provides a valuable means of identifying in routine clinical practice patients who may be eligible for treatment with tolvaptan. The impact of a new threshold for age and eGFR may increase the percentage of patients to be treated.

Generation of integration-free induced pluripotent stem cell lines derived from two patients with X-linked Alport syndrome (XLAS)

Skin biopsies were obtained from two male patients with X-linked Alport syndrome (XLAS) with hemizygous COL4A5 mutations in exon 41 or exon 46. Dermal fibroblasts were extracted and reprogrammed by nucleofection with episomal plasmids carrying OCT3/4, SOX2, KLF4 LIN28, L-MYC and p53 shRNA. The generated induced Pluripotent Stem Cell (iPSC) lines AS-FiPS2-Ep6F-28 and AS-FiPS3-Ep6F-9 were free of genomically integrated reprogramming genes, had the specific mutations, a stable karyotype, expressed pluripotency markers and generated embryoid bodies which were differentiated towards the three germ layers in vitro. These iPSC lines offer a useful resource to study Alport syndrome pathomechanisms and drug testing.

Integration-free induced pluripotent stem cells derived from a patient with autosomal recessive Alport syndrome (ARAS)

A skin biopsy was obtained from a 25-year-old female patient with autosomal recessive Alport syndrome (ARAS) with the homozygous COL4A3 mutation c.345delG, p.(P166Lfs*37). Dermal fibroblasts were derived and reprogrammed by nucleofection with episomal plasmids carrying OCT3/4, SOX2, KLF4 LIN28, L-MYC and p53shRNA. The generated induced Pluripotent Stem Cell (iPSC) clone AS FiPS1 Ep6F-2 was free of genomically integrated reprogramming genes, had the specific homozygous mutation, a stable karyotype, expressed pluripotency markers and generated embryoid bodies which were differentiated towards the three germ layers in vitro. This iPSC line offers a useful resource to study Alport syndrome pathomechanisms and drug testing.