Multicenter Long-Term Real World Data on Treatment With Lumasiran in Patients With Primary Hyperoxaluria Type 1.

Introduction: The RNA interference (RNAi) medication lumasiran reduces hepatic oxalate production in primary hyperoxaluria type 1 (PH1). Data outside clinical trials are scarce. Methods: We report on retrospectively and observationally obtained data in 33 patients with PH1 (20 with preserved kidney function, 13 on dialysis) treated with lumasiran for a median of 18 months. Results: Among those with preserved kidney function, mean urine oxalate (Uox) decreased from 1.88 (baseline) to 0.73 mmol/1.73 m2 per 24h after 3 months, to 0.72 at 12 months, and to 0.65 at 18 months, but differed according to vitamin B6 (VB6) medication. The highest response was at month 4 (0.55, -70.8%). Plasma oxalate (Pox) remained stable over time. Glomerular filtration rate increased significantly by 10.5% at month 18. Nephrolithiasis continued active in 6 patients, nephrocalcinosis ameliorated or progressed in 1 patient each. At last follow-up, Uox remained above 1.5 upper limit of normal (>0.75 mmol/1.73 m2 per 24h) in 6 patients. Urinary glycolate (Uglyc) and plasma glycolate (Pglyc) significantly increased in all, urine citrate decreased, and alkali medication needed adaptation. Among those on dialysis, mean Pox and Pglyc significantly decreased and increased, respectively after monthly dosing (Pox: 78-37.2, Pglyc: 216.4-337.4 µmol/l). At quarterly dosing, neither Pox nor Pglyc were significantly different from baseline levels. An acid state was buffered by an increased dialysis regimen. Systemic oxalosis remained unchanged. Conclusion: Lumasiran treatment is safe and efficient. Dosage (interval) adjustment necessities need clarification. In dialysis, lack of Pox reduction may relate to dissolving systemic oxalate deposits. Pglyc increment may be a considerable acid load requiring careful consideration, which definitively needs further investigation.

Use of rasburicase to improve kidney function in children with hyperuricemia and acute kidney injury.

BACKGROUND: Hyperuricemia contributes to decrease in kidney function and induces additional renal damage in children with acute kidney injury (AKI). Rasburicase oxidizes uric acid (UA), decreasing its serum quantities in less than 24 h. METHODS: This is a retrospective study involving hospitalized patients under 18 years of age with underlying pathology diagnosed with AKI and severe hyperuricemia treated with rasburicase over a 4-year period. RESULTS: We describe 15 patients from 4 days of life to 18 years (median: 4.4 years). Seventy-three percent had known underlying pathologies. All presented worsening of basal renal function or AKI data. All received the usual medical treatment for AKI without response. Twenty percent received an extrarenal depuration technique. All had hyperuricemia with a mean (± SD) of 13.1 (± 2.19) mg/dl. After rasburicase administration UA levels fell to a mean (± SD) of 0.76 (± 0.62) mg/dl (p < 0.001) in less than 24 h. In parallel, a decrease in the mean plasma creatinine was observed (2.92 mg/dl to 1.93 mg/dl (p = 0.057)) together with a significant improvement of the mean glomerular filtration rate (16.3 ml/min/1.73 m2 to 78.6 ml/min/1.73 m2) (p = 0.001)). No side effects were recorded. Kidney function normalized in all cases or returned to baseline levels. CONCLUSIONS: Although the use of rasburicase is not routinely approved in pediatric patients with severe hyperuricemia and AKI, it has been used successfully without complications, and helped prevent progressive kidney damage. This study could serve as a basis for suggesting the off-label use of rasburicase for the management of complex pediatric patients in whom UA plays an important role in the development of AKI.

Genotypic variability in patients with clinical diagnosis of Bartter syndrome type 3.

Bartter syndrome (BS) is a salt-losing hereditary tubulopathy characterized by hypokalemic metabolic alkalosis with secondary hyperaldosteronism. Confirmatory molecular diagnosis may be difficult due to genetic heterogeneity and overlapping of clinical symptoms. The aim of our study was to describe the different molecular findings in patients with a clinical diagnosis of classic BS. We included 27 patients (26 families) with no identified pathogenic variants in CLCNKB. We used a customized Ion AmpliSeq Next-Generation Sequencing panel including 44 genes related to renal tubulopathies. We detected pathogenic or likely pathogenic variants in 12 patients (44%), reaching a conclusive genetic diagnosis. Variants in SLC12A3 were found in 6 (Gitelman syndrome). Median age at diagnosis was 14.6 years (range 0.1-31), with no history of prematurity or polyhydramnios. Serum magnesium level was low in 2 patients (33%) but urinary calcium excretion was normal or low in all, with no nephrocalcinosis. Variants in SLC12A1 were found in 3 (BS type 1); and in KCNJ1 in 1 (BS type 2). These patients had a history of polyhydramnios in 3 (75%), and the mean gestational age was 34.2 weeks (SD 1.7). The median age at diagnosis was 1.8 years (range 0.1-6). Chronic kidney disease and nephrocalcinosis were present in 1 (25%) and 3 (75%) patients, respectively. A variant in CLCN5 was found in one patient (Dent disease), and in NR3C2 in another patient (Geller syndrome). Genetic diagnosis of BS is heterogeneous as different tubulopathies can present with a similar clinical picture. The use of gene panels in these diseases becomes more efficient than the study gene by gene with Sanger sequencing.

Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study.

BACKGROUND: Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. METHODS: Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). RESULTS: A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate-standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. CONCLUSIONS: Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.

Acidosis tubular renal distal hereditaria: correlación genotípica, evolución a largo plazo y nuevas perspectivas terapéuticas / Hereditary distal renal tubular acidosis: Genotypic correlation, evolution to long term, and new therapeutic perspectives

La acidosis tubular renal distal (ATRD) es una enfermedad rara que se debe al fallo del proceso normal de acidificación de la orina a nivel tubular distal y colector. Se caracteriza por una acidosis metabólica hiperclorémica persistente, con anión gap normal en plasma, en presencia de un pH urinario elevado y baja excreción urinaria de amonio. Se han descrito hasta el momento 5 genes cuyas mutaciones dan lugar a ATRD primaria. Las alteraciones de los genes ATP6V1B1 y ATP6V0A4 se heredan de forma recesiva y están asociadas a formas de inicio más precoces y con sordera neurosensorial en muchos casos. Las variantes patogénicas en el gen SLC4A1 se heredan habitualmente de forma dominante y dan lugar a cuadros más leves, con un diagnóstico más tardío y alteraciones electrolíticas menores. Sin embargo, la evolución a nefrocalcinosis y litiasis, y el desarrollo de enfermedad renal crónica a medio-largo plazo se ha descrito de forma similar en estos 3grupos. Por último, se han descrito también formas recesivas de ATRD asociadas a mutaciones en los genes FOXI1 y WDR72. El manejo clínico de la ATRD se basa en sales de bicarbonato o citrato, que no logran corregir en todos los casos las alteraciones metabólicas descritas y, por lo tanto, las consecuencias asociadas a ellas. Recientemente, un nuevo tratamiento basado en sales de bicarbonato y citrato de liberación prolongada ha recibido la denominación de medicamento huérfano en Europa para el tratamiento de la ATRD. (AU)

Distal renal tubular acidosis (DRTA) is a rare disease resulting from a failure in the normal urine acidification process at the distal tubule and collecting duct level. It is characterised by persistent hyperchloremic metabolic acidosis, with a normal anion gap in plasma, in the presence of high urinary pH and low urinary excretion of ammonium. To date, 5 genes whose mutations give rise to primary DRTA have been described. Alterations in the ATP6V1B1 and ATP6V0A4 genes are inherited recessively and are associated with forms of early onset and, in many cases, with neurosensorial deafness. Pathogenic variants in the SLC4A1 gene are habitually inherited dominantly and give rise to milder symptoms, with a later diagnosis and milder electrolytic alterations. Nonetheless, evolution to nephrocalcinosis and lithiasis, and the development of chronic kidney disease in the medium to long term has been described in a similar manner in all 3groups. Lastly, recessive forms of DTRA associated to mutations in the FOXI1 and WDR72 genes have also been described. The clinical management of DTRA is based on bicarbonate or citrate salts, which do not succeed in correcting all cases of the metabolic alterations described and, thus, the consequences associated with them. Recently, a new treatment based on slow-release bicarbonate and citrate salts has received the designation of orphan drug in Europe for the treatment of DTRA. (AU)

Molecular aspects and long-term outcome of patients with primary distal renal tubular acidosis.

BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder caused by impaired distal mechanisms of urinary acidification. Most cases are secondary to pathogenic variants in ATP6V0A4, ATP6V1B1, and SLC4A1 genes, which encode transporters regulating acid-base balance in the collecting duct. METHODS: Retrospective study of molecular and clinical data from diagnosis and long-term follow-up (10, 20, and 40±10 years) of 16 patients with primary dRTA diagnosed in childhood. RESULTS: Molecular analyses revealed nine patients had ATP6V0A4 pathogenic variants, five in ATP6V1B1, and two in SLC4A1. A novel intragenic deletion and a common ATP6V0A4 gene variant (c.1691 + 2dupT) in ATP6V0A4 occurred in two-thirds of these patients, suggesting a founder effect. Median age at diagnosis was 3.25 months (IQR 1, 13.5), which was higher in the SLC4A1 group. Median SDS height at diagnosis was -1.02 (IQR -1.79, 0.14). Delayed clinical diagnosis was significantly related to growth failure (P = 0.01). Median SDS height at 20 years follow-up was -1.23 (IQR -1.71, -0.48), and did not significantly improve from diagnosis (P = 0.76). Kidney function declined over time: at last follow-up, 43% had moderate to severe chronic kidney disease (CKD). Adequate metabolic control was not related to CKD development. Incidence of sensorineural hearing loss (SNHL) was high in ATP6V1B1 patients, though not universal. Patients harboring ATP6V0A4 variants also developed SNHL at a high rate (80%) over time. CONCLUSIONS: Patients with dRTA can develop moderate to severe CKD over time with a high frequency despite adequate metabolic control. Early diagnosis ameliorates long-term height prognosis.

Hereditary distal renal tubular acidosis: Genotypic correlation, evolution to long term, and new therapeutic perspectives.

Distal renal tubular acidosis (DRTA) is a rare disease resulting from a failure in the normal urine acidification process at the distal tubule and collecting duct level. It is characterised by persistent hyperchloremic metabolic acidosis, with a normal anion gap in plasma, in the presence of high urinary pH and low urinary excretion of ammonium. To date, 5 genes whose mutations give rise to primary DRTA have been described. Alterations in the ATP6V1B1 and ATP6V0A4 genes are inherited recessively and are associated with forms of early onset and, in many cases, with neurosensorial deafness. Pathogenic variants in the SLC4A1 gene are habitually inherited dominantly and give rise to milder symptoms, with a later diagnosis and milder electrolytic alterations. Nonetheless, evolution to nephrocalcinosis and lithiasis, and the development of chronic kidney disease in the medium to long term has been described in a similar manner in all 3 groups. Lastly, recessive forms of DTRA associated to mutations in the FOXI1 and WDR72 genes have also been described. The clinical management of DTRA is based on bicarbonate or citrate salts, which do not succeed in correcting all cases of the metabolic alterations described and, thus, the consequences associated with them. Recently, a new treatment based on slow-release bicarbonate and citrate salts has received the designation of orphan drug in Europe for the treatment of DTRA.

Hyperechogenic kidneys and polyhydramnios associated with HNF1B gene mutation.

BACKGROUND: HNF1B mutation is the leading cause of isolated hyperechogenic fetal kidneys with normal or moderately large size. Although most cases have normal amniotic fluid volume, some cases present with early oligohydramnios and renal failure associated with high perinatal mortality. CASE DIAGNOSIS/TREATMENT: Here we report on seven fetuses from six unrelated families, carrying an HNF1B mutation, and presenting with polyhydramnios during the second or third trimester of pregnancy. Polyhydramnios was transitory in two cases. None of the mothers was presenting gestational diabetes. Bilateral hyperechogenic kidneys with size between -2.5 and +2 SD was the most common renal phenotype at prenatal US. Two patients were born prematurely at 28 and 32 weeks of gestation, respectively. Both presented high urine output the first days of life with urinary salt and potassium loss requiring hydro-electrolytic compensation. All mutations were large deletions removing the whole HNF1B gene. CONCLUSIONS: In the absence of maternal diabetes, HNF1B mutation can be associated with polyhydramnios, probably due to fetal polyuria. Thus, HNF1B mutation represents a differential diagnosis of polyhydramnios associated with hyperechogenic (and sometimes enlarged) kidneys.