Hypouricemia with hypercalciuria: Longitudinal study and review of the topic.

BACKGROUND AND OBJECTIVE: The association of hypouricemia and hypercalciuria is rare. In 1974 a new syndrome named Hypouricemia with hypercalciuria and decreased bone density was described. Afterwards, some cases with such association were published in which the fractional excretion of urate was higher than 20ml/100ml FGR. We have analyzed a series of children who were diagnosed with hypouricemia and hypercalciuria and who were monitored. The aim of this study was to determine whether our patients could be affected by the aforementioned syndrome or be carriers of a variant of idiopathic hypercalciuria. PATIENTS AND METHODS: Retrospective longitudinal study in which the medical records of eight patients (5V, 3M) diagnosed with hypouricemia and hypercalciuria in childhood. Clinical features at diagnosis, ultrasound and densitometric findings and selected biochemical variables were noted, with special emphasis on renal tubular handling of urate. Results were compared with 36 children with idiopathic hypercalciuria without hypouricemia (14V, 22M). RESULTS: In the hypouricemia group baseline urate levels were 1.9 (0.3) mg/dl (range: 1.5-2) and first day urine calcium/creatinine ratio 0.27 (0.05) mg/mg (range: 0.23-0.31). In all cases fractional urate excretion was less than 20ml/100ml FGR. The z-DMO values were less than -1 in 4/8 cases. At the last follow-up only three cases still had an elevated calcium/creatinine ratio and in all of them the urates levels was greater than 2mg/dl. The z-DMO value had improved in five cases and worsened in three others. In relation to the group without hypouricemia, no differences were observed between the various parameters studied including the z-DMO value, with the exception of fractional excretion and tubular urate reabsorption although plasmatic uric acid levels were still significantly lower. CONCLUSION: Our patients with hypercalciuria and hypouricemia would be affected by a variant of idiopathic hypercalciuria in which, due to an unknown cause, the proximal tubular reabsorption of urate is modestly reduced and improves over time. Hypouricemia with hypercalciuria and decreased bone density may not be a specific entity.

Renal diseases that course with hypomagnesemia. Comments on a new hereditary hypomagnesemic tubulopathy.

Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In this paper, we review the initial description, the clinical expressiveness and etiology of four of the first hypomagnesemic tubulopathies described: type 3 Bartter and Gitelman diseases, Autosomal recessive hypomagnesemia with secondary hypocalcemia and Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The basic biochemical patterns observed in renal tubular hypomagnesemias and the modalities of transport and interaction that occur between the transporters involved in the reabsorption of magnesium in the distal convoluted tubule are described below. Finally, the recent report of a new renal disease with hypomagnesemia, type 2 hypomagnesemia with secondary hypocalcemia caused by reduced TRPM7 channel activity is described.

Pathogenic Variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) in Spanish Patients with Renal Hypouricemia: Founder Effect of SLC2A9 Variant c.374C>T; p.(T125M).

Renal hypouricemia (RHUC) is a rare inherited disorder characterized by impaired urate reabsorption in the proximal tubule resulting in low urate serum levels and increased urate excretion. Some patients may present severe complications such as exercise-induced acute renal failure and nephrolithiasis. RHUC is caused by inactivating mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, which encode urate transporters URAT1 and GLUT9, respectively. In this study, our goal was to identify mutations associated with twenty-one new cases with RHUC through direct sequencing of SLC22A12 and SLC2A9 coding exons. Additionally, we carried out an SNPs-haplotype analysis to determine whether the rare SLC2A9 variant c.374C>T; p.(T125M), which is recurrent in Spanish families with RHUC type 2, had a common-linked haplotype. Six intragenic informative SNPs were analyzed using PCR amplification from genomic DNA and direct sequencing. Our results showed that ten patients carried the SLC22A12 mutation c.1400C>T; p.(T467M), ten presented the SLC2A9 mutation c.374C>T, and one carried a new SLC2A9 heterozygous mutation, c.593G>A; p.(R198H). Patients carrying the SLC2A9 mutation c.374C>T share a common-linked haplotype, confirming that it emerged due to a founder effect.

Reflections on TRP and TP/GFR in the definition of renal phosphate loss: conceptual review.

BACKGROUND: Fractional tubular reabsorption of phosphate (TRP) has been used for over 60 years to establish the existence of renal phosphate loss. It is a parameter of corrected volume per decilitre of glomerular filtration rate (GFR). Later, a mass parameter per dl GFR called TP/GFR (tubular PO4 reabsorption per dl GFR) was devised which some authors have sought to substitute for TRP. The aim of the present work is to attempt to demonstrate that TRP and TP/GFR are similar parameters and, in certain aspects, TRP is more effective for diagnosis. METHODS: Data were gathered on the metabolism of phosphate corresponding to a group of healthy children without hypophosphatemia (n = 47), a group of patients with idiopathic hypercalciuria (n = 27), and ten patients diagnosed with X-linked hypophosphatemia (XLH). The TRP, the TP/GFR, and the percent tubular reabsorption of phosphate were calculated. RESULTS: All the patients with XLH presented TRP values lower than 95 ml/dl GFR and of TP/GFR equal to or lower than 2.8 mg/dl GFR. In the total sample, a direct correlation was observed between TRP and TP/GFR (r = 0.65; p = 0.01). The TRP and the percent tubular reabsorption of phosphate values were the same in the three groups (r = 1; p = 0.01). CONCLUSIONS: TRP and TP/GFR are similar parameters. TRP is more effective than TP/GFR given that in renal hypophosphatemia it is always below 95% and above 95% in reduced phosphatemia and normal kidney proximal tubular function. There is no solid reason for using TP/GFR rather than TRP. A higher resolution version of the Graphical abstract is available as Supplementary information.

Reflux nephropathy and scarring nephropathy: So close and yet so different.

OBJECTIVES: Reflux nephropathy is a radiologic condition commonly used to express the existence of renal morphological lesions in patients who have or had vesicoureteral reflux (VUR). This morphological concept is used based on the image data collected, without conducting basic complementary renal function studies. The present study was designed to demonstrate that patients with active VUR present different functional renal alterations from those shown by patients with disappeared VUR. METHODS: Longitudinal descriptive retrospective analysis including 89 children (46M, 43F) with VUR diagnosis through a standard voiding cystourethrogram (VCUG). The basic renal function tests collected were the maximum urinary osmolality (UOsm) and the urinary albumin/creatinine and NAG/creatinine ratios. The data collected corresponded to two moments, when VUR was diagnosed and when it had already disappeared. RESULTS: Quantitative differences were verified in the three functional parameters when comparing those corresponding to both moments of the study. In the qualitative analysis, in relation to the intensity of the VUR, differences were observed in UOsm at diagnosis and in the albumin/creatinine ratio once the VUR had cured. At this last moment, a significant increase in the albumin/creatinine ratio was observed in patients with loss of renal parenchyma in relation to those without residual morphological lesions. CONCLUSIONS: Concentrating ability defect is the most frequent finding in children with active reflux (true reflux nephropathy), whereas the most frequent functional disturbance found, once VUR has cured, is an increase in urinary albumin excretion, related to parenchymal damage. The term dysplastic-scarring nephropathy, could be more appropriate for patients with residual morphological lesions and impaired renal function, once VUR is cured.

Clinical practice recommendations for the diagnosis and treatment of X-linked hypophosphatemia: A consensus based on the ADAPTE method. / Recomendaciones de práctica clínica para el diagnóstico y el tratamiento de la hipofosfatemia ligada al cromosoma X: un consenso basado en el método ADAPTE.

BACKGROUND AND OBJECTIVE: The objective of this project was to adapt to our setting following a systematic process based on the ADAPTE method the first clinical practice guidelines on X-linked hypophosphatemia (XLH) that were published in 2019. MATERIALS AND METHODS: The adaptation of the guidelines to our application and implementation setting was carried out in three phases -start-up, adaptation, and finalization- by a group of experts involved in the management of patients with XLH. RESULTS: Following the original guide, the recommendations agreed by the group that elaborated the guidelines for diagnosis, frequency and scope of visits and specific follow-up in children and adults are presented. On the other hand, recommendations are established for both age groups with conventional treatment, as well as with burosumab in children or adults and those related to the controversial use of growth hormone in children. Suggestions are also proposed regarding the monitoring and management of musculoskeletal disorders and orthopedic treatment in children, dental health and hearing, and neurosurgical complications. Finally, a series of questions and areas are raised in order to deepen the possible future investigation. CONCLUSIONS: These recommendations constitute the systematic adaptation to our setting of the first evidence-based clinical practice guide for the diagnosis and management of XLH and we hope that they can contribute to the adequate management of the disease.

[Reflux nephropathy and scarring nephropathy: So close and yet so different]. / Nefropatía de reflujo y nefropatía cicatricial. Dos entidades tan cercanas pero funcionalmente tan distintas.

OBJECTIVES: Reflux nephropathy is a radiologic condition commonly used to express the existence of renal morphological lesions in patients who have or had vesicoureteral reflux (VUR). This morphological concept is used based on the image data collected, without conducting basic complementary renal function studies. The present study was designed to demonstrate that patients with active VUR present different functional renal alterations from those shown by patients with disappeared VUR. PATIENTS AND METHODS: Longitudinal descriptive retrospective analysis including 89 children (46M, 43F) with VUR diagnosis through a standard voiding cystourethrogram (VCUG). The basic renal function tests collected were the maximum urinary osmolality (UOsm) and the urinary albumin/creatinine and NAG/creatinine ratios. The data collected corresponded to two moments, when VUR was diagnosed and when it had already disappeared. RESULTS: Quantitative differences were verified in the three functional parameters when comparing those corresponding to both moments of the study. In the qualitative analysis, in relation to the intensity of the VUR, differences were observed in UOsm at diagnosis and in the albumin/creatinine ratio once the VUR had cured. At this last moment, a significant increase in the albumin/creatinine ratio was observed in patients with loss of renal parenchyma in relation to those without residual morphological lesions. CONCLUSIONS: Concentrating ability defect is the most frequent finding in children with active reflux (true reflux nephropathy), whereas the most frequent functional disturbance found, once VUR has cured, is an increase in urinary albumin excretion, related to parenchymal damage. The term dysplastic-scarring nephropathy, could be more appropriate for patients with residual morphological lesions and impaired renal function, once VUR is cured.

The use of urinary osmolality to evaluate postoperative renal function in children with ureteropelvic junction obstruction.

INTRODUCTION: Split renal function measured in a diuretic renogram is the most popular tool in initial assessment and follow-up of patients with ureteropelvic junction obstruction (UPJO). This study aims to evaluate the use of maximum urinary osmolality after desmopressin administration (DDAVP) to detect renal dysfunction. PATIENTS AND METHODS: 56 children (33 males, 23 females) diagnosed with UPJO underwent quantification of the maximum urinary osmolality (UOsm) at diagnosis. 41 of these children (28 males, 13 females) underwent surgery for UPJO and quantification of the UOsm before and after the surgical intervention (six to 18 months postoperatively) and were included in this longitudinal study. RESULTS AND DISCUSSION: At diagnosis, UOsm measured after desmopressin administration was abnormal in 64% of patients. After surgical intervention, this rate decreased to 53%. At initial assessment, high creatinine levels were found in 32% of infants younger than one year of age. Albumin/Cr and NAG/Cr ratios were elevated in 12% and 7% of cases, respectively. After surgical intervention, an improvement in the NAG/creatinine ratio and creatinine levels was observed. Preoperative split renal function of the affected kidney was less than 45% in 39% of cases, normal in 44%, and greater than 55% in 17%; in these three subgroups, no differences in renal function markers were found. CONCLUSIONS: The most sensitive parameter to detect alterations in renal function in children with UPJO is the UOsm and, therefore, the most useful in the follow-up after surgery. No correlation was found between other functional and morphological parameters obtained on renal ultrasound and renogram.

Phenotypic characterization of X-linked hypophosphatemia in pediatric Spanish population.

BACKGROUND: X-linked hypophosphatemia (XLH) is a hereditary rare disease caused by loss-of-function mutations in PHEX gene leading tohypophosphatemia and high renal loss of phosphate. Rickets and growth retardation are the major manifestations of XLH in children, but there is a broad phenotypic variability. Few publications have reported large series of patients. Current data on the clinical spectrum of the disease, the correlation with the underlying gene mutations, and the long-term outcome of patients on conventional treatment are needed, particularly because of the recent availability of new specific medications to treat XLH. RESULTS: The RenalTube database was used to retrospectively analyze 48 Spanish patients (15 men) from 39 different families, ranging from 3 months to 8 years and 2 months of age at the time of diagnosis (median age of 2.0 years), and with XLH confirmed by genetic analysis. Bone deformities, radiological signs of active rickets and growth retardation were the most common findings at diagnosis. Mean (± SEM) height was - 1.89 ± 0.19 SDS and 55% (22/40) of patients had height SDS below-2. All cases had hypophosphatemia, serum phosphate being - 2.81 ± 0.11 SDS. Clinical manifestations and severity of the disease were similar in both genders. No genotype-phenotype correlation was found. Conventional treatment did not attenuate growth retardation after a median follow up of 7.42 years (IQR = 11.26; n = 26 patients) and failed to normalize serum concentrations of phosphate. Eleven patients had mild hyperparathyroidism and 8 patients nephrocalcinosis. CONCLUSIONS: This study shows that growth retardation and rickets were the most prevalent clinical manifestations at diagnosis in a large series of Spanish pediatric patients with XLH confirmed by mutations in the PHEX gene. Traditional treatment with phosphate and vitamin D supplements did not improve height or corrected hypophosphatemia and was associated with a risk of hyperparathyroidism and nephrocalcinosis. The severity of the disease was similar in males and females.

Correction to: Panel Discussion: Some Aspects of the Management of Patients with X-Linked Hypophosphataemic Rickets.

In the original article, third author name has been published incorrectly.

Longitudinal study of kidney water management in patients diagnosed with idiopathic hypercalciuria in childhood. / Estudio longitudinal del manejo renal del agua en pacientes diagnosticados de hipercalciuria idiopática en la infancia.

INTRODUCTION: There is much debate about whether idiopathic hypercalciuria (IH) affects kidney water management. For the first time in the literature, we carried out a longitudinal study of kidney water management (KWM) in patients diagnosed with IH in childhood and followed-up until adulthood (mean follow-up 17.7±1.4 years). METHODS: Twenty-nine patients (7 M, 22 F) over the age of 24 years (mean 28.2±2.9 years, range: 24.1-35.9) who were diagnosed with IH in childhood (mean 7.6±3.2 years, range: 1-14) were included. Maximum urine osmolality (UO) and/or urine volume adjusted for 100ml of glomerular filtration rate (V/GFR) in both age groups (paediatric and adult) were determined. Moreover, whenever possible, in both age groups plasma creatinine levels, plasma sodium levels, uric acid levels, the citrate/creatinine ratio and the calcium/citrate ratio were recorded and a renal and bladder ultrasound was performed. RESULTS: In the paediatric age group, KWM was altered in 9/29 cases (31%) (4 with reduced maximum UO and 5 with elevated V/GFR). In adulthood, KWM was found to be affected in 7/29 cases (24.1%) (6 with reduced UO and one with elevated V/GFR). Compared to the paediatric age group, adult patients had lower V/GFR, calcium/creatinine and citrate/creatinine values, as well as higher plasma creatinine, uric acid and calcium/citrate. There were no differences in the maximum UO in both age groups. However, UO in adulthood was significantly lower in subjects who had renal colic compared to those who did not (P=.04). CONCLUSIONS: KWM was affected in approximately one third of patients with IH, which persisted 20 years after diagnosis. We think that these results may be due to adherence to the recommended protective diet and to the pharmacological treatment administered at the diagnosis of IH during childhood.

The idiopathic hypercalciuria reviewed. Metabolic abnormality or disease? / La hipercalciuria idiopática revisada. ¿Anomalía metabólica o enfermedad?

Idiopathic hypercalciuria (IH) is defined as that clinical situation in which an increase in urinary calcium excretion is observed, in the absence of hypercalcemia and other known causes of hypercalciuria. In recent years, its diagnosis in pediatric age has been more frequent because it has been known that it can debut with very different symptoms, in the absence of kidney stone formation. The discovery of genetic hypercalciuric stone-forming rats has allowed us to glimpse the pathophysiological mechanism of IH since they show many data in common with humans with IH as normal levels of blood calcium, intestinal calcium hyperabsorption, increased bone resorption and a defect in the renal tubular calcium reabsorption. In 1993, it was shown that in these animals there is an increase in the number of vitamin D receptors (VDR) in the intestine, which favors an increase in the functional capacity of calcitriol-VDR complexes that explains the increase in intestinal transport of calcium. The same happens at the bone level producing a greater resorption. In our opinion, IH is a 'metabolic anomaly' or, better, an inheritable constitutive metabolic characteristic. In this sense, what patients with IH would inherit is the availability of having a greater number of VDRs in their cells than those with normal urinary calcium excretion. IH cannot be considered a sensu stricto disease, so pharmacological treatment must be individualized.

Renal tubular markers as screening tools for severe vesicoureteral reflux.

Severe (grades IV and V) vesicoureteral reflux (VUR) is a risk factor for acute pyelonephritis, renal scars, and renal failure. This study evaluates albumin and N-acetylglucosaminidase (NAG) urinary excretion, and renal concentrating ability as screening tools to select patients for voiding cystourethrogram (VCUG). Children (111 M, 52 F) aged 10.97 ± 21.17 months (mean + SD), diagnosed with UTI, and who had undergone renal ultrasound and a VCUG, underwent a desmopressin test and had albumin/creatinine and NAG/creatinine urinary excretion measured. Urine osmolality was significantly lower in 27 children with severe VUR (375.3 ± 171.8 mOsm/kg; mean + SD) compared to 100 patients with normal VCUG (611.5 ± 175.8 mOsm/kg), p < 0.001, and to 36 patients with VUR grades I to III (636.2 ± 180.2 mOsm/kg), p < 0.001. NAG/creatinine ratio was significantly elevated in 20 children with severe VUR (26.4 (28.3) U/g); median and interquartile range compared to 67 children with normal VCUG (10.8 (17.9) U/g), p = 0.003, and to 20 patients with VUR grades I to III (7.6 (21.1) U/g), p = 0.009.Conclusions: Urinary osmolality is significantly decreased and urinary excretion of NAG is significantly increased in patients with severe VUR. These tests could select patients for VCUG to assess for severe VUR. What is Known: • Severe vesicoureteral reflux (SVUR) may contribute to renal damage. Severe vesicoureteral reflux is diagnosed by voiding cystourethrogram and represents about 10% of all patients with VUR. Currently, there are no reliable tests used prior to VCUG to help on the decision of obtaining a VCUG to diagnose SVUR. What is New: • This study shows that renal tubular markers (concentrating ability and N-acetylglucosaminidase (NAG) excretion) are useful tests prior to voiding cystourethrogram to screen for severe vesicoureteral reflux. • This study suggests the use of renal concentrating ability and urinary N-acetylglucosaminidase (NAG) excretion to screen for severe vesicoureteral reflux before requesting a voiding cystourethrogram.

Quantification of the risk of urinary calcium stone formation in the urine collected at 2 times of the day in a group of children studied to rule out prelithiasis. / Cuantificación del riesgo de formación de cálculos cálcicos en la orina correspondiente a 2 momentos del día en un grupo de niños estudiados para descartar prelitiasis.

BACKGROUND: Various genetic and environmental factors are involved in urolithiasis. The 2 most common metabolic abnormalities are the increase in urinary calcium and low urinary citrate excretion. The ratio calculated between the concentrations of both substances is a good risk marker for the formation of calcium stones. OBJECTIVES: To determine whether the risk of urinary calcium stone formation changes throughout the day in the same patient. METHODS: We studied 56 children (23V, 33M) to check if they had prelithiasis. Calcium, citrate, and creatinine concentrations were determined in two urine samples collected one before dinner and the other in the morning. It was collected if they had ultrasound stones and if there was a history of urolithiasis in first and/or second degree relatives. RESULTS: In 25 patients (44.6%), renal ultrasound was positive for lithiasis (stones [n=9] and microlithiasis [n=16]). Forty of the 56 families (71.4%) had a history of urolithiasis. The percentage of abnormal urinary calcium (28.6%) concentrations and an abnormal calcium/citrate ratio (69.6%) was higher in the first urine of the day. The calcium/citrate ratio was the only studied parameter that was related to a family history of urolithiasis. There were no differences in urinary parameters between patients with and without ultrasound-confirmed kidney stones. CONCLUSIONS: Urinary concentrations of calcium and the calcium/citrate ratio vary throughout the day. Urine produced at night has a higher risk of urinary calcium stone formation.