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.

II National Congress of Paediatrics: The fight against child mortality.

In the present work, we present an overview of the contents of the communications presented at the Second National Congress of Paediatrics, held in San Sebastian in 1923, on the occasion of the 100th year anniversary. The problem of infant mortality stands out as a common thread, which in those years was very high in Spain and was a concern of politicians, intellectuals and the medical profession. It is worth noting that some of the proposals and concerns of the paediatricians who attended that congress continue to be relevant today.

Autosomal dominant distal renal tubular acidosis in two pediatric patients with mutations in the SLC4A1 gene. Can the maximum urinary pCO2 test be normal?

Primary distal renal tubular acidosis (dRTA) is a rare tubulopathy characterised by the presence of hyperchloremic metabolic acidosis. It is caused by the existence of a defect in the function of the H+ -ATPase located on the luminal side of the α-intercalated cells or the Cl - HCO3- (AE1) anion exchanger located on the basolateral side. Patients do not acidify the urine after acid overload (NH4Cl) or after stimulating H+ secretion by obtaining a high intratubular concentration of an anion such as chlorine (pH is measured) or HCO3- (urinary pCO2 is measured). We present a family with autosomal dominant dRTA produced by a heterozygous mutation in the SLC4A1 gene in which the two paediatric members showed a test of normal maximum urinary pCO2. Our hypothesis is that since the H + -ATPase is intact, at least initially, the stimulation induced by intratubular electronegativity to secrete H + could be effective, which would allow the maximum urinary pCO2 to be paradoxically normal, which could explain the onset, moderate presentation of symptoms and late diagnosis in patients with this mutation. This is the first documented case of a dominant dRTA in Mexico.

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.

Gout associated with reduced renal excretion of uric acid. Renal tubular disorder that nephrologists do not treat.

Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout include non-modifiable factors such as gender, age, ethnicity and genetics, and modifiable factors such as diet and lifestyle. It has been shown that the heritability of uric acid levels in the blood is greater than 30%, which indicates that genetics play a key role in these levels. Hyperuricaemia is often a consequence of reduced renal urate excretion since more than 70% is excreted by the kidneys, mainly through the proximal tubule. The mechanisms that explain that hyperuricaemia associated with reduced renal urate excretion is, to a large extent, a proximal renal tubular disorder, have begun to be understood following the identification of two genes that encode the URAT1 and GLUT9 transporters. When they are carriers of loss-of-function mutations, they explain the two known variants of renal tubular hypouricaemia. Some polymorphisms in these genes may have an opposite gain-of-function effect, with a consequent increase in urate reabsorption. Conversely, loss-of-function polymorphisms in other genes that encode transporters involved in urate excretion (ABCG2, ABCC4) can lead to hyperuricaemia. Genome-wide association study (GWAS) methods have made it possible to locate new gout-related loci associated with reduced renal urate excretion (NIPAL1, FAM35A).

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.

Hereditary kidney diseases associated with hypomagnesemia.

In the kidney, a set of proteins expressed in the epithelial cells of the thick ascending loop of Henle and the distal convoluted tubule directly or indirectly play important roles in the regulation of serum magnesium levels. Magnesium reabsorption in the thick ascending loop of Henle occurs through a passive paracellular pathway, while in the distal convoluted tubule, the final magnesium concentration is established through an active transcellular pathway. The players involved in magnesium reabsorption include proteins with diverse functions including tight junction proteins, cation and anion channels, sodium chloride cotransporter, calcium-sensing receptor, epidermal growth factor, cyclin M2, sodium potassium adenosine triphosphatase subunits, transcription factors, a serine protease, and proteins involved in mitochondrial function. Mutations in the genes that encode these proteins impair their function and cause different rare diseases associated with hypomagnesemia, which may lead to muscle cramps, fatigue, epileptic seizures, intellectual disability, cardiac arrhythmias, and chronic kidney disease. The purpose of this review is to describe the clinical and genetic characteristics of these hereditary kidney diseases and the current research findings on the pathophysiological basis of these diseases.

[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.

Gout associated with reduced renal excretion of uric acid. Renal tubular disorder that nephrologists do not treat. / La gota asociada a reducción de la excreción renal de ácido úrico. Esa tubulopatía que no tratamos los nefrólogos.

Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout include non-modifiable factors such as gender, age, ethnicity and genetics, and modifiable factors such as diet and lifestyle. It has been shown that the heritability of uric acid levels in the blood is greater than 30%, which indicates that genetics play a key role in these levels. Hyperuricaemia is often a consequence of reduced renal urate excretion since more than 70% is excreted by the kidneys, mainly through the proximal tubule. The mechanisms that explain that hyperuricaemia associated with reduced renal urate excretion is, to a large extent, a proximal renal tubular disorder, have begun to be understood following the identification of two genes that encode the URAT1 and GLUT9 transporters. When they are carriers of loss-of-function mutations, they explain the two known variants of renal tubular hypouricaemia. Some polymorphisms in these genes may have an opposite gain-of-function effect, with a consequent increase in urate reabsorption. Conversely, loss-of-function polymorphisms in other genes that encode transporters involved in urate excretion (ABCG2, ABCC4) can lead to hyperuricaemia. Genome-wide association study (GWAS) methods have made it possible to locate new gout-related loci associated with reduced renal urate excretion (NIPAL1, FAM35A).

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.

Evolution of bone mineral density in patients with idiopathic hypercalciuria: a 20-year longitudinal study.

BACKGROUND: Several recent studies reported bone mineral density (BMD) reduction in pediatric patients with idiopathic hypercalciuria (IH). This longitudinal study aimed to evaluate BMD evolution in IH patients through three bone densitometry studies conducted over 20 years on average. A second objective was to evaluate urine calcium and citrate excretion during this period. METHODS: Case notes of 34 patients diagnosed with IH at age 7.9 ± 3, alongside results of two bone densitometry studies, performed at 10.5 ± 2.7 (BMD1) and 14.5 ± 2.7 (BMD2) years of age, were reviewed. Patients underwent a third densitometry study in adulthood (BMD3) aged 28.3 ± 2.9. Mean follow-up duration (time-lapse between BMD1 and BMD3) was 17.7 ± 1.4 years. RESULTS: Statistically significant differences were found between z-BMD3 (- 0.85 ± 1.10) and z-BMD1 (- 1.47 ± 0.99) (P = 0.001) as well as between z-BMD3 and z-BMD2 (- 1.33 ± 1.20) (P = 0.016). At the end of follow-up, z-BMD3 was superior to z-BMD2 in 23 adult patients (67.6%) and lower in 11 patients (5M, 6F; 32.3%). Both men and women showed increased bone mass over time, although such increases were significant only for women. The gradual decrease observed in calcium/creatinine and citrate/creatinine ratios could be related to improvement in osteoblastic activity and especially reduction in osteoclastic activity. CONCLUSIONS: In patients with IH, BMD improves, which may be related especially to female sex, increment of body mass, and reduction in bone resorption. Upon reaching adulthood, urine calcium and citrate excretion tend to decrease so lithogenic risk still remains. The cause of the latter is unknown, although it likely relates to changes in bone activity.