[Uric Acid Metabolism, Uric Acid Transporters and Dysuricemia].

Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.

Xanthine Oxidoreductase Inhibitors Suppress the Onset of Exercise-Induced AKI in High HPRT Activity Urat1-Uox Double Knockout Mice.

BACKGROUND: Hereditary renal hypouricemia type 1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced AKI (EIAKI). However, because there is no useful experimental RHUC1 animal model, the precise pathophysiologic mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI and the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). METHODS: The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. RESULTS: Urat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine and BUN as renal injury markers, and decreased creatinine clearance observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. CONCLUSIONS: Urat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1ß via NLRP3 inflammasome signaling and Na+-K+-ATPase dysfunction associated with excessive urinary urate excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.

Effects of Type of Antibody to EGFR and Hypomagnesemia on Overall Survival in First-line Treatment of Patients With Unresectable Advanced/Recurrent Colorectal Cancer.

AIM: To clarify the differences in overall survival (OS) depending on the presence or absence of hypomagnesemia and the type of epidermal growth factor receptor antibody as first-line therapy for metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We retrospectively compared the OS in 68 patients who received cetuximab or panitumumab for mCRC at Ogaki Municipal Hospital (Ogaki, Japan) between January 2010 and December 2019. RESULTS: The complete and partial response rates in the cetuximab and panitumumab groups were 60.0% and 72.0%, respectively (p=0.470). The OS was significantly longer in the panitumumab group (median=1,007 days, range=208-1,433 days) than in the cetuximab group (median=735 days, range=181-2,391 days; p=0.047). Hypomagnesemia did not contribute to differences in OS in the two groups. CONCLUSION: Panitumumab may lead to a longer OS than cetuximab as first-line treatment of mCRC. The presence or absence of hypomagnesemia in cetuximab- or panitumumab-treated patients did not affect OS.

Disturbances of calcium homeostasis in a child with acute lymphoblastic leukemia.

Hypercalcemia is a rare presentation of childhood acute lymphoblastic leukemia (ALL), and presents with nonspecific symptoms. A 11-year old boy developed severe hypercalcemia during initial presentation and relapse of ALL. Both times, he subsequently developed transient symptomatic hypocalcemia, associated with hypomagnesemia and renal tubulopathy. Disturbances in calcium homeostasis may rarely be the sole presenting feature of ALL in children, as a paraneoplastic syndrome, or may arise as a consequence of the malignancy and its treatment. Along with other measures, early recognition of malignancy and initiation of treatment play a key role in correcting calcium disturbances.

Non-urate transporter 1, non-glucose transporter member 9-related renal hypouricemia and acute renal failure accompanied by hyperbilirubinemia after anaerobic exercise: a case report.

BACKGROUND: Renal hypouricemia (RHUC) is an inherited heterogenous disorder caused by faulty urate reabsorption transporters in the renal proximal tubular cells. Anaerobic exercise may induce acute kidney injury in individuals with RHUC that is not caused by exertional rhabdomyolysis; it is called acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE). RHUC is the most important risk factor for ALPE. However, the mechanism of onset of ALPE in patients with RHUC has not been elucidated. The currently known genes responsible for RHUC are SLC22A12 and SLC2A9. CASE PRESENTATION: A 37-year-old man presented with loin pain after exercising. Despite having a healthy constitution from birth, biochemical examination revealed hypouricemia, with a uric acid (UA) level of < 1 mg/dL consistently at every health check. We detected acute kidney injury, with a creatinine (Cr) level of 4.1 mg/dL, and elevated bilirubin; hence, the patient was hospitalized. Computed tomography revealed no renal calculi, but bilateral renal swelling was noted. Magnetic resonance imaging detected cuneiform lesions, indicating bilateral renal ischemia. Fractional excretion values of sodium and UA were 0.61 and 50.5%, respectively. Urinary microscopy showed lack of tubular injury. The patient's older sister had hypouricemia. The patient was diagnosed with ALPE. Treatment with bed rest, fluid replacement, and nutrition therapy improved renal function and bilirubin levels, and the patient was discharged on day 5. Approximately 1 month after onset of ALPE, his Cr, UA, and TB levels were 0.98, 0.8, and 0.9 mg/dL, respectively. We suspected familial RHUC due to the hypouricemia and family history and performed genetic testing but did not find the typical genes responsible for RHUC. A full genetic analysis was opposed by the family. CONCLUSIONS: To the best of our knowledge, this is the first report of ALPE with hyperbilirubinemia. Bilirubin levels may become elevated as a result of heme oxygenase-1 activation, occurring in exercise-induced acute kidney injury in patients with RHUC; this phenomenon suggests renal ischemia-reperfusion injury. A new causative gene coding for a urate transporter may exist, and its identification would be useful to clarify the urate transport mechanism.

Extreme hypomagnesemia: characteristics of 119 consecutive inpatients.

Extreme hypomagnesemia (hypoMg) can be encountered in many situations, but little data currently exist. Our aim is to describe the epidemiological, clinical, etiological characteristics, and the biological abnormalities of consecutive inpatients with extreme hypomagnesemia. In our observational monocentric study, between 1st July 2000 and April 2015, all inpatients with extreme hypomagnesemia, defined by at least one plasma magnesium concentration (PMg) below 0.3 mmol/L, were included. Demographic, clinical, biological characteristics and the drugs prescribed before the qualifying PMg measurement were retrospectively collected. 41,069 patients had at least one PMg assessment. The prevalence of extreme hypomagnesemia is 0.3% (119 inpatients). The median age is 70 years, 52% are women. The patients were mainly hospitalized in intensive care (n = 37, 31.1%), oncology (n = 21, 17.6%), gastroenterology (n = 18, 15.1%) and internal medicine (n = 16, 13.4%) departments. One hundred patients (84%) had a medical history of gastrointestinal disease (39% with bowel resections, 24% with stoma), and 50 (42%) had a cancer history. The drugs most commonly prescribed (known to induce hypoMg) are proton pump inhibitors (PPI) (n = 77, 70%), immunosuppressive regimens (n = 25, 22.5%), platinum salt-based chemotherapies (n = 19, 17.1%), and diuretics (n = 22, 19.8%). The suspected causes of hypomagnesemia are often multiple, but drugs (46%, including PPI in 19%) and chronic gastrointestinal disorders (37%) are prominent. Associated electrolyte disturbances include hypocalcemia (77%) and mild hypokalemia (51%). The 1-month mortality from all causes is 16%. Extreme hypomagnesemia is rare in inpatients, and is frequently associated with severe hypocalcemia. Digestive disorders and drugs are the main contributory causes.

Stimulation of V1a receptor increases renal uric acid clearance via urate transporters: insight into pathogenesis of hypouricemia in SIADH.

BACKGROUND: Hypouricemia is pathognomonic in syndrome of inappropriate secretion of antidiuretic hormone (SIADH) but the underlying mechanism remains unclear. Based on the previous studies, we hypothesized that V1a receptor may play a principal role in inducing hypouricemia in SIADH and examined uric acid metabolism using a rat model. METHODS: Terlipressin (25 ng/h), a selective V1a agonist, was subcutaneously infused to 7-week-old male Wistar rats (n = 9). Control rats were infused with normal saline (n = 9). The rats were sacrificed to obtain kidney tissues 3 days after treatment. In addition to electrolyte metabolism, changes in expressions of the urate transporters including URAT1 (SLC22A12), GLUT9 (SLC2A9), ABCG2 and NPT1 (SLC17A1) were examined by western blotting and immunohistochemistry. RESULTS: In the terlipressin-treated rats, serum uric acid (UA) significantly decreased and the excretion of urinary UA significantly increased, resulting in marked increase in fractional excretion of UA. Although no change in the expression of URAT1, GLUT9 expression significantly decreased whereas the expressions of ABCG2 and NPT1 significantly increased in the terlipressin group. The results of immunohistochemistry corroborated with those of the western blotting. Aquaporin 2 expression did not change in the medulla, suggesting the independence of V2 receptor stimulation. CONCLUSION: Stimulation of V1a receptor induces the downregulation of GLUT9, reabsorption urate transporter, together with the upregulation of ABCG2 and NPT1, secretion urate transporters, all changes of which clearly lead to increase in renal UA clearance. Hypouricemia seen in SIADH is attributable to V1a receptor stimulation.

Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B: A Case Series and Literature Review.

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease subtype HNF1B (ADTKD-HNF1B) is caused by a mutation in hepatocyte nuclear factor 1 homeobox beta (HNF1B). Although 50-60% of ADTKD-HNF1B patients develop hypomagnesemia, HNF1B mutations are mainly identified in patients with structural kidney defects or diabetes. CASES: The current case series describes 3 patients in whom hypomagnesemia proved to be the first clinical manifestation of ADTKD-HNF1B. All patients presented with hypomagnesemia with a high fractional excretion of Mg2+ and hypocalciuria. Exome sequencing performed for analysis of known and candidate hypomagnesaemia genes and subsequent multiplex ligation-dependent probe amplification analysis revealed a large deletion at the chromosome 17q12. Follow-up analysis showed increased blood glucose concentrations in all 3 patients and high hemoglobin A1c levels in 2 out of 3 patients, indicating diabetes mellitus. Although all patients suffered from mild renal insufficiency, only 1 of the 3 patients was shown to have renal cysts on CT. CONCLUSION: The prevalence of HNF1B mutations and the relative contribution of hypomagnesemia to its symptoms are underestimated. Therefore, patients with primary renal magnesium wasting should be tested for HNF1B mutations to ensure early detection and optimal management of ADTKD-HNF1B.

FGF23 associated bone diseases.

Recently, fibroblast growth factor 23 (FGF23) has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism. In this review, we summarized the FGF superfamily, the mechanism of FGF23 on phosphate and vitamin D metabolism, and the FGF23 related bone disease.

[Emergent adverse effects of proton pump inhibitors]. / Effets indésirables émergents des inhibiteurs de la pompe à protons.

BACKGROUND: Recent literature reports of potential adverse effects (AEs) of proton pump inhibitors (PPIs), especially during long-term treatments. PURPOSE: To present a literature review of major AEs: digestive infections, pneumonia, bone fracture, hypomagnesemia, interstitial nephritis, gastric cancer and neutropenia. DATA SOURCES: The authors used Pubmed; articles in English or French, published between August 2006 and August 2011 were analyzed. STUDY SELECTION: Two reviewers analyzed the references of title and summary to retain mainly observational studies, controlled clinical trials, meta-analyzes, case reports. RESULTS: For digestive infections: observational studies have shown a link moderate to high (OR 1.4 to 8.3) with exposure to PPIs. For pneumonia: some case-control studies reported a modest significative risk (OR 1.2 to 1.6), some not. The risk appears dose dependent and greater in subjects at risk. For fractures: the majority of observational studies report a significative increase in low to moderate risk (OR 1.2 to 3.1), correlated with the dose and duration of treatment. For magnesium deficiency: rare but potentially severe, they are described in case reports. Interstitial nephritis are described in case reports and for different PPIs, suggesting a class effect. For the stomach neoplasm: if three observational studies show an increased cancer risk (OR 1.5 to 2, 3), confounding factors make the causal link uncertain. Neutropenia is reported in a clinical observation, a class effect is suggested. LIMITATIONS: One can regret the absence of controlled clinical trials; indeed the observational studies have the interest to move closer to "real life", but often have methodological bias. CONCLUSION: Although AEs PPIs do not call into question the usefulness of this drug class, they show the need to limit their prescribing to indications for which efficacy has been proven. Moreover, PPIs treatment must be regularly reassessed to avoid exposing patients to unnecessary risks.

[A case of hypomagnesemia linked to refractory hypokalemia and hypocalcemia with short bowel syndrome].

We report a case of a 59-year old Japanese woman with short bowel syndrome, whose hypokalemia and hypocalcemia were successfully treated with magnesium (Mg) supplementation. Two years previously, she underwent Mile's operation for advanced rectal cancer, which could have been the cause of subsequent extensive resection of the small intestine by strangulation. After serial resection, she gradually developed chronic diarrhea and anorexia. Three weeks before admission, she developed general fatigue and tetany, and was hospitalized at another hospital. On admission, her serum K and Ca were 2.5 mEq/L and 4.3 mg/dL, respectively, hence regular fluid therapy containing potassium (K) and calcium (Ca) was provided following admission. However, her hypokalemia and hypocalcemia persisted, and she also displayed renal dysfunction and thereafter was transferred to our department for further evaluation and treatment. Since the laboratory tests revealed severe hypomagnesemia (0.4 mg/dL), we started intravenous Mg supplementation together with fluid therapy containing K and Ca. After the combination therapy, her clinical symptoms and electrolyte disorders were remarkably improved within a week. As Mg is essential for PTH secretion in response to hypocalcemia and to inhibit the K channel activity that controls urinary K excretion, hypomagnesemia can cause hypocalcemia and hypokalemia, which is refractory to repletion therapy unless Mg is administered. Therefore, for patients who present with signs of Mg deficiency, early and accurate diagnosis of Mg deficiency should be made and corrected.

A case of exercise-induced acute renal failure with G774A mutation in SCL22A12 causing renal hypouricemia.

Acute renal failure with severe loin pain which develops after anaerobic exercise is rare. One of predisposing factors of exercise-induced acute renal failure is renal hypouricemia. Idiopathic renal hypouricemia is a genetic disorder characterized by hypouricemia with abnormally high renal tubular uric acid excretion. The mutation in SCL22A12 gene which encodes renal uric acid transporter, URAT1, is the known major cause of this disorder. We here described a 25-yr-old man showing idiopathic renal hypouricemia with G774A mutation in SCL22A12 who presented exercise-induced acute renal failure. There have been a few reports of mutational analysis in Korean idiopathic renal hypouricemia without acute renal failure. This is the first report of genetically diagnosed idiopathic renal hypouricemia with exercise-induced acute renal failure in Korea.

Two cases of nephrotic syndrome (NS)-induced acute kidney injury (AKI) associated with renal hypouricemia.

Renal hypouricemia is a clinical disorder attributed to an increased renal urate excretion rate and is well known to involve a high risk of urolithiasis and exercise-induced acute kidney injury (AKI). This report concerns two interesting cases of nephrotic syndrome (NS)-induced AKI associated with renal hypouricemia. A 64-year-old female (Case 1) and a 37-year-old male (Case 2) were hospitalized because of AKI (serum creatinine: 2.07 mg/dl and 3.3 mg/dl, respectively), oliguria and NS. They were treated with prednisolone and temporary hemodialysis. Renal function improved, but hypouricemia persisted during hospitalization. Histological findings in both cases led to a diagnosis of minimal change nephrotic syndrome and identification of the diuretic phase of tubulointerstitial damage because of findings such as acute tubular necrosis. Furthermore, distal tubules of Case 2 showed an amorphous mass, possibly a uric acid crystal. Analysis of the two cases with the URAT1 gene, encoded by SLC22A12, found a homozygous mutation in exon 4 (W258stop) of each one. Our cases show that patients with renal hypouricemia may be susceptible to AKI without involvement of exercise if they possess some facilitators. Renal hypouricemic patients should therefore be carefully examined for all complications from renal hypouricemia because of high risk of AKI.

URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews.

BACKGROUND: Hereditary renal hypouricemia may be complicated by nephrolithiasis or exercise-induced acute renal failure. Most patients described so far are of Japanese origin and carry the truncating mutation W258X in the uric acid transporter URAT1 encoded by SLC22A12. Recently, we described severe renal hypouricemia in Israeli patients with uric acid transporter GLUT9 (SLC2A9) loss-of-function mutations. Renal hypouricemia in Iraqi Jews has been previously reported, but its molecular basis has not been ascertained. METHODS: Three Jewish Israeli families of Iraqi origin with hereditary hypouricemia and hyperuricosuria were clinically characterized. DNA was extracted and the URAT1 gene was sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of URAT1 mutants found. RESULTS: A missense URAT1 mutation, R406C, was detected in all three families. Two affected siblings were found to carry in addition a homozygous missense URAT1 mutation, G444R. Both mutations dramatically impaired urate uptake into X. laevis oocytes. Moreover, we demonstrate for the first time that URAT1 facilitates urate efflux, which was abolished in the mutants, indicating also a secretion defect. Homozygous patients had serum uric acid concentrations of 0.5-0.8 mg% and a fractional excretion of uric acid of 50-85%. Most individuals studied were asymptomatic, two had nephrolithiasis and none developed exercise-induced acute renal failure. CONCLUSIONS: The URAT1 R406C mutation detected in all three families is likely to be the founder mutation in Iraqi Jews. Our findings contribute to a better definition of the different types of hereditary renal hypouricemia and suggest that the phenotype of this disorder depends mainly on the degree of inhibition of uric acid transport.

Electrolyte disturbances and acute kidney injury in patients with cancer.

The interrelation between kidney disease and cancer is complex and reciprocal. Among the most frequent cancer-associated kidney diseases are the electrolyte and acid-base disturbances, which occur frequently and often are associated with an ominous prognosis, and acute kidney injury. Tumor lysis syndrome is a potentially life-threatening condition that frequently occurs in patients with a high tumor burden and high cellular turnover after cytotoxic therapy (including steroids in steroid-sensitive hematologic malignancies). Electrolyte and acid-base disturbances are the consequence of neoplastic spread, anticancer treatment, or, more rarely, paraneoplastic phenomena of all types of tumors. This article reviews hyponatremia and hypernatremia, hypokalemia and hyperkalemia, hypomagnesemia, hypercalcemia and hypocalcemia, hypophosphatemia, and the most important disturbances in acid-base balance in cancer patients. Acute kidney injury (AKI) is a frequent occurrence in cancer patients and has the potential to substantially alter the outcome of patients with cancer and jeopardize their chances of receiving optimal cancer treatment and a potential cure. As in many other circumstances, the etiology of AKI in cancer patients is multifactorial. Initiation and/or continuation of dialysis in the AKI cancer patient should be based on the general clinical condition and overall life expectancy and the personal patient expectations on quality of life after eventual recovery.

Despistaje de acidosis tubular renal distal en preescolares del jardín de infancia Guiri Guire La Guardia, Estado Nueva Esparta: mayo 2005 / Search of acidosis renal distal in preeschool of the childhood garden Guiri Guire La Guardia, Nueva Esparta: may 2005

La acidosis tubular renal distal es un trastorno congénito o adquirido de la acidificación renal consecuencia de disfunción tubular, no presenta manifestaciones clínicas evidentes. Realizar despistaje en preescolares del Jardín de infancia Guiri Guire, La Guardia, Estado Nueva Esparta, en mayo 2005. Estudio Transversal mixto, muestra de 104 preescolares, se tallaron, pesaron, se llenó cuestionario respecto a hábitos alimentarios. Se realizó examen simple de primera orina en ayunas. Aquellos cuyo pH urinario resultó alcalino y/o presentaban cristales de oxalato de calcio pasaron a segunda etapa del estudio que consistió en recolectar muestra de 1ª y 2ª orina en ayunas, 2 muestras de sangre (en ayunas, post prandial) para determinar electrolitos séricos, urinarios, calcio, creatinina séricos, urinarios, y equilibrio ácido base. Los que presentaron acidosis metabólica hiperclorémica con hiato aniónico urinario positivo, se diagnósticaron como acidosis tubular renal distal. La incidencia es de 1,9 por ciento. Se evidenció alta prevalencia de cristales de oxalato de calcio en orina (26,92 por ciento). Del total se encontró un caso con acidosis metabólica hiperclorémica con hiato aniónico urinario negativo. La asociación entre talla baja y acidosis no fue estadísticamente significativa (p=0,906). La asociación entre déficit ponderal y acidosis no fue significativa (p=0,799). La prevalencia de esta patología (2/104) es significativamente mayor que la mundial (1/10000) (Probabilidad de Poisson = 0,00005352). Se recomienda realizar estudios con muestras de mayor tamaño para resultados más precisos del comportamiento de la enfermedad a nivel estatal.

Renal tubular dysfunction in children with systemic lupus erythematosus.

Renal tubular and glomerular function was studied in patients under 18 years of age with childhood-onset systemic lupus erythematosus (SLE) in relation to disease activity in two groups: patients with clinical or laboratory evidence of lupus nephritis and those without (lupus non-nephritis). We reviewed 11 patients with lupus non-nephritis and 10 patients with lupus nephritis over a 12-month period. The measured glomerular filtration rates had a tendency to be lower in the lupus nephritis group. Glomerular dysfunction was manifest in the lupus nephritis group with elevated urinary albumin/creatinine ratios (P <0.001). Markers of tubular function were measured and compared with data from 94 controls. The lupus nephritis group had elevated urinary NAG [N-acetyl-beta-D-glucosaminidase (P =0.001)] and RBP [retinol-binding protein (P =0.03)] levels. Tubular dysfunction with elevated urinary NAG levels was present in 2 lupus non-nephritis patients with no evidence of glomerular disease. The cohort of patients in this study was followed and 2 lupus non-nephritis patients with the highest urinary RBP levels developed evidence of glomerular dysfunction and biopsy-proven lupus nephritis. Evidence of tubular dysfunction in lupus non-nephritis patients may help to identify lupus nephritis prior to the onset of albuminuria.

Renal tubular disorders in the neonate.

Renal tubular disorders are uncommon in the newborn period, but, when present, they may produce complex life-threatening alterations in the composition of the intracellular and extracellular fluid compartments. Because of the infrequency with which these disorders are encountered; clinicians are often uncertain of the appropriate diagnostic evaluation. The authors believe that localizing major neonatal renal tubular disorders to the proximal and distal nephron will assist physicians in developing a pathophysiologic understanding of these conditions.