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.

Tubular calcium, magnesium, and phosphate excretion during therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy: A prospective study.

OBJECTIVES: Hypocalcemia, hypomagnesemia, and hyperphosphatemia are common electrolyte disturbances in perinatal asphyxia (PA). Different reasons have been proposed for these electrolyte disturbances. This study investigated the effect of the urinary excretion of calcium (Ca), magnesium (Mg), and phosphorus (P) on the serum levels of these substances in babies who were treated using therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) caused by PA. This study sheds light on the pathophysiology that may cause changes in the serum values of these electrolytes. METHODS: This study included 21 healthy newborns (control group) and 38 patients (HIE group) who had undergone therapeutic hypothermia due to HIE. Only infants with a gestational age of 36 weeks and above and a birth weight of 2000 g and above were evaluated. The urine and serum Ca, Mg, P, and creatinine levels of all infants were evaluated at 24, 48, and 72 h. RESULTS: The lower serum Ca value and the higher serum P value of the HIE group were found to be statistically significant compared to the control group (p<0.05). There was no significant difference in serum Mg values between the groups. However, hypomagnesemia was detected in five patients from the HIE group. The urine excretion of FeCa and FeMg at 24 h, and FeP excretion at 48 and 72 h were found to be significantly higher in the HIE group compared to the control group. CONCLUSIONS: This study determined that the urinary excretion of Ca, Mg, and P has an effect on the serum Ca, Mg, and P levels of infants with HIE.

Early initiation of sodium-glucose linked transporter inhibitors (SGLT-2i) and associated metabolic and electrolyte outcomes in diabetic kidney transplant recipients.

There is a paucity of data on the use of SGLT2 inhibitors on outcomes in kidney transplant recipients. There may be concern in initiating these agents, especially within the first year post-transplant when renal function is more labile and immunosuppression more intense, due to a presumed high risk of urinary infections and acute kidney injury. This is a retrospective study on 50 kidney transplant recipients, half of whom were started on therapy within the first year of transplant. Over a follow-up period of 6 months, overall patients had a statistically significant improvement in weight by -2.95 kg [SD 3.54, P = <.0001 (CI: 3.53, 1.50)] as well as hypomagnesemia 0.13 [SD 1.73, P = .0004 (CI: 0.06, 0.20)]. Overall insulin usage declined by -3.7 units [SD 22.8, P = .17]. 14% of patients had at least one urinary tract infection although this rate is not different (~20%) than that reported historically in this high-risk population.

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.

Proteinuria-associated renal magnesium wasting leads to hypomagnesemia: a common electrolyte abnormality in chronic kidney disease.

BACKGROUND: Hypomagnesemia (Hypo-Mg) predicts mortality and chronic kidney disease (CKD) progression. However, in CKD, its prevalence, kidney-intrinsic risk factors, and the effectiveness of oral magnesium (Mg) therapy on serum Mg levels is uncertain. METHODS: In a cross-sectional study enrolling pre-dialysis outpatients with CKD, the prevalence of electrolyte abnormalities (Mg, sodium, potassium, calcium and phosphorus) was compared. In an open-label randomized controlled trial (RCT), we randomly assigned CKD patients to either the magnesium oxide (MgO) or control arm. The outcome was serum Mg levels at 1 year. RESULTS: In 5126 patients, Hypo-Mg was the most common electrolyte abnormality (14.7%) with similar prevalence across stages of CKD. Positive proteinuria was a risk factor of Hypo-Mg (odds ratio 2.2; 95% confidence interval 1.2-4.0). However, stratifying the analyses by diabetes mellitus (DM), it was not significant in DM (Pinteraction = 0.04). We enrolled 114 patients in the RCT. Baseline analyses showed that higher proteinuria was associated with higher fractional excretion of Mg. This relationship between proteinuria and renal Mg wasting was mediated by urinary tubular markers in mediation analyses. In the MgO arm, higher proteinuria or tubular markers predicted a significantly lower 1-year increase in serum Mg. In patients with a urinary protein-to-creatinine ratio (uPCR) <0.3 g/gCre, serum Mg at 1 year was 2.4 and 2.0 mg/dL in the MgO and control arms, respectively (P < 0.001), with no significant between-group difference in patients whose uPCR was ≥0.3 g/gCre (Pinteraction=0.001). CONCLUSIONS: Proteinuria leads to renal Mg wasting through tubular injuries, which explains the high prevalence of Hypo-Mg in CKD.

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.

Magnesium supplementation: A consideration in dialysis patients.

Even though disorders of magnesium (Mg) balance are common in dialyzed patients, this cation is often neglected. Many factors interfere with serum magnesium including diet, medications (eg, antacids or phosphate binders), and the dialysis prescription. Mg supplementation may help reduce serum phosphate concentration, PTH, and interfere with vascular calcification and bone mineralization. It could also decrease the all-cause and cardiovascular mortalities, although the results of current studies are conflicting. As with many other variables that influence hard endpoints in nephrology, additional research directly targeting the role of Mg supplementation in dialyzed patients are required. Nevertheless, a current risk/benefit assessment suggests that supplementation of Mg targeting high normal serum levels may represent a plausible option to improve the outcome of dialysis patients.

A young man with recurrent paralysis.

Hypokalemia can cause reactions from mild muscular cramping to life-threatening paralysis and cardiac dysrhythmias. This article describes a patient whose unusual, recurrent muscular symptoms and electrolyte abnormalities were eventually identified as Gitelman syndrome, a rare genetic disorder resulting in severe refractory hypokalemia.

Prevalence and complications of hypouricemia in a general population: A large-scale cross-sectional study in Japan.

BACKGROUNDS: Hypouricemia was reported as a risk factor for exercise-induced acute renal injury (EIAKI) and urinary stones. However, the prevalence of kidney diseases among hypouricemic subjects has not been evaluated. This study was conducted to clarify the prevalence of hypouricemia and the association of hypouricemia with kidney diseases by using a large-scale Japanese population data. METHODS: This study is a retrospective cross-sectional study at the Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, Japan, and Sanin Rousai Hospital, Yonago, Japan. We analyzed the medical records of 90,143 Japanese subjects at the center in St. Luke's International Hospital, Tokyo, and 4,837 subjects in Sanin Rousai Hospital, Yonago, who underwent annual regular health check-up between January 2004 and June 2010. We defined hypouricemia as serum uric acid level of ≤2.0 mg/dL. We checked the medical history of all the study subjects and compared the rates of complications including urinary stones and kidney diseases among those with or without hypouricemia. RESULTS: The prevalence of hypouricemia was 0.19% in St. Luke's International Hospital, Tokyo, and 0.58% in Sanin Rousai Hospital, Yonago. The prevalence of hypouricemia in women was larger than that in men both in Tokyo (0.31% vs 0.068%, p<0.001) and in Yonago (1.237% vs 0.318%, p<0.001). Among 172 hypouricemic subjects (30 men), the rates of previous urinary stones and kidney diseases (including nephritis/nephrosis) were 1.2% (3.3% men, 0.7% women) and 2.3% (10% men, 0.7% women), respectively. Hypouricemic men had a 9-fold higher rate of previously having kidney diseases compared to non-hypouricemic men (p<0.001). However, the rates of other diseases including urinary stones were not significantly different between the two groups. CONCLUSIONS: Hypouricemia was associated with a history of kidney disease especially in men.

Usefulness of laboratory and radiological investigations in the management of supraventricular tachycardia.

OBJECTIVE: Although ED patients presenting with supraventricular tachycardia (SVT) are commonly investigated, the value of these investigations has been questioned. We aimed to determine the frequency and utility of investigations in patients with SVT. METHODS: We undertook an explicit retrospective medical record audit of patients with SVT who presented to a single ED (January 2004 to June 2014). Data on demographics, presenting complaints, investigations and outcomes were extracted. The outcomes were nature and utility of investigations. RESULTS: A total of 633 patients were enrolled (mean [SD] age 55.4 [17.7] years, 62% female). Laboratory investigations were common: electrolytes (83.7% of patients), full blood count (81.2%), magnesium (57.5%), calcium (39.3%) and thyroid function (30.3%). These investigations revealed many mildly abnormal results but resulted in electrolyte supplementation in only 19 patients: eight with mild hypokalaemia (potassium 3.0-3.5 mmol/L) and 11 with mild hypomagnesia (magnesium 0.49-1.1 mmol/L). Troponin was ordered for 302 (47.7%) patients, many of whom had no history or risk factors for cardiac disease, or ischaemic symptoms associated with their SVT. The troponin was normal, mildly and moderately elevated in 65.2, 24.5 and 10.2% of cases, respectively. Only seven (1.1%) patients were diagnosed with acute myocardial ischemia. Although 190 (30.0%) patients had a chest X-ray (CXR), it was normal in 78.4% of cases. All CXR abnormalities were incidental and not relevant to the immediate ED management. CONCLUSION: Patients with uncomplicated SVT are over-investigated. Guidelines for ED SVT investigation are recommended. Further research is recommended to determine the indications for each investigation in the setting of SVT.

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.

Hypomagnesaemia in kidney transplantation.

In the era of calcineurin inhibitors, hypomagnesaemia is a very common finding in kidney transplant recipients. Especially the first weeks after transplantation it is the rule rather than the exception. Hypomagnesaemia or low magnesium intake have been associated with a higher mortality or more cardiovascular events in the general population, but this association has never been explored in kidney transplant recipients, despite their increased cardiovascular risk. Kidney transplant recipients with pre- or post-transplant hypomagnesaemia seem to have an aberrant glucose metabolism and develop diabetes mellitus more frequently. Moreover, observations from alternate study populations, animal experiments or in vitro studies suggest a possible role of magnesium deficiency in graft dysfunction, bone metabolism and transplant immunology. Future observational and especially interventional studies should further define whether and to what extent we should make effort to correct this electrolyte disturbance in transplant recipients. Considering the mechanism of renal magnesium wasting, normalizing the serum magnesium concentration by oral supplementation alone might turn out to be cumbersome in kidney transplant recipients.

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.

Electrolyte disorders in community subjects: prevalence and risk factors.

BACKGROUND: Electrolyte disorders have been studied mainly in hospitalized patients, whereas data in the general population are limited. The aim of this study was to determine the prevalence and risk factors of common electrolyte disorders in older subjects recruited from the general population. METHODS: A total of 5179 subjects aged 55 years or more were included from the population-based Rotterdam Study. We focused on hyponatremia, hypernatremia, hypokalemia, hyperkalemia, and hypomagnesemia. Multivariable logistic regression was used to study potential associations with renal function, comorbidity, and medication. The adjusted mortality also was determined for each electrolyte disorder. RESULTS: A total of 776 subjects (15.0%) had at least 1 electrolyte disorder, with hyponatremia (7.7%) and hypernatremia (3.4%) being most common. Diabetes mellitus was identified as an independent risk factor for hyponatremia and hypomagnesemia, whereas hypertension was associated with hypokalemia. Diuretics were independently associated with several electrolyte disorders: thiazide diuretics (hyponatremia, hypokalemia, hypomagnesemia), loop diuretics (hypernatremia, hypokalemia), and potassium-sparing diuretics (hyponatremia). The use of benzodiazepines also was associated with hyponatremia. Hyponatremic subjects who used both thiazides and benzodiazepines had a 3 mmol/L lower serum sodium concentration than subjects using 1 or none of these drugs (P < .001). Hyponatremia and hypomagnesemia were independently associated with an increased mortality risk. CONCLUSIONS: Electrolyte disorders are common among older community subjects and mainly associated with diabetes mellitus and diuretics. Subjects who used both thiazides and benzodiazepines had a more severe degree of hyponatremia. Because even mild electrolyte disorders were associated with mortality, monitoring of electrolytes and discontinuation of offending drugs may improve outcomes.