Unmasking the silent culprit: recurrent exercise-induced acute kidney injury in a Chinese adolescent with renal hypouricemia.

Primary renal hypouricemia (RHUC) is a rare autosomal recessive disorder with a mean duration of end-stage acute kidney injury (EIAKI) of 14 days. The pathogenesis of EIAKI in patients with RHUC remains unclear. Several hypotheses have been proposed, including those related to the renal vasoconvulsive effect and the elevating effect of xanthine oxidase (XO). The effect of xanthine oxidase (XO) is most often observed following strenuous anaerobic exercise, which is frequently accompanied by low back pain, nausea, and acute kidney injury (AKI). Consequently, we postulate that EIAKI could be prevented by avoiding strenuous exercise, thus preventing the onset and recurrence of EIAKI. In this paper, we present a case of recurrent EIAKI in a patient with RHUC and a mutation in the SLC2A9 gene.

Raised CK and acute kidney injury following intense exercise in three patients with a history of exercise intolerance due to homozygous mutations in SLC2A9.

Acute rhabdomyolysis (AR) leading to acute kidney injury has many underlying etiologies, however, when the primary trigger is exercise, the most usual underlying cause is either a genetic muscle disorder or unaccustomed intense exercise in a healthy individual. Three adult men presented with a history of exercise intolerance and episodes of acute renal impairment following intense exercise, thought to be due to AR in the case of two, and dehydration in one. The baseline serum CK was mildly raised between attacks in all three patients and acutely raised during attacks in two of the three patients. Following referral to a specialized neuromuscular centre, further investigation identified very low serum urate (<12 umol/L). In all three men, genetic studies confirmed homozygous mutations in SLC2A9, which encodes for facilitated glucose transporter member 9 (GLUT9), a major regulator of urate homeostasis. Hereditary hypouricaemia should be considered in people presenting with acute kidney injury related to intense exercise. Serum urate evaluation is a useful screening test best undertaken after recovery.

Diagnostic Dilemma in an Adolescent Girl with an Eating Disorder, Intellectual Disability, and Hypomagnesemia.

Neurological disorders, including seizures, migraine, depression, and intellectual disability, are frequently associated with hypomagnesemia. Specifically, magnesium (Mg2+) channel transient receptor potential melastatin (TRPM) 6 and TRPM7 are essential for brain function and development. Both channels are also localized in renal and intestinal epithelia and are crucial for Mg2+(re)absorption. Cyclin M2 (CNNM2) is located on the basolateral side of the distal convoluted tubule. In addition, it plays a role in the maintenance of plasma Mg2+ levels along with TRPM6, which is present at the apical level. The CNNM2 gene is crucial for renal magnesium handling, brain development, and neurological functioning. Here, we identified a novel mutation in the CNNM2 gene causing a cognitive delay in a girl with hypomagnesemia. We suggest testing for CNNM2 mutation in patients with neurological impairment and hypomagnesemia.

Deciphering genetic signatures by whole exome sequencing in a case of co-prevalence of severe renal hypouricemia and diabetes with impaired insulin secretion.

BACKGROUND: Renal hypouricemia (RHUC) is a hereditary disorder where mutations in SLC22A12 gene and SLC2A9 gene cause RHUC type 1 (RHUC1) and RHUC type 2 (RHUC2), respectively. These genes regulate renal tubular reabsorption of urates while there exist other genes counterbalancing the net excretion of urates including ABCG2 and SLC17A1. Urate metabolism is tightly interconnected with glucose metabolism, and SLC2A9 gene may be involved in insulin secretion from pancreatic ß-cells. On the other hand, a myriad of genes are responsible for the impaired insulin secretion independently of urate metabolism. CASE PRESENTATION: We describe a 67 year-old Japanese man who manifested severe hypouricemia (0.7 mg/dl (3.8-7.0 mg/dl), 41.6 µmol/l (226-416 µmol/l)) and diabetes with impaired insulin secretion. His high urinary fractional excretion of urate (65.5%) and low urinary C-peptide excretion (25.7 µg/day) were compatible with the diagnosis of RHUC and impaired insulin secretion, respectively. Considering the fact that metabolic pathways regulating urates and glucose are closely interconnected, we attempted to delineate the genetic basis of the hypouricemia and the insulin secretion defect observed in this patient using whole exome sequencing. Intriguingly, we found homozygous Trp258* mutations in SLC22A12 gene causing RHUC1 while concurrent mutations reported to be associated with hyperuricemia were also discovered including ABCG2 (Gln141Lys) and SLC17A1 (Thr269Ile). SLC2A9, that also facilitates glucose transport, has been implicated to enhance insulin secretion, however, the non-synonymous mutations found in SLC2A9 gene of this patient were not dysfunctional variants. Therefore, we embarked on a search for causal mutations for his impaired insulin secretion, resulting in identification of multiple mutations in HNF1A gene (MODY3) as well as other genes that play roles in pancreatic ß-cells. Among them, the Leu80fs in the homeobox gene NKX6.1 was an unreported mutation. CONCLUSION: We found a case of RHUC1 carrying mutations in SLC22A12 gene accompanied with compensatory mutations associated with hyperuricemia, representing the first report showing coexistence of the mutations with opposed potential to regulate urate concentrations. On the other hand, independent gene mutations may be responsible for his impaired insulin secretion, which contains novel mutations in key genes in the pancreatic ß-cell functions that deserve further scrutiny.

Relation of Low Serum Magnesium to Mortality and Cardiac Allograft Vasculopathy Following Heart Transplantation.

Hypomagnesemia is commonly observed in heart transplant (HT) recipients receiving calcineurin inhibitors. Since low serum magnesium (s-Mg) has been implicated in the progression of atherosclerosis, potentially leading to worsening coronary heart disease, arrhythmias and sudden death, we investigated the association between s-Mg and HT outcomes. Between 2002 and 2017, 150 HT patients assessed for s-Mg were divided into high (≥1.7 mg/dL) and low s-Mg groups according to the median value of all s-Mg levels recorded during the first 3 months post-HT. Endpoints included survival, cardiac allograft vasculopathy (CAV), any-treated rejection (ATR) and NF-MACE. Kaplan-Meier analysis showed that at 15 years after HT, both survival (76 vs 33%, log-rank p = 0.007) and freedom from CAV (75 vs 48%, log-rank p = 0.01) were higher in the high versus low s-Mg group. There were no significant differences in freedom from NF-MACE or ATR. Multivariate analyses consistently demonstrated that low s-Mg was independently associated with a significant 2.6-fold increased risk of mortality and 4-fold increased risk of CAV (95%CI 1.06 to 6.4, p = 0.04; 95%CI 1.12 to 14.42, p = 0.01, respectively). In conclusion, low s-Mg is independently associated with increased mortality and CAV in HT patients. Larger multi-center prospective studies are needed to confirm these findings and to examine the effect of Mg supplementation.

Modified forearm ischemic test in hypouricemic patients.

Renal hypouricemia sometimes leads to exercise-induced acute kidney injury (EIAKI) of unknown pathogenesis. In order to elucidate the various pathological conditions associated with hypouricemia, we analyzed the effects of low uric acid level on energy metabolism. We have modified semi-ischemic forearm exercise test and performed this test in one Japanese healthy volunteer, three patients with hereditary renal hypouricemia and one patient with hereditary xanthinuria of Czech origin. Forearm exercise was performed by squeezing a hand dynamometer with the sphygmomanometer cuff pressure kept at the mean arterial pressure. Venous blood was drawn five times (before exercise, 3, 10, 30, 45 minutes after the start of exercise) in each tests. The mean plasma lactate concentration increased from a baseline of 1.3 (range 0.7-1.8 mmol/L) to 4.0 (range 2.0-5.5 mmol/L) at 3 minutes after the start of exercise. The plasma hypoxanthine concentrations were quite low before exercise (0-2.9 µmol/L), but increased markedly to a range of 13.6-28.8 µmol/L after 10 minute forearm ischemia. Our protocol allowed us to conclude that the load was sufficient for observing metabolic changes in temporally hypoxia and in following recovery phase. The test was well tolerated and safe, we did not observe any adverse reactions including EIAKI.

Gitelman syndrome associated with chondrocalcinosis and severe neuropathy: a novel heterozygous mutation in SLC12A3 gene.

Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.

Coexistence of autosomal dominant polycystic kidney disease type 1 and hereditary renal hypouricemia type 2: A model of early-onset and fast cyst progression.

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluid-filled cyst development leading to end-stage renal disease. The rate of disease progression in ADPKD exhibits high inter- and intrafamilial variability suggesting involvement of modifier genes and/or environmental factors. Renal hypouricemia (RHUC) is an inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and chronic kidney disease (CKD). However, the two disorders have distinct and well-delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and RHUC (type 1) in a single individual have been reported. We report a family with two members: an ADPKD 24-year-old female which presented bilateral renal cysts in utero and hypouricemia since age 5, and her mother with isolated hypouricemia. Next-generation sequencing identified two mutations in two genes PKD1 and SLC2A9 in this patient and one isolated SLC2A9 mutation in her mother, showing RHUC type 2, associated to CKD. The coexistence of these two disorders provides evidence of SLC2A9 variant could act as a modifier change, with synergistic actions, that could promote cystogenesis and rapid ADPKD progression. This is the first case of coexistence of PKD1 and SLC2A9 mutations treated with tolvaptan.

Case report: extreme coronary calcifications and hypomagnesemia in a patient with a 17q12 deletion involving HNF1B.

BACKGROUND: 17q12 deletion syndrome encompasses a broad constellation of clinical phenotypes, including renal magnesium wasting, maturity-onset diabetes of the young (MODY), renal cysts, genitourinary malformations, and neuropsychiatric illness. Manifestations outside of the renal, endocrine, and nervous systems have not been well described. CASE PRESENTATION: We report a 62-year-old male referred to the Undiagnosed Diseases Program (UDP) at the National Institutes of Health (NIH) who presented with persistent hypermagnesiuric hypomagnesemia and was found to have a 17q12 deletion. The patient exhibited several known manifestations of the syndrome, including severe hypomagnesemia, renal cysts, diabetes and cognitive deficits. Coronary CT revealed extensive coronary calcifications, with a coronary artery calcification score of 12,427. Vascular calcifications have not been previously reported in this condition. We describe several physiologic mechanisms and a review of literature to support the expansion of the 17q12 deletion syndrome to include vascular calcification. CONCLUSION: Extensive coronary and vascular calcifications may be an extension of the 17q12 deletion phenotype, particularly if hypomagnesemia and hyperparathyroidism are prevalent. In patients with 17q12 deletions involving HNF1B, hyperparathyroidism and hypomagnesemia may contribute to significant cardiovascular risk.

Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules.

Twin and genealogy studies suggest a strong genetic component of nephrolithiasis. Likewise, urinary traits associated with renal stone formation were found to be highly heritable, even after adjustment for demographic, anthropometric and dietary covariates. Recent high-throughput sequencing projects of phenotypically well-defined cohorts of stone formers and large genome-wide association studies led to the discovery of many new genes associated with kidney stones. The spectrum ranges from infrequent but highly penetrant variants (mutations) causing mendelian forms of nephrolithiasis (monogenic traits) to common but phenotypically mild variants associated with nephrolithiasis (polygenic traits). About two-thirds of the genes currently known to be associated with nephrolithiasis code for membrane proteins or enzymes involved in renal tubular transport. The thick ascending limb of Henle and connecting tubules are of paramount importance for renal water and electrolyte handling, urinary concentration and maintenance of acid-base homeostasis. In most instances, pathogenic variants in genes involved in thick ascending limb of Henle and connecting tubule function result in phenotypically severe disease, frequently accompanied by nephrocalcinosis with progressive CKD and to a variable degree by nephrolithiasis. The aim of this article is to review the current knowledge on kidney stone disease associated with inherited defects in the thick ascending loop of Henle and the connecting tubules. We also highlight recent advances in the field of kidney stone genetics that have implications beyond rare disease, offering new insights into the most common type of kidney stone disease, i.e., idiopathic calcium stone disease.

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.

Genetic causes of hypomagnesemia, a clinical overview.

Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg2+ by the thick ascending limb of Henle's loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg2+ wasting, as evidenced by an inappropriately high fractional Mg2+ excretion. Familial renal Mg2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16, CLDN19, CASR, CLCNKB), Gitelman-like hypomagnesemias (CLCNKB, SLC12A3, BSND, KCNJ10, FYXD2, HNF1B, PCBD1), mitochondrial hypomagnesemias (SARS2, MT-TI, Kearns-Sayre syndrome) and other hypomagnesemias (TRPM6, CNMM2, EGF, EGFR, KCNA1, FAM111A). Although identification of these genes has not yet changed treatment, which remains Mg2+ supplementation, it has contributed enormously to our understanding of Mg2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome.

Posterior reversible encephalopathy syndrome (PRES) and hypomagnesemia: A frequent association?

Posterior reversible encephalopathy syndrome (PRES) is a serious neurological condition encountered in various medical fields. Pathophysiological factor(s) common to PRES cases of apparently unrelated etiologies are yet to be found. Based on the hypothesis that hypomagnesemia might participate in the cascade leading to PRES, our study sought to verify whether hypomagnesemia is frequently associated with PRES regardless of etiology. From a retrospective study of a cohort of 57 patients presenting with PRES of different etiologies, presented here are the findings of 19 patients with available serum magnesium levels (SMLs) during PRES. In the acute phase of PRES, hypomagnesemia was present in all 19 patients in spite of differences in etiology (including immunosuppressive drugs, hypertensive encephalopathy, eclampsia, systemic lupus erythematosus, iatrogenic etiology and unknown). SMLs were within normal ranges prior to PRES and below normal ranges during the first 48h of PRES, with a significant decrease in SMLs during the acute phase. In this retrospective study, constant hypomagnesemia was observed during the acute phase of PRES regardless of its etiology. These results now require larger studies to assess the particular importance of acute hypomagnesemia in PRES and especially the possible need to treat PRES with magnesium sulfate.

Modification of Total Magnesium level in pregnant Saudi Women developing gestational diabetes mellitus.

BACKGROUND: The aim of our study is to measure total Magnesium in pregnant women screened for GDM and to compare total magnesium between whom were diagnosed having GDM and those having normal pregnancy. METHODS: Our study is a prospective study involved 99 pregnant women referred to Maternity and Child Hospital Al Ahsa (Kingdom of Saudi Arabia) for 100g Oral Glucose Tolerance test. All included pregnant women were in their 24-28 weeks of gestation with free past medical history and were free for any medicine. A 100-g Oral Glucose Tolerance (OGTT) with total plasma magnesium measurement were done to all included women. All patient were followed tell delivery. RESULTS: Among 99 patients enrolled in our study, GDM was diagnosed in 19 patients (19.2%). Fifteen patients have normal fasting glycaemia and were diagnosed having GDM on 100-g OGTT. Four patients have fasting glycaemia more than 126mg/dl (7mmol/l) confirming the diagnosis of GDM. Hypomagnesemia was confirmed in eight patients (8.08%). no one of them had GDM. The serum magnesium concentration in GDM women was lower that of normal pregnant women but the difference was not significant. (0.89±0.1 vs 0.92±0.2mmol/l, p=0.51). BMI, systolic and diastolic blood pressure were not significantly different between the pregnant women who developed or not gestational diabetes. CONCLUSION: In our study, the development of GDM cannot be explained by low total serum magnesium. The low total serum magnesium in patient diagnosed having GDM compared to whom free of GDM and the importance of magnesium in the genesis of insulin resistance should encourage more large trial to explain the exact role of magnesium in the pathophysiology of GDM.

Mechanisms and causes of hypomagnesemia.

PURPOSE OF REVIEW: Identification of the mechanisms of magnesium absorption and reabsorption has markedly enhanced our understanding of the causes of hypomagnesemia. RECENT FINDINGS: New gastrointestinal and renal causes of hypomagnesemia have been recently documented. SUMMARY: The recognition of new mechanisms and causes of magnesium absorption and reabsorption should enhance the ability to monitor patients at risk for hypomagnesemia and improve our ability to mitigate the serious symptoms associated with this disorder.

Rare case of nephrocalcinosis in the distal tubules caused by hereditary renal hypouricaemia 3 months after kidney transplantation.

We report a rare case of nephrocalcinosis caused by hereditary renal hypouricaemia 3 months after kidney transplantation. A 41-year-old man who underwent living-related kidney transplantation from his father was admitted to our hospital for a protocol biopsy; he had a serum creatinine (S-Cr) of 1.37 mg/dL and no proteinuria. Histologically, there was no evidence of rejection or calcineurin inhibitor toxicity, although scattered nephrocalcinosis was observed in the distal tubules. Perioperatively, the patient had a serum uric acid (S-UA) of 1.9 mg/dL with a fractional excretion of uric acid (FEUA) of 29% (normal, <10%) and UA clearance of 26.8 mL/min (normal, 7.3-14.7 mL/min) 3 days after kidney transplantation. The donor also had a relatively low S-UA of 2.4 mg/dL and high FEUA of 10.3%. Subsequent DNA direct sequencing followed by restriction fragment length polymorphism revealed that both the recipient's and donor's urate transporter 1 (URAT1) gene had a heterozygous nonsense mutation in exon 5 (C889T). Further, the immunoreactivity of antibodies for the C terminus of URAT1 revealed a partial deletion. De Galantha and von Kossa staining revealed that the nephrocalcinosis was due to urate crystals and calcium stones. Therefore, we diagnosed hereditary renal hypouricaemia. We directed the patient to avoid hard exercise, drink plenty of water, and alkalize the urine. The 1-year follow-up allograft biopsy showed no evidence of nephrocalcinosis in the distal tubules. This is the first report of nephrocalcinosis in the distal tubules as a diagnostic clue to hereditary renal hypouricaemia. We also review the related literature.

Pathophysiology and clinical presentations of salt-losing tubulopathies.

At least three renal tubular segments are involved in the pathophysiology of salt-losing tubulopathies (SLTs). Whether the pathogenesis starts either in the thick ascending limb of the loop of Henle (TAL) or in the distal convoluted tubule (DCT), it is the function of the downstream-localized aldosterone sensitive distal tubule (ASDT) to contribute to the adaptation process. In isolated TAL defects (loop disorders) ASDT adaptation is supported by upregulation of DCT, whereas in DCT disorders the ASDT is complemented by upregulation of TAL function. This upregulation has a major impact on the clinical presentation of SLT patients. Taking into account both the symptoms and signs of primary tubular defect and of the secondary reactions of adaptation, a clinical diagnosis can be made that eventually leads to an appropriate therapy. In addition to salt wasting, as occurs in all SLTs, characteristic features of loop disorders are hypo- or isosthenuric polyuria and hypercalciuria, whereas characteristics of DCT disorders are hypokalemia and (symptomatic) hypomagnesemia. In both SLT categories, replacement of urinary losses is the primary goal of treatment. In loop disorders COX inhibitors are also recommended to mitigate polyuria, and in DCT disorders magnesium supplementation is essential for effective treatment. Of note, the combination of a salt- and potassium-rich diet together with an adequate fluid intake is always the basis of long-term treatment in all SLTs.