The Prognostic Value of Anti-PLA2R Antibodies Levels in Primary Membranous Nephropathy.

Anti-PLA2R antibodies (Ab) are a diagnostic and prognostic biomarker in primary membranous nephropathy (PMN). We assessed the relationship between the levels of anti-PLA2R Ab at diagnosis and different variables related to disease activity and prognosis in a western population of PMN patients. Forty-one patients with positive anti-PLA2R Ab from three nephrology departments in Israel were enrolled. Clinical and laboratory data were collected at diagnosis and after one year of follow-up, including serum anti-PLA2R Ab levels (ELISA) and glomerular PLA2R deposits on biopsy. Univariable statistical analysis and permutation-based ANOVA and ANCOVA tests were performed. The median [(interquartile range (IQR)) age of the patients was 63 [50-71], with 28 (68%) males. At the time of diagnosis, 38 (93%) of the patients had nephrotic range proteinuria, and 19 (46%) had heavy proteinuria (≥8 gr/24 h). The median [IQR] level of anti-PLA2R at diagnosis was 78 [35-183] RU/mL. Anti-PLA2R levels at diagnosis were correlated with 24 h proteinuria, hypoalbuminemia and remission after one year (p = 0.017, p = 0.003 and p = 0.034, respectively). The correlations for 24 h proteinuria and hypoalbuminemia remained significant after adjustment for immunosuppressive treatment (p = 0.003 and p = 0.034, respectively). Higher levels of anti-PLA2R Ab at diagnosis in patients with active PMN from a western population are associated with higher proteinuria, lower serum albumin and remission one year after the diagnosis. This finding supports the prognostic value of anti-PLA2R Ab levels and their possible use in stratifying PMN patients.

Treatment of Severe Renal Artery Stenosis with Acute Kidney Injury Requiring Hemodialysis by Percutaneous Transluminal Renal Angioplasty and Stent Implantation.

PURPOSE: To evaluate the outcomes of percutaneous transluminal renal angioplasty with stent implantation (PTRAS) among patients with renal artery stenosis (RAS) who become dialysis-dependent due to acute deterioration of renal function. MATERIALS AND METHODS: This was a single-center retrospective cohort study of all PTRAS procedures performed from 2003 to 2019 in a referral hospital. A total of 109 procedures were performed in 92 patients. Eleven patients (12%) presented with anuric acute kidney injury (AKI) secondary to high-grade RAS (defined as intraluminal stenosis above 70% per angiography) and underwent PTRAS after starting hemodialysis. Data collected included demographic parameters, medical background, creatinine, blood pressure, indication for intervention, procedure characteristics, adverse events, and long-term data including dialysis treatment and mortality. Among the dialysis-dependent AKI group, outcome measures were defined based on the postprocedural improvement in kidney function and discontinuation of dialysis. RESULTS: Following PTRAS, 8 of 11 patients (73%) demonstrated improved kidney function and were able to discontinue dialysis. The median time on dialysis was 18 days (range, 2-35 days) before PTRAS and 4.5 days (range, 1-24 days) to recovery of kidney function after the time of intervention. CONCLUSIONS: Patients with atherosclerotic RAS who develop RAS-related AKI may benefit from PTRAS even after several weeks of anuria and dialysis dependence.

Amyloid storm: acute kidney injury and massive proteinuria, rapidly progressing to end-stage kidney disease in AA amyloidosis of familial Mediterranean fever.

OBJECTIVE: Amyloid A nephropathy of FMF usually progresses over many years to end-stage renal disease (ESRD). We aim to describe an acute condition, termed here 'amyloid storm', typically manifesting with a rapid (≤2 weeks) increase in serum creatinine and urine protein, that has never been characterized in FMF amyloidosis. METHODS: This retrospective analysis features amyloid storm by comparing between FMF amyloidosis patients who have experienced an episode of amyloid storm (study group) and matched patients who have not (control group). The primary outcome was ESRD or death within 1 year from study entry. Featured data were retrieved from hospital files. RESULTS: The study and control groups, each comprising 20 patients, shared most baseline characteristics. However, they differed on the time from FMF onset to reaching serum creatinine of 1.2 mg/dl [26.5 years (s.d. 15.15) vs 41.55 (10.98), P = 0.001] and the time from the onset of proteinuria to study entry [8.8 years (s.d. 6.83) vs 15.75 (13.05), P = 0.04], culminating in younger age at study entry [39.95 years (s.d. 16.81) vs 48.9 (9.98), respectively, P = 0.05] and suggesting an accelerated progression of kidney disease in the study group. Within 1 year from study entry, 16 patients in the study and 3 in the control groups reached the primary endpoint (P = 0.000). The major triggers of amyloid storm were infections, occurring in 17 of 20 patients. CONCLUSION: Amyloid storm is a complication of FMF amyloidosis, induced by infection and associated with poor prognosis and death.

Congestive heart failure treated with peritoneal dialysis or hemodialysis: Typical patient profile and outcomes in real-world setting.

BACKGROUND: Peritoneal dialysis (PD) is increasingly used for the long-term management of hypervolemic refractory congestive heart failure (CHF) patients, in particular when complicated by renal insufficiency. While PD has many advantages over hemodialysis (HD) in those patients, there is a controversy concerning survival superiority of PD compared with HD in this population. The aim of the study was to define typical patient profile and to compare outcomes of patients with CHF and renal failure treated with HD or PD. METHODS: This retrospective cohort study enrolled CHF patients treated with chronic PD or HD between the years 2009-2018. Information at dialysis initiation included age, gender, body weight, blood pressure, cause of renal disease, comorbidities, hospitalisations, echocardiographic and laboratory parameters. Survival was compared between PD and HD patients using a Kaplan-Meier model and Cox regression analysis. RESULTS: CHF patients treated with PD had significantly higher eGFR and lower systolic blood pressure compared with HD treated patients. Median survival time was 13.32 (7.08, 23.28) months in the PD group and 19.68 (9.48, 39.24) months in the HD group, P = .013. After adjustment for confounders the mortality risk amongst PD and HD patients was not significantly different: adjusted HR for death in PD vs HD patients was 1.44, P = .35 for 1- year and 1.69, P = .10 for 2-year mortality. Number of hospitalisations was similar in both groups. CONCLUSIONS: CHF patient profile was different in PD and HD. Two modalities were equally effective in the treatment of patients with CHF and renal failure considering different patient characteristics.

Effect of Peritoneal Dialysis on Serum Fibrosis Biomarkers in Patients with Refractory Congestive Heart Failure.

BACKGROUND: Cardiac collagen remodeling is important in the progression of heart failure. Estimation of cardiac collagen turnover by serum levels of serological markers is used for monitoring cardiac tissue repair and fibrosis. Peritoneal dialysis (PD) is used for the long-term management of refractory congestive heart failure (CHF). In this study, we investigated the effect of PD treatment on circulating fibrosis markers levels in patients with refractory CHF and fluid overload. METHODS: Twenty-five patients with refractory CHF treated with PD were prospectively enrolled in the study. Circulating fibrosis markers procollagen type III C-peptide (PIIINP), matrix metalloproteinase 2 (MMP-2), and tissue inhibitor of metalloproteinases I (TIMP-1) levels were checked at baseline and after three and six months of treatment. RESULTS: The clinical benefit of PD manifested by improved NYHA functional class and reduced hospitalization rate. Serum brain natriuretic peptide (BNP) levels decreased significantly during the treatment. Serum MMP-2 and TIMP-1 decreased significantly on PD. Circulating PIIINP showed two patterns of change, either decreased or increased following PD treatment. Patients in whom circulating PIIINP decreased had significantly lower baseline serum albumin, lower baseline mean arterial blood pressure, higher serum CRP, and a less significant improvement in hospitalization rate compared to the patients in whom circulating PIIINP increased. Patients in whom all three markers decreased demonstrated a trend to longer survival compared to patients whose markers increased or did not change. CONCLUSION: In refractory CHF patients PD treatment was associated with a reduction in circulating fibrosis markers.

Intraperitoneal antibiotic administration for prevention of postoperative peritoneal catheter-related infections.

BACKGROUND: It is recommended that systemic prophylactic antibiotics be given immediately prior to peritoneal catheter insertion. This administration requires intravenous access and could be inconvenient in dynamic and unpredictable operation room schedule. Intraperitoneal antibiotics could be an alternative simple way for prevention of postoperative peritoneal catheter infections. METHODS: Medical records from 109 patients undergoing permanent PD catheter placement procedures were reviewed retrospectively. Group I patients (66 patients) received intraperitoneal cefazolin through the inserted Tenckhoff catheter in operation room. Group II (43 patients) received intravenous cefazolin 2 h prior to the surgery. The effect of prophylactic antibiotics on the occurrence of peritonitis and exit site infection in the 14 days following surgical peritoneal dialysis catheter placement was evaluated. RESULTS: During the follow-up period, one patients from group II (2.3%) and none from group I developed peritonitis (P = 0.3945). One patient from each group developed exit site infection (P = 1.000). CONCLUSION: It was found that intraperitoneal antibiotics have the similar efficacy compared with intravenous antibiotics for postoperative peritoneal catheter-related infections' prevention. It does not require intravenous access and overcome the issue of unpredictable operation room schedule.

Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency.

BACKGROUND: Inherited metabolic disorders associated with nephrocalcinosis are rare conditions. The aim of this study was to identify the genetic cause of an Israeli-Arab boy from a consanguineous family with severe nephrocalcinosis and kidney insufficiency. METHODS: Clinical and biochemical data of the proband and family members were obtained from both previous and recent medical charts. Genomic DNA was isolated from peripheral blood cells. The coding sequence and splice sites of candidate genes (CYP24A1, CYP27B1, FGF23, KLOTHO, SLC34A3 and SLC34A1) were sequenced directly. Functional studies were performed in Xenopus laevis oocytes and in transfected opossum kidney (OK) cells. RESULTS: Our patient was identified as having nephrocalcinosis in utero, and at the age of 16.5 years, he had kidney insufficiency but no bone disease. Genetic analysis revealed a novel homozygous missense mutation, Arg215Gln, in SLC34A1, which encodes the renal sodium phosphate cotransporter NaPiIIa. Functional studies of the Arg215Gln mutant revealed reduced transport activity in Xenopus laevis oocytes and increased intracellular cytoplasmic accumulation in OK cells. CONCLUSIONS: Our findings show that dysfunction of the human NaPiIIa causes severe renal calcification that may eventually lead to reduced kidney function, rather than complications of phosphate loss.

Maternal and infantile hypercalcemia caused by vitamin-D-hydroxylase mutations and vitamin D intake.

BACKGROUND: Hypercalcemia is caused by many different conditions and may lead to severe complications. Loss-of-function mutations of CYP24A1, encoding vitamin D-24-hydroxylase, have recently been identified in idiopathic infantile hypercalcemia and in adult kidney stone disease. The aim of this study was to investigate the genetics and clinical features of both infantile and maternal hypercalcemia. METHODS: We studied members of four unrelated Israeli families with hypercalcemia, namely, one woman during pregnancy and after delivery and three infants. Clinical and biochemical data were obtained from probands' medical charts. Genomic DNA was isolated from peripheral blood and CYP24A1 was sequenced. RESULTS: Typical symptoms of hypercalcemia associated with the intake of recommended doses of vitamin D developed in the infants and pregnant woman. Four different loss-of-function CYP24A1 mutations were identified, two of which are reported here for the first time (p.Trp134Gly and p.Glu315*). The infants from families 1 and 2, respectively, were found to be compound heterozygotes, and the infant from family 3 and the pregnant woman were found to be homozygous. CONCLUSIONS: This is the first report of maternal hypercalcemia caused by a CYP24A1 mutation, showing that not only infants are at risk for this complication. Our findings emphasize the importance of recognition, genetic diagnosis and proper treatment of this recently identified hypercalcemic disorder in this era of widespread vitamin D supplements.

Chronic hypercalcaemia from inactivating mutations of vitamin D 24-hydroxylase (CYP24A1): implications for mineral metabolism changes in chronic renal failure.

BACKGROUND: Loss-of-function mutations of vitamin D-24 hydroxylase have recently been recognized as a cause of hypercalcaemia and nephrocalcinosis/nephrolithiasis in infants and adults. True prevalence and natural history of this condition are still to be defined. METHODS: We describe two adult patients with homozygous mutations and six related heterozygous carriers. Mineral and hormonal data in these patients were compared with that in 27 patients with stage 2-3 chronic kidney disease and 39 healthy adult kidney donors. RESULTS: Probands had recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four). Corticosteroids did not reduce plasma and urine calcium levels, but ketoconazole did, indicating that 1,25(OH)(2)D production is not maximally depressed despite coexisting hypercalcaemia, high 1,25(OH)(2)D and depressed PTH, and that 1,25(OH)(2)D degradation through vitamin D-24 hydroxylase is a regulator of plasma 1,25(OH)(2)D levels. Both probands had vascular calcifications and high bone mineral content. One developed stage 3b renal failure: in this patient 1,25(OH)(2)D decreased within normal limits as glomerular filtration rate (GFR) fell and PTH rose to high-normal values, yet hypercalcaemia persisted and the ratio of 1,25(OH)(2)D to GFR remained higher than normal for any degree of GFR. CONCLUSIONS: This natural model indicates that vitamin D-24 hydroxylase is a key physiologic regulator of calcitriol and plasma calcium levels, and that balanced reduction of 1,25(OH)(2)D and GFR is instrumental for the maintenance of physiologic calcium levels and balance in chronic kidney diseases.

Loss-of-function mutations of CYP24A1, the vitamin D 24-hydroxylase gene, cause long-standing hypercalciuric nephrolithiasis and nephrocalcinosis.

PURPOSE: Hypercalciuria is the most common cause of kidney stone disease and genetic factors have an important role in nearly half of these cases. Recently loss-of-function mutations of CYP24A1, the gene encoding vitamin D 24-hydroxylase, were identified in idiopathic infantile hypercalcemia. We describe the clinical and molecular basis of severe long-standing kidney stone disease in adults caused by CYP24A1 mutations. MATERIALS AND METHODS: Three subjects from 2 Israeli families with nephrolithiasis and nephrocalcinosis were clinically characterized. Genomic DNA was isolated from peripheral blood and sequencing of CYP24A1 was performed. RESULTS: All subjects presented with severe kidney stone disease, the cause of which was not discovered for decades despite extensive evaluation. They all had hypercalciuria, nephrocalcinosis and intermittent hypercalcemia, and chronic kidney insufficiency developed in the oldest subject. All patients had a typical pattern of test results, including normal-high serum calcium, low parathyroid hormone levels, high vitamin D 25-(OH)D3 and 1,25-(OH)2D3, and low 24,25-(OH)2D3. Overall 3 CYP24A1 loss-of-function mutations were identified, including a homozygous deletion (delE143) in consanguinous family 1, and compound heterozygous mutations L409S and the novel W268-stop in family 2. CONCLUSIONS: Loss-of-function mutations of CYP24A1 gene, encoding for 1,25-dihydroxyvitamin D3 24-hydroxylase, cause severe hypercalciuric nephrolithiasis and nephrocalcinosis. The mutations may present in adults and may lead to chronic renal insufficiency. Our results support a recessive mode of inheritance. CYP24A1 mutations should be considered in the differential diagnosis of hypercalciuric nephrolithiasis, especially as many adults are now prescribed supplemental oral vitamin D.

Peritoneal dialysis in patients with refractory congestive heart failure: potential prognostic factors.

BACKGROUND: Peritoneal dialysis (PD) is increasingly used for long-term management of refractory congestive heart failure (CHF). In this study, we investigated the outcome of patients with refractory CHF treated with PD, aiming to identify potential prognostic factors for long term-survival. METHODS: This was a prospective observational study over a period of 42 months which included 37 refractory CHF patients. RESULTS: Median survival on PD was 14 months (1-41 months). Long survivors had serum sodium >132 mEq/l (p < 0.001), serum albumin >3.2 g/dl (p < 0.001) and hospitalization rate <2 days per month a year before starting the treatment (p = 0.008). Patients in the lowest survival quartile had lower serum albumin (2.8 vs. 3.5 g/dl in longer survivors, p = 0.003) and serum sodium (126 vs. 137 mEq/l, p < 0.0001), higher serum leukocyte count (7,500 vs. 6,800/µl in long survivors, p = 0.033), higher glomerular filtration rate (39.4 vs. 29.9 ml/min/1.73 m(2), p = 0.035), had more hospitalization before starting the treatment (3.4 vs. 1.9 days per month, p = 0.003) and lower estimated left ventricular mass index (113 vs. 137 g/m(2), p = 0.035). Long-term survivors demonstrated significant improvement in the New York Heart Association functional class by a median of one class, reduced hospitalization rate by 55% and decrease in dependence on intravenous diuretics and vasoactive medications (73% drop in CHF day care visits during the first year of treatment). CONCLUSIONS: Survival of patients with refractory CHF treated with PD is highly variable. Serum sodium, serum albumin and hospitalization rate are important prognostic factors for long-term survival. Long survivors demonstrated improved functional status, reduced hospitalization and mortality rates.

Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family.

Magnesium is an essential ion involved in many biochemical and physiological processes. Homeostasis of magnesium levels is tightly regulated and depends on the balance between intestinal absorption and renal excretion. However, little is known about specific proteins mediating transepithelial magnesium transport. Using a positional candidate gene approach, we identified mutations in TRPM6 (also known as CHAK2), encoding TRPM6, in autosomal-recessive hypomagnesemia with secondary hypocalcemia (HSH, OMIM 602014), previously mapped to chromosome 9q22 (ref. 3). The TRPM6 protein is a new member of the long transient receptor potential channel (TRPM) family and is highly similar to TRPM7 (also known as TRP-PLIK), a bifunctional protein that combines calcium- and magnesium-permeable cation channel properties with protein kinase activity. TRPM6 is expressed in intestinal epithelia and kidney tubules. These findings indicate that TRPM6 is crucial for magnesium homeostasis and implicate a TRPM family member in human disease.

Urinary organic anion transporter protein profiles in AKI.

BACKGROUND: Organic anion transporters (OATs) are located on either the basolateral or the apical membrane of the proximal tubule cell and mediate the absorption and secretion of various drugs and endogenous metabolites. It has been shown that cellular damage in acute kidney injury (AKI) involves three forms of injury: sublethal damage resulting in loss of cell polarity, cell death through apoptosis and necrosis. We hypothesize that cellular mistargeting of OAT proteins in AKI will change the profile of OAT proteins in urine. METHODS: Thirty AKI patients were included in the study. AKI was defined by clinical course, daily urine output, response to fluid repletion, urinary sediment, fractional excretion of sodium (FeNa) and urine osmolality. Urinary OAT1, OAT3 and OAT4 protein abundance was measured from semiquantitative immunoblots of urine membrane fraction samples (exosome) collected from patients with AKI and from control subjects. RESULTS: Although all patients studied reached a similar severity of renal failure measured by serum creatinine, some of them recovered from AKI with supportive care only, while others required renal replacement therapy (RRT). OAT1 and OAT3, which are normally localized in the basolateral membrane of the proximal tubule cell, were detected at low levels in urine from control subjects and were increased significantly in all patients with AKI. OAT4 protein, which is normally localized in the luminal membrane of proximal tubule cells, was present in abundance in urine of control subjects. Interestingly, in patients with AKI who eventually recovered, urinary OAT4 was found to be significantly lower than in controls, while in patients who needed RRT, it was higher than in controls. CONCLUSIONS: We have shown that OATs are mistargeted in AKI. The urinary OAT protein profile can help us to learn about the pathophysiology of the disease and might be a marker of AKI severity. AKI patients with early reversible proximal tubular damage will have high urine OAT1 and OAT3 and low OAT4, while patients with severe AKI will have high urine OAT1, OAT3 and OAT4.

Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2.

BACKGROUND: Elevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2). METHODS: Two unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations. RESULTS: Two novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 ± 0.06 mg/dL and fractional excretion of UA was 89-150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions. CONCLUSIONS: This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.

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.

Molecular study of proteinuria in patients treated with B12 supplements: do not forget megaloblastic anemia type 1.

BACKGROUND/AIMS: Current consensus supports the notion that proteinuria is a marker of renal disease with prognostic implications. Whereas most chronic kidney disease patients with proteinuria would often require antiproteinuric agents, there are some exceptions. Megaloblastic anemia type 1 (MGA1) is characterized by megaloblastic anemia due to congenital selective vitamin B(12) malabsorption and proteinuria. In the present study, we describe 2 Israeli Jewish patients with MGA1 and isolated proteinuria. METHODS: Because of their origin, the patients were screened for the presence of the already studied Tunisian AMN mutation, by direct sequencing the corresponding region from genomic DNA. PCR products were purified and sequenced. RESULTS: Genomic DNA sequencing of the AMN gene of both patients confirmed that the acceptor splice site in intron 3 was changed from CAG to CGG (208-2A→G). CONCLUSION: We determined the molecular basis of MGA1 in both patients and discuss the involvement of the cubilin/AMN complex in this pathology and its role in the development of the proteinuria. We also discuss the questionable significance of antiproteinuric treatment for these patients.

Homozygous SLC2A9 mutations cause severe renal hypouricemia.

Hereditary hypouricemia may result from mutations in the renal tubular uric acid transporter URAT1. Whether mutation of other uric acid transporters produces a similar phenotype is unknown. We studied two families who had severe hereditary hypouricemia and did not have a URAT1 defect. We performed a genome-wide homozygosity screen and linkage analysis and identified the candidate gene SLC2A9, which encodes the glucose transporter 9 (GLUT9). Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. In vitro, the L75R mutation dramatically impaired transport of uric acid. The mean concentration of serum uric acid of seven homozygous individuals was 0.17 +/- 0.2 mg/dl, and all had a fractional excretion of uric acid >150%. Three individuals had nephrolithiasis, and three had a history of exercise-induced acute renal failure. In conclusion, homozygous loss-of-function mutations of GLUT9 cause a total defect of uric acid absorption, leading to severe renal hypouricemia complicated by nephrolithiasis and exercise-induced acute renal failure. In addition to clarifying renal handling of uric acid, our findings may provide a better understanding of the pathophysiology of acute renal failure, nephrolithiasis, hyperuricemia, and gout.

Childhood Hypercalciuric Hypercalcemia With Elevated Vitamin D and Suppressed Parathyroid Hormone: Long-Term Follow Up.

Purpose: Hypercalcemia with low parathyroid hormone (PTH) level, hypercalciuria, nephrocalcinosis, or nephrolithiasis, was recently reported as caused by mutations in CYP24A1 and SLC34A genes. These encode for vitamin D-24A-hydroxylase and for the renal phosphate transporters NaPiIIa and NaPiIIc, respectively. We aimed to describe the clinical course of these monogenic disorders in patients with and without found mutations during long-term follow-up. Methods: Ten patients with hypercalcemia, hypercalciuria, elevated 1,25-(OH)2D levels and suppressed PTH were followed in our center during 1998-2019. Relevant laboratory and imaging data and results of genetic evaluation were retrieved from medical files. Results: The median age at presentation was 9.5 months (range 1 month-11 years), six were males, and the median follow-up time was 3.8 (1.1-14) years. Mutations in CYP24A1 and SLC34A3 were identified in three and one patients, respectively. Five patients presented with nephrocalcinosis, three with nephrolithiasis, and two had normal renal ultrasound. High blood calcium and 1,25-(OH)2D levels at presentation decreased during follow-up [11.1 ± 1 vs. 9.9 ± 0.5 mg/dl (p = 0.012), and 307 ± 130 vs. 209 ± 65 pmol/l (p = 0.03), respectively]; this paralleled an increase in suppressed PTH levels (5.8 ± 0.9 vs. 11.8 ± 7.3 pg/ml, p = 0.2). Substantial improvements in hypercalciuria and renal sonography findings were not observed. Two patients had impaired renal function (eGFR 84-88 ml/min/1/73 m2) at the last follow up. Interventions included appropriate diet, citrate supplementation, and thiazides. Conclusion: Despite improvement in hypercalcemia and 1,25-(OH)2D levels, not all the patients showed improvements in hypercalciuria and nephrocalcinosis. Deterioration of renal function was also observed. Long-term follow up and intervention to prevent nephrocalcinosis and nephrolithiasis are recommended in these children.