OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis

PurposeNephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.MethodsExome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.ResultsExome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ² = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca²⁺ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca²⁺ uptake, demonstrating loss of function.ConclusionRare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.     

腹腔镜下肾窦内肾盂切开取石术疗效分析

目的 报告腹腔镜下肾窦内肾盂切开取石术的初步临床经验。方法 经腹腔途径腹腔镜下施行肾窦内肾盂切开取石术治疗肾结石19例，21侧；同期处理其他上尿路疾病9例。男14例，女5例。年龄16～67岁，平均41岁。结石直径1．2～3．5cm。结石位于右侧11例，左侧6例，双侧2例。合并输尿管结石5例，其中双侧输尿管多发性结石同侧石街形成1例；肾盂息肉2例，其中致巨大肾积水1例；开放性输尿管切开取石术后狭窄伴巨大肾积水1例；妊娠期肾盂结石致巨大肾积水时放置双J管内引流术后1例。12例13侧曾行体外冲击波碎石术（ESWL）治疗失败，1例曾行微创经皮肾镜取石术（MPCNL）取石不净。结果 手术均获成功。手术时间75～240min，平均115min。术中出血量30～100m1．平均50ml。术后漏尿者1例，5d后自愈。术后住院时间5～9d，平均6d。留置双J管4～6周。随访3～36个月，KUB及IVU显示除1例肾下盏残留1枚0．7cm结石外，余无结石残留，肾盂出口输尿管无狭窄，双肾输尿管均显影。结论 腹腔镜下肾窦内肾盂切开取石术是治疗肾结石可选择的一种微创手术，且可同期处理上尿路合并症，可部分替代开放性手术。     

Lithiase rénale : des mécanismes au traitement médical préventif

Renal lithiasis is a frequent pathology (prevalence ranging from 10 to 12% in France) and a recurrent condition. It is associated with chronic kidney disease and is responsible for 2 to 3% of cases of end-stage renal disease, especially if it is associated with nephrocalcinosis and/or is part of a monogenic disease (1.6% of lithiasis in adults, including 1% of cystinuria). In order to understand the pathophysiology of the nephrolithiasis, the analysis of stones (morphological and by infrared spectrophotometry) as well as a minimal biological evaluation including crystalluria must be carried out. Calcium nephrolithiasis is the most common form (more than 80%). Its preventive medical treatment relies on simple hygienic dietetics: non-alkaline hyperdiuresis greater than 2 liters/day, normalization of calcium intakes (1 g/day to be distributed over the three meals), restriction of sodium intakes (6 g/day) and of protein intakes (0.8–1 g/kg of theoretical weight/day), and avoidance of foods rich in oxalate. If there is a hypercalciuria (greater than 0.1 mmol/kg of theoretical weight/day with normal calcium intakes), its mechanism should be explored with an oral calcium load test. In the absence of primary hyperparathyroidism, thiazide diuretics can be prescribed, taking care to prevent hypokalemia and iatrogenic hypocitraturia. The treatment of uric acid lithiasis includes alkaline hyperdiuresis (urinary pH 6.2 to 6.8). Allopurinol is only justified if the urinary excretion of uric acid exceeds 4 mmol/day. With a well-managed medical treatment, more than 80% of recurrent lithiasis can be stopped, making nephrolithiasis one of the kidney diseases the more accessible to the preventive medical treatment.     

Fecal incontinence,anal skin irritation,and metabolic concerns associated with pelvic pouches

Mechanical and inflammatory complications of pelvic pouch surgery have been well described but there has been limited recognition of problems such as fecal incontinence, anal skin irritation and metabolic changes that may develop after surgery. Reported rates of daytime and nighttime fecal incontinence rates are 29% and 47% respectively. We discuss strategies for managing fecal incontinence and associated anal skin irritation that can develop. Metabolic consequences of pelvic pouch surgery are also increasingly being recognized. Patients with IPAA who are doing well with no evidence of pouch inflammation have low rates of nutrient deficiencies but should be monitored for vitamin B12, vitamin D and zinc deficiencies. In contrast, patients with IPAA who develop pouchitis, diarrhea, and/or rectal bleeding are more susceptible to nutrient deficiencies and should have a broader assessment of nutrient status. In additions, there appears to be an increased risk of bone loss among patients with IPAA and thus these patients should undergo appropriate risk screening and testing. Finally, patients with IPAA have physiologic changes that predispose to formation of calcium oxalate and uric acid renal stones.     

Bone and primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is a disease caused by excessive and inappropriate secretion of parathyroid hormone resulting in hypercalcemia. It is usually diagnosed incidentally in case of hypercalcemia, osteoporosis or, more rarely, renal involvement such as lithiasis. The clinical presentation reflects hypercalcemia and involves several organs, mainly the cardiovascular system, bone, and kidneys. However, most patients with PHPT are asymptomatic. The diagnosis is biological, obvious when serum calcium and parathyroid hormone levels are high, but difficult when one of these two values is normal. The diagnosis of normocalcemic PHPT is possible only after ruling out all causes of secondary hyperparathyroidism. Parathyroid imaging does not contribute to the positive diagnosis but guides surgery and rules out an associated thyroid abnormality. Parathyroid surgery is the gold standard treatment. Parathyroid surgery is indicated in the presence or risk of complications, and it is the only treatment that prevents fractures. Pharmaceutical treatments have only limited effects on complications and are limited to cases where surgery is contraindicated. After parathyroid surgery, the use of bisphosphonates must be avoided as they seem to interfere with the parathyroidectomy's fracture-preventing effects. In the absence of surgical indication, medical monitoring of patients includes assessment of laboratory values, bone density, and renal function.     

Taurine protected kidney from oxidative injury through mitochondrial-linked pathway in a rat model of nephrolithiasis

Hyperoxaluria and crystal deposition induce oxidative stress (OS) and renal epithelial cells injury, both mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are considered as the main sources of reactive oxygen species (ROS). Taurine is known to have antioxidant activity and shows renoprotective effect. We investigate the effect of taurine treatment on renal protection, and the putative source of ROS, in a rat model of calcium oxalate nephrolithiasis. Rats were administered with 2.5% (V/V) ethylene glycol + 2.5% (W/V) ammonium chloride (4 ml/day), with restriction on intake of drinking water (20 ml/day) for 4 weeks. Simultaneous treatment with taurine (2% W/W, mixed with the chow) was performed. At the end of the study, indexes of OS and renal injury were assessed. Renal tubular ultrastructure changes were analyzed under transmission electron microscopy. Crystal deposition in kidney was scored under light microscopy. Angiotensin II in kidney homogenates was determined by radioimmunoassay. Expression of NADPH oxidase subunits p47phox and Nox-4 mRNAs in kidney was evaluated by real time-polymerase chain reaction. The data showed that oxidative injury of the kidney occurred in nephrolithiasis-induced rats. Hyperplasia of mitochondria developed in renal tubular epithelium. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in mitochondria decreased and the mitochondrial membrane showed oxidative injury. Taurine treatment alleviated the oxidative injury of the kidney, improved SOD and GSH-Px activities, as well as the mitochondrial membrane injury, with lesser crystal depositions in the kidney. We could not detect statistical changes in the renal angiotensin II level, and the renal p47phox and Nox-4 mRNAs expression in those rats. The results suggest that mitochondria but not NADPH oxidase may account for the OS and taurine protected kidney from oxidative injury through mitochondrial-linked pathway in this rat model.     

Hyperoxaluria-induced oxidative stress and antioxidants for renal protection

Renal cellular exposure to oxalate (Ox) and/or CaOx crystals leads to the production of reactive oxygen species (ROS), development of oxidative stress followed by injury and inflammation. Renal injury and inflammation appear to play a significant role in stone formation. ROS are produced from many sources and involve a variety of signaling pathways. Tissue culture and animal model studies show that treatments with anti-oxidants and free radical scavengers reduce Ox/CaOx crystal induced injuries. In addition, CaOx crystal deposition in kidneys is significantly reduced by treatments with antioxidants and free radical scavengers, indicating their efficacy. These results point towards a great potential for the therapeutic application of antioxidants and free radical scavengers to reduce stone recurrence particularly after shock wave lithotripsy, which is itself known to generate ROS and cause renal damage.     

Pyridoxamine lowers oxalate excretion and kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria

In order to prevent kidney stones and nephrolithiasis in hyperoxaluria, a new treatment that specifically reduces oxalate production and therefore urinary oxalate excretion would be extremely valuable. Pyridoxamine(PM) could react with the carbonyl intermediates of oxalate biosynthesis, glycolaldehyde and glyoxylate, and prevent their metabolism to oxalate. In PM treated rats, endogenous urinary oxalate levels were consistently lower and became statistically different from controls after 12 days of experiment. In ethylene glycol-induced hyperoxaluria, PM treatment resulted in significantly lower (by ~50%) levels of urinary glycolate and oxalate excretion compared to untreated hyperoxaluric animals, as well as in a significant reduction in calcium oxalate crystal formation in papillary and medullary areas of the kidney. These results, coupled with favorable toxicity profiles of PM in humans, show promise for the therapeutic use of PM in primary hyperoxaluria and other kidney stone diseases.