A Summary of Current Guidelines and Future Directions for Medical Management and Monitoring of Patients with Cystinuria.

Cystinuria is the most common genetic cause of recurrent kidney stones. As the result of a genetic defect in proximal tubular reabsorption of filtered cystine, increased urine levels of the poorly soluble amino acid result in recurrent cystine nephrolithiasis. Recurrent cystine stones not only adversely affect the quality of patients suffering from cystinuria but also may result in chronic kidney disease (CKD) from recurrent renal injury. Thus, the mainstay of medical management revolves around prevention of stones. Recently published consensus statements on guidelines for managing cystinuria were released from both the United States and Europe. The purpose of this review is to summarize guidelines for medical management of patients with cystinuria, to provide new insight into the utility and clinical significance of cystine capacity-an assay for monitoring cystinuria, and to discuss future directions for research on treatment of cystinuria. We discuss future directions, including the potential use of cystine mimetics, gene therapy, V2-receptor blockers, and SGLT2 inhibitors, topics which have not appeared in more recent reviews. It is notable that in the absence of randomized, controlled trials, the recommendations cited here and in the guidelines are based on our best understanding of the disorder's pathophysiology, observational studies, and clinical experience.

24-Hydroxylase Deficiency Due to CYP24A1 Sequence Variants: Comparison With Other Vitamin D-mediated Hypercalcemia Disorders.

CONTEXT: CYP24A1 encodes 24-hydroxylase, which converts 25(OH)D3 and 1,25(OH)2D3 to inactive metabolites. Loss-of-function variants in CYP24A1 are associated with 24-hydroxylase deficiency (24HD), characterized by hypercalcemia, nephrolithiasis, and nephrocalcinosis. We retrospectively reviewed laboratory, imaging, and clinical characteristics of patients with suspected or confirmed 24HD and patients with other vitamin D-mediated hypercalcemia disorders: sarcoidosis, lymphoma, and exogenous vitamin D toxicity (EVT). OBJECTIVE: To identify features that differentiate 24HD from other vitamin D-mediated hypercalcemia disorders. METHODS: Patients seen at the Mayo Clinic (Rochester, MN) from January 1, 2008, to 31 December, 2016, with the following criteria were retrospectively identified: serum calcium ≥9.6 mg/dL, parathyroid hormone <30 pg/mL, and 1,25(OH)2D3 >40 pg/mL. Patients were considered to have 24HD if they had (1) confirmed CYP24A1 gene variant or (2) 25(OH)D3:24,25(OH)2D ratio ≥50. Patients with sarcoidosis, lymphoma, and EVT were also identified. Groups were compared using the Fisher exact test (categorical variables) or the Wilcoxon rank sum test (continuous variables). RESULTS: We identified 9 patients with 24HD and 28 with other vitamin D-mediated disorders. Patients with 24HD were younger at symptom onset (median 14 vs 63 years; P = .001) and had positive family history (88.9% vs 20.8%; P < .001), nephrocalcinosis (88.9% vs 6.3%; P < .001), lower lumbar spine Z-scores (median -0.50 vs 1.20; P = .01), higher peak serum phosphorus (% of peak reference range, median 107 vs 84; P = .01), and higher urinary calcium:creatinine ratios (median 0.24 vs 0.17; P = .047). CONCLUSION: Patients with 24HD had clinical and laboratory findings that differed from other vitamin D-mediated hypercalcemia disorders. 24HD should be suspected in patients with hypercalcemia who present at younger age, have positive family history, and have nephrocalcinosis.

Hemostatic prophylaxis and colonoscopy outcomes for patients with bleeding disorders: A retrospective cohort study and review of the literature.

INTRODUCTION: Hemostatic prophylaxis (HP) is recommended for patients with bleeding disorders (PWBD) before invasive procedures. However, evidence-based guidelines are needed to determine optimal HP strategies. AIM: To determine outcomes of HP for PWBD undergoing colonoscopy. METHODS: We undertook a retrospective cohort study of HP and outcomes of colonoscopy procedures performed between 9 November 1993 and 13 February 2018 for PWBD who received care in the Mayo Clinic Comprehensive Hemophilia Treatment Center. RESULTS: During the study period, 73 PWBD (58 with milder phenotypes: haemophilia, von Willebrand disease [subtypes 1 and 2; II, VII and XI deficiency]) underwent 141 procedures. Preprocedural HP was given to 61%, and interventions were performed in 47%. Of the 39% without preprocedural HP, postprocedural HP was given for 11%. One major (0.7%; 6 days postprocedure despite HP) and 10 minor (7%) bleeding complications occurred, which tended to be in patients with severe disease and/or after excision of larger polyps. There was no significant difference in the rate of bleeding complications with or without preprocedural HP (8.1% vs 5.5%, respectively; P = .74, Fisher's exact test). CONCLUSION: The low bleeding rates in our cohort suggest that preprocedure HP may be withheld for patients with mild bleeding disorders who undergo colonoscopy with a low likelihood of requiring an intervention or who require only low-risk intervention. This strategy may be best used in experienced centres, provided optimal local hemostasis measures are undertaken and postprocedural HP is rapidly available if high-risk intervention is required. Further studies are needed to determine optimal evidence-based HP strategies for PWBD undergoing colonoscopy.

Oral Glycine and Sodium Thiosulfate for Lethal Cyanide Ingestion.

OBJECTIVE: Accidental or intentional cyanide ingestion is an-ever present danger. Rapidly acting, safe, inexpensive oral cyanide antidotes are needed that can neutralize large gastrointestinal cyanide reservoirs. Since humans cannot be exposed to cyanide experimentally, we studied oral cyanide poisoning in rabbits, testing oral sodium thiosulfate with and without gastric alkalization. SETTING: University research laboratory. SUBJECTS: New Zealand white rabbits. INTERVENTIONS: Seven animal groups studied; Groups 1-5 received high dose oral NaCN (50 mg, >LD100) and were treated immediately with oral (via nasogastric tube): 1) saline, 2) glycine, 3) sodium thiosulfate or 4) sodium thiosulfate and glycine, or 5) after 2 min with intramuscular injection of sodium nitrite and sodium thiosulfate plus oral sodium thiosulfate and glycine. Groups 6-7 received moderate dose oral NaCN (25 mg, LD70) and delayed intramuscular 6) saline or 7) sodium nitrite-sodium thiosulfate. MEASUREMENTS AND MAIN RESULTS: All animals in the high dose NaCN group receiving oral saline or glycine died very rapidly, with a trend towards delayed death in glycine-treated animals; saline versus glycine-treated animals died at 10.3+3.9 and 14.6+5.9 min, respectively (p=0.13). In contrast, all sodium thiosulfate-treated high dose cyanide animals survived (p<0.01), with more rapid recovery in animals receiving both thiosulfate and glycine, compared to thiosulfate alone (p<0.03). Delayed intramuscular treatment alone in the moderate cyanide dose animals increased survival over control animals from 30% to 71%. Delayed treatment in high dose cyanide animals was not as effective as immediate treatment, but did increase survival time and rescued 29% of animals (p<0.01 versus cyanide alone). CONCLUSIONS: Oral sodium thiosulfate with gastric alkalization rescued animals from lethal doses of ingested cyanide. The combination of oral glycine and sodium thiosulfate may have potential for treating high dose acute cyanide ingestion and merits further investigation. The combination of systemic and oral therapy may provide further options.