Goldfarb, David S

Key Points Fibroblast growth factor 23 and 24,25-dihydroxyvitamin D are positively correlated and are significantly lower in Dent disease than in idiopathic calcium kidney stones patients. Dent patients with low 24,25-dihydroxyvitamin D had greater hypercalciuria and proteinuria, and, among adults, higher 1,25-dihydroxyvitamin D concentrations. Moderate phosphate supplementation mitigates hypercalciuria. Background Hypercalciuria is a prominent characteristic in Dent disease type 1 (DD1) and is associated with kidney stones and nephrocalcinosis. The objectives of this study were to assess fibroblast growth factor 23 (FGF23) and 24,25-dihydroxyvitamin D (24,25(OH) 2 D) in DD1 patients and investigate the effects of phosphate supplementation on urinary calcium excretion. Methods Serum and 24-hour urine assessments from adult and pediatric DD1 patients ( N =10 adults; N =9 pediatrics) were compared with adult control subjects with a history of idiopathic calcium kidney stones and hypercalciuria ( N =9). Adult DD1 patients and control participants completed an oral phosphate supplementation intervention (1 g/d×14 days) with reassessment immediately after intervention. Results FGF23 was significantly lower in DD1 than in the control cohort (adults, P = 0.006) and positively correlated with 24,25(OH) 2 D across all study cohorts. The concentrations of 24,25(OH) 2 D were low with conversion ratios (25-hydroxyvitamin D: 24,25(OH) 2 D) exceeding the clinical reference limit for five of 10 adults and six of 9 pediatric DD1 patients. The DD1 cohorts were then stratified by the 24,25(OH) 2 D ratio into “normal” and “low” 24,25(OH) 2 D. Adult DD1 patients with low 24,25(OH) 2 D ( n =5) had lower FGF23, higher 1,25-dihydroxyvitamin D, greater urine calcium, and greater urine protein. Pediatric stratified data mirrored that in adults with the exception of no difference in serum 1,25-dihydroxyvitamin D. Phosphate supplementation was effective in decreasing urine calcium in both adult DD1 and control adult cohorts. Conclusions Clinical measurement of 24,25(OH) 2 D is a novel and useful analysis for evaluating the severity of calcium and protein dysregulation in DD1. In addition, moderate phosphate supplementation effectively mitigates urine calcium excretion in DD1 adult patients. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT02016235.

Key Points Genetic testing of individuals suspected of monogenic urinary stone disease resolved 34% of families with 22 different genes detected. Resolved individuals had a lower baseline and last visit eGFR and earlier age of stone presentation than the unresolved group. Specific phenotypes and younger diagnostic age were associated with a monogenic cause, allowing refinement of future screenings. Background Urinary stone disease with a clear genetic cause, monogenic stone disease (MSD), is increasingly recognized as a significant proportion of the total population. When MSD is suspected, genetic testing provides a firm diagnosis that can alter management and treatment. Here, we present testing results from a large cohort with suspected MSD. Methods Patients with features suggestive of MSD (early onset, family history, frequent stones, nephrocalcinosis [NC], and/or CKD) were recruited by the Rare Kidney Stone Consortium and genotyped for up to 160 known or candidate MSD genes via a targeted massively parallel sequencing panel. We compared clinical and biochemical features between genetically resolved MSD and unresolved individuals. Results Of 426 families (657 patients) enrolled, 145 (34%) were resolved with identified disease associated variants in 22 known MSD genes. Ninety-nine families were biallelic, 37 monoallelic, and two digenic. An additional 21 of the 231 screened family members were resolved. Genes identified in ten or more families include the following: AGXT , HOGA1 , SLC34A3 , CYP24A1 , SLC3A1 , and CLCN5 . Compared with the unresolved group, MSD probands had a lower baseline and last visit eGFR, earlier age of stone presentation, and more stone events and procedures/year of life. The resolve rate was higher in those <16 years, and NC was seen earlier in the MSD group. Overall, NC was a risk factor for lower eGFR. Among the specific disorders, patients with primary hyperoxaluria had the earliest age of stone and NC diagnosis, and as expected, the highest urinary oxalate level. Conclusions Our study emphasizes the value of selecting patients enriched for factors associated with MSD, and comprehensive genetic testing to achieve a high yield of genetic diagnoses. Significant clinical and biochemical characteristics of patients with MSD were defined. A definitive MSD diagnosis facilitates individualized management and strategies to delay disease progression in probands and affected family members.

Purpose: Cystinuria is a genetic disorder with both autosomal recessive and incompletely dominant inheritance. The disorder disrupts cystine and other dibasic amino acid transport in proximal tubules of the kidney, resulting in recurrent kidney stone formation. Currently, there are no consensus guidelines on evaluation and management of this disease. This article represents the consensus of the author panel and will provide clinicians with a stepwise framework for evaluation and clinical management of patients with cystinuria based on evidence in the existing literature. Materials and Methods: A search of MEDLINE ® /PubMed ® and Cochrane databases was performed using the following key words: “cystine nephrolithiasis,” “cystinuria,” “penicillamine, cystine,” and “tiopronin, cystine.” In total, as of May 2018, these searches yielded 2335 articles, which were then evaluated for their relevance to the topic of evaluation and management of cystinuria. Evidence was evaluated by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results: Twenty-five articles on the topic of cystinuria or cystine nephrolithiasis were deemed suitable for inclusion in this study. The literature supports a logical evaluation process and step-wise treatment approach beginning with conservative measures: fluid intake and dietary modification. If stone formation recurs, proceed to pharmacotherapeutic options by first alkalinizing the urine and then using cystine-binding thiol drugs. Conclusions: The proposed clinical pathways provide a framework for efficient evaluation and treatment of patients with cystinuria, which should improve overall outcomes of this rare, but highly recurrent, form of nephrolithiasis.

Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidney thick ascending limb (TAL) of loop of Henle. Despite the unique location and recent association of THP gene mutations with hereditary uromodulin-associated kidney disease and THP single nucleotide polymorphisms with chronic kidney disease and hypertension, the physiological function(s) of THP and its pathological involvement remain incompletely understood. By studying age-dependent changes of THP knockout (KO) mice, we show here that young KO mice had significant salt and water wasting but were partially responsive to furosemide, due to decreased luminal translocation of Na-K-Cl cotransporter 2 (NKCC2) in the TAL. Aged THP KO mice were, however, markedly oliguric and unresponsive to furosemide, and their NKCC2 was localized primarily in the cytoplasm as evidenced by lipid raft floatation assay, cell fractionation, and confocal and immunoelectron microscopy. These aged KO mice responded to metolazone and acetazolamide, known to target distal and proximal tubules, respectively. They also had marked upregulation of renin in juxtaglomerular apparatus and serum, and they were hypertensive. Finally, the aged THP KO mice had significant upregulation of Na-coupled urate transporters Slc5a8 and Slc22a12 as well as sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule and elevated serum uric acid and allantoin. Collectively, our results suggest that THP deficiency can cause progressive disturbances in renal functions via initially NKCC2 dysfunction and later compensatory responses, resulting in prolonged activation of the renin-angiotensin-aldosterone axis and hyperuricemia.

Dual-energy computed tomography (DECT) has recently been suggested as the imaging modality of choice for kidney stones due to its ability to provide information on stone composition. Standard postprocessing of the dual-energy images accurately identifies uric acid stones, but not other types. Cystine stones can be identified from DECT images when analyzed with advanced postprocessing. This case report describes clinical implications of accurate diagnosis of cystine stones using DECT.

Mammalian urine contains a range of macromolecule proteins that play critical roles in renal stone formation, among which Tamm-Horsfall protein (THP) is by far the most abundant. While THP is a potent inhibitor of crystal aggregation in vitro and its ablation in vivo predisposes one of the two existing mouse models to spontaneous intrarenal calcium crystallization, key controversies remain regarding the role of THP in nephrolithiasis. By carrying out a long-range follow-up of more than 250 THP-null mice and their wild-type controls, we demonstrate here that renal calcification is a highly consistent phenotype of the THP-null mice that is age and partially gene dosage dependent, but is gender and genetic background independent. Renal calcification in THP-null mice is progressive, and by 15 mo over 85% of all the THP-null mice develop spontaneous intrarenal crystals. The crystals consist primarily of calcium phosphate in the form of hydroxyapatite, are located more frequently in the interstitial space of the renal papillae than intratubularly, particularly in older animals, and lack accompanying inflammatory cell infiltration. The interstitial deposits of hydroxyapatite observed in THP-null mice bear strong resemblances to the renal crystals found in human kidneys bearing idiopathic calcium oxalate stones. Compared with 24-h urine from the wild-type mice, that of THP-null mice is supersaturated with brushite (calcium phosphate), a stone precursor, and has reduced urinary excretion of citrate, a stone inhibitor. While less frequent than renal calcinosis, renal pelvic and ureteral stones and hydronephrosis occur in the aged THP-null mice. These results provide direct in vivo evidence indicating that normal THP plays an important role in defending the urinary system against calcification and suggest that reduced expression and/or decreased function of THP could contribute to nephrolithiasis.