Urinary Calcium Excretion Research Articles

Abstract 108: Rejuvenation Potential Of Extracellular Vesicles From Renal Distal Tubular Cells - A Promising Strategy To Prevent Aging-associated Hypertension And Renal Function Impairment

Ageing is characterized by progressive multi-organ functional decline and disrupted homeostasis adaptation. Hypertension and kidney damage become increasingly prevalent as individuals age. Given its high metabolic activity and constant exposure to reactive oxygen species, the kidney is particularly susceptible to age-related deterioration. In our study, aged mice exhibited a notable decline in glomerular filtration rate (GFR) and urinary excretion of sodium, potassium, and calcium, alongside elevated urinary creatinine levels, indicating impaired renal function associated with ageing. Histologically, aged kidneys showed glomerular collapse, thickening of the glomerular basement membrane, and increased glomerular sclerosis. Cellular senescence plays a critical role in renal ageing. Senescent cells display an array of changes in gene and protein expression and thus also altered the contents packaged into extracellular vesicles (EVs), secreted into the extracellular milieu. The protein and RNA composition of EVs varied depending on the age and pathological status of the originating parent cells. Our data showed an increased expression of EV biogenesis protein HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) in aged DCT cells (aDCTs). Consistently, with an increase in EV secretion in aDCTs. Administration of young DCT (yDCT)-derived EVs into aged kidneys resulted in a significant improvement of GFR and urinary ion excretion, accompanied by a reduction in age-associated elevation of systolic blood pressure (SBP). Conversely, when administering aDCT-derived EVs to young mice, we saw a significant decrease in GFR and an increase in SBP, indicating a detrimental effect of aDCT-EVs. Proteomic analysis revealed distinct protein expression profiles between yDCT-EVs and aDCT-EVs. These differentially expressed proteins are highly enriched in ageing regulatory pathways, underscoring the crucial role of DCT-EVs in kidney rejuvenation. Intriguingly, we identified a subset of proteins exclusively present in either yDCT-EVs or aDCT-EVs. Our future research will focus on identifying the key components of DCT-EVs responsible for driving kidney rejuvenation.

Genotypic variability in patients with clinical diagnosis of Bartter syndrome type 3

Bartter syndrome (BS) is a salt-losing hereditary tubulopathy characterized by hypokalemic metabolic alkalosis with secondary hyperaldosteronism. Confirmatory molecular diagnosis may be difficult due to genetic heterogeneity and overlapping of clinical symptoms. The aim of our study was to describe the different molecular findings in patients with a clinical diagnosis of classic BS. We included 27 patients (26 families) with no identified pathogenic variants in CLCNKB. We used a customized Ion AmpliSeq Next-Generation Sequencing panel including 44 genes related to renal tubulopathies. We detected pathogenic or likely pathogenic variants in 12 patients (44%), reaching a conclusive genetic diagnosis. Variants in SLC12A3 were found in 6 (Gitelman syndrome). Median age at diagnosis was 14.6 years (range 0.1–31), with no history of prematurity or polyhydramnios. Serum magnesium level was low in 2 patients (33%) but urinary calcium excretion was normal or low in all, with no nephrocalcinosis. Variants in SLC12A1 were found in 3 (BS type 1); and in KCNJ1 in 1 (BS type 2). These patients had a history of polyhydramnios in 3 (75%), and the mean gestational age was 34.2 weeks (SD 1.7). The median age at diagnosis was 1.8 years (range 0.1–6). Chronic kidney disease and nephrocalcinosis were present in 1 (25%) and 3 (75%) patients, respectively. A variant in CLCN5 was found in one patient (Dent disease), and in NR3C2 in another patient (Geller syndrome). Genetic diagnosis of BS is heterogeneous as different tubulopathies can present with a similar clinical picture. The use of gene panels in these diseases becomes more efficient than the study gene by gene with Sanger sequencing.

24-h Urinary Calcium Excretion and Renal Outcomes in Hospitalized Patients with and without Chronic Kidney Disease.

This study investigated the impact of 24-h urinary calcium excretion (UCaE) on renal function decline in hospitalized patients with and without chronic kidney disease (CKD). This study enrolled 3815 CKD patients in stages 1-4 and 1133 non-CKD patients admitted to the First Center of the Chinese PLA General Hospital between January 2014 and July 2022. The primary outcome for CKD patients was a composite of CKD progression, defined as a 40% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease. Annual eGFR change was the secondary outcome. For non-CKD patients, the primary outcome was an eGFR decline of ≥20% or CKD incidence, while annual eGFR change was the secondary outcome. The association between UCaE and kidney function decline was assessed using Cox proportional hazards and generalized linear models. Primary outcomes were observed in 813 CKD patients and 109 non-CKD patients over a median follow-up of 3.0 and 4.1 years, respectively. For CKD patients, every 1-mmol/d increase in UCaE was associated with a 15% decreased risk of CKD progression. The hazard ratio (HR) was 0.85, with a 95% confidence interval (CI) of 0.77-0.93. For non-CKD patients, the risk of renal function decline decreased by 11%. The multivariate models indicated that there was an annual decrease in eGFR in both CKD and non-CKD patients, with a reduction of 0.122 mL/min/1.73 m2/year (p < 0.001) and 0.046 mL/min/1.73 m2/year (p = 0.004), respectively, for every 1-mmol/d increase in UCaE. CKD experiences a decrease in 24-h UCaE as early as stage 1, with a significant decline in stage 4. CKD and non-CKD patients with lower UCaE levels are at an increased risk of renal decline, regardless of other variables.

Hypoparathyroidism – management, information needs, and impact on daily living from the patients’ perspective: results from a population-based survey

PurposeHypoparathyriodism (hypoPT) is a rare endocrine disorder. It is not known how hypoPT is managed in Germany or whether patients have unmet information needs or impairments in their daily living.MethodsHypoPT patients at a minimum of 6 months’ post-diagnosis were invited to participate in an online survey through their treating physician or through patient organizations. An extensive questionnaire, which was developed and pilot-tested with hypoPT patients, was administered.ResultsA total of 264 patients with a mean age of 54.5 years (SD: 13.3), 85.2% female and 92% with postsurgical hypoPT, participated in the study. In total, 74% of the patients reported regular monitoring of serum calcium at least every 6 months, with lower control frequencies for phosphate (47%), magnesium (36%), creatinine (54%), and parathyroid hormone (50%), and 24-h urine calcium excretion (36%) on a yearly basis. Information on symptoms of hypo- and hypercalcemia was available in 72 and 45% of the patients. Information needs were related to the disease and its treatment as well as to nutrition, physical activities/sports, and support opportunities. Statistically significant differences for all information needs in association with symptom burden were observed. Hospitalization for hypocalcemia was reported by 32%, nutritional impairments (38%) or impact on work ability (52%) was available among patients with hypoPT.ConclusionHypoPT patients experience impairments in daily living and report unmet information needs. Patient and physician education regarding hypoPT is one of the key concepts for improving the management of patients with hypoPT.

Pre-flight body weight effects on urinary calcium excretion in space

Microgravity-induced bone loss increases urinary calcium excretion which increases kidney stone formation risk. Not all individuals show the same degree of increase in urinary calcium and some pre-flight characteristics may help identify individuals who may benefit from in-flight monitoring. In weightlessness the bone is unloaded, and the effect of this unloading may be greater for those who weigh more. We studied whether pre-flight body weight was associated with increased in-flight urinary calcium excretion using data from Skylab and the International Space Station (ISS). The study was reviewed and approved by the National Aeronautics and Space Administration (NASA) electronic Institutional Review Board (eIRB) and data were sourced from the Longitudinal Study of Astronaut Health (LSAH) database. The combined Skylab and ISS data included 45 participants (9 Skylab, 36 ISS). Both weight and day in flight were positively related to urinary calcium excretion. There was also an interaction between weight and day in flight with higher weight associated with higher calcium excretion earlier in the mission. This study shows that pre-flight weight is also a factor and could be included in the risk assessments for bone loss and kidney stone formation in space.

Determinants on urinary excretion of oxalate and other key factors related to urolithiasis among patients with chronic kidney disease: a single center study

PurposeUrolithiasis is a known risk factor for chronic kidney disease (CKD). However, how CKD might affect the risk of incidence of urolithiasis is not widely studied.MethodsUrinary excretion of oxalate as well as other key factors related to urolithiasis was analyzed in a single center study of 572 patients with biopsy-proven kidney disease.ResultsThe mean age of the cohort was 44.9 years and 60% were males. The mean eGFR was 65.9 ml/min/1.73 m2. Median urinary excretion of oxalate was 14.7 (10.4–19.1) mg/24-h and associated with current urolithiasis (OR 12.744, 95% CI: 1.564–103.873 per one logarithm transformed unit of urinary oxalate excretion). Oxalate excretion was not associated with eGFR and urinary protein excretion. Oxalate excretion was higher in patients with ischemia nephropathy as compared with patients with glomerular nephropathy and tubulointerstitial nephropathy (16.4 vs 14.8 vs 12.0 mg, p = 0.018). And ischemia nephropathy (p = 0.027) was associated with urinary oxalate excretion on adjusted linear regression analysis. Urinary excretion of calcium and uric acid was correlated with eGFR and urinary protein excretion (all p < 0.001), with ischemia nephropathy and tubulointerstitial nephropathy associated with uric acid excretion (both p < 0.01) as well. Citrate excretion was correlated with eGFR (p < 0.001) on adjusted linear regression.ConclusionExcretion of oxalate and other key factors related to urolithiasis was differentially associated with eGFR, urinary protein, and pathological changes in CKD patients. The influence of these intrinsic traits of the underlining kidney disease should be considered when evaluating urolithiasis risk in patients with CKD.

#3069 CIRCULATING SCLEROSTIN AFFECTS URINARY CALCIUM EXCRETION AMONG STONE FORMERS

Abstract Background and Aims Sclerostin plays an important role in bone metabolism and adipose tissue. Experimental studies suggest that sclerostin also influences urinary calcium excretion (Uca), but this relationship has not been addressed in humans. We aimed to study the association of UCa levels with serum sclerostin, bone mineral density (BMD) and body composition among stone-formers (SF). Method We retrieved data from patient records, including clinical characteristics, nutritional, biochemistry and hormonal data as well as BMD and body composition determined by dual energy X-ray absorptiometry. Serum sclerostin levels were measured using ELISA kits. Determinants of UCa were studied using multivariate linear regression. Results A total of 107 SF (35.8 ± 9.3 years, 54% male) with eGFR of 99.8 ± 14.5 mL/min/1.73 were included. The subjects were divided by sex and clustered into tertiles according to UCa as shown in Table 1. Men in the highest UCa tertile had higher body mass index (BMI) and serum sclerostin levels, were more likely to have hypertension and metabolic syndrome, had lower lean mass, a trend towards higher fat mass (p = 0.06), and no statistical differences in BMD. Women in the highest UCa tertile had higher BMI and a trend towards higher serum sclerostin levels (p = 0.06), were more likely to have hypertension and metabolic syndrome, with no differences in BMD. Sclerostin was positively correlated with fat mass (r = 0.38, p = 0.004) and inversely correlated with lean mass (r = -0.32, p = 0.01) among men, but not among women. To further adjust for the influence of weight load on BMD for both sexes, the latter was also expressed as a ratio per BMI (BMD/BMI). Although lumbar spine BMD/BMI was inversely associated with UCa (β -0.26, p = 0.01) in univariate analysis, it lost significance in the multivariate model (Table 2). Hypertension, metabolic syndrome and serum sclerostin were independent determinants of UCa (Table 2). Conclusion Present findings disclosed that serum sclerostin, hypertension and metabolic syndrome were independent determinants of urinary calcium in stone formers. These data suggest that in addition to the hormones traditionally thought to alter calcium reabsorption in the kidney, sclerostin may play a significant additional role, warranting further intervention studies in order to test potential medication strategies to reduce calciuria in this population.

#6875 COMPLICATIONS AND TREATMENT OF HYPERCALCIURIA IN FAMILIAL HYPERKALAEMIC HYPERTENSION (FHHT)

Abstract Background and Aims Hypertension is frequently associated with hypercalciuria1, nephrolithiasis2 and low bone mineral density. Familial Hyperkalaemic Hypertension (FHHt) causes hypercalciuria3, although complications of this are not reported. Method We examined a cohort of 9 patients with genetically confirmed FHHt. Biochemical, radiological, and clinical data was obtained in patients before and after thiazide treatment. All patients gave informed consent. The study had ethics committee approval. Data were compared using paired t tests. Results 5 of the 9 patients were female (median age 41.7 years). The genetic diagnosis was confirmed in all patients, 5 patients had variants in KLHL3, 3 patients had variants of WNK4, and one had a variant of WNK1 (Table 1). Pre-treatment potassium was high (median 5.6 IQR 5.2-6.2 mmol/L). Pre-treatment calcium was in the normal range (2.34 IQR 2.29-2.38 mmol/L). There was significant hypercalciuria with a raised urinary calcium/creatinine ratio (0.69 IQR 0.41-1.13). However, PTH (4 IQR 3.95-4.35 pmol/L), phosphate (1.15 IQR 1.25mmol/L) and alkaline phosphatase (57 IQR 45-84 mmol/L) were all in the normal range. Thiazide treatment significantly reduced hypercalciuria (calcium/creatinine ratio 0.15 IQR 0.05-0.29 p = 0.04) as well as the serum potassium (3.9 IQR 3.5-4.4 mmol/L p = 0.0167) (Table 1). Patients also developed complications of hypercalciuria. 3 patients had kidney stones demonstrated on cross-sectional imaging (Figure 1). One of these patients (male, 30 years old) had DXA criteria for osteoporosis (T score Femoral neck -1.5, lumbar spine -2.4). Conclusion This is the first case series to demonstrate complications of hypercalciuria (i.e. kidney stones) in patients with FHHt. We demonstrate that thiazide treatment normalises urinary calcium excretion. Thiazide treatment may have clinical utility in FHHt even if hypertension or hyperkalaemia are not problematic in order to avoid the complications of hypercalciuria.

Longitudinal trends in serum calcium, parathormone and bone mineral density in breast cancer survivors on aromatase inhibitor therapy: A single institutional cohort study.

e12531 Background: Aromatase inhibitors (AIs), when used as adjuvant treatment of hormone receptor positive breast cancer, have been associated with bone density loss. However, any impact on PTH and by extension calcium (Ca) homeostasis is yet to be elucidated as no study till date has investigated longitudinal trends in parathyroid hormone (PTH) while on AI therapy. We explored these to determine if long term AI therapy was associated with hyperparathyroidism. Methods: This is a retrospective study of female breast cancer patients at the Cleveland Clinic Foundation started on AIs (anastrozole, letrozole and exemestane) from January 2015 to April 2022. Included patients had both baseline and subsequent data (after starting AI therapy), on serum Ca, PTH and lumbar spine T-scores (LsTs). These values were compared using paired t-test. Results: We identified n=9657 patients on AI therapy and included n=249 with pre and post AI PTH values. Among these, n= 209 received anastrozole, n=34 received letrozole and n=6 received exemestane. Cohort median age was 68 (IQR 62-72) years and median duration of AI therapy was 3 years. While we observed a significant positive correlation between change in Ca and change in PTH (p=0.02), the differences between baseline and treatment median serum Ca and PTH were not statistically significant. There was no significant association between changes in either serum Ca or PTH and change in LsTs (p-value: 0.69 and p-value: 0.05 respectively). Notably, 4% patients had elevated PTH and Ca after AI therapy was initiated among whom n=4 had markedly elevated PTH with low urinary Ca. Three of these four patients also had a diagnosis of chronic kidney disease (CKD) with normal vitamin D levels. Two patients with elevated PTH were on biotin supplements. There was an overall downtrend in LsTs (p-value: 0.0039) with no significant difference between the three AIs (p-value 0.0613). However, in comparison to other AIs, letrozole had the least depreciation in LsTs. Conclusions: Our findings do not suggest any correlation between AI therapy and hyperparathyroidism among breast cancer survivors. No significant increase in PTH levels occurred during AI therapy and majority of patients with clinically significant PTH elevation also had CKD, which may have contributed also to elevation of PTH level and low urinary calcium excretion.[Table: see text]

A Phase I Randomized Trial of Once-Daily Versus Twice-Daily Recombinant Human Parathyroid Hormone (1-84) for Hypoparathyroidism.

Recombinant human parathyroid hormone (1-84), rhPTH(1-84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1-84). This was a phase I, open-label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1-84) administered subcutaneously at 25 μg BID, 50 μg BID, and 100 μg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1-84), both BID and QD, over the short-term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline-adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1-84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1-84) dosing. Future long-term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Influence Mechanism of Osteopontin on Renal Injury in Patients with hereditary hypercalcemia by Enzyme-linked immunosorbent assay.

This study was to investigate the role and mechanism of osteopontin(OPN) in renal injury in patients with inherited hypercalciuria-bearing urinary calculi. The genetic hypercalcemia urolithiasis (GHS) rat model was established, and GHS rats were set as the experimental group (12 cases) and normal SD rats as the control group (12 cases). OPN and calcification levels in the kidney tissues of the two groups were compared by ELISA. According to calcium intervention or not, GHS rats were rolled into an intervention group (the intervention group was divided into 0.2g/L group, 0.4g/L group, and 0.7g/L group regarding the calcium injection dose, each group with 2 cases) and a normal group, each group with 6 cases. The levels of OPN and kidney injury in the two groups after 5h, 20h, and 40h were compared. Seventy patients with idiopathic hypercalciuria (IH) were rolled into a control group (injected with normal saline) and an observation group (injected with saline and OPN). The levels of OPN and calcification in kidney tissue of GHS rats in the experimental group were higher than those in the control group (P<0.05). The OPN level of GHS rats in the 0.2g/L group, 0.4g/L group, and 0.7g/L group was higher than that in the intervention group, and the OPN level at 5h, 10h, and 20h showed an upward trend (P<0.05). The incidence of renal injury in the intervention group (100%) was higher than that in the non-intervention group (16.67%) (P<0.05). Clinical verification results showed that urinary calcium excretion of IH patients in the observation group significantly decreased at 6 and 12 days, with statistical significance (P<0.05). The high probability of overactivation of OPN was one of the pathogeneses of hypercalciuria and calcium-bearing urolithiasis. The results suggested that OPN was closely related to the formation of urinary calculi and may cause certain damage to the kidney, which may be a key step in the prevention and treatment of urinary calculi.

Normal 24-hour urine calcium concentrations after long-term daily oral intake of vitamin D in doses ranging from 5000 to 50,000 international units in 14 adult hospitalized psychiatric patients

Many controversies exist regarding vitamin D3 supplementation. These include not only diseases that are responsive to vitamin D supplementation, but also the long-term safety of prolonged daily oral vitamin D3 intake above 4000–10,000 International Units (IU). In particular, supplementation levels that do not result in adverse events, and the upper limits of safe serum 25-hydroxyvitamin D (25OHD) concentrations. Adverse reactions reported to occur with excessive vitamin D intake include hypercalcemia, renal failure, calcium crystal formation, undetectable parathyroid hormone concentrations, and hypercalciuria, all of which are reported to be reversible. To address the long-term safety of vitamin D supplementation, we previously reported data from patients in our hospital who have been voluntarily supplemented with vitamin D3 ranging from 5,000 to 10,000 IU/day since July 2011 as a standard of care for the prevention and treatment of vitamin D deficiency. Historically 90% of patients have agreed to daily supplementation, with most taking 10,000 IU/day. These data indicate no evidence for hypercalcemia, renal failure, calcium crystal formation, nephrolithiasis. or undetectable parathyroid hormone concentrations in patients taking 5000 or 10,000 IU/day for extended periods of time. As another measure for potential vitamin D toxicity, we retrospectively assessed 24-hour urine calcium excretion in 14 individuals on long-term daily oral vitamin D intake ranging from 5000 to 50,000 IU/day to further assess the safety of supplementation using these doses. This included patients taking either 5000 (4), 10,000 (9), or 50,000 (1) IU/day. Time on supplementation ranged from 10 to 102 months. A patient taking 400 IU/day and getting frequent sun exposure was also included. All fifteen 24-hour urine calcium measurements were normal. The current findings complement our experience with over 7000 patients in the past 13 years, indicating that prolonged daily oral intake of vitamin D3 ranging from 5000 to 10,000 IU/day is safe.

Resolving the thiazide-induced hypocalciuria conundrum using single cell transcriptomics

Thiazide diuretics lower urinary calcium excretion and are used to prevent calcium stone recurrence. Thiazides inhibit the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). Hypocalciuria also occurs in Gitelman syndrome, caused by mutations in SLC12A3, encoding NCC. The mechanism by which loss of NCC function affects calcium handling remains very controversial. The two prevailing hypotheses invoked are 1) hypocalciuria results from volume-dependent increases in proximal tubule reabsorption; 2) thiazides activate calcium reabsorption along the DCT. Here we combined single nucleus RNA sequencing with physiologic analysis to unravel the causes of hypocalciuria.Eight to 10-week old male mice were given 50 mg/kg/day metolazone (MTZ) orally in food for 4 days. Littermates receiving only vehicle were used as controls. As DCT cells comprise a small percentage of the kidney mass, we used the NCC-Cre +/- - INTACT +/- mouse line to enrich for DCT via Cre-dependent GFP expression in DCT nuclei. After nuclei isolation, GFP+ events (DCT nuclei) were enriched by fluorescence assisted nuclei sorting. The purified DCT nuclei were sequenced using 10X Chromium controller. Reads were then analyzed using a standard transcriptomic bioinformatics pipeline with Seurat.The MTZ-treated mice showed lower urinary calcium excretion compared to controls recapitulating thiazide-induced hypocalciuria. Our snRNAseq integrated dataset contained 51,876 mapped genes across 45,953 samples from 3 MTZ-treated and 3 control mice. Roughly 99% of the nuclei were singlets expressing Slc12a3 showing successful enrichment for the DCT. Dimensional reduction analysis and projection confirmed two clusters, DCT1 and DCT2, based on canonical segment markers consistent with previously published transcriptomic atlases. Gene expression analysis showed the DCT2 contained a calcium cassette consisting of the known calciotropic genes Trpv5, Calb1, S100g, Slc8a1, Ryr2, Vdr, Casr, and Atp2b1. These genes were also expressed in the connecting tubule (CNT), as documented using the Calb1-Cre-INTACT system. From this set of genes, we defined a calcium score computed from the pooled average expression of all these genes in a single cell. Although all calcium cassette genes, and the average calcium score, were lower in the MTZ-treated group, the proportion of DCT2/DCT1 cells increased (0.27 ± 0.03 vs 0.35 ± 0.03; p = 0.027). These data suggest that lower calcium delivery to the DCT reduces calcium cassette expression per cell, but that distal fractional reabsorption is nonetheless increased owing to hypertrophy and elongation of the calcium transporting segments, DCT2 and CNT.We propose a modified mechanism to account for thiazide -induced hypocalciuria: 1) volume-dependent increase in proximal tubule reabsorption; 2) increased fractional (not absolute) DCT2 reabsorption owing to structural remodeling of DCT2 and CNT providing more surface area for calcium reabsorption. Funding: NIH DK51496, NIH DK054983, VA 1I01BX002228, LeDucq Foundation, DOST-PCHRD-ASTHRDP This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract #1399984: Hypercalcemia Secondary to Vitamin D Toxicity Treated with Glucocorticoids

Vitamin D toxicity is a rare cause of hypercalcemia and there is no consensus on active treatment. Though glucocorticoids can decrease intestinal calcium absorption, increase urinary calcium excretion, and reduce levels of biologically active vitamin D metabolites, its use in vitamin D toxicity is controversial. Here we present a case of hypercalcemia secondary to hypervitaminosis D treated with glucocorticoids. A 77-year-old female with a history of vitamin D deficiency and prior admission for hypercalcemia attributed to lithium use (discontinued in December 2021) presented to the emergency room for hypercalcemia on outpatient labs. Labs were notable for calcium 14.6 mg/dL, albumin 3.8 g/dL, ionized calcium above detectable limits (>7.3 mg/dL), PTH 22.9 pg/mL, 25-OH vitamin D 135 ng/mL, 1,25-OH vitamin D 67.2 pg/mL (reference range: 19.9-79.3 pg/mL), estimated GFR 23 mL/min/1.73 m2, and undetectable lithium level. Additional workup included normal SPEP/UPEP, parathyroid hormone-related peptide, retinol and retinyl palmitate vitamin A, and computed-tomography of the chest, abdomen, and pelvis without signs of malignancy. History obtained from family revealed the patient had been supplementing with at least 10,400 IU of cholecalciferol daily, along with at least 180 mg of calcium daily (unknown if elemental or calcium carbonate). She was hydrated with isotonic intravenous fluids, given calcitonin 4 units/kg for 3 days, and prednisone 20 mg daily for 2 days. Following day 3 of calcitonin, prednisone was replaced with hydrocortisone 40 mg twice daily. Calcium improved to 10.8 mg/dL and she was discharged on hydrocortisone at same dose and frequency. Upon two-week follow up, calcium had improved to 10.0 mg/dL thus hydrocortisone was tapered to 20 mg twice daily. Due to a misunderstanding, she discontinued hydrocortisone resulting in an increased calcium of 12.2 mg/dL several weeks later. Four weeks upon resumption of hydrocortisone, the calcium improved to 10.2 mg/dL and the hydrocortisone was tapered to 10 mg twice daily. Five weeks later (approximately 4 months since starting hydrocortisone), the calcium was 10.4 mg/dL, the PTH was 19 pg/mL, and 25-OH vitamin D was 37.1 ng/mL. There are no guidelines or consensus on the treatment for vitamin D-induced hypercalcemia. In this case, glucocorticoids were shown to be an effective treatment for hypercalcemia secondary to vitamin D toxicity; the worsening of hypercalcemia upon accidental discontinuation and resolution following resumption of hydrocortisone further supports this conclusion. Though the expected duration of treatment is unclear, our case suggests long-term glucocorticoids are likely necessary.

Furosemide rescues hypercalciuria in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis model

Aim: Impaired calcium homeostasis limits life expectancy and quality in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC). This rare disease is caused by loss-of-function mutations in CLDN16 or CLDN19 genes leading to impaired paracellular reabsorption of divalent cations along the cortical thick ascending limb (cTAL). The ensuing late distal nephron and collecting duct system partially compensate for the defect in cTAL by increased transcellular Ca 2+ reabsorption via the luminal transient receptor potential channel V5 (TRPV5), as well as basolateral plasma membrane calcium ATPase (PMCA) and sodium-potassium exchanger (NCX1). The loop diuretic furosemide induces compensatory activation in these distal segments due to blockade of NaCl and divalent cation reabsorption in the preceeding TAL. Although furosemide enhances urinary calcium excretion via inhibition of the aforementioned cTAL in general population, this effect is not expected in FHHNC patients with already severely impaired Ca 2+ transport in the cTAL. The present study follows the hypothesis that furosemide may alleviate hypercalciuria in this disease by activation of the distal transcellular Ca 2+ transport proteins. Methods: Cldn16-deficient mice (Cldn16-/- ) served as a FHHNC model. Wild-type (WT) and Cldn16-/- mice were treated with furosemide (7 days of 40 mg/kg bw) or vehicle. We assessed renal electrolyte handling (metabolic cages) and key divalent transport proteins. Results: Cldn16-/- mice show increased Ca 2+ excretion than WT and compensatory stimulation of Cldn2 in the proximal tubule, as well as of TRPV5, and NCX1 in the distal nephron at baseline. Furosemide reduced hypercalciuria in Cldn16-/- mice and enhanced TRPV5 and PMCA levels in Cldn16-/- but not in WT mice. Conclusions: Furosemide alleviated hypercalciuria in a mouse FHHNC model, likely via stimulation of transcellular luminal and basolateral Ca 2+ transport systems in the distal nephron and collecting duct. These results may have a clinical implication in FHHNC patients. No conflict of interests This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Nephrolithiasis and Multicystic Kidneys in a Young Patient: A Quiz

Nephrolithiasis and Multicystic Kidneys in a Young Patient: A Quiz

MP10-02 DIETARY INTERVENTION IN ENTERIC HYPEROXALURIA

You have accessJournal of UrologyCME1 Apr 2023MP10-02 DIETARY INTERVENTION IN ENTERIC HYPEROXALURIA William DeFoor, Joonsue Lee, Nehus Edward, Marion Schulte, Sydney Huesman, Ashleigh Libs, and Prasad Devarajan William DeFoorWilliam DeFoor More articles by this author , Joonsue LeeJoonsue Lee More articles by this author , Nehus EdwardNehus Edward More articles by this author , Marion SchulteMarion Schulte More articles by this author , Sydney HuesmanSydney Huesman More articles by this author , Ashleigh LibsAshleigh Libs More articles by this author , and Prasad DevarajanPrasad Devarajan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003225.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Medically complex, gastrostomy-fed children are particularly vulnerable to forming kidney stones. We have previously shown that there are elevated urinary oxalate levels in patients using enteral feeding formulas primarily based on soy protein, a known high oxalate food. Enteric hyperoxaluria may predispose patients to calcium oxalate stones. The objective of this study is assess if targeted dietary intervention decreases urinary oxalate excretion. METHODS: A retrospective cohort study was performed on medically complex children with cerebral palsy and severe developmental delay presenting to a high-volume Pediatric Stone Center with nephrolithiasis from 2015 to 2020. Inclusion criteria included those who underwent a dietary and urinary metabolic evaluation before and after the index visit. Diets were analyzed by a registered dietitian. Urinary metabolites including calcium, oxalate, and citrate as well as the supersaturations of calcium oxalate and calcium phosphate were analyzed via two 24-hour urine collections. Dietary oxalate load was determined by evaluating individual recipes for known high oxalate ingredients or soy-based formulas. Patients were stratified into those on a low versus high oxalate diet. Statistical analysis was performed using paired t-tests. RESULTS: A total of 13 medically complex stone-forming children met inclusion criteria. All patients were non-ambulatory. 11 of 13 (85%) were primarily fed via gastrostomy. Of the 13 patients, 4 were on a low oxalate diet and 9 were found to have a diet of high oxalate foods. The baseline urinary oxalate excretion (26 vs. 71 mg/m2/day, P = 0.001) and supersaturation of calcium oxalate (6.1 vs. 14.3, P=0.01) were lower in those with a low oxalate diet. Four patients on high oxalate diets were targeted for lowering the enteral oxalate load. A follow-up urinary metabolic evaluation was performed a mean of 6.5 months after the dietary intervention. The urinary oxalate level decreased from 71 to 33 mg/m2/day (P=0.049). Urinary excretion of calcium and citrate as well as the supersaturation of calcium phosphate were similar following dietary modifications. CONCLUSIONS: Urinary oxalate excretion and supersaturation of calcium oxalate were elevated in medically complex stone-forming children with high dietary oxalate content. Targeted dietary intervention to reduce the oxalate load in enteral formulas can lead to a substantial decrease in urinary oxalate excretion. Further investigation is required to determine if this leads to lower stone recurrence, hospitalizations, and the need for surgical interventions. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e114 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information William DeFoor More articles by this author Joonsue Lee More articles by this author Nehus Edward More articles by this author Marion Schulte More articles by this author Sydney Huesman More articles by this author Ashleigh Libs More articles by this author Prasad Devarajan More articles by this author Expand All Advertisement PDF downloadLoading ...

Rifampin monotherapy for children with idiopathic infantile hypercalcemia

Idiopathic Infantile Hypercalcemia (IIH) is characterized by hypercalcemia and hypercalciuria owing to PTH-independent increases in circulating concentrations of 1,25(OH)2D. At least 3 forms of IHH can be distinguished genetically and mechanistically: infantile hypercalcemia-1 (Hypercalcemia, Infantile, 1; HCINF1) due to CYP24A1 mutations results in decreased inactivation of 1,25(OH)2D; HCINF2 due to SLC34A1 mutations results in excessive 1,25(OH)2D production; and HCINF3 in which a variety of gene variants of uncertain significance (VUS) have been identified and where the mechanism for increased 1,25 (OH)2D is unclear. Conventional management with dietary calcium and vitamin D restriction has only limited success. Induction of the P450 enzyme CYP3A4 by rifampin can provide an alternate pathway for inactivation of 1,25(OH)2D that is useful in HCINF1 and may be effective in other forms of IIH.We sought to assess the efficacy of rifampin to decrease levels of serum 1,25(OH)2D and calcium, and urinary calcium concentrations in subjects with HCINF3, and to compare the response to a control subject with HCINF1.Four subjects with HCINF3 and the control subject with HCINF1 completed the study using rifampin 5 mg/kg/day and 10 mg/kg/day each for 2 months separated by a 2-month washout period. Patients had age-appropriate intake of dietary calcium plus 200 IU vitamin D/day. Primary outcome was efficacy of rifampin to lower serum concentrations of 1,25(OH)2D. The secondary outcomes included the reduction of serum calcium, urinary calcium excretion (as random urine calcium: creatinine (ca:cr) ratio) and serum 1,25(OH)2D/PTH ratio.Rifampin was well tolerated and induced CYP3A4 at both doses in all subjects. The control subject with HCINF1 showed significant response to both rifampin doses with decreases in the serum concentration of 1,25(OH)2D and the 1,25(OH)2D/PTH ratio while the serum and urine ca:cr levels were unchanged. The four patients with HCINF3 showed reductions in 1,25(OH)2D and urinary ca:cr after 10 mg/kg/d, but hypercalcemia did not improve and there were variable responses in 1,25(OH)2D/PTH ratios. These results support further longer-term studies to clarify the usefulness of rifampin as a medical therapy for IIH.

Effects of parathyroid hormone on renal tubular calcium and phosphate handling.

Central to the maintenance of calcium homeostasis is the regulated reabsorption of calcium along the nephron. To this end, parathyroid hormone (PTH) is released from the parathyroid gland in response to lowered plasma calcium levels. This hormone acts through the PTH 1 receptor along the nephron to increase urinary phosphate excretion and decrease urinary calcium excretion. In the proximal tubule, PTH inhibits phosphate reabsorption by reducing the abundance of sodium phosphate cotransporters in the apical membrane. PTH likely decreases calcium reabsorption from the proximal tubule, by reducing the reabsorption of sodium, an event necessary for the paracellular movement of calcium across this segment. In the thick ascending limb (TAL), PTH increases calcium permeability and may increase the electrical driving force thereby increasing calcium reabsorption in the TAL. Finally, in the distal convolution, PTH acts to increase transcellular calcium reabsorption by increasing the activity and abundance of the apically expressed calcium channel TRPV5.

Calcium and Bone Disorders in Pregnancy and Post-Partum Assessed through Radiological Imaging

Aim: To determine the calcium and bone disorders in pregnancy assessed through radiological imaging. Study design: Prospective study. Place and duration of study: Department of Radiology, Chandka Medical College Hospital, Larkana from 1st July 2022 to 31st December 2022 Methodology: One hundred pregnant women were enrolled. The blood calcium levels were assessed through serum calcium at these stages through 3 cc blood withdrawal. Dietary intake of calcium was also assessed through food frequency charts. Urinary-excretion of calcium was analyzed through cross-linked N-telopeptides (NTx) type I collagen. Each participant was assessed at 3 points including baseline assessment at 1st trimester, then at 2nd trimester and finally at post-partum 4 weeks. At the 2nd trimester ultrasound bone measurement was conducted at distal radius. Quantitative ultrasound was used for this purpose. In the post-partum women, a radiological imaging including DEXA (Dual-energy X-ray absorptiometry) bone scan was performed. Results: The mean age was 26.9±5.5 years. The mean pregnancy was 2.0±1.1 while the mean number of children was 0.9±0.7. The previous months of breast feeding as mean were 6.8±7.9. The calcium intake from food as well as serum calcium levels was below recommended levels in women during their pregnancy and post-delivery. Through the quantitative ultasound and bone density DEXA scan images presented obvious osteoporotic changes in bone density. There were 24% had 2.5 or less meant osteoporosis formation. Conclusion: Women often lead to calcium deficiency during gestation and lactation and thus chances of musculoskeletal disorders escalate manifolds. Radiological imaging can facilitate in detecting these calcium deficiencies. Keywords: Hemostasis, Regulation, Pregnancy, Mineral absorption