scholarly journals Evidence for increased postprandial distal nephron calcium delivery in hypercalciuric stone-forming patients

2008 ◽  
Vol 295 (5) ◽  
pp. F1286-F1294 ◽  
Author(s):  
Elaine M. Worcester ◽  
Fredric L. Coe ◽  
Andrew P. Evan ◽  
Kristin J. Bergsland ◽  
Joan H. Parks ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Stone Formation ◽  
Selective Reduction ◽  
Normal Subjects ◽  
Idiopathic Hypercalciuria ◽  
Calcium Excretion ◽  
Distal Nephron ◽  
Clinical Research Center ◽  
Calcium Reabsorption ◽  
New Finding

A main mechanism of idiopathic hypercalciuria (IH) in calcium stone-forming patients (IHSF) is postprandial reduction of renal tubule calcium reabsorption that cannot be explained by selective reduction of serum parathyroid hormone levels; the nephron site(s) responsible are not as yet defined. Using fourteen 1-h measurements of the clearances of sodium, calcium, and endogenous lithium during a three-meal day in the University of Chicago General Clinical Research Center, we found reduced postprandial proximal tubule reabsorption of sodium and calcium in IHSF vs. normal subjects. The increased distal sodium delivery is matched by increased distal reabsorption so that urine sodium excretions do not differ, but distal calcium reabsorption does not increase enough to match increased calcium delivery, so hypercalciuria results. In fact, urine calcium excretion and overall renal fractional calcium reabsorption both are high in IHSF vs. normal when adjusted for distal calcium delivery, strongly suggesting a distal as well as proximal reduction of calcium reabsorption. The combination of reduced proximal tubule and distal nephron calcium reabsorption in IHSF is a new finding and indicates that IH involves a complex, presumably genetic, variation of nephron function. The increased calcium delivery into the later nephron may play a role in stone formation via deposition of papillary interstitial apatite plaque.

scholarly journals Sex differences in proximal and distal nephron function contribute to the mechanism of idiopathic hypercalcuria in calcium stone formers

2015 ◽  
Vol 309 (1) ◽  
pp. R85-R92 ◽  
Author(s):  
Benjamin Ko ◽  
Kristin Bergsland ◽  
Daniel L. Gillen ◽  
Andrew P. Evan ◽  
Daniel L. Clark ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Distal Tubule ◽  
Normal Subjects ◽  
Idiopathic Hypercalciuria ◽  
Distal Nephron ◽  
Stone Formers ◽  
Calcium Reabsorption ◽  
Normal Women ◽  
Normal Males ◽  
Normal Men

Idiopathic hypercalciuria (IH) is a common familial trait among patients with calcium nephrolithiasis. Previously, we have demonstrated that hypercalciuria is primarily due to reduced renal proximal and distal tubule calcium reabsorption. Here, using measurements of the clearances of sodium, calcium, and endogenous lithium taken from the General Clinical Research Center, we test the hypothesis that patterns of segmental nephron tubule calcium reabsorption differ between the sexes in IH and normal subjects. When the sexes are compared, we reconfirm the reduced proximal and distal calcium reabsorption. In IH women, distal nephron calcium reabsorption is decreased compared to normal women. In IH men, proximal tubule calcium reabsorption falls significantly, with a more modest reduction in distal calcium reabsorption compared to normal men. Additionally, we demonstrate that male IH patients have lower systolic blood pressures than normal males. We conclude that women and men differ in the way they produce the hypercalciuria of IH, with females reducing distal reabsorption and males primarily reducing proximal tubule function.

scholarly journals Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria

2013 ◽  
Vol 305 (4) ◽  
pp. F592-F599 ◽  
Author(s):  
Kristin J. Bergsland ◽  
Elaine M. Worcester ◽  
Fredric L. Coe
Keyword(s):  
Proximal Tubule ◽  
Stone Formation ◽  
Idiopathic Hypercalciuria ◽  
Sodium Absorption ◽  
Distal Nephron ◽  
Urine Ph ◽  
Stone Formers ◽  
Vasa Recta ◽  
Clinical Research Center ◽  
Stone Growth

The most common metabolic abnormality found in calcium (Ca) kidney stone formers is idiopathic hypercalciuria (IH). Using endogenous lithium (Li) clearance, we previously showed that in IH, there is decreased proximal tubule sodium absorption, and increased delivery of Ca into the distal nephron. Distal Ca reabsorption may facilitate the formation of Randall's plaque (RP) by washdown of excess Ca through the vasa recta toward the papillary tip. Elevated Ca excretion leads to increased urinary supersaturation (SS) with respect to calcium oxalate (CaOx) and calcium phosphate (CaP), providing the driving force for stone growth on RP. Thiazide (TZ) diuretics reduce Ca excretion and prevent stone recurrence, but the mechanism in humans is unknown. We studied the effect of chronic TZ administration on renal mineral handling in four male IH patients using a fixed three meal day in the General Clinical Research Center. Each subject was studied twice: once before treatment and once after 4–7 mo of daily chlorthalidone treatment. As expected, urine Ca fell with TZ, along with fraction of filtered Ca excreted. Fraction of filtered Li excreted also fell sharply with TZ, as did distal delivery of Ca. Unexpectedly, TZ lowered urine pH. Together with reduced urine Ca, this led to a marked fall in CaP SS, but not CaOx SS. Since CaOx stone formation begins with an initial CaP overlay on RP, by lowering urine pH and decreasing distal nephron Ca delivery, TZ might diminish stone risk both by reducing CaP SS, as well as slowing progression of RP.

Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis

2007 ◽  
Vol 292 (1) ◽  
pp. F66-F75 ◽  
Author(s):  
Elaine M. Worcester ◽  
Daniel L. Gillen ◽  
Andrew P. Evan ◽  
Joan H. Parks ◽  
Katrina Wright ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Serum Magnesium ◽  
Normal Subjects ◽  
Urinary Calcium ◽  
Idiopathic Hypercalciuria ◽  
Calcium Excretion ◽  
Stone Formers ◽  
Calcium Reabsorption ◽  
Renal Tubular ◽  
Filtered Load

Idiopathic hypercalciuria (IH) is common among calcium stone formers (IHSF). The increased urinary calcium arises from increased intestinal absorption of calcium, but it is unclear whether increased filtered load or decreased renal tubular reabsorption of calcium is the main mechanism for the increased renal excretion. To explore this question, 10 IHSF and 7 normal subjects (N) were studied for 1 day. Urine and blood samples were collected at 30- to 60-min intervals while subjects were fasting and after they ate three meals providing known amounts of calcium, phosphorus, sodium, protein, and calories. Fasting and fed, ultrafiltrable calcium levels, and filtered load of calcium did not differ between N and IHSF. Urine calcium rose with meals, and fractional reabsorption fell in all subjects, but the change was significantly higher in IHSF. The changes in calcium excretion were independent of sodium excretion. Serum parathyroid hormone levels did not differ between N and IHSF, and they could not account for the greater fall in calcium reabsorption in IHSF. Serum magnesium and phosphorus levels in IHSF were below N throughout the day, and tubule phosphate reabsorption was lower in IHSF than N after meals. The primary mechanism by which kidneys ferry absorbed calcium into the urine after meals is via reduced tubule calcium reabsorption, and IHSF differ from N in the magnitude of the response. Parathyroid hormone is not likely to be a sufficient explanation for this difference.

scholarly journals Paracellular calcium transport in the proximal tubule and the formation of kidney stones

2019 ◽  
Vol 316 (5) ◽  
pp. F966-F969
Author(s):  
Joshua N. Curry ◽  
Alan S. L. Yu
Keyword(s):  
Proximal Tubule ◽  
Kidney Stones ◽  
Calcium Transport ◽  
Kidney Stone ◽  
Stone Formation ◽  
Idiopathic Hypercalciuria ◽  
Recent Developments ◽  
Calcium Reabsorption ◽  
Kidney Stone Formation

The proximal tubule (PT) is responsible for the majority of calcium reabsorption by the kidney. Most PT calcium transport appears to be passive, although the molecular facilitators have not been well established. Emerging evidence supports a major role for PT calcium transport in idiopathic hypercalciuria and the development of kidney stones. This review will cover recent developments in our understanding of PT calcium transport and the role of the PT in kidney stone formation.

scholarly journals Claudin-12 Knockout Mice Demonstrate Reduced Proximal Tubule Calcium Permeability

2020 ◽  
Vol 21 (6) ◽  
pp. 2074
Author(s):  
Allein Plain ◽  
Wanling Pan ◽  
Deborah O’Neill ◽  
Megan Ure ◽  
Megan R. Beggs ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Ex Vivo ◽  
Protein S ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Thick Ascending Limb ◽  
Calcium Reabsorption ◽  
Calcium Permeability ◽  
Claudin 14 ◽  
Junction Proteins

The renal proximal tubule (PT) is responsible for the reabsorption of approximately 65% of filtered calcium, primarily via a paracellular pathway. However, which protein(s) contribute this paracellular calcium pore is not known. The claudin family of tight junction proteins confers permeability properties to an epithelium. Claudin-12 is expressed in the kidney and when overexpressed in cell culture contributes paracellular calcium permeability (PCa). We therefore examined claudin-12 renal localization and its contribution to tubular paracellular calcium permeability. Claudin-12 null mice (KO) were generated by replacing the single coding exon with β-galactosidase from Escherichia coli. X-gal staining revealed that claudin-12 promoter activity colocalized with aquaporin-1, consistent with the expression in the PT. PTs were microperfused ex vivo and PCa was measured. PCa in PTs from KO mice was significantly reduced compared with WT mice. However, urinary calcium excretion was not different between genotypes, including those on different calcium containing diets. To assess downstream compensation, we examined renal mRNA expression. Claudin-14 expression, a blocker of PCa in the thick ascending limb (TAL), was reduced in the kidney of KO animals. Thus, claudin-12 is expressed in the PT, where it confers paracellular calcium permeability. In the absence of claudin-12, reduced claudin-14 expression in the TAL may compensate for reduced PT calcium reabsorption.

scholarly journals Evidence for increased renal tubule and parathyroid gland sensitivity to serum calcium in human idiopathic hypercalciuria

2013 ◽  
Vol 305 (6) ◽  
pp. F853-F860 ◽  
Author(s):  
Elaine M. Worcester ◽  
Kristin J. Bergsland ◽  
Daniel L. Gillen ◽  
Fredric L. Coe
Keyword(s):  
Serum Calcium ◽  
Renal Tubule ◽  
Multivariable Analysis ◽  
Fractional Excretion ◽  
Normal Subjects ◽  
Idiopathic Hypercalciuria ◽  
Dominant Effect ◽  
Urine Calcium ◽  
Calcium Reabsorption ◽  
Meal Effect

Patients with idiopathic hypercalciuria (IH) have decreased renal calcium reabsorption, most marked in the postprandial state, but the mechanisms are unknown. We compared 29 subjects with IH and 17 normal subjects (N) each fed meals providing identical amounts of calcium. Urine and blood samples were collected fasting and after meals. Levels of three candidate signalers, serum calcium (SCa), insulin (I), and plasma parathyroid hormone (PTH), did not differ between IH and N either fasting or fed, but all changed with feeding, and the change in SCa was greater in IH than in N. Regression analysis of fractional excretion of calcium (FECa) was significant for PTH and SCa in IH but not N. With the use of multivariable analysis, Sca entered the model while PTH and I did not. To avoid internal correlation we decomposed FECa into its independent terms: adjusted urine calcium (UCa) and UFCa molarity. Analyses using adjusted Uca and unadjusted Uca parallel those using FECa, showing a dominant effect of SCa with no effect of PTH or I. The effect of SCa may be mediated via vitamin D receptor-stimulated increased abundance of basolateral Ca receptor, which is supported by the fact PTH levels also seem more responsive to serum Ca in IH than in N. Although our data support an effect of SCa on FECa and UCa, which is more marked in IH than in N, it can account for only a modest fraction of the meal effect, perhaps 10–20%, suggesting additional mediators are also responsible for the exaggerated postprandial hypercalciuria seen in IH.

Calcium stones

2015 ◽  
Author(s):  
David A. Bushinsky ◽  
Orson Moe
Keyword(s):  
Risk Factors ◽  
Stone Formation ◽  
Epidemiological Studies ◽  
Idiopathic Hypercalciuria ◽  
Calcium Excretion ◽  
Urine Calcium ◽  
Calcium Stones ◽  
Renal Tubular ◽  
Urine Calcium Excretion ◽  
Predisposing Conditions

Key predisposing factors in calcium stone formation are idiopathic hypercalciuria, primary hyperparathyroidism, and hyperoxaluria (dietary, enteric, idiopathic, sometimes genetic). These are described in detail. Other predisposing conditions include renal tubular acidosis, and risk factors identified in epidemiological studies such as hypocitraturia, increased urinary urate. is defined as an excess of urine calcium excretion without a discernible metabolic cause.

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