Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats

Bushinsky, David A.; Asplin, John R.; Grynpas, Marc D.; Evan, Andrew P.; Parker, William R.; Alexander, Kristen M.; Coe, Fredric L.

doi:10.1046/j.1523-1755.2002.00190.x

Cited by 100 publications

(130 citation statements)

References 46 publications

Supporting

Mentioning

127

Contrasting

Order By: Relevance

“…These rats have now been bred for 70 generations, and consistently excrete 8-10 times as much calcium as control rats from the same background strain; they form kidney stones composed of calcium oxalate or calcium phosphate, depending on dietary components [20].…”

Section: The Genetic Hypercalciuric Ratmentioning

confidence: 99%

New Insights Into the Pathogenesis of Idiopathic Hypercalciuria

Worcester

Coe

2008

Seminars in Nephrology

Self Cite

146

125

View full text Add to dashboard Cite

Idiopathic hypercalciuria (IH) is the commonest metabolic abnormality in patients with calcium kidney stones. It is characterized by normocalcemia, absence of diseases that cause increased urine calcium, and calcium excretion that is above 250 mg/day in women and 300 mg/day in men. Subjects with IH have a generalized increase in calcium turnover, which includes increased gut calcium absorption, decreased renal calcium reabsorption, and a tendency to lose calcium from bone. Despite the increase in intestinal calcium absorption, negative calcium balance is commonly seen in balance studies, especially on a low calcium diet. The mediator of decreased renal calcium reabsorption is not clear; it is not associated with either an increase in filtered load of calcium or altered PTH levels. There is an increased incidence of hypercalciuria in first-degree relatives of those with IH, but IH appears to be a complex polygenic trait with a large contribution from diet to expression of increased calcium excretion. Increased tissue vitamin D response may be responsible for the manifestations of IH in at least some patients. Definition of HypercalciuriaCalcium, the most abundant cation in human beings, is an important participant in many physiologic processes, including hormonal secretion, cardiac contraction, blood clotting, and neurotransmission. In addition, growth and repair of our skeleton demands an adequate supply of calcium, and careful maintenance of extracellular calcium concentrations. For this reason, prevailing levels of intracellular and extracellular calcium are tightly regulated, by a complex system of control mechanisms. These mechanisms control calcium absorption by gut and renal tubular epithelia, as well as fluxes of calcium on and off bone, during varying dietary calcium intakes. In healthy, non-pregnant adults, whose skeleton is no longer growing, net intestinal calcium absorption is matched by renal excretion, and provides sufficient calcium for skeletal maintenance; however, under pathologic conditions, some urine calcium may derive from bone loss.Abnormalities of calcium homeostasis could result in a number of undesired consequences, including abnormally high or low serum calcium levels, or inadequate maintenance of bone mineral. Hypercalciuria might be defined as any level of urine calcium that exceeds net intestinal absorption, leading to net loss of calcium. However, in practice net intestinal absorption is seldom measured, and under the assumption that urine calcium is primarily derived from intestinal absorption, the working definition of hypercalciuria is urine calcium excretion that exceeds that found in the majority of healthy adults eating their usual diets. In practice, this is usually defined as a daily calcium excretion over 250 mg/day in women or 300Mailing address: Elaine Worcester, M.D., Nephrology Section, Suite 511 / MC 5100, University of Chicago, 5841 S. Maryland Avenue, Chicago, Illinois 60637, Phone: 773-702-7459, Fax: 773-702-5818. Publisher's Disclaimer: This is a PDF file ...

show abstract

Section: The Genetic Hypercalciuric Ratmentioning

confidence: 99%

New Insights Into the Pathogenesis of Idiopathic Hypercalciuria

Worcester

Coe

2008

Seminars in Nephrology

Self Cite

146

125

View full text Add to dashboard Cite

show abstract

“…Each rat was initially provided with 13 g/d food, an amount that we have previously shown is completely consumed by a rat of this size (35), and deionized distilled water ad libitum. At 12 wk, the amount of food was increased to 15 g/d to account for the increased dietary needs of the now larger rats (6,20). Any rat that ate Ͻ12 g/d food until week 12 or ate Ͻ14 g/d food from week 12 until the conclusion of the study or drank Ͻ15 ml of water on any day would have been excluded from the remainder of the study; however, all rats met these prospective criteria throughout the study.…”

Section: Study Protocolmentioning

confidence: 99%

“…The stones formed by the GHS rats contain only calcium and phosphate, without oxalate, and by x-ray diffraction, the stones are exclusively poorly crystalline apatite (8,10,12,15). When fed additional hydroxyproline, a common amino acid that is metabolized to oxalate (21), the GHS rats formed CaOx kidney stones (6,20), the most common solid phase found in humans (6,20).…”

mentioning

confidence: 99%

Thiazides Reduce Brushite, but not Calcium Oxalate, Supersaturation, and Stone Formation in Genetic Hypercalciuric Stone–Forming Rats

Bushinsky¹,

Asplin²

2005

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Over 59 generations, a strain of rats has been inbred to maximize urine calcium excretion. The rats now excrete eight to 10 times as much calcium as controls. These rats uniformly form calcium phosphate (apatite) kidney stones and have been termed genetic hypercalciuric stone-forming (GHS) rats. The addition of a common amino acid and oxalate precursor, hydroxyproline, to the diet of the GHS rats leads to formation of calcium oxalate (CaOx) kidney stones. Hydroxyproline-supplemented GHS rats were used to test the hypothesis that the thiazide diuretic chlorthalidone would decrease urine calcium excretion, supersaturation, and perhaps stone formation. All GHS rats received a fixed amount of a standard 1.2% calcium diet with 5% trans-4-hydroxy-L-proline (hydroxyproline) so that the rats would exclusively form CaOx stones. Half of the rats had chlorthalidone (Thz; 4 to 5 mg/kg per d) added to their diets. Urine was collected weekly, and at the conclusion of the study, the kidneys, ureters, and bladders were radiographed for the presence of stones. Compared with control, the addition of Thz led to a significant reduction of urine calcium and phosphorus excretion, whereas urine oxalate excretion increased. Supersaturation with respect to the calcium hydrogen phosphate fell, whereas supersaturation with respect to CaOx was unchanged. Rats that were fed Thz had fewer stones. As calcium phosphate seems to be the preferred initial solid phase in patients with CaOx kidney stones, the reduction in supersaturation with respect to the calcium phosphate solid phase may be the mechanism by which thiazides reduce CaOx stone formation.

show abstract

“…Noteworthy, stone composition is mostly apatite (CaHPO4) when animals are fed with a standard 1.2% calcium diet, probably explained by urine CaHPO4 supersaturation which increases faster than CaOx supersaturation [26] . Conversely, an additional diet supplement of HyP 5% induces CaOx stones formation [27] with crystal deposits mainly in contact with urothelial cells lining the papilla and in the fornix areas. Interestingly, similarly to tubular cells surrounding crystals, some urothelial cells in contact with crystals are indeed proliferating and also expressing high levels of OPN [28] .…”

Section: Genetic Hypercalciuric Stone Forming Ratsmentioning

confidence: 98%

Experimental models of renal calcium stones in rodents

Bilbault¹,

Haymann²

2016

WJN

View full text Add to dashboard Cite

In human nephrolithiasis, most stones are containing calcium and are located within urinary cavities; they may contain monohydrate calcium oxalate, dihydrate calcium oxalate and/or calcium phosphates in various proportion. Nephrolithiasis may also be associated with nephrocalcinosis, i.e., crystal depositions in tubular lumen and/or interstitium, an entity which suggests specific pathological processes. Several rodents models have been developed in order to study the pathophysiology of intrarenal crystal formation. We review here calcium rodent models classified upon the presence of nephrolithiasis and/or nephrocalcinosis. As rodents are not prone to nephrolithiasis, models require the induction of a long standing hypercalciuria or hyperoxaluria (thus explaining the very few studies reported), conversely to nephrocalcinosis which may occur within hours or days. Whereas a nephrotoxicity leading to tubular injury and regeneration appears as a critical event for crystal retention in nephrocalcinosis models, surprisingly very little is known about the physiopathology of crystal attachment to urothelium in nephrolithiasis. Creating new models of nephrolithiasis especially in different genetic mice strains appears an important challenge in order to unravel the early mechanisms of urinary stone formation in papilla and fornices. Core tip: We review here calcium rodent models classified upon the presence of nephrolithiasis or nephrocalcinosis which appear as two different entities. Nephrocalcinosis appears related to tubular cell injuries in the setting of urinary supersaturation whereas the pathophysiology of nephrolithiasis is mostly unraveled. Though few models are available, attachment of crystals in the fornix or in the MINIREVIEWS

show abstract

Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats

Cited by 100 publications

References 46 publications

New Insights Into the Pathogenesis of Idiopathic Hypercalciuria

New Insights Into the Pathogenesis of Idiopathic Hypercalciuria

Thiazides Reduce Brushite, but not Calcium Oxalate, Supersaturation, and Stone Formation in Genetic Hypercalciuric Stone–Forming Rats

Experimental models of renal calcium stones in rodents

Contact Info

Product

Resources

About