Abstract
Autosomal dominant polycystic kidney disease (ADPKD), a genetic disease caused by mutations in PKD1 or PKD2 genes, is associated with a high prevalence of nephrolithiasis. The underlying mechanisms may encompass structural abnormalities resulting from cyst growth, urinary metabolic abnormalities or both. An increased frequency of hypocitraturia has been described in ADPKD even in the absence of nephrolithiasis, suggesting that metabolic alterations may be associated with ADPKD per se. We aimed to investigate whether non-cystic Pkd1-haploinsufficient (Pkd1 +/−) and/or nestin-Cre Pkd1-targeted cystic (Pkd1 cond/cond:Nestincre) mouse models develop urinary metabolic abnormalities potentially related to nephrolithiasis in ADPKD. 24-h urine samples were collected during three non-consecutive days from 10–12 and 18–20 week-old animals. At 10–12 weeks of age, urinary oxalate, calcium, magnesium, citrate and uric acid did not differ between test and their respective control groups. At 18–20 weeks, Pkd1 +/− showed slightly but significantly higher urinary uric acid vs. controls while cystic animals did not. The absence of hypocitraturia, hyperoxaluria and hyperuricosuria in the cystic model at both ages and the finding of hyperuricosuria in the 18–20 week-old animals suggest that anatomic cystic distortions per se do not generate the metabolic disturbances described in human ADPKD-related nephrolithiasis, while Pkd1 haploinsufficiency may contribute to this phenotype in this animal model.
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References
Wilson PD, Goilav B (2007) Cystic disease of the kidney. Annu Rev Pathol 2:341–368
Peters DJ, Breuning MH (2001) Autosomal dominant polycystic kidney disease: modification of disease progression. Lancet 358:1439–1444
Grantham JJ, Chapman AB, Torres VE (2006) Volume progression in autosomal dominant polycystic kidney disease: the major factor determining clinical outcomes. Clin J Am Soc Nephrol 1:148–157
Bajwa ZH, Sial KA, Malik AB, Steinman TI (2004) Pain patterns in patients with polycystic kidney disease. Kidney Int 66:1561–1569
Eloi SRM, Nishiura JL, Heilberg IP (2010) Translation, cultural adaptation and application of a pain questionnaire for patients with polycystic kidney disease. J Bras Nefrol 32:386–399
Nishiura JL, Neves RFCA, Eloi SRM et al (2009) Evaluation of nephrolithiasis in autosomal dominant polycystic kidney disease patients. Clin J Am Soc Nephrol 4:838–844
Torres VE, Erickson SB, Smith LH et al (1988) The association of nephrolithiasis and autosomal dominant polycystic kidney disease. Am J Kidney Dis 11:318–325
Levine E, Grantham JJ (1992) Calcified renal stones and cyst calcifications in autosomal dominant polycystic kidney disease: clinical and CT study in 84 patients. AJR Am J Roentgenol 159:77–81
Grampsas SA, Chandhoke PS, Fan J et al (2000) Anatomic and metabolic risk factors for nephrolithiasis in patients with autosomal dominant polycystic kidney disease. Am J Kidney Dis 36:53–57
Amar AD, Das S, Egan RM (1981) Management of urinary calculous disease in patients with renal cysts: review of 12 years of experience in 18 patients. J Urol 125:153–156
Gambaro G, Fabris A, Puliatta D, Lupo A (2006) Lithiasis in cystic kidney disease and malformations of the urinary tract. Urol Res 34:102–107
Piontek K, Menezes LF, Garcia-Gonzalez MA et al (2007) A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med 13:1490–1495
Takakura A, Contrino L, Beck AW, Zhou J (2008) Pkd1 inactivation induced in adulthood produces focal cystic disease. J Am Soc Nephrol 19:2351–2363
Takakura A, Contrino L, Zhou X et al (2009) Renal injury is a third hit promoting rapid development of adult polycystic kidney disease. Hum Mol Genet 18:2523–2531
Torres VE, Harris PC (2009) Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int 76:149–168
Grantham JJ, Mulamalla S, Swenson-Fields KI (2011) Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol 7:556–566
Piontek KB, Huso DL, Grinberg A et al (2004) A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo. J Am Soc Nephrol 15:3035–3043
Ferraz RR, Baxmann AC, Ferreira LG et al (2006) Preservation of urine samples for metabolic evaluation of stone-forming patients. Urol Res 34:329–337
Hallson PC, Rose GA (1974) A simplified and rapid enzymatic method for determination of urinary oxalate. Clin Chim Acta 55:29–39
Holt C, Cowley DM, Chalmers AH (1985) Rapid estimation of urinary citrate by use of a centrifugal analyzer. Clin Chem 31:779–780
Fossati P, Prencipe L, Berti G (1980) Use of 3,5-dichloro-2-hydroxybenzenesulfonic acid/4-aminophenazone chromogenic system in direct enzymic assay of uric acid in serum and urine. Clin Chem 26:227–231
Strufaldi B (1987) Prática de bioquímica clínica. Faculdade de Ciências Farmacêuticas da Universidade de Sao Paulo, Sao Paulo
Macfate RP, Cohn C, Eichelberger L, Cooper JA (1954) Symposium on azotemia. Am J Clin Pathol 24:511–571
Fonseca JM, Bastos AP, Amaral AG, et al. (2014) Renal cyst growth is the main determinant for hypertension and concentrating deficit in Pkd1-deficient mice. Kidney Int [Epub ahead of print]
Torres VE, Wilson DM, Hattery RR, Segura JW (1993) Renal stone disease in autosomal dominant polycystic kidney disease. Am J Kidney Dis 22:513–519
Ogbron MR, Sareen S, Prychitko J et al (1997) Altered organic anion and osmolyte content and excretion in rat polycystic kidney disease: an NMR study. Am J Physiol 272:F63–F69
Tanner GA, Tanner JA (2003) Dietary citrate treatment of polycystic kidney disease in rats. Nephron Physiol 93:P14–P20
Kelly S, Delnomdedieu M, Oliverio M et al (2001) Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase. J Am Soc Nephrol 12:1001–1009
Torres VE, Keith DS, Offord KP et al (1994) Renal ammonia in autosomal dominant polycystic kidney disease. Kidney Int 45:1745–1753
Bastos AP, Piontek K, Silva AM et al (2009) Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion. J Am Soc Nephrol 20:2389–2402
Khan SR (2010) Nephrocalcinosis in animal models with and without stones. Urol Res 38:429–438
Bushinsky DA, Asplin JR, Grynpas MD et al (2002) Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats. Kidney Int 61:975–987
Jiang Z, Asplin JR, Evan AP et al (2006) Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat Genet 38:474–478
Acknowledgments
This research was supported by Grants from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Grant 150638/2009-4, Fundação Oswaldo Ramos, and Fundação de Amparo à Pesquisa (FAPESP) Grant 2010/17424-0.
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Ferraz, R.R.N., Fonseca, J.M., Germino, G.G. et al. Determination of urinary lithogenic parameters in murine models orthologous to autosomal dominant polycystic kidney disease. Urolithiasis 42, 301–307 (2014). https://doi.org/10.1007/s00240-014-0664-1
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DOI: https://doi.org/10.1007/s00240-014-0664-1