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Re: Hydroxyproline Metabolism in Mouse Models of Primary Hyperoxaluria
1928
UROLITHIASIS/ENDOUROLOGY
shown to be transported via this pathway. These findings should stimulate several important translational studies. Dean Assimos, M.D.
Re: Hydroxyproline Metabolism in Mouse Models of Primary Hyperoxaluria J. Knight, R. P. Holmes, S. D. Cramer, T. Takayama and E. C. Salido Wake Forest University School of Medicine, Winston-Salem, North Carolina Am J Physiol Renal Physiol 2011; Epub ahead of print.
Primary hyperoxaluria Type 1 (PH1) and Type 2 (PH2) are rare genetic diseases that result from deficiencies in glyoxylate metabolism. The increased oxalate synthesis that occurs can lead to kidney stone formation, deposition of calcium oxalate in the kidney and other tissues, and renal failure. Hydroxyproline (Hyp) catabolism, which occurs mainly in the liver and kidney, is a prominent source of glyoxylate and could account for a significant portion of the oxalate produced in PH. To determine the sensitivity of mouse models of PH1 (AGXT KO) and PH2 (GRHPR KO) to Hyp-derived oxalate, animals were fed diets containing 1% Hyp. Urinary excretions of glycolate and oxalate were used to monitor Hyp catabolism and the kidneys were examined to assess pathological changes. Both strains of KO mice excreted more oxalate than wild type animals with Hyp feeding. After 4 weeks of Hyp feeding all GRHPR KO mice developed severe nephrocalcinosis in contrast to AGXT KO animals where nephrocalcinosis was milder and with a lower frequency. Plasma cystatin C measurements over 4 weeks Hyp feeding indicated no significant loss of renal function in WT and AGXT KO animals, and significant and severe loss of renal function in GRHPR KO animals after 2 weeks and 4 weeks, respectively. These data suggest that GRHPR activity may be vital in the kidney for limiting the conversion of Hyp-derived glyoxylate to oxalate. As Hyp catabolism may make a major contribution to the oxalate produced in PH patients, Hyp feeding in these mouse models should be useful in understanding the mechanisms associated with calcium oxalate deposition in the kidney. Editorial Comment: The metabolism of hydroxyproline is a source of glyoxylate, the immediate precursor of oxalate. The results of these experiments demonstrate that mouse models for type I and type II primary hyperoxaluria produce substantially more oxalate when administered hydroxyproline. Those with the type II defect are more sensitive and are more apt to develop renal damage with this dietary challenge. In contrast, humans with PH1 are more apt to exhibit end-stage renal disease. These results suggest that the intake of collagen and hydroxyproline rich foods should be avoided in individuals afflicted with either of these disorders. Dean Assimos, M.D.
Re: Hypercalciuria Associated With High Dietary Protein Intake is Not Due to Acid Load N. M. Maalouf, O. W. Moe, B. Adams-Huet and K. Sakhaee Department of Internal Medicine, and Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas J Clin Endocrinol Metab 2011; 96: 3733–3740.
Context and Objective: Dietary intake of animal proteins is associated with an increase in urinary calcium and nephrolithiasis risk. We tested the hypothesis that the acid load imposed by dietary proteins causes this hypercalciuria. Design and Setting: In a short-term crossover metabolic study, an alkali salt was provided with a high-protein diet (HPD) to neutralize the acid load imparted by dietary proteins. Participants and Interventions: Eleven healthy volunteers were evaluated at the end of each of four phases while consuming metabolic diets with fixed calcium and sodium content. Phases 1 and
UROLITHIASIS/ENDOUROLOGY
shown to be transported via this pathway. These findings should stimulate several important translational studies. Dean Assimos, M.D.
Re: Hydroxyproline Metabolism in Mouse Models of Primary Hyperoxaluria J. Knight, R. P. Holmes, S. D. Cramer, T. Takayama and E. C. Salido Wake Forest University School of Medicine, Winston-Salem, North Carolina Am J Physiol Renal Physiol 2011; Epub ahead of print.
Primary hyperoxaluria Type 1 (PH1) and Type 2 (PH2) are rare genetic diseases that result from deficiencies in glyoxylate metabolism. The increased oxalate synthesis that occurs can lead to kidney stone formation, deposition of calcium oxalate in the kidney and other tissues, and renal failure. Hydroxyproline (Hyp) catabolism, which occurs mainly in the liver and kidney, is a prominent source of glyoxylate and could account for a significant portion of the oxalate produced in PH. To determine the sensitivity of mouse models of PH1 (AGXT KO) and PH2 (GRHPR KO) to Hyp-derived oxalate, animals were fed diets containing 1% Hyp. Urinary excretions of glycolate and oxalate were used to monitor Hyp catabolism and the kidneys were examined to assess pathological changes. Both strains of KO mice excreted more oxalate than wild type animals with Hyp feeding. After 4 weeks of Hyp feeding all GRHPR KO mice developed severe nephrocalcinosis in contrast to AGXT KO animals where nephrocalcinosis was milder and with a lower frequency. Plasma cystatin C measurements over 4 weeks Hyp feeding indicated no significant loss of renal function in WT and AGXT KO animals, and significant and severe loss of renal function in GRHPR KO animals after 2 weeks and 4 weeks, respectively. These data suggest that GRHPR activity may be vital in the kidney for limiting the conversion of Hyp-derived glyoxylate to oxalate. As Hyp catabolism may make a major contribution to the oxalate produced in PH patients, Hyp feeding in these mouse models should be useful in understanding the mechanisms associated with calcium oxalate deposition in the kidney. Editorial Comment: The metabolism of hydroxyproline is a source of glyoxylate, the immediate precursor of oxalate. The results of these experiments demonstrate that mouse models for type I and type II primary hyperoxaluria produce substantially more oxalate when administered hydroxyproline. Those with the type II defect are more sensitive and are more apt to develop renal damage with this dietary challenge. In contrast, humans with PH1 are more apt to exhibit end-stage renal disease. These results suggest that the intake of collagen and hydroxyproline rich foods should be avoided in individuals afflicted with either of these disorders. Dean Assimos, M.D.
Re: Hypercalciuria Associated With High Dietary Protein Intake is Not Due to Acid Load N. M. Maalouf, O. W. Moe, B. Adams-Huet and K. Sakhaee Department of Internal Medicine, and Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas J Clin Endocrinol Metab 2011; 96: 3733–3740.
Context and Objective: Dietary intake of animal proteins is associated with an increase in urinary calcium and nephrolithiasis risk. We tested the hypothesis that the acid load imposed by dietary proteins causes this hypercalciuria. Design and Setting: In a short-term crossover metabolic study, an alkali salt was provided with a high-protein diet (HPD) to neutralize the acid load imparted by dietary proteins. Participants and Interventions: Eleven healthy volunteers were evaluated at the end of each of four phases while consuming metabolic diets with fixed calcium and sodium content. Phases 1 and