lama nazzal - nyu langone health · pdf fileuric acid or sodium urate precipitation provides a...
TRANSCRIPT
LAMA NAZZAL
Moe OW. Curr Opin Nephrol Hypertens. 2006 Jul;15(4):366-73.
Moe OW. Curr Opin Nephrol Hypertens. 2006 Jul;15(4):366-73.
UA handling
More than 70% of urate is excreted by the kidneys
Almost all urate transport occurs in the proximal tubule
The predominant mode of urate transport is reabsorption. Under normal conditions, only 5% to 10% of filtered urate is excreted in the urine
Probenecid benzbromarone, losartan
Lipkowitz M. Curr Rheumatol Rep (2012) 14:179–188
Uric acid stones account
for ~10% of urinary tract stones in US.
Uric acid or sodium urate
precipitation provides a nidus for formation of calcium oxalate stones
Risk factors:
Genetic predisposition Geographical location Dietary indiscretion Metabolic characteristics
Maalouf NM et al. Curr Opin Nephrol Hypertens 2004, 13:181–189.
Ekuruo WO et al. J Urol. 2004 Jul;172(1):159-63.
Pathophysiology
Uric acid <—> Urate- + H+ pH= 5.35 + log ([urate] /[uric acid]) UA precipitation promoted by high UA
concentration and acidic urine.
Acidic urine is the cardinal risk factor for developing uric acid stones.
Maalouf NM et al. Curr Opin Nephrol Hypertens 2004, 13:181–189.
Postprandial alkaline tide
Maalouf NM et al. Curr Opin Nephrol Hypertens 2004, 13:181–189.
Loss of diurnal variation in stone formers
• In uric acid stone formers, urinary pH was constantly low throughout the entire day.
• In CaOX/CaOX–CaP stone formers, they had diurnal variation of urinary pH (low in the early morning, high in the daytime and low again in the night.
Murayama T et al. Int J Urol 2001; 8:525–532.
Insulin resistance and UA stones
Maalouf NM et al. Curr Opin Nephrol Hypertens 2004, 13:181–189.
Maalouf NM et al. Curr Opin Nephrol Hypertens 2004, 13:181–189.
Low urine pH and Metabolic syndrome
148 adults non stone formers
Cross-sectional study.
Height, weight, BP, fasting blood, and 24-h urine chemistries were obtained.
The following features of the metabolic syndrome were evaluated: BP; BMI ; and serum triglyceride, glucose, and HDL cholesterol.
The degree of insulin resistance was assessed by the homeostasis model assessment of insulin resistance.
Maalouf NM et al. Clin J Am Soc Nephrol 2: 883-888, 2007
Maalouf NM et al. Clin J Am Soc Nephrol 2: 883-888, 2007
9 non–stone-forming pts with DM2 and low urine pH vs 16 age- and BMI–matched non–stone-forming without DM2.
Both groups were maintained on a constant metabolic diet for 7 days
24-hour urine was collected on the last 2 days of the diet.
Maalouf NM et al. Clin J Am Soc Nephrol 5: 1277–1281, 2010
Maalouf NM et al. Clin J Am Soc Nephrol 5: 1277–1281, 2010
Maalouf NM et al. Clin J Am Soc Nephrol 5: 1277–1281, 2010
Examined renal fat accumulation, urinary biochemical abnormalities and the proximal tubular NHE3 in Zucker diabetic fatty (ZDF) rats
Examined urinary acidification and renal fat in an animal model of diet-induced weight gain, Sprague-Dawley rats fed a high fat diet.
Examined the direct effect of fat accumulation on NHE3 activity, NHE3 regulation by agonists, and NH4 secretion in opossum kidney (OKP) cells, a cell culture model of the proximal tubule
Bobulescu IA et al. Am J Physiol Renal Physiol 294: F1315–F1322, 2008.
ZDF rats were fed standard chow diet Sixteen 4-wk-old SD male rats were
randomly assigned to a high-fat hypercaloric diet or the corresponding low-fat control diet.
After 12 wk on the experimental diets, the rats were switched to standard chow diet for 1 wk before death
Eight SD rats were studied after 1 wk of feeding with the experimental diets, without a switch to normal rodent chow before death.
Bobulescu IA et al. Am J Physiol Renal Physiol 294: F1315–F1322, 2008.
Role of Na/H exchanger Proximal tubule
Plasma and renal lipid abnormalities in the Zucker diabetic fatty (ZDF) rat model
Urinary acidification defects in ZDF rats
Bobulescu IA et al. Am J Physiol Renal Physiol 294: F1315–F1322, 2008.
Reduced proximal tubule brush border Na/H exchanger (NHE3) antigen and function in ZDF rats.
Dietary effects in Sprague-Dawley rats fed a high-fat diet
Bobulescu IA et al. Am J Physiol Renal Physiol 294: F1315–F1322, 2008.
Fat accumulation results in reduced NHE3 activity, NHE3 function, and NH4 production in opossum kidney (OKP) cells
Bobulescu IA et al. Am J Physiol Renal Physiol 294: F1315–F1322, 2008.
Defective NHE3 regulation in OKP cells incubated with FFA
Insulin signaling in OKP cells incubated with FFA
Bobulescu IA et al. Am J Physiol Renal Physiol 294: F1315–F1322, 2008.
Treatment
lifestyle modification Pharmacologic reduction in uric acid
excretion urinary alkalinization
Dietary modifications Pharmacological treatment
Fluid intake to maintain a urinary volume of approximately 2 L/d.
Decrease consumption of animal proteins
Recommended Dietary Allowances of 0.8 g/kg/d
Allopurinol Febuxostat Rasburicase Pegloticase
Cameron MA et al. Urol Clin N Am 34 (2007) 335–346
Alkali treatment Potassium citrate and Sodium citrate to prevent and dissolve existing UA stones
Potassium citrate is preferred because: It reduces urinary calcium It is more soluble than sodium urate in the urinary
environment
The initial recommended alkali dose is 30 to 40 mEq/d to maintain urinary pH above 6.1, but less than 7.0. Carbonic anhydrase inhibitors (acetazolamide, topiramate) may be used as alternative alkalinizing agents Orange and grapefruit juice
Cameron MA et al. Urol Clin N Am 34 (2007) 335–346
Cameron MA et al. Urol Clin N Am 34 (2007) 335–346