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