Recent Advances in Uric Acid Nephrolithiasis—Role of the Metabolic Syndrome
Figure 1: Urine pH in (A) Uric Acid Stone formers, (B) Diabetic Non-stone Formers, and (C) Normal Subjects with Increasing Features of the Metabolic Syndrome
AB 7.0
p<0.001 C 7.0 p<0.01 6.4 6.2 6.5 6.5 6.0 5.83 6.0 6.0 5.8 5.6 5.5 5.5 5.4 5.0 5.0 5.2 4.5
Controls N=68
UA
Stone Formers N=77
4.5
Controls N=16
T2DM
Non–Stone Formers N=77
Reproduced with permission from: (A) Pak et al., 2001;59 (B) Maalouf et al., 2010;25 and (C) Maalouf et al., 2007.10
novo synthesis, tissue catabolism, and dietary purine load. In de novo synthesis, inosinic acid is produced by the incorporation of ribose and phosphate into the backbone of glycine, which gives rise to UA. With the provision of ribonucleic acid and purine bases such as adenine and guanine, dietary purine increases production of UA.35
Fifty per cent of the
typical daily urate load is provided by de novo synthesis and tissue catabolism, with the remainder coming from dietary sources.35
Twenty-five
per cent of sensitized UA is excreted through the intestinal tract and the remainder by the kidney.36
Renal Uric Acid Handling
UA is freely filtered in the renal glomerulus and urate excretion approximates 5–10 % of the filtered load in humans.37
Urate handling has
been proposed to include filtration, reabsorption, and secretion.38 Although post-secretory reabsorption has been suggested, its role has not been fully established.39
The complexities in understanding renal UA
However, recent progress has been made in the identification of major proteins involved in the renal transport of UA.
Previous studies have primarily measured net UA transport with no differentiation between the contribution of reabsorption or secretion.40,41
handling are based upon its heterogeneous nature in various species and its bi-directional transport mechanisms across the renal tubular cell.34
It has recently been shown that an apical membrane electroneutral urate-anion exchanger protein, URAT1, is responsible for UA reabsorption.42
secretion.43,44
Organic anion transporter 1 (OAT1) is an electroneutral urate/organic anion exchanger that has been localized to the basolateral membrane of the proximal convoluted tubule.45,46
5.0 01 2 3
Number of features of the MS in normal Subjects N=148
4+ 5.72 6.14 6.09 6.00 p for trend<0.001
This transporter is
responsible for the peritubular uptake and ultimate secretion of UA. OAT3 has also been localized to the basolateral membrane of the proximal convoluted tubule, the thick ascending limb of Henle, the distal tubule, the connecting tubule, and collecting duct cells.47 UA transport function of OAT3 has not been fully elucidated.
However, the
Etiologic Causes and Pathophysiologic Mechanisms of Uric Acid Nephrolithiasis Etiologic mechanism(s) for UA nephrolithiasis can be classified as either genetic23,48,49
or acquired,50–52 cause of UA stone formation.5–7,10,21–25
mechanisms accounting for UA nephrolithiasis are low urine volume, hyperuricosuria, and an unduly acidic urinary environment.
Low Urinary Volume
Since the concentrated urinary environment is known to be supersaturated with respect to UA salt, low urine volume is one of the primary contributing factors of UA stone formation. Chronic diarrhea and/or excessive sweating are the main causes of low urine volume.50,51 Under these circumstances low urine volume is associated with unduly acidic urine as a result of gastrointestinal (GI) alkali loss or increased acid production with strenuous physical exercise.50,51
The inactivated mutation of this transporter protein has been demonstrated to be responsible for hypouricemia and hyperuricosuria in humans.42
(UAT) is an electrogenic uniporter expressed in the apical membrane of the renal proximal tubular cell that plays a principal role in UA
US NEPHROLOGY Hyperuricosuria In addition, urate transporter/channel
Both genetic and acquired conditions are operative in the development of hyperuricosuria. In certain circumstances such as primary gout, both dietary and genetic influences contribute to
11
with the MS emerging as the most prevalent The primary pathophysiologic
24-hour Urinary pH
24-hour Urinary pH
24-hour Urinary pH
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