CME Renal medicine Clinical Medicine 2012, Vol 12, No 5: 467–71 More recent theories focus on the role of primary hyperparathyroidism, deactivating Kidney stone disease: cell surface molecules which favour or vitamin D receptor (VDR) polymorphisms inhibit crystal adhesion.4,5 Urothelial injury and activating fibroblast growth factor pathophysiology, and repair after a stone episode may (FGF) 23 polymorphism.12,13 increase surface expression of these mole- investigation and 6 cules to favour further crystal adhesion. Deactivating VDR variants Thus ‘stones beget stones’7 because there medical treatment may be a residual nucleus on which further The development of stone disease is likely stones may form and/or upregulation of to occur only in the presence of additional Charlotte H Dawson, SpR clinical molecules favouring crystal adhesion. Stone risk factors. For example, patients with biochemistry, University Hospitals Bristol prevention focuses on identifying and deactivating VDR variants form stones if NHS Foundation Trust; Charles R V Tomson, ameliorating the risk factors for crystal there is associated hypocitraturia. VDR consultant nephrologist, North Bristol NHS formation. activity promotes citrate excretion14 which Trust increases the solubility of calcium salts. A Risk factors diet low in fruit and vegetables (which also Renal colic accounts for about 1% of hos- boosts citrate excretion) may predispose to Low fluid intake pital admissions worldwide and is the stone formation in these patients. Citrate supplementation may be a particularly reason for 80,000 emergency department The single most important determinant of effective therapeutic intervention. visits per year in the UK. The initial episode stone formation is low fluid intake. A low is normally dealt with by urologists, but fluid intake results in the production of physicians are increasingly encountering concentrated urine, causing supersatura- Primary hyperparathyroidism patients with nephrolithiasis because of its tion and crystallisation of stone–forming In primary hyperparathyroidism, activated association with hypertension, obesity, dia- compounds. In addition, low urine flow extracellular calcium–sensing receptor betes and osteoporosis. rates favour crystal deposition on the (CaSR) causes urinary dilution and acidifi- urothelium. cation, protecting against stone formation Epidemiology by preventing supersaturation of urine Hypercalciuria Kidney stone disease typically presents with insoluble calcium salts. Stones develop between the ages of 20 and 60 and is more About 80% of stones are calcium based, in hyperparathyroid patients with allelic prevalent in hot climates.1 It affects about predominantly either calcium oxalate variants that cause reduced expression of 10% of people over their lifetime, incidence (70%) or calcium phosphate (10%). High the CaSR, with associated loss of its urinary 15 increasing with age; 50% will have a recur- urine calcium is the single most common dilution and acidification effect. rence within 5–10 years and 75% within abnormality of urine chemistry in recur- 20 years.2 Developed countries have seen rent stone formers, but until recently the High salt diet rapid increases over the last 30 years, espe- relative contributions of altered gut cially in women in whom incidence is now absorption, bone turnover, and renal han- A high salt diet increases urinary calcium 16 almost equal to that of men.3 dling were poorly understood. US texts output. The sodium/chloride co–trans- This article focuses on the pathophysi- promote the concept that hypercalciuria porter at the loop of Henle drives the elec- ology, investigation and management of can be divided into ‘absorptive’ and ‘renal’ tric gradient required for paracellular cal- recurrent stone disease. phenotypes, but there is scant evidence cium uptake. Sodium bicarbonate does not that these phenotypes are reproducible or cause hypercalciuria, provided that dietary that different therapeutic approaches are chloride is kept low,17 suggesting that it is Pathophysiology justified in patients with different pheno- chloride rather than sodium that determines Stone growth starts with the formation of types.8 An appreciation of the mecha- calcium uptake. In one trial a reduced salt crystals in supersaturated urine which then nisms of calcium homeostasis helps to intake was one component of a successful adhere to the urothelium, thus creating the understand how hypercalciuria may intervention to reduce nephrolithiasis 18 nidus for subsequent stone growth. The develop (Fig 1). rates. However, a high salt intake may also biological processes that anchor crystals to An underlying genetic basis for help to increase spontaneous water intake, 19 the urothelium are incompletely under- ‘idiopathic’ hypercalciuria is evident from offsetting the effect on calcium excretion. stood. Many, but not all, calcium oxalate the observation that high urine calcium is the most consistent difference between stones develop on Randall’s plaques which Factors contributing to high urine stone–formers with and without a family are composed of calcium phosphate oxalate (= hydroxyapatite) crystals. These grow to history of stones.9–11 erode the urothelium, forming a nucleus Hypercalciuria and an excess risk of Most stones are calcium oxalate. There are for calcium oxalate deposition. stone formation is seen in patients with very high urine oxalate levels in patients © Royal College of Physicians, 2012. All rights reserved. 467 CCMJ-1205-467-471-CME-Tomson.inddMJ-1205-467-471-CME-Tomson.indd 446767 99/21/12/21/12 66:58:16:58:16 PPMM CME Renal Medicine Bone resorption stimulated by PTH, is proven,22,23 reflecting Enteric hyperoxaluria acidosis, inflammatory cytokines 1,25D permissive action on the ability of dietary PTH-mediated bone Patients with short bowel syndrome and a resorption calcium to limit functioning colon develop hyperoxaluria Urine calcium increased by intestinal oxalate effects of serum [Ca] via absorption.18 (‘enteric hyperoxaluria’) and kidney stones. CaSR In this condition, increased colonic absorp- gut bone urine tion of oxalate occurs by a combination of Hypocitraturia decreased luminal calcium activity (as the blood Citrate reduces calcium result of calcium binding to unabsorbed fatty activity in the urine by acids) and increased colonic permeability to [Ca] [Ca] [Ca] forming soluble com- oxalate (caused by unabsorbed bile salts). plexes with calcium and is an important inhib- Primary hyperoxaluria itor of crystallisation. Endogenous oxalate metabolism is a key Its excretion is partly determinant of urinary oxalate. The primary GI calcium absorption Calcium reabsorption determined by filtered hyperoxalurias (PH) are a paradigm for the stimulated by 1,25D increased by PTH: 1,25D has load of citrate and acting on VDR a permissive action consequences of disturbed oxalate metabo- partly by systemic lism. They are autosomal recessive condi- Fig 1. Determinants of urine calcium excretion. Increased acid–base balance. tions characterised by urine oxalate output urinary calcium excretion can be caused by increased Hypocitraturia is found typically exceeding 800 µmol/24 hours, sub- gastrointestional absorption, increased bone resorption or increased in hypokalaemia, tubular reabsorption. All three processes are influenced by a typed according to the affected enzyme: chronic acidosis complex series of feedback loops with PTH and 1,25D being the PH1 is the most severe and PH3 the least. (including that caused major hormones involved. 1,25D acts via the vitamin D receptor. Genetic analysis distinguishes subtypes. 97% of filtered calcium is normally reabsorbed, so urine calcium by ileostomy diarrhoea) In a milder variant of PH1, there is mis– excretion is controlled by changes in reabsorption. A rise in serum and in distal renal targeting rather than complete absence of calcium increases calcium excretion by acting on the CaSR. Calcium tubular acidosis.24 reabsorption is stimulated by PTH, with 1,25D playing a permissive the enzyme. Patients are responsive to role. High sodium chloride intake also reduces renal tubular calcium high–dose pyridoxine, a co–factor for the reabsorption (not shown). Decreased renal tubular phosphate High animal protein enzyme. It is likely that other genetic poly- reabsorption may also indirectly affect calcium excretion by intake stimulating increased 1,25D. PTH is increased by low serum [Ca], low morphisms affecting oxalate metabolism will be identified. serum [1,25D], high serum [PO4] and low serum [FGF23]. 1,25D is Animal protein (meat, increased by PTH and low serum [PO4]. 1,25D ϭ 1,25 poultry, fish) is metab- dihydroxyvitamin D; CaSR ϭ extracellular calcium receptor; [Ca] ϭ Investiga tions calcium; FGF23 ϭ fibroblast growth factor; PO4 ϭ phosphate; olised to oxalate and PTH ϭ parathyroid hormone. uric acid. Uric acid Not all patients with kidney stones should causes nucleation of be investigated with a view to defining the with both primary and enteric oxaluria calcium oxalate crystals. Metabolism of underlying abnormality. After a single stone (see below). No underlying cause is animal protein generates fixed acid, episode, many patients would not be con- identified in most calcium oxalate stone– reducing intake of animal protein lowers vinced of the need to modify their lifestyle formers and urine oxalate is often within urine oxalate and raises urine pH, reducing or take regular drug treatment to avoid the the reference range. Intestinal oxalate the risk of both oxalate