CME Renal medicine Clinical Medicine 2012, Vol 12, No 5: 467–71

More recent theories focus on the role of primary , deactivating stone : cell surface molecules which favour or receptor (VDR) polymorphisms inhibit crystal adhesion.4,5 Urothelial 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 of salts. A Risk factors diet low in fruit and vegetables (which also Renal 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 , causing supersatura- Primary hyperparathyroidism patients with nephrolithiasis because of its tion and crystallisation of stone–forming In primary hyperparathyroidism, activated association with , , dia- compounds. In addition, low urine flow extracellular calcium–sensing receptor betes and . rates favour crystal deposition on the (CaSR) causes urinary dilution and acidifi- urothelium. cation, protecting against stone formation Epidemiology by preventing of urine 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 variants that cause reduced expression of 10% of people over their lifetime, (70%) or calcium (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, 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 /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. 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 oxalate (= ) 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 467467 99/21/12/21/12 6:58:166:58:16 PPMM CME Renal Medicine

Bone resorption stimulated by PTH, is proven,22,23 reflecting Enteric acidosis, inflammatory cytokines 1,25D permissive action on the ability of dietary PTH-mediated bone Patients with and a resorption calcium to limit functioning colon develop hyperoxaluria Urine calcium increased by intestinal oxalate effects of [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- itor of crystallisation. Endogenous oxalate 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 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 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 . . 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 and uric acid risk of recurrence. The presence of a absorption is higher on average in stone- stones.25,26 number of ‘red flag’ features warrants formers than in non–stone– formers: it is possible that intestinal oxalate transporter Key points polymorphisms contribute to the risk of ‘Red flag’ features warrant further investigation calcium oxalate stone formation.20 Dietary modification leading to small reductions in A high fluid intake and vegetarian diet are important preventative measures for the urinary oxalate, even within the reference majority of recurrent stone–formers range, can significantly reduce the risk of Further treatment is guided by urine chemistry calcium oxalate stones.21 The presence of an underlying condition should be considered in patients with pure calcium phosphate or uric acid stones Low calcium intake Enteric hyperoxaluria, primary hyperoxaluria, and are ideally managed in The inverse association between dietary renal or metabolic stone clinics calcium intake and stone formation seems counterintuitive. In fact, the association KEY WORDS: nephrolithiasis, hypercalciuria, hyperoxaluria, cystinuria, uric acid

468 © Royal College of Physicians, 2012. All rights reserved.

CCMJ-1205-467-471-CME-Tomson.inddMJ-1205-467-471-CME-Tomson.indd 468468 99/21/12/21/12 6:58:176:58:17 PPMM CME Renal Medicine

further investigations being offered summarised in Table 2. If distal renal and features of . (Box 1). tubular acidosis (dRTA) is identified,28,29 Measurement of serum urate, glycated A detailed investigation algorithm is an underlying cause should be sought. haemoglobin (HbA1c) and blood pressure available in a recent review.27 The min- Calcium phosphate stones are a feature of should form part of the investigation. Patients imum initial investigations we recommend many rare monogenic diseases30 including with an ileostomy are at risk of uric acid are outlined in Table 1. Diurnal calcium inherited forms of dRTA and the X–linked stones because of high bicarbonate and fluid excretion is highly variable. Ideally, there- condition, Dent’s disease. losses. Increased cell turnover, occurring for fore, patients should provide two 24–hour example in myeloproliferative disorder and Urine phosphate. Measurement of urine urine collections. If urine oxalate output inflammatory bowel disease, is also associated phosphate is of no proven value in the exceeds 800 µmol/24 hours, genetic analysis with uric acid stones. Screening for myelo- diagnosis or management of stone formers. for PH is advised. If cystinuria is suspected proliferative disorder is with a full blood In hyperphosphaturic patients, the risk of and stone analysis not available, a spot count. Measurement of urinary uric acid stone formation is determined by urine urine sample for urine amino acids ( output is unhelpful because the solubility of pH. Relatively soluble monocalcium concentration) should be collected. uric acid in urine is highly pH–dependent: at phosphate (Ca(H PO ) ) salts form at Analysis of the biochemical composition 2 4 2 low pH, even small amounts will precipitate, pH 6, whilst at pH 8 insoluble dicalcium of kidney stones, either passed spontane- whereas the reverse is true at high pH.31 phosphate (CaHPO ) salts form. Hence, ously or retrieved during percutaneous or 4 alkaline urine favours formation of calcium endoscopic surgery, is extremely valuable phosphate stones. Cystine stones in directing further investigation and treat- High urinary phosphate excretion is nor- ment. Where this is not available, The only situation in which cystine stones mally associated with low urinary pH may provide some clues – uric acid and occur is cystinuria, an autosomal recessive because most dietary phosphate is acidic. cystine stones are characteristically radi- condition caused by abnormal transport of The presence of other cations such as sodium olucent on plain radiology. Stone density dibasic amino acids, including cystine. and , which form soluble phos- (Hounsfield units) on unenhanced com- Affected individuals experience recurrent phate salts in alkaline urine, may also deter- puted tomography may be helpful for larger stone formation from a young age and may mine the extent to which insoluble calcium stones. Additional investigations may be ultimately develop . phosphate salts form at high urine pH. indicated in non–calcium oxalate stone formers (see below). Management Uric acid stones Calcium phosphate stones All patients in whom further management is Uric acid stones, or mixed uric acid and cal- appropriate should receive dietary and life- cium oxalate stones, are most commonly seen Targeted additional investigations for cal- style advice. In temperate climates, a fluid in patients with concentrated acidic urine cium phosphate stone–formers are intake of at least two litres a day halves recurrence rates.32 A diet high in fruit and Box 1. ‘Red flag’ features warranting further investigation. vegetables is recommended because the high • First stone episode under the age of 25 potassium content promotes urinary citrate • Recurrent stones excretion. These foods are also a source of • Bilateral or multiple stones, or phytates which, like citrate, increase calcium • Strong family history of stones salt solubility. An adequate calcium intake, with restricted animal protein, reduces urine • Impaired renal function (eGFR <60 ml/min/1.73m2) associated with stones oxalate. A limited salt and intake is • Non–calcium oxalate stones also advised. Where possible, an underlying • Radiolucent stones (may be urate or cystine) disorder predisposing to stone formation • Stone episode associated with underlying condition (eg inflammatory bowel disease, gastric should be identified and treated. bypass surgery or metabolic syndrome)

Further treatment Table 1. Initial investigations in patients with ‘red flag’ features. Sample Test Additional treatment should be guided by Serum sample , creatinine, potassium, bicarbonate, chloride, calcium, urine chemistry (Table 3): phosphate, , 25–hydroxyvitamin D, urate • reduce urinary cal- Whole blood (EDTA tube) Parathyroid hormone cium and halve stone risk in hypercal- Fresh spot urine sample Urine pH (pH meter better than dipstick) ciuric patients.33 2 ϫ 24–hour urine collections Calcium, oxalate, citrate, sodium (and creatinine – to assess • The addition of amiloride may boost (acidified sample) completeness when comparing repeated 24h collections from citrate excretion by its potassium– the same patient) sparing effect.

© Royal College of Physicians, 2012. All rights reserved. 469

CCMJ-1205-467-471-CME-Tomson.inddMJ-1205-467-471-CME-Tomson.indd 469469 99/21/12/21/12 6:58:176:58:17 PPMM CME Renal Medicine

• is indicated in hypoc- tion of oxalate combined with an ade- in chronic , is logical but itraturia and is also used as a urine quate calcium intake. clinical studies proving benefit in enteric alkalinising agent. • As in all types of kidney stone disease, hyperoxaluria have not been reported. • Urine alkalinisation with citrate or a high volume dilute urine is desirable • (triple phosphate) stones are bicarbonate increases the solubility of in enteric hyperoxaluria. However, in the staghorn calculi associated with uric acid, cystine and calcium oxalate patients with short bowel, a high water and precipitate stones. Doses are titrated to achieve an intake can exacerbate diarrhoea in alkaline urine. Treatment is with ideal urine pH 7. A higher pH exposes without improving urine dilution. A antibiotics and stone clearance. patients to the risk of calcium phos- containing and phate stones, particularly in the pres- glucose (eg St Mark’s solution) may be Management in or ence of hypercalciuria. preferable to plain water. metabolic stone clinics • In enteric hyperoxaluria the mainstay • The administration of ‘oxalate binders’, of treatment is rigorous dietary restric- analogous to the use of phosphate binders Both enteric hyperoxaluria and PH are ide- ally managed in nephrology or metabolic Table 2. Targeted investigations for calcium phosphate stone–formers stone clinics because they can lead to pro- (CT ϭ computed tomography). gressive renal failure as a consequence of kidney stones, their treatment and oxalate Condition Additional features Specific investigations deposition within the kidney. End–stage Primary hyperparathyroidism Symptoms of Parathyroid hormone, bone renal failure can be complicated by sys- May be asymptomatic profile temic oxalosis and multi–organ failure. Autoimmune interstitial Other features of autoimmune Autoimmune profile, In cystinuria, cystine–binding drugs may nephritis disease complement (C3, C4) be indicated if stones recur despite conservative Haematuria or recurrent urinary Intravenous urography (or measures and urine alkalinisation. This tract infection high–resolution CT scan) should ideally be monitored in a nephrology May be asymptonmatic or metabolic stone clinic. Distal Alkaline urine Urine acidification test Hypokalaemia, (furosemide/ Conclusions and future work hyperchloraemia, metabolic fludrocortisone ϩ/Ϫ acidosis with normal anion gap ammonium chloride) The great majority of recurrent stone If positive, investigate for formers do not have a recognised underlying underlying cause cause for their condition. A careful history Dent’s syndrome (X–linked) Family history of stones in Spot urine for amino acids may reveal a number of dietary and lifestyle males and retinol binding protein risk factors contributing to an individual’s Rickets in childhood (variable) risk of stone disease. A more complete understanding of the influence of dietary and lifestyle factors on the phenotypic Table 3. Abnormalities of urine chemistry that increase risk of kidney stones and expression of genetic polymorphisms warrant further investigation (PH ϭ primary hyperoxaluria). which predispose to stone formation may Possible effect on stone facilitate a more tailored approach to stone Urine chemistry risk factor formation Treatment prevention in the future. Hypercalciuria Most stones contain Dietary salt and sugar calcium restriction References Thiazide ϩ/Ϫ amiloride 1 Fakheri RJ, Goldfarb DS. Ambient temper- Hyperoxaluria Common component of Dietary restriction of animal ature as a contributor to kidney stone for- NB: urine oxalate often within stones protein and high oxalate foods mation: implications of global warming. the ‘reference range’ in Adequate dietary calcium Kidney Int 2011;79:1178–85. calcium oxalate stone formers intake 2 Moe OW. Kidney stones: pathophysiology (specific treatments required and medical management. Review. Lancet for PH and enteric 2006;367:333–44. hyperoxaluria) 3 Lieske JC, Pena de la Vega LS, Slezak JM et al. Renal stone epidemiology in Hypocitraturia Reduced solubility of High fruit and vegetable intake Rochester, Minnesota: an update. Kidney calcium salts Citrate supplementation Int 2006;69:760–4. Low urine pH Reduced solubility of Urine alkalinisation with citrate 4 Asselman M, Verhulst A, De Broe ME, calcium oxalate, uric acid or bicarbonate (avoid in calcium Verkoelen CF. Calcium oxalate crystal and cystine phosphate nephrolithiasis) adherence to hyaluronan–, –, and CD44–expressing injured/regenerating

470 © Royal College of Physicians, 2012. All rights reserved.

CCMJ-1205-467-471-CME-Tomson.inddMJ-1205-467-471-CME-Tomson.indd 470470 99/21/12/21/12 6:58:176:58:17 PPMM CME Renal Medicine

tubular epithelial cells in rat kidneys. J Am the phosphoenolpyruvate carboxykinase 25 Nguyen QV, Kälin A, Drouve U et al. Soc Nephrol 2003;14:3155–66. gene. J Biol Chem 2000;275:3446–54. Sensitivity to meat protein intake and 5 Randall A. Recent Advances in Knowledge 15 Vezzoli G, Terranegra A, Arcidiacono T et hyperoxaluria in idiopathic calcium stone Relating to the Formation, Recognition and al. Calcium kidney stones are associated formers. Kidney Int 2001;59:2273–81. Treatment of Kidney Calculi. Bull N Y Acad with a haplotype of the calcium–sensing 26 Reddy ST, Wang CY, Sakhaee K et al. Effect Med 1944;20:473–84. receptor gene regulatory region. Nephrol of low–carbohydrate high–protein diets on 6 Asselman M, Verhulst A, Van Ballegooijen Dial Transplant 2010;25:2245–52. acid–base balance, stone–forming propen- ES et al. Hyaluronan is apically secreted 16 Silver J, Rubinger D, Friedlaender MM, sity, and . Am J Kidney and expressed by proliferating or regener- Popovtzer MM. Sodium–dependent idio- Dis 2002;40:265–74. ating renal tubular cells. Kidney Int pathic hypercalciuria in renal–stone 27 Johri N, Cooper B, Robertson W et al. An 2005;68:71–83. formers. Lancet 1983;2:484–6. update and practical guide to renal stone 7 Parks JH, Coe FL. An increasing number of 17 Muldowney FP, Freaney R, Barnes E. management. Nephron Clin Pract calcium oxalate stone events worsens treat- Dietary chloride and urinary calcium in 2010;116:c159–71. ment outcome. Kidney Int 1994;45:1722–30. stone disease. QJM 1994;87:501–9. 28 Gault MH, Chafe LL, Morgan JM et al. 8 Tomson CR. Prevention of recurrent cal- 18 Borghi L, Schianchi T, Meschi T et al. Comparison of patients with idiopathic cium stones: a rational approach. Review. Comparison of two diets for the preven- calcium phosphate and calcium oxalate Br J Urol 1995;76:419–24. tion of recurrent stones in idiopathic stones. Medicine Baltimore 1991;70:345–59. 9 Park C, Ha YS, Kim YJ et al. Comparison of hypercalciuria. N Engl J Med 2002;346:77– 29 Buckalew VM Jr. Nephrolithiasis in renal Metabolic Risk Factors in Urolithiasis 84. tubular acidosis. J Urol 1989;141(3 Pt 2): Patients according to Family History. 19 Stoller ML, Chi T, Eisner BH et al. Changes 731–7. Korean J Urol 2010;51:50–3. in urinary stone risk factors in hypocitra- 30 Vezzoli G, Terranegra A, Arcidiacono T, 10 Resnick M, Pridgen DB, Goodman HO. turic calcium oxalate stone formers treated Soldati L. and calcium nephro- Genetic predisposition to formation of cal- with dietary sodium supplementation. lithiasis. Review. Kidney Int cium oxalate renal calculi. N Engl J Med J Urol 2009;181:1140–4. 2011;80:587–93. 1968;278:1313–8. 20 Robijn S, Hoppe B, Vervaet BA et al. 31 Asplin JR. Uric acid stones. Semin Nephrol 11 Goldfarb DS, Fischer ME, Keich Y, Hyperoxaluria: a gut–kidney axis? Kidney 1996;16:412–24. Goldberg J. A twin study of genetic and Int 2011;80:1146–58. 32 Borghi L, Meschi T, Amato F et al. Urinary dietary influences on nephrolithiasis: a 21 Robertson WG, Peacock M. The cause of volume, water and recurrences in idio- report from the Vietnam Era Twin (VET) idiopathic calcium stone disease: hypercal- pathic calcium nephrolithiasis: a 5–year Registry. Kidney Int 2005;67:1053–61. ciuria or hyperoxaluria? Nephron randomized prospective study. J Urol 12 Rendina D, Esposito T, Mossetti G et al. A 1980;26:105–10. 1996;155:839–43. functional allelic variant of the FGF23 gene 22 Curhan GC, Willett WC, Rimm EB, 33 Pearle MS, Roehrborn CG, Pak CY. Meta– is associated with renal phosphate leak in Stampfer MJ. A prospective study of die- analysis of randomized trials for medical calcium nephrolithiasis. J Clin Endocrinol tary calcium and other nutrients and the prevention of calcium oxalate nephrolithi- Metab 2012;97:E840–4. risk of symptomatic kidney stones. N Engl asis. J Endourol 1999;13:679–85. 13 Morrison NA, Qi JC, Tokita A et al. J Med 1993;328:833–8. Prediction of bone density from vitamin D 23 Curhan GC, Willett WC, Speizer FE et al. receptor alleles. Nature 1994;367:284–7. Comparison of dietary calcium with 14 Sugiyama T, Wang JC, Scott DK, Granner supplemental calcium and other nutrients as Address for correspondence: DK. Transcription activation by the orphan factors affecting the risk for kidney stones in Dr Charlie Tomson, Department of nuclear receptor, chicken ovalbumin women. Ann Intern Med 1997;126:497–504. Renal Medicine, Southmead Hospital, upstream promoter–transcription factor I 24 Zuckerman JM, Assimos DG. (COUP–TFI). Definition of the domain Hypocitraturia: pathophysiology and med- Bristol BS10 5NB. involved in the glucocorticoid response of ical management. Rev Urol 2009;11:134–44. Email: [email protected]

© Royal College of Physicians, 2012. All rights reserved. 471

CCMJ-1205-467-471-CME-Tomson.inddMJ-1205-467-471-CME-Tomson.indd 471471 99/21/12/21/12 6:58:176:58:17 PPMM