Kidney stone disease: pathophysiology, investigation and medical treatment

Low fluid intake

The single most important determinant of stone formation is low fluid intake. A low fluid intake results in the production of concentrated urine, causing supersaturation and crystallisation of stone–forming compounds. In addition, low urine flow rates favour crystal deposition on the urothelium.

Hypercalciuria

About 80% of stones are calcium based, predominantly either calcium oxalate (70%) or calcium phosphate (10%). High urine calcium is the single most common abnormality of urine chemistry in recurrent stone formers, but until recently the relative contributions of altered gut absorption, bone turnover, and renal handling were poorly understood. US texts promote the concept that hypercalciuria can be divided into ‘absorptive’ and ‘renal’ phenotypes, but there is scant evidence that these phenotypes are reproducible or that different therapeutic approaches are justified in patients with different phenotypes.⁸ An appreciation of the mechanisms of calcium homeostasis helps to understand how hypercalciuria may develop (Fig 1).

An underlying genetic basis for ‘idiopathic’ hypercalciuria is evident from the observation that high urine calcium is the most consistent difference between stone–formers with and without a family history of stones.^9–11

Hypercalciuria and an excess risk of stone formation is seen in patients with primary hyperparathyroidism, deactivating vitamin D receptor (VDR) polymorphisms and activating fibroblast growth factor (FGF) 23 polymorphism.^12,13

Deactivating VDR variants

The development of stone disease is likely to occur only in the presence of additional risk factors. For example, patients with deactivating VDR variants form stones if there is associated hypocitraturia. VDR activity promotes citrate excretion¹⁴ which increases the solubility of calcium salts. A diet low in fruit and vegetables (which also boosts citrate excretion) may predispose to stone formation in these patients. Citrate supplementation may be a particularly effective therapeutic intervention.

Primary hyperparathyroidism

In primary hyperparathyroidism, activated extracellular calcium–sensing receptor (CaSR) causes urinary dilution and acidification, protecting against stone formation by preventing supersaturation of urine with insoluble calcium salts. Stones develop in hyperparathyroid patients with allelic variants that cause reduced expression of the CaSR, with associated loss of its urinary dilution and acidification effect.¹⁵

High salt diet

A high salt diet increases urinary calcium output.¹⁶ The sodium/chloride co–transporter at the loop of Henle drives the electric gradient required for paracellular calcium uptake. Sodium bicarbonate does not cause hypercalciuria, provided that dietary chloride is kept low,¹⁷ suggesting that it is chloride rather than sodium that determines calcium uptake. In one trial a reduced salt intake was one component of a successful intervention to reduce nephrolithiasis rates.¹⁸ However, a high salt intake may also help to increase spontaneous water intake, offsetting the effect on calcium excretion.¹⁹

Low calcium intake

The inverse association between dietary calcium intake and stone formation seems counterintuitive. In fact, the association is proven,^22,23 reflecting the ability of dietary calcium to limit intestinal oxalate absorption.¹⁸

Hypocitraturia

Citrate reduces calcium activity in the urine by forming soluble complexes with calcium and is an important inhibitor of crystallisation. Its excretion is partly determined by filtered load of citrate and partly by systemic acid–base balance. Hypocitraturia is found in hypokalaemia, chronic acidosis (including that caused by ileostomy diarrhoea) and in distal renal tubular acidosis.²⁴

High animal protein intake

Animal protein (meat, poultry, fish) is metabolised to oxalate and uric acid. Uric acid causes nucleation of calcium oxalate crystals. Metabolism of animal protein generates fixed acid, reducing intake of animal protein lowers urine oxalate and raises urine pH, reducing the risk of both oxalate and uric acid stones.^25,26

Enteric hyperoxaluria

Patients with short bowel syndrome and a functioning colon develop hyperoxaluria (‘enteric hyperoxaluria’) and kidney stones. In this condition, increased colonic absorption of oxalate occurs by a combination of decreased luminal calcium activity (as the result of calcium binding to unabsorbed fatty acids) and increased colonic permeability to oxalate (caused by unabsorbed bile salts).

Primary hyperoxaluria

Endogenous oxalate metabolism is a key determinant of urinary oxalate. The primary hyperoxalurias (PH) are a paradigm for the consequences of disturbed oxalate metabolism. They are autosomal recessive conditions characterised by urine oxalate output typically exceeding 800 μmol/24 hours, subtyped according to the affected enzyme: PH1 is the most severe and PH3 the least. Genetic analysis distinguishes subtypes.

In a milder variant of PH1, there is mis–targeting rather than complete absence of the enzyme. Patients are responsive to high–dose pyridoxine, a co–factor for the enzyme. It is likely that other genetic polymorphisms affecting oxalate metabolism will be identified.

Calcium phosphate stones

Targeted additional investigations for calcium phosphate stone–formers are summarised in Table 2. If distal renal tubular acidosis (dRTA) is identified,^28,29 an underlying cause should be sought. Calcium phosphate stones are a feature of many rare monogenic diseases³⁰ including inherited forms of dRTA and the X–linked condition, Dent's disease.

Uric acid stones

Uric acid stones, or mixed uric acid and calcium oxalate stones, are most commonly seen in patients with concentrated acidic urine and features of metabolic syndrome. Measurement of serum urate, glycated haemoglobin (HbA1c) and blood pressure should form part of the investigation. Patients with an ileostomy are at risk of uric acid stones because of high bicarbonate and fluid losses. Increased cell turnover, occurring for example in myeloproliferative disorder and inflammatory bowel disease, is also associated with uric acid stones. Screening for myeloproliferative disorder is with a full blood count. Measurement of urinary uric acid output is unhelpful because the solubility of uric acid in urine is highly pH–dependent: at low pH, even small amounts will precipitate, whereas the reverse is true at high pH.³¹

Cystine stones

The only situation in which cystine stones occur is cystinuria, an autosomal recessive condition caused by abnormal transport of dibasic amino acids, including cystine. Affected individuals experience recurrent stone formation from a young age and may ultimately develop kidney failure.

Further treatment

Additional treatment should be guided by urine chemistry (Table 3):

• Thiazide diuretics reduce urinary calcium and halve stone risk in hypercalciuric patients.³³

• The addition of amiloride may boost citrate excretion by its potassium–sparing effect.

• Potassium citrate is indicated in hypocitraturia and is also used as a urine alkalinising agent.

• Urine alkalinisation with citrate or bicarbonate increases the solubility of uric acid, cystine and calcium oxalate stones. Doses are titrated to achieve an ideal urine pH 7. A higher pH exposes patients to the risk of calcium phosphate stones, particularly in the presence of hypercalciuria.

• In enteric hyperoxaluria the mainstay of treatment is rigorous dietary restriction of oxalate combined with an adequate calcium intake.

• As in all types of kidney stone disease, a high volume dilute urine is desirable in enteric hyperoxaluria. However, in patients with short bowel, a high water intake can exacerbate diarrhoea without improving urine dilution. A solution containing electrolytes and glucose (eg St Mark's solution) may be preferable to plain water.

• The administration of ‘oxalate binders’, analogous to the use of phosphate binders in chronic kidney disease, is logical but clinical studies proving benefit in enteric hyperoxaluria have not been reported.

• Struvite (triple phosphate) stones are the staghorn calculi associated with urinary tract infection and precipitate in alkaline urine. Treatment is with antibiotics and stone clearance.

Management in nephrology or metabolic stone clinics

Both enteric hyperoxaluria and PH are ideally managed in nephrology or metabolic stone clinics because they can lead to progressive renal failure as a consequence of kidney stones, their treatment and oxalate deposition within the kidney. End–stage renal failure can be complicated by systemic oxalosis and multi–organ failure.

In cystinuria, cystine–binding drugs may be indicated if stones recur despite conservative measures and urine alkalinisation. This should ideally be monitored in a nephrology or metabolic stone clinic.