Part 2 book “Practical nephrology” has contents: Renal stone disease, kidney cancer, inherited renal tumour syndromes, polycystic kidney disease, other cystic kidney diseases, inherited metabolic disease, anaemia management in chronic kidney disease, setting up and running a haemodialysis service, peritoneal dialysis prescription,… and other contents.
Renal Stone Disease 36 Shabbir H Moochhala and Robert J Unwin Changes in Epidemiology Associations with Other Disorders Urinary tract stone disease is common, important and increasing: the lifetime prevalence of stones is ~10 % in developed countries, and it disproportionately affects people of working age After passage of a first stone, the risk of recurrence is 40 % at years and 75 % at 20 years [1] The incidence of stone disease has always been higher in certain areas such as the Arabian Gulf countries but is increasing internationally [2, 3] Some of this is due to improvements in stone detection using CT scanning, but changes in dietary and fluid intake habits [4–7] and increased rates of obesity and metabolic syndrome [7, 8] are more important contributors The incidence of stones in children has increased by 19 % in the last 10 years, the age at first presentation is reducing, and the traditional male to female ratio of 3:1 is changing to a greater proportion of women Stone disease is a major contributor to the total number of urological procedures performed in the UK, with an increase of 63 % between 2000 and 2010 [3] In 2009–2010 there were over 83,000 stone-related hospital attendances in England This results in a major cost burden, with direct and indirect costs associated with kidney stones estimated at over $5 billion annually in the USA [9] There is increasing evidence that calcium renal stone disease is a generalised metabolic disorder in its own right, rather than simply an associated feature or merely a cause of urinary tract obstruction Stone formers of all types: Are at increased risk of developing CKD compared to non-stone formers (over 8-year follow-up) [10] Have lower bone mineral density when compared with the general population [11] Are associated with a higher incidence of metabolic syndrome and increased cardiovascular risk [12], with a 30 % increased risk of myocardial infarction over a 9-year period [13] Presentations Stone disease is unusual in that the first presentation is rarely to a nephrologist Patients with acute renal colic may present to A&E, ‘recurrent urinary tract infections’ may be a presentation of ureteric stone disease in general practice and stones found incidentally on imaging may be referred directly to a urologist Patients who have suffered a previous stone are more likely to recognise the symptoms Common Presentations S.H Moochhala, MRCP, PhD (*) UCL Centre for Nephrology, Royal Free Hospital, London NW3 2QG, UK e-mail: smoochhala@nhs.net R.J Unwin, BM, FRCP, PhD, FSB, CBiol UCL Centre for Nephrology, UCL Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK e-mail: robert.unwin@ucl.ac.uk M Harber (ed.), Practical Nephrology, DOI 10.1007/978-1-4471-5547-8_36, © Springer-Verlag London 2014 • Visible haematuria (important differentials: tumour, infection, glomerular disease) • Renal colic (implies ureteric stone) Important differentials: clots due to any other cause of haematuria, papillary necrosis, and other causes of abdominal pain with incidental finding of stone • Dysuria, frequency and urgency (only for bladder stones or suggestive of infection contributing to stone formation) • Increasingly, as an incidental finding on CT or USS scanning for an unrelated indication 413 414 Rarer Presentations • • • • AKI Fever/septicaemia (pyonephrosis + obstruction) Recurrent UTI and xanthogranulomatous pyelonephritis Other features of the underlying medical condition (e.g hypercalcaemia/hyperuricaemia) Differential diagnoses always include obstruction, infection and tumour Pathophysiology While traditional classification is by stone type, it is more useful to differentiate abnormal physicochemical properties of urine that may increase the risk of stone formation (metabolic causes) from structural causes Within each category, causes can be genetic or acquired Metabolic Risk Factors A recent survey of young stone formers found that 64 % had a single metabolic risk factor, with 27 % having more than one [14] Below is a breakdown of the commonly found metabolic risk factors present in a typical cohort of stone formers: • Hypercalciuria 50 % • Hypocitraturia 25 % • Hypomagnesuria 10 % • Hyperuricosuria % • Hyperoxaluria % Structural Risk Factors Any macro- or microanatomical defect causing stasis can also predispose to stones These include pelviureteric junction (PUJ) obstruction; vesicoureteric reflux; a malformed kidney, such as horseshoe or duplex; and medullary sponge kidney • Medullary sponge kidney (MSK) is characterised by congenital ectasia and cystic dilatation of the medullary collecting ducts, which is associated with hypercalciuria and hypocitraturia There is often a family history and sometimes an association with hemi-hypertrophy No genetic cause has yet been identified Hence, both anatomical and biochemical features predispose to stone formation in MSK MSK itself is not a cause of progressive CKD Genetic Causes and Rarer Stone Types A family history is present in up to 50 % of stone-forming patients Despite this, the genes contributing to renal stone S.H Moochhala and R.J Unwin risk are still largely unknown However, some monogenic stone diseases are known; the most common in adult clinical practice1 are: • Primary hyperoxaluria (autosomal recessive; PH types 1, and 3) (CaOx) • Cystinuria (autosomal recessive) (cystine) • Familial distal renal tubular acidosis (autosomal recessive and dominant) (CaPi) • Dent’s disease (X-linked recessive) (CaPi and mixed CaPi/CaOx) It is important to detect these conditions because: • Primary hyperoxaluria and Dent’s disease are associated with long-term progression to ESRD • There may be implications for other family members • They are potentially treatable The more common genetic causes of calcium renal stone disease in adults are shown in Table 36.1, with the rarer causes shown in Table 36.2 Rarer Genetic Causes of Non-calcium Renal Stone Disease Other even rarer causes of renal stones should always be considered in patients with radiolucent kidney stones, after excluding urate stones (see Table 36.3) These diagnoses are treatable, but are often diagnosed late, leading to renal impairment in many cases Further information on these conditions, international registries and trials can be obtained from the Rare Kidney Stone Consortium website: http:// www.rarekidneystones.org Causes and Pathophysiology of Metabolic Risk Factors Hypercalciuria Most hypercalciuria noted on screening is ‘idiopathic’, i.e not associated with hypercalcaemia Idiopathic hypercalciuria is due to one or more of: • Increased calcium resorption from bone This account for the increased incidence of stones in postmenopausal women (especially where osteoporosis is treated with calcium and vitamin D supplements instead of hormone replacement therapy Men with hypercalciuria are also often found to have osteopaenia, particularly of the lumbar spine, but the mechanism of this increase in bone loss is unknown • Increased calcium resorption from the gut • Decreased calcium reabsorption in the nephron A common cause is excessive dietary sodium intake with low CaOx calcium oxalate, CaPi calcium phosphate 36 Renal Stone Disease 415 Table 36.1 More common genetic causes of calcium renal stone disease in adults Disease Primary hyperoxaluria type (80 % of PH) Stone composition Inheritance Calcium Autosomal oxalate recessive Defect Alanine-glyoxylate aminotransferase (AGT1 – liver enzyme which converts glyoxylate to glycine) Diagnosis Previously liver biopsy showing decreased AGT1 function Nowadays mutation analysis of AGXT gene Mutation analysis of GRHPR gene Primary hyperoxaluria type (10 % of PH) Calcium oxalate Autosomal recessive Primary hyperoxaluria type (5–10 % of PH) Familial distal renal tubular acidosis Calcium oxalate Autosomal recessive Hydroxypyruvate reductase (GRHPR – converts glyoxylate to glycolate) 4-hydroxy-2oxoglutarate aldolase Calcium phosphate Autosomal dominant/ autosomal recessive Impaired activity of Mutation analysis H-ATPase pump or AE1 chloride-bicarbonate exchanger Mutation analysis of HOGA1 gene Diagnostic clue Progressive chronic kidney disease; systemic deposition (oxalosis) when plasma oxalate >30 μM childhood presentation, urinary oxalate >0.7 mmol/24 h, 100 % calcium oxalate stones Milder phenotype than type disease May present in adulthood; urinary oxalate 0.4–0.7 mmol/24 h Normal anion gap metabolic acidosis Treatment Combined kidney-liver transplantation Low-oxalate diet Low-oxalate diet Potassium citrate Table 36.2 Rarer genetic causes of calcium renal stone disease Monogenic disease Dent’s disease Causative gene CLCN5 Location of defect Proximal tubule Inheritance X-linked recessive Hypophosphataemic nephrolithiasis/osteoporosis Familial hypomagnesaemia, hypercalciuria, nephrocalcinosis (‘FHHNC’) Bartter syndrome SLC34A1 (sodium phosphate co-transporter) CLDN16, CLDN19 (claudins 16 and 19) Proximal tubule Autosomal dominant Autosomal recessive Various Autosomal dominant hypocalcaemia CaSR (calcium sensing receptor) Thick ascending limb of loop of Henle Parathyroid gland; thick ascending limb of loop of Henle Thick ascending limb of loop of Henle; distal tubule Autosomal recessive Autosomal dominant Clues in addition to stone disease Proximal tubulopathy, progressive CKD, predominantly calcium phosphate stone type Phosphate wasting Renal magnesium wasting, nephrocalcinosis on imaging Hypokalaemic alkalosis, presentation in infancy Stone formation usually only noted during inappropriate treatment with calcium/vitamin D Table 36.3 Rarer genetic causes of non-calcium renal stone disease Disease Cystinuria Stone composition Cystine Inheritance Autosomal recessive Autosomal recessive Xanthinuria (xanthine Xanthine oxidase deficiency causes purine excretion as xanthine rather than uric acid) Adenine 2,8-dihydroxyadenine Autosomal phosphoribosyltransferase recessive (APRT) deficiency Diagnosis Typical crystals, stone analysis Hypouricaemia with hypouricosuria (i.e underproduction of uric acid) Typical crystals, stone analysis, assay of enzyme activity in red cell lysates dietary potassium (i.e diet lacking fresh fruits and vegetables), but rare genetic causes can cause a urinary ‘leak’ of calcium, e.g hereditary hypophosphataemic rickets with hypercalciuria (caused by defective proximal tubular sodium reabsorption via the transporter SLC34A3) Diagnostic clue Often few; necessitates screening Extreme hypouricaemia with radiolucent stones in person of Middle Eastern/Mediterranean origin Symptoms improve with allopurinol but not with alkalinisation (unlike uric acid stones) Treatment Urinary alkalinisation, chelating agents Low-purine diet and high fluid intake (allopurinol is not indicated) Allopurinol 5-10 mg/ kg/day (or febuxostat) completely prevents 2,8-DHA crystalluria Before diagnosing idiopathic hypercalciuria, it is important to specifically exclude primary hyperparathyroidism (~1 % of hypercalciuria) It presents with often vague symptoms, not necessarily including stone disease, but with clear biochemical evidence: elevated PTH, inappropriately normal 416 or raised plasma calcium, reduced plasma phosphate and reduced TMPi/GFR (this is an index of PTH-induced reduced tubular phosphate reabsorption) Treatments Bisphosphonates reduce hypercalciuria due to bone loss and can be used if GFR >30 mL/min They have the advantage of also inhibiting the crystallisation of calcium salts It is worth noting that vitamin D itself, given as 25-OH vitamin D (e.g cholecalciferol) without a calcium supplement, does not increase hypercalciuria Restricting dietary calcium intake is never recommended Thiazide diuretics reduce hypercalciuria by inducing a mild volume depletion which encourages proximal tubular sodium and hence calcium reabsorption They should be used only once a primary cause of hypercalciuria has been excluded Their tendency to cause increased urinary potassium loss results in mild potassium deficiency which can reduce the urinary excretion of citrate (a stone inhibitor) This effect can be lessened by combination with amiloride Hyperoxaluria Hyperoxaluria is usually secondary to increased gut absorption: • Dietary due to excessive intake of oxalate-rich foods, e.g chocolate, tea, bran, nuts and also spinach and rhubarb • Enteric hyperoxaluria refers to increased intestinal absorption of oxalate due to: – Inappropriately low-calcium diet (sometimes, but incorrectly, advocated in hypercalciuria) – Malabsorption due to small intestinal or pancreatic exocrine disease or surgery, e.g ileal resection, Roux-en-Y gastric bypass for obesity Malabsorption increases free fatty acid availability in the colon The excess fatty acids preferentially complex with dietary calcium, reducing the calcium available for complexing with oxalate in the colon which is the main site of oxalate absorption • Megadose vitamin C (rare) • Ethylene glycol toxicity (rare) The primary hyperoxalurias (see Table 36.3) are caused by autosomal recessive defects in the enzymes that metabolise glyoxylate, causing metabolism to oxalate Type is the more common form Normal oxalate excretion is variably defined with an upper limit of ~ 0.4 mmol/24 h Primary hyperoxaluria (PH) types or are only suspected when excretion exceeds 0.7 mmol/24 h and usually present in childhood However, PH type may present in adulthood, suggesting that values >0.4 mmol/24 h should also be followed up (and S.H Moochhala and R.J Unwin reviewed after dietary advice), even in the absence of a history of recurrent stones and especially if any stone analysis reports a composition of 100 % calcium oxalate Note that only about 20 % of excreted oxalate is dietary in origin, that a low-calcium diet (never recommended in stone formers) can lead to an increase in absorption of dietary oxalate (see below) and that even small decreases in urinary oxalate can have a large impact on stone risk (due to the relatively small total daily amount of oxalate excretion) Mechanisms of Calcium Stone Formation The three main mechanisms have some overlap between them (Fig 36.1): The free particle theory Crystals spontaneously precipitate in supersaturated urine The fixed particle theory Crystals adhere to damaged tubular cell membranes Randall’s plaque theory Calcium phosphate is deposited in papillary interstitium, causing damage to overlying epithelium, to which calcium oxalate can then adhere These mechanisms are balanced by inhibitors of calcium stone formation: Citrate Hypocitraturia is the most easily measured and is currently the most clinically modifiable inhibitor Citrate occurs naturally in fruit and fruit juices and is metabolised to bicarbonate It is easily replaced orally as potassium citrate, e.g in the management of distal renal tubular acidosis and sometimes in medullary sponge kidney Magnesium Although can sometimes participate in stone formation Pyrophosphate A structural analogue of bisphosphonates Tubular proteins such as uromodulin ↑ Calcium ↑ Oxalate ↓ ↑ pH ↓ Volume ↓ Citrate ↓ Magnesium ↑ Supersaturation ↓ Inhibitors (Citrate) Abnormal Crystalluria Stone ↑ Promoters (Abnormal [polymerised] Tamm-Horsfall) ↑ Uric acid Fig 36.1 Mechanisms of calcium stone formation 36 Renal Stone Disease 417 Cystine ~1 % Radio-lucent Uric acid ~5 % Rare stones and crystals ~1 % Infection stones ~5 % Calcium phosphate 15–20 % Calcium oxalate 50–60 % Fig 36.2 Overall prevalence of stone types Stone Types Stones are made up of 90 % mineral and the rest is water plus organic matrix Figure 36.2 shows an overall breakdown of stone types (Fig 36.3) Rare stone types consist of: xanthine, 2,8-dihydroxyadenine (APRT), silica, ammonium urate and insoluble drugs (indinavir, acyclovir, methyldopa, triamterene, sulphonamides) Stones due to protease inhibitors such as indinavir are actually large, often pure, crystals Urinary pH This is an important factor that affects solubility of many stone types and hence their formation, although calcium oxalate is pH independent Note that pH measured on dipstick is unreliable; the most accurate assessment is by pH meter measured soon after voiding As a guide, the normal pH range of early-morning urine sample is 5.3–6.8 Fig 36.3 Light microscopy of 2,8-dihydroxyadenine crystals (Kindly provided by Vidar Edvardsson, MD and Runolfur Palsson, MD, Landspitali-The National University Hospital of Iceland, and the APRT Deficiency Programme of The Rare Kidney Stone Consortium) of uric acid stones Patients with ileostomies are also at risk of forming uric acid stones from a combination of ileal losses of bicarbonate-rich fluid, leading to low urine volumes and acid urine • Cystine is increasingly soluble at higher pH, but this effect is overwhelmed if urinary cystine excretion is massive • Some drug-induced crystals: sulphonamides, e.g co-trimoxazole Forming at High pH • Calcium phosphate (pH > 6.2) stones are suggestive of an acidification defect (deficient proton secretion in type renal tubular acidosis) • Magnesium ammonium phosphate (MgNH4Pi; radioopaque, pH > 7.0) and ammonium urate (radiolucent) stones are caused by: – Infection with a urea-splitting organism – urease from Proteus, Klebsiella or Pseudomonas species causes ammonia release – Laxative abuse – this results in chronic potassium depletion and reduced urinary citrate excretion • Most drug-induced crystals typically form at higher pH: – Protease inhibitors – Ciprofloxacin (pH > 7.3) Nephrocalcinosis Forming at Low pH (Uric Acid, Cystine) • Acid urine (consistently less than pH 5.3) occurs in those with metabolic syndrome and/or obesity, who are also more likely to have hyperuricaemia, increasing their risk Nephrocalcinosis means a generalised increase in calcification of the renal parenchyma due to increased urinary excretion of calcium, phosphate or oxalate This is distinct from 418 S.H Moochhala and R.J Unwin Table 36.4 Causes of nephrocalcinosis Cause Acute hyperphosphaturia Hypercalciuria + hypercalcaemia Hypercalciuria + normocalcaemia Hyperoxaluria Structural or other disease Drugs Disease Acute phosphate nephropathy (due to sodium phosphate bowel prep), tumour lysis syndrome Primary hyperparathyroidism (20 % have nephrocalcinosis), sarcoidosis, Vitamin D or milk-alkali syndrome Tubulopathies (dRTA, MSK) Rarer tubulopathies (all causes listed in ‘genetic causes of calcium stones’ table (Tables 36.1 and 36.2)) Primary or secondary hyperoxaluria (see above) Severe disease of renal cortex (chronic glomerulonephritis, renal allograft rejection, renal cortical necrosis), renal tuberculosis Analgesic nephropathy (chronic papillary necrosis) calcium renal stone disease which represents more discrete calcification, usually in the collecting system, although both conditions may coexist It should be regarded as being a clue to an underlying cause of abnormal calcification Nephrocalcinosis always requires investigation because (a) there is a high likelihood of finding an underlying metabolic defect and (b) progression of the underlying disease process may cause renal failure The calcium deposits are composed of calcium phosphate or calcium oxalate (the latter known as ‘oxalosis’ especially if systemic) and once present are usually permanent, even if the cause is treated The largest nephrocalcinosis registry [15] found that 97 % of nephrocalcinosis affected the medulla and that these correlated with metabolic causes, most of which are also causes of calcium renal stone disease The remaining % (cortical) comprised structural causes The main causes are categorised in Table 36.4 Nephrocalcinosis is usually asymptomatic, but symptoms can occur due to the underlying cause or hypercalcaemia itself (if present) or due to consequences including calcium renal stone disease and sometimes polyuria (medullary nephrocalcinosis affects concentrating ability) Location of nephrocalcinosis Intracellular; cortical or medullary Medullary Medullary Medullary Medullary Cortical Medullary • Screening reduces health-care costs, by around £2,000 per avoided surgical episode [16] as well as indirect costs (reduced sick-pay, etc.) • The European Association of Urology (EAU) guidelines [17] recommend that first-time, solitary stone formers should have a basic metabolic screen and estimation of renal function For recurrent stone formers/high-risk patients, a more complete evaluation is recommended In many cases screening results will identify only subtle abnormalities Validated algorithms (e.g APCaOx, EQUIL, Psf) have been developed which combine parameters to quantify the risk of recurrence in these patients But even with this information, clinical evaluation of underlying conditions, diet, lifestyle and medication is required in order to provide meaningful advice to the individual patient Practical Management Acute Setting In the acute situation, the priority is rapid imaging and diagnosis of urinary tract obstruction, as well as any accompanying AKI or infection This will allow appropriate emergency treatment (see Surgical Treatment of Ureteric and Renal Stones) Clinical Assessment The aims of management are to treat the stone and to institute longer-term measures to reduce recurrence Rationale for Metabolic Screening To a nephrologist, urinary tract stones are a symptom rather than a diagnosis, whose cause should be investigated General advice to patients to reduce stone risk should of course be provided but an individualised management plan is more likely to reduce recurrence The high recurrence rate, rising incidence, number of procedures and associated costs justify preventative strategies: • 64 % of young adult stone formers had a single metabolic risk factor and 27 % had more than one, the commonest being hypercalciuria and hypocitraturia [14] Initial Investigations in the Urology Clinic Initial investigations should occur in the urology clinic for all patients with confirmed stones but not in those who have had a procedure or acute renal colic within the last month They should include: One biochemistry blood sample for: • Urea and electrolytes, venous bicarbonate, serum calcium, serum urate Two universal containers of urine for: • Urine dipstick (pH estimation, blood, protein, nitrites/ leucocytes) and then sent for culture • Qualitative cystine screen Stone analysis (of any collected stones; give patient a universal container and ask to sieve urine, especially if post-procedure) A mechanism should be in place for reviewing the results and making referrals for further screening where necessary 36 Renal Stone Disease 419 No studies have ascertained the sensitivity or specificity of this limited screen, and in our view, it forms the initial part of the advanced screen It allows assessment of renal function and detection of obvious abnormalities including systemic acid-base abnormalities, hypercalcaemia and urinary infections Instituting this simple protocol will require liaison with local urologists Prioritisation for formal metabolic assessment can then occur from this initial screen [18], and the presence of risk factors listed in Table 36.5 Table 36.5 Suggested referral criteria for metabolic screening Suggested referral criteria for metabolic screening Any of the following: First presentation at age