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Renal calculi in children
SYMPOSIUM: NEPHROLOGY
Renal calculi in children
are differentiated from cortical (e.g. in acute cortical necrosis) and diffuse nephrocalcinosis. The incidence of UL in adults is approximately 1.5 % and the prevalence rate is said to be 5.2%. About 12% of men and 5% of women in industrialized countries will pass a kidney stone at least once in their life. The incidence of paediatric UL is estimated to be approximately 10% of that in adults. In around 15e40% of children kidney stones are incidentally discovered. Due to the high proportion of non-specific symptoms the real incidence is almost certainly higher. In the 20th century it was reported that one in 1000 to one in 7500 paediatric hospital admissions were related to UL. More recently a nearly five-fold increase in hospital admissions for paediatric nephrolithiasis has been observed. Childhood UL affects all ages, but younger children more often present with renal calculi, older children with ureteral stones. The sex distribution has changed over time and the historical male predisposition for UL is no longer found. A more pronounced risk of stone disease is now found in women. A recent study analyzing the sex distribution in more than 2 million children hospitalized because of UL reported a changing sex distribution according to age: boys were more affected during the first decade (1.2:1 for 0e5 years, 1.3:1 for 6e10 years), while girls were more affected during the second decade of life (0.96:1 for 11e15 years, 0.3:1 for 16e20 years). Underlying metabolic disorders and a higher lithogenic risk is frequently found in children, but not in adults. Early diagnosis of a metabolic abnormality is important as treatment can prevent recurrence of UL, which is seen in up to 39% of children. Specific lithogenic risk factors are observed in up to 76% of children and, in some countries, hypocitraturia appears to be the most frequent. Known paediatric risk factors include genetic abnormalities in epithelial transport, metabolic disturbances, anatomical abnormalities and urinary tract infections. The increasing incidence of stone disease in adults, however, is much more based on environmental factors mainly reflected by diet, e.g. an increased intake of salt, animal protein, carbonated beverages and vitamin C. Changes in climate may also have had a significant impact on stone disease, at least in specific regions of the world. Obesity is an important risk factor for UL. Up to 30% of paediatric patients with UL diagnosed between 2003 and 2005 were reported to be overweight (more than 90th percentile). Nonetheless, a genetic background is much more obvious in the younger population with a lot of genetic diseases having their onset already in childhood.
Bernd Hoppe
Abstract An increasing number of paediatric patients of all ages with renal calculi are being seen in outpatient clinics worldwide. This is attributed to changes in environmental factors like diet, fluid intake and obesity. In children however, genetic and/or metabolic disorders are still the main reason for kidney stones. Next to hypercalciuria, which is generally considered to be the most frequent risk factor, other lithogenic or stone-inhibitory disorders like hypocitraturia or hyperoxaluria and a variety of renal tubular diseases have to be evaluated by urine and/or blood analysis. Non-specific symptoms like growth retardation, intestinal malabsorption or bone demineralization are to be considered not only to avoid further complications, but for diagnostic purposes. In preterm infants a high incidence of nephrocalcinosis is observed. These infants often have a combination of immature kidney function or medication that leads to relative hypocitraturia. Concise evaluation to diagnose the underlying patho-mechanism as early as possible is mandatory in all paediatric patients. In more than three-quarters of children a metabolic basis of urolithiasis/nephrocalcinosis will be found. Early treatment by reducing urinary saturation index by increasing fluid intake, by providing crystallization inhibitors, but also by disease specific medication prevents recurrent kidney stones and/or progressive nephrocalcinosis and therefore deterioration of renal function.
Keywords diagnosis; hypercalciuria; hyperoxaluria; hypocitraturia; nephrocalcinosis; paediatric urolithiasis; treatment
Introduction A significant increase in incidence and prevalence rates of adult nephrolithiasis has been noted in the industrialized countries. This increase is believed to mostly relate to environmental factors like dietary habits, fluid intake and obesity (metabolic syndrome). Although this is gaining importance in the paediatric population, genetic, metabolic and anatomical causes are still the main culprits for childhood stone disease. Nonetheless, paediatric outpatient visits and subsequently hospitalization for kidney stone disease have also increased over recent years. Around 80% of kidney stones contain calcium. Most consist of calcium-oxalate and metabolic disorders including hypercalciuria, hyperoxaluria and hypocitraturia are the most prominent risk factors for both nephrocalcinosis and nephrolithiasis. Urolithiasis (UL) is defined as stones formed in the kidney, but localized anywhere in the urinary tract. The term nephrolithiasis (NL) is used for stones remaining in the kidneys. Nephrocalcinosis (NC) describes calcium salts deposited in the tubules, the tubular epithelium and/or the interstitial tissue of the kidneys. NC frequently is classified based on the anatomic area involved: the three subtypes of medullary NC are rated according the degree of increase in parenchymal echogenicity and
Lithogenic risk factors of stone disease Hypercalciuria Hypercalciuria is the most frequently found urinary risk factor for UL. Primary (or idiopathic) hypercalciuria, is traditionally divided into a renal and an absorptive subtype. Primary hypercalciuria is the most common cause of calcium-containing stones. In the renal subtype, an elevated fasting urinary calcium excretion is found. However, many paediatric patients cannot easily be classified. Idiopathic calcium NL is considered a multifactorial disease characterized by a complex interaction of environmental and individual, or genetic factors. Genetic factors undoubtedly contribute to stone formation. In up to 50% of patients with
Bernd Hoppe MD is a Consultant at the University Hospital, Department of Pediatrics, Division of Pediatric Nephrology, Bonn, Germany. Conflict of interest: none declared.
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SYMPOSIUM: NEPHROLOGY
idiopathic hypercalciuria a positive family history is found. Also, calcium excretion is positively correlated between parents and their progeny and between siblings, but not between spouses. Genetic-derived risks appear to be greater than diet-related risks. So far, genetic research has focused on monogenic disorders and autosomal dominant, recessive and X-linked inherited genetic disorders have been identified.
adrenal insufficiency and metastatic malignant bone disease. Acidebase disturbances associated with long-term ventilation and parenteral nutrition can lead to hypercalciuria. Conditions with elevated serum calcium Other clinical entities lead to hypercalcaemia and secondary hypercalciuria. Here, primary hyperparathyroidism, the most frequent cause of hypercalcemic hypercalciuria in adults, is rather rare in children. Hypervitaminosis D, e.g. based on the application of multivitamin preparations including vitamin D, or on vitamin D added to milk preparations, or even due to vitamin D prophylaxis in (preterm) infants, may induce hypercalcaemia and hypercalciuria (Table 1). An excessive intake of vitamin A, more than 10,000 units/day, may also lead to hypercalcaemia and can therefore induce hypercalciuria. Short-term immobilization reduces bone mass rapidly (w15e20%) and is also accompanied by hypercalciuria.
Conditions leading to elevated urinary calcium with normal serum calcium Medullary NC and calcium phosphate stones are frequently seen in patients with distal renal tubular acidosis (d-RTA, Figure 1). Here, a high urinary pH, hypercalciuria and hypocitraturia combine to predispose the child to renal calculi. Medullary NC with or without cortical NC is also described in tyrosinemia, a rare disease (1:100.000 live births) which often is combined with impaired renal function, aminoaciduria, hypercalciuria and tubular acidosis. In Dent’s disease I, a rare but extremely severe X-linked hypercalciuric nephropathy with tubular proteinuria, early progressive NC and renal failure occur. Hypercalciuria also occurs after long-term administration of furosemide, dexamethasone or ACTH. Hypercalciuria is also found in several syndromes ie Bartter’s syndrome, William’s syndrome or can occur secondary to renal tubular damage (Wilson’s disease, Dent II syndrome, Table 1). Other conditions known to lead to hypercalciuria are hyper- and hypothyroidism, Cushing syndrome,
Hyperoxaluria An increased urinary oxalate excretion (hyperoxaluria) is an important promoter of crystallization processes. Primary (endogenous oxalate overproduction) is distinguished from secondary causes (Table 1). Primary hyperoxaluria: currently, three forms of primary hyperoxaluria (PH), which are rare, autosomal-recessive
Figure 1 (a) Bladder stone in a 3-year-old girl with hypocitraturia, (b) kidney stones in a 20 months old girl with dystrophy and chronic urinary tract infections, (c) kidney stones in a patient with primary hyperoxaluria type III and (d) medullary nephrocalcinosis in a patient with renal tubular acidosis. Source: Images provided by Mark Born, MD, Department of Radiology, Division of Pediatric Radiology, University of Bonn, Germany.
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Non genetic reasons
Genetic reasons (monogenetic diseases) Hyperoxaluria
Most frequent reason of normo-calcemic hypercalciuria 9 PTHY = PTH[ big overlapping ; PTH[
C
C
Hypercalcemic hypercalciuria
C
C
Normo-calcemic hypercalciuria
Hyperparathyroidism, tumour/bone metastasis, hypervitaminosis D/A, hypophosphatasia, immobilization, hyperthyroidism, sarcoidosis, adrenal insufficiency, corticosteroid excess RTA, furosemide treatment, hyperalimentation, juvenile rheumatoid arthritis, hypophosphatemia, familial hypomagnesaemia hypercalciuria and nephrocalcinosis syndrome (FHHNC), high sodium intake
C
Mostly renal symptoms Fanconi syndrome (hypercalciuria, proteinuria, glycosuria, amino-aciduria, phosphaturia), NC, rickets, progress to early end stage renal failure Dent 2 disease (Lowe) Fanconi syndrome, rickets, cataract, mental retardation, chronic kidney disease Familial hypomagnesaemia and hyperHypercalciuria, hypomagnesaemia, medullary calciuria syndrome (FFHNC) NC, chronic kidney disease Dent 1 disease
C
CYP24A1 mutations
C
Bartter syndrome
Vitamin D sensitivity, hypercalciuria, early (infantile) nephrocalcinosis Hypokalemia with hypochloremic metabolic alkalosis, hypercalciuria and NC ¼ classic BS
In the context of systemic diseases C Tyrosinemia type 1 C Wilson’s disease C Glycogen-storage disease type 1a C WilliamseBeuren syndrome (WBS) Hyperoxaluria C
Enteric/diet
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Inflammatory bowel diseases (Crohn’s), malabsorption syndromes, e.g. cystic fibrosis, post bowel resections/short bowel syndrome, fat malabsorption, dietary calcium restrictions, lack of intestinal oxalate degrading bacteria (Oxalobacter formigenes)
C
Prim. hyperoxaluria type I (PH I)
In urine: oxalate þ glycolate [, in plasma: oxalate [ In infantile oxalosis: diffuse NC (“white kidney") and early end stage renal failure Childhood: rec. urolithiasis, kidney failure variable either in childhood, or as late as the 5th decade of life Vitamin B6 treatment leads to normalization of urinary oxalate excretion in some patients with missense mutations (continued on next page)
SYMPOSIUM: NEPHROLOGY
Idiopathic hypercalciuria Absorptive HC Renal (loss) HC Resorptive (bone) HC
C
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Reasons of urolithiasis (UL) or nephrocalcinosis (NC) in childhood. ADPKD [ autosomal dominant polycystic kidney disease, FHHNC [ familial hypomagnesaemia and hypercalciuria syndrome, HC [ Hypercalciuria, HOG [ hydroxyl-oxo-glutarate, PH [ primary hyperoxaluria, PTH [ parathyroid hormone, RTA [ renal tubular acidosis, UTI [ urinary tract infection
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Non genetic reasons
Genetic reasons (monogenetic diseases) Hyperoxaluria
C
Drugs/intoxications
Vitamin C overdosage, ethylene-glycolintoxication
C
Prim. hyperoxaluria II (PH II)
C
Prim. hyperoxaluria III (PH III)
In urine: oxalate þ L-glyceric acid [, in plasma: oxalate [ In comparison to PH type I more benign phenotype, with ESRD in about 20% of patients In urine: oxalate (þcalcium [ þ uric acid [) and HOG [, in plasma: oxalate [ Already in infancy severe recurrent kidney stone disease, less severe symptoms in further follow up, even stop of symptoms possible, no end stage renal failure reported yet
Hypocitraturia Preterm infants
Especially <1500 g birth weight and <30. Gestation age, NC persistent in 15e50% of cases
C
Transplantation/immunosuppressive medication Dietary
Medication induced hypocitraturia, e.g. calcineurine inhibitors Diet high in animal protein
C
Renal tubular acidosis
C
Distal RTA (type 1) with reduced urinary Hþexcretion and significant hypocitraturia and NC Proximal RTA (type 2) with urinary bicarbonate wasting þ less severe hypocitraturia and milder NC/UL Further subforms or secondary forms accompanying other systemic diseases
Other risk factors
C
Urinary tract infections Anatomic anomalies of kidney and urinary tract Hyperuricosuria
C
Drugs
C C
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Table 1
Infectious stones, e.g. Proteus mirabilis UTI Obstruction, ADPKD (uric acid stones), megacalicosis e.g. Tumor lysis syndrome, dietary (metabolic syndrome), Colitis ulcerosa Sulfonamide, Ceftriaxone, Amoxicilline, Magnesium silicates (antacida), Allopurinol (Xanthine), Indinavir, Triamterene
C
Hyperuricosuria
C
Cystinuria
C
Xanthinuria
LescheNyhan syndrome, with gout, UL, automutilation Type I, non-type I and mixed type high urinary cystine excretion, hexagonal cystine crystals in sediment, recurrent kidney stone formation Extremely rare, most often subclinical course, elevated urinary xanthine excretion, in 50% of patients UL in childhood
SYMPOSIUM: NEPHROLOGY
C
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Table 1 (continued )
SYMPOSIUM: NEPHROLOGY
Cystinuria The overall prevalence of the autosomal-recessive form of cystinuria is one in 7000. It is the cause of up to 10% of all urinary stones in children. More than half of the patients present with bilateral urolithiasis, most frequently during the first two decades of life. Without treatment frequent stone formation and passage is the case. Cystinuria is the result of a defective transport of cystine and the dibasic amino acids lysine, ornithine and arginine through the epithelial cells of the renal tubule and the intestinal tract. Only cystine however, is insoluble enough to form stones. At urine pH more than 8, cystine solubility is increased threefold. According to the disease specific genotype three types of cystinuria are now distinguished: type A with mutations on chromosome 2, type B on chromosome 19 and type AB with mutations on both. There is no obvious clinical difference based on the different genotype.
inherited defects of the glyoxylate metabolism, are known. Primary hyperoxaluria type I with low or absent activity of liver specific peroxisomal alanine:glyoxylate aminotransferase (AGT) is the most prevalent and the most disastrous form not only of PH, but also of urolithiasis per se. The encoding AGXT-gene is found on chromosome 2q36-37 and diagnosis is made by genetic mutation analysis. PH I is rare with a prevalence of approximately two patients per million population. Both urinary oxalate and glycolate excretion are highly increased, which causes recurrent calcium-oxalate calculi, medullary, or in infantile oxalosis generalized NC, or both (Figure 1). Inflammatory processes in the kidney induced by oxalate itself lead to rapid decline in renal function, which aggravates calcium-oxalate crystals accumulation and its deposition in the parenchyma of other organs, as well as in bones and retina. A very large clinical, biochemical and genetic heterogeneity is known, ranging from infantile oxalosis, prompt renal failure and all too often death to patients just having occasional passage of stones in adult life with preserved renal function. Therefore it is a disaster if the diagnosis of PH I is delayed for many years, and it should be excluded in all repeated calcium-oxalate stone formers. In primary hyperoxaluria type II (PH II), which is less frequently observed than PH I, urinary excretion of oxalate and Lglyceric acid is increased due to a defect of both liver specific Dglycerate dehydrogenase and hydroxypyruvate reductase (GRHPR). Its clinical course is much milder than in PH I, although symptoms are comparable. However, end stage renal failure is rather the exception (5e10% of patients). Mutation analysis of the GRHPR gene is the diagnostic gold standard. Primary hyperoxaluria type III is probably the second most common form of the PH’s. It starts in early childhood with severe urolithiasis and often stone removal procedures are necessary. In PH type III mutations of the hydroxy-oxo-glutarate gene HOGA1 lead to a loss of function of the encoded enzyme and hence to elevated urinary excretions of oxalate and hydroxy-oxoglutarate. The patho-mechanism leading to the elevated oxalate production is still a matter of debate. Currently, no patient with type III PH has developed chronic kidney failure and most reports show that the clinical situation improves over time. However, hyperoxaluria and sometimes even hypercalciuria may persist.
Purine stones Hyperuricosuria: uric acid stones are a seldom seen in the paediatric population. Hyperuricosuria is found in those with high-purine diets, myeloproliferative disorders, tumour lysis syndrome, or enzymatic defects. Drugs like probenecid, salicylates or contrast media also increase uric acid excretion. The strongest risk factors for uric acid stones are a low urine pH and low urine volume. Rare inherited deficiencies of the purine salvage enzymes hypoxanthine-phosphoribosyl-transferase (HPRT) and adeninePRT (APRT) induce primary purine overproduction. Complete HPRT deficiency leads to the X-linked LescheNyhan syndrome. This is characterized by mental retardation, automutilation, choreoathetosis, gout and uric acid NC, whereas partial deficiency of HPRT results in urolithiasis and renal failure alone. Gout and urolithiasis are also found in glycogen-storage disease type I. Rarer purine stones 2,8-Dihydroxyadeninuria: APRT deficiency has an autosomalrecessive inheritance. Here, serum uric acid is normal but there is an elevation of urinary 2,8-dihydroxyadenine which can also form stones. The stones are radiolucent and may be confused with uric acid stones. Urine microscopy reveals characteristic brownish round crystals, diagnosis will be confirmed by decreased APRT activity in red blood cells or from urinary excretion of dihydroxyadenine.
Secondary hyperoxaluria: it is frequently found in patients with chronic inflammatory bowel disease (e.g. Crohn’s), with malabsorption syndromes (cystic fibrosis, celiac disease, a-ß lipoproteinemia), or in patients with short bowel syndrome, e.g. after necrotizing enterocolitis. Normally, intestinal oxalate binds to calcium to form insoluble calcium-oxalate, which is not absorbed. In malabsorptive states calcium instead binds to fatty acids and more soluble oxalate is available for absorption, this leads to enteric hyperoxaluria. A lack of intestinal oxalate degrading bacteria, e.g. Oxalobacter formigenes, is another reason for increased oxalate absorption, e.g. in patients with cystic fibrosis. If intestinal oxalate degradation does not take place, more oxalate is again available for absorption. The prevalence of UL is reported to be as high as 17% in patients with Crohn’s disease. Up to 50% of our patients with cystic fibrosis have hyperoxaluria and about one in ten develop UL or NC. Enteric hyperoxaluria may also lead to severe NC and/or recurrent urolithiasis, even renal failure and systemic oxalosis.
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Xanthinuria: deficiency of xanthine-oxidase, which converts xanthine to uric acid, leads to xanthinuria, where serum uric acid concentration is very low. Characteristic findings in xanthinuria are an orange-brown urinary sediment or orange-stained nappies, but later xanthine stones. Hypocitraturia: urinary citrate will inhibit calcium stone formation. Hypocitraturia is a characteristic finding in the complete form of d-RTA, but is also observed in persistent mild or latent metabolic acidosis, in hypokalemia and in patients with malabsorption syndromes. Idiopathic hypocitraturia may be secondary to low intestinal alkali absorption. In some regions of the world, as well as in specific patient populations (e.g. preterm infants), hypocitraturia is the most important risk factor for stone disease (Table 1). Also, hypocitraturia was reported to be one of the major determinants of preterm nephrocalcinosis.
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SYMPOSIUM: NEPHROLOGY
Infectious stones Infectious stones are often only composed of struvite (magnesium ammonium phosphate), but can also contain carbonateapatite, which crystallizes at high urinary pH (more than 7.0). Urease-producing bacteria induce hydrolysation of urea to ammonium ions which in turn results in a high urinary pH. Many gram-positive and gram-negative bacteria produce urease, but Proteus species are the predominant organisms. Struvite stones are mostly found in the kidney, but they may also form in the bladder (Figure 1). Often, an additional primary anomaly of the urinary tract, like uretero-pelvic junction obstruction, primary mega-ureter, or more rarely ureterocele or urethral valves is found. Neurogenic bladder patients, particularly those based on a meningomyelocele, are particularly prone to struvite stones. Infectious stones may also form on a nidus of different composition and therefore it is important not to miss an underlying metabolic disorder.
substantial information on concomitant diseases, fluid intake, diet, medications, but also about possible genetic disorders (Figure 2). Clinical symptoms may be analogous to adults, as most children present with flank or abdominal pain. Atypical and nonspecific complaints are more likely in younger children especially in infants. Nausea and vomiting, the presence of flank pain, or haematuria are all positively associated with UL in children. Nephrocalcinosis, however, is mostly asymptomatic and often only diagnosed when ultrasound is performed in patients with haematuria. An approach to the evaluation of childhood UL is shown in Figure 2. The gold standard for diagnosis is an analysis of repeated 24-hour urine samples for lithogenic and stone-inhibitory parameters. In the smaller infant spot urine evaluations might only be possible (age related molar creatinine ratios, Table 2). The first-line imaging procedure is an ultrasound scan of the kidneys, ureters and bladder. Whilst unenhanced computed tomography (CT) will depict stones more accurately than ultrasound (ultrasound detects 90% of kidney stones, but only 38% of ureteral stones compared to CT). However, in infants and young children, ultrasound should always be the first choice to minimize radiation exposure and as there is no need for sedation.
Medication and intoxications Only a small proportion (1e2%) of renal stones in children is solely drug related. Poorly soluble drug components either form stones itself, e.g. indinavir, or provide a nidus for stone formation. Other medications precipitating in the urine but rarely causing stones include ceftriaxone, sulfonamides, ampicillin, amoxicillin, triamterene, acyclovir and oxypurine. Medication can increase the excretion of lithogenic substances (e.g. loop diuretics, calcium/vitamin D supplementation) or reduce the excretion of anti-lithogenic substances (carbonicanhydrase inhibitors, topiramate). Hypercalciuria induced by loop diuretics is known as one major risk factor in nephrocalcinosis of prematurity. Many patients with drug-induced nephrolithiasis, however, have additional metabolic abnormalities as risk factors. Nephrolithiasis due to melamine contamination of powdered milk formula was reported in 2008 with more than 50,000 children suffering from urolithiasis and acute or chronic kidney injury. Melamine is a synthetic chemical added to milk or animal feed to boost the protein because of its high nitrogen content. Children exposed to high-melamine formula display a 5.4e7.0 fold increased risk of urolithiasis. Ethylene glycol intoxication, usually observed after accidental ingestion of antifreeze or because of suicide attempts, leads to severe hyperoxaluria based on its conversion to glycolic acid, formalin and oxalic acid via alcohol dehydrogenase. An extreme anion-gap and abundant calcium-oxalate crystals in the urine are found, the latter inducing acute renal failure due to calciumoxalate crystal agglomeration in the renal parenchyma. For treatment administration of ethanol or 4-methylpyrazole is necessary to block the alcohol dehydrogenase, bicarbonate to treat the metabolic acidosis and haemodialysis to remove both ethylene glycol and its metabolites.
Treatment Acute stone passage Patients with acute renal colic present with severe pain and analgesia will be required (Figure 3). Stone passage can often be induced by a combination of high fluid intake plus medication like calcium channel blockers, alpha-blockers and/or corticosteroids. When obstruction is obvious, renal function is impaired or a urinary tract infection is present, prompt stone removal is indicated. Minimally invasive procedures for stone removal are the usual first choice (not lithotripsy). Initial urine drainage by a nephrostomy tube can be performed to facilitate urine excretion and to avoid further kidney damage. It is important to try to catch the stone for further analysis. Conservative, preventive measures Preventive management is mainly based on the reduction of the solute concentration in the urine. Independent of the underlying disorder, hyperhydration (more than 1.5e2 L/1.73 m2 body surface area/day) is the precondition for all further treatment. Fluid intake must be distributed over the whole day to provide peaks of high concentration levels of the soluble. Dietary recommendations should only carefully be given. Dietary restrictions, for example, a low calcium diet in any patient with calcium stones is obsolete, as it will lead to secondary hyperoxaluria. Also, a low oxalate diet in patients with secondary hyperoxaluria is restricted to food with a very high oxalate content. Crystallization inhibitors Crystallization inhibitors (mainly citrate and magnesium) are an effective treatment option to increase urinary solubility. Urinary citrate binds to calcium forming a soluble complex and thus reducing the precipitation of calcium with other substances. Also, urinary calcium excretion can be reduced by approximately 30%. Citrate treatment has been shown to decrease stone production and to reduce progression of nephrocalcinosis.
Clinical presentation and diagnostic pathway in children It is important to realize that nephrocalcinosis and urolithiasis are the symptom of underlying diseases and not the disease itself. Therefore, a thorough diagnostic evaluation is required in each child after the first stone event, or when nephrocalcinosis is detected. A thorough personal and family history provides
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SYMPOSIUM: NEPHROLOGY
Micro-/ macrohematuria
Recurrent flank pain
Known NL/NC
Tubulopathy
Recurrent UTI
Known genetic stone disease
Diagnostic algorithm History Prematurity? Intestinal diseases, malabsorption syndromes? Fluid intake? Vitamin supplementation, especially Vitamin D and/or A? Medication, especially steroids, immune suppressants, diuretics? Anatomic anomalies? Rec. UTI? (secondary) Enuresis → urine concentration defects?
Family history Known NC/NL Consanguinity? Cases of unclassified kidney failure or chronic renal insufficiencey?
Clinics Acute Symptoms Renal colic, flank pain? Hematuria? Dysuria, urine stasis? Stone passage?
Chronic symptoms Recurrent abdominal pain of unknown origin? (Secondary) enuresis? Micro-/Macrohematuria? Malabsortion/failure to thrive?
Labs Urine analysis Dipstick spot urine (pH, density, osmolarity, hematuria, proteinuria, glucosuria), cylinder? Non glomerular hematuria? Spot urine: Molar creatinine ratios for oxalate/calcium/citrate/uric acid Better: 24-h-urine with calcium, oxalate, citrate, uric acid excretion, pH, density, volume Specific diagnostics Amino acid screen (cystine)
Serum analysis Blood gas analysis, pH, bicarbonate elektrolytes, creatinine, (cystatine C), urea, uric acid, calcium, phosphate, iPTH, alkaline phosphatase Stone analysis Specific diagnostic evaluation Plasma oxalate Vitamin D, A FGF23 Genetic analysis Imaging
Ultrasound of kidneys and urinary tract
CT (low enhanced) to identify small stones, microcalculi
Figure 2 Diagnostic algorithm of evaluation of children with nephrocalcinosis or nephrolithiasis.
latter, the potassium-sparing diuretic amiloride may occasionally be given.
The recommended daily dosage is 0.1e0.2 g/kg body weight (0.3 e0.6 mmol/kg body weight) as sodiumepotassium or potassium citrate, but in patients with distal RTA, the dosage will be higher and should be adapted to the serum pH and serum potassium levels. The alkalinization of urine produced by oral citrate increases the solubility of cystine, uric acid and calcium-oxalate. However, urinary pH has to be monitored to avoid very high levels increasing the risk of calcium-phosphate precipitation.
Specific treatment in primary hyperoxaluria Patients with PH I are treated with pyridoxal-phosphate, the cofactor of the defective enzyme. Treatment in supra-physiological doses (5e20 mg/kg body weight per day), help to reduce the endogenous oxalate production and hence the urinary oxalate excretion in approximately a third of patients. Side effects are polyneuropathy, but sometimes also bullous skin eruptions, as well as acne. Future treatment options in primary, but also secondary hyperoxaluria might include the oral administration of intestinal oxalate degrading bacteria, e.g. O. formigenes, which already showed its efficacy in reducing urinary oxalate excretion in two pilot trials. No renal replacement therapy is capable of removing sufficient amounts of oxalate. Hence, patients with PH and renal
Thiazides in hypercalciuria In patients with severe hypercalciuria thiazides help to reduce the renal calcium excretion by increasing calcium uptake in the distal tubule and stimulation of calcium reabsorption in the proximal tubule. In patients with a reduced bone density due to hypercalciuria, thiazide treatment is indicated, as it may also improve bone density. A daily dosage of 0.5e1 mg per kg body weight is given twice daily but side effects like hypotension and hypokalemia should be monitored for. To avoid the
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Calcium
Citrate
Cystine
Oxalate
Urate
24 hours Urine excretion parameters <10 years <55 umol/1.73 m2/24 hours All age <0.5 mmol/1.73 m2/24 hours <1 year All age <0.1 mmol/kg/24 hours All age Boys: <70 umol/kg/24 hours 2 <13 mg/1.73 m2/24 hours groups <45 mg/1.73 m2/24 hours <1.3 mg/kg/24 hours groups <4 mg/kg/24 hours groups >1.9 mmol/1.73 m /24 hours >365 mg/1.73 m2/24 hours 1e5 years <65 umol/kg/24 hours Girls: >10 years <200 umol/1.73 m2/24 hours 2 <1.1 mg/kg/24 hours >1.6 mmol/1.73 m /24 hours <48 mg/1.73 m2/24 hours >310 mg/1.73 m2/24 hours >5 years <55 umol/kg/24 hours <0.9 mg/kg/24 hours Soluble/creatinine ratio (spot urine samples) mol/mol g/g <12 months 1e3 years 3e5 years 5e7 years >7 years Table 2
<2.2 <1.5 <1.1 <0.8 <0.6
<0.8 <0.53 <0.4 <0.3 <0.21
mol/mol
g/g
0-5 years
>0.12e0.25
>0.2e0.42
>5 years
>0.08e0.15
>0.14e0.25
mmol/mol
mg/g
<1 month
<85
<180
1e6 months
<53
<112
>6 months
<18
<38
0e6 months 7e24 months 2e5 years 5e14 years >14 years
mmol/mol
mg/g
<325e360 <132e174 <98e101 <70e82 <40
<260e88 <110e39 <80e81 <60e65 <32
<12 months 1e3 years 3e5 years 5e10 years >10 years
mol/mol
g/g
<1.5 <1.3 <1.0 <0.6 <0.4
<2.2 <1.9 <1.5 <0.9 <0.6
SYMPOSIUM: NEPHROLOGY
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Normal values for lithogenic and stone-inhibitory parameters in 24 hours urine samples (excretion), or spot urines (molar creatinine ratios). Urine samples are preserved with either thymol 5% in isopropanol, or 2 N HCl before start of collection. Repeated collections are necessary for verification of results. Adequate collection is checked by 24 hours urine volume and creatinine excretion (2 mg/kg 0.8 mg)
SYMPOSIUM: NEPHROLOGY
Acute colicky abdominal pain
Sonography Without evidence, but still clinical signs Nephrolithiasis with severe obstruction/ infection
Nephrolithiasis (non-obstructive)
Low enhanced CT
Without evidence
Other reasons for abdominal pain
Conservative measures: i.v.-hydration Analgesia + Spasmolytics Steroids and Calcium-channel-blockers
No clinical improvement
Stone passage
Prompt intervention by pediatric urologist
Stone analysis and further diagnostic evaluation
Figure 3 Therapeutic algorithm in acute colicky abdominal pain.
Specific treatment in purine stones In patients with uric acid stones urine alkalinization to keep a urinary pH above 6.5 is the main goal. In addition excess protein intake should be avoided. Allopurinol, an inhibitor of the xanthineoxidase, reduces serum uric acid and therefore its excretion. A careful dosing regimen is necessary, as it can lead to significant xanthinuria. Xanthine solubility does not increase in alkalinized urine, thus hyperhydration is the main means of therapy. In patients with dihydroxyadenine stones, urine dilution, allopurinol dietary restrictions of adenine and purine are all helpful measures.
failure should be transplanted as early as possible. Combined liverekidney transplantation is the method of choice in PH I to cure the liver specific enzyme defect. Isolated kidney transplantation is performed in PH type II and can be considered in the PH I patient being pyridoxine sensitive. Also, pre-emptive liver transplantation was performed in PH I, but timing of the procedure is difficult due to the clinical heterogeneity of the disease. Specific treatment in cystinuria A careful methionine (protein) restricted diet is recommended in patients with cystinuria, as it is metabolized to cysteine. Cystine is then formed by the oxidation of two cysteine molecules linked by a disulfide bond. Urine alkalinization is the main goal of pharmacotherapy as cystine has a higher solubility at urinary pH more than 8. Chelating agents cleave the disulfide bond of cystine to cysteine, a 50 times more soluble homodimer of cystine. D-Penicillamine and alpha-mercaptopropionyl-glycine (MPG) are equally effective (20e40 mg/kg body weight per day in two divided doses). Side effects include rash, arthralgia, exanthema, thrombocytopenia, polymyositis and nephritic syndrome, which limits treatment. ACE inhibitors act equivalent to MPG in increasing cystine solubility and may also be accompanied by less severe side effects. D-Penicillamine reduces the level of pyridoxine, which therefore has to be supplemented. Ascorbic acid can reduce cystine to cysteine when administered in very high doses, however, there is ongoing debate about the efficacy and it can induce hyperoxaluria.
PAEDIATRICS AND CHILD HEALTH --:-
Infectious stones For children with recurrent infectious stones, stone removal and surgical management of anatomic anomalies are the most important therapeutic steps. Failure to remove the stones increases the risk of further infection.
Conclusion In children with renal calculi or nephrocalcinosis prompt metabolic evaluation should be performed. The stone or the crystal deposition is not the disease itself, it is only its (first) symptom. In approximately 75% of children a metabolic or genetic background for UL/NC will be found and can be treated in most of the patients. In these cases recurrent kidney stones or progressive NC, or eventual renal failure, e.g. in the primary hyperoxalurias, can be prevented.
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SYMPOSIUM: NEPHROLOGY
Schell-Feith EA, Kist-van Holthe JE, Conneman N, et al. Etiology of nephrocalcinosis in preterm neonates: association of nutritional intake and urinary parameters. Kidney Int 2000; 58: 2102e10. Sternberg K, Greenfield SP, Williot P, Wan J. Pediatric stone disease: an evolving experience. J Urol 2005; 174: 1711e4. discussion 1714. Straub M, Strohmaier WL, Berg W, et al. Diagnosis and metaphylaxis of stone disease. Consensus concept of the National Working Committee on Stone Disease for the upcoming German Urolithiasis Guideline. World J Urol 2005 Nov; 23: 309e23. Thomas BG. Management of stones in childhood. Curr Opin Urol 2010; 20: 159e62. van’t Hoff WG. Aetiological factors in paediatric urolithiasis. Nephron Clin Pract 2004; 98: 45e8.
Only minimally invasive procedures for stone removal should be performed in children, silent stones may be left in place. Infectious stones, however, have to be removed to prevent recurrent urinary tract infections. It is, of course, always better to perform prophylactic treatment, which is cheaper and less harmful, than repeated stone removals. Conservative treatment is most efficient in the majority of patients. A FURTHER READING Beck BB, Baasner A, Buescher A, et al. Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies. Eur J Hum Genet 2013; 21: 162e72. Cameron MA, Sakhaee K, Moe OW. Nephrolithiasis in children. Pediatr Nephrol 2005; 20: 1587e92. Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med 2013; 369: 649 e58. Erratum in: N Engl J Med 2013;369(22):2168. Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and urolithiasis in children. Kidney Int 2011; 80: 1278e91. Hollingsworth JM, Rogers MAM, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006; 368: 1171e9. Hoppe B, Leumann A, Milliner DS. Urolithiasis and nephrocalcinosis in childhood. Philadelphia. In: Geary DF, Schaefer F, eds. Comprehensive pediatric nephrology 2008; 499e525. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol 2012; 8: 467e75. pez M, Hoppe B. History, epidemiology and regional diversities of Lo urolithiasis. Pediatr Nephrol 2010; 25: 49e59. Palmer JS, Donaher ER, O’Riordan MA, Dell KM. Diagnosis of pediatric urolithiasis: role of ultrasound and computerized tomography. J Urol 2005; 174: 1413e6.
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Practice points C
C
C
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The first kidney stone and every nephrocalcinosis should lead to a thorough diagnostic evaluation in every child and should start with a thorough patient and family history Urine examinations and stone analysis are helpful in defining underlying lithogenic pathology and are followed by specific blood chemistry analysis and genetic testing Try to prevent stone recurrence to avoid kidney damage. Recurrent kidney stones and progressive nephrocalcinosis can lead to end stage renal failure, if the underlying pathology is not adequately diagnosed and treated High fluid intake, medication to increase urine solubility and disease specific therapy, e.g. pyridoxine in primary hyperoxaluria type I, can be successful when diagnosis is made early
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Renal calculi in children
are differentiated from cortical (e.g. in acute cortical necrosis) and diffuse nephrocalcinosis. The incidence of UL in adults is approximately 1.5 % and the prevalence rate is said to be 5.2%. About 12% of men and 5% of women in industrialized countries will pass a kidney stone at least once in their life. The incidence of paediatric UL is estimated to be approximately 10% of that in adults. In around 15e40% of children kidney stones are incidentally discovered. Due to the high proportion of non-specific symptoms the real incidence is almost certainly higher. In the 20th century it was reported that one in 1000 to one in 7500 paediatric hospital admissions were related to UL. More recently a nearly five-fold increase in hospital admissions for paediatric nephrolithiasis has been observed. Childhood UL affects all ages, but younger children more often present with renal calculi, older children with ureteral stones. The sex distribution has changed over time and the historical male predisposition for UL is no longer found. A more pronounced risk of stone disease is now found in women. A recent study analyzing the sex distribution in more than 2 million children hospitalized because of UL reported a changing sex distribution according to age: boys were more affected during the first decade (1.2:1 for 0e5 years, 1.3:1 for 6e10 years), while girls were more affected during the second decade of life (0.96:1 for 11e15 years, 0.3:1 for 16e20 years). Underlying metabolic disorders and a higher lithogenic risk is frequently found in children, but not in adults. Early diagnosis of a metabolic abnormality is important as treatment can prevent recurrence of UL, which is seen in up to 39% of children. Specific lithogenic risk factors are observed in up to 76% of children and, in some countries, hypocitraturia appears to be the most frequent. Known paediatric risk factors include genetic abnormalities in epithelial transport, metabolic disturbances, anatomical abnormalities and urinary tract infections. The increasing incidence of stone disease in adults, however, is much more based on environmental factors mainly reflected by diet, e.g. an increased intake of salt, animal protein, carbonated beverages and vitamin C. Changes in climate may also have had a significant impact on stone disease, at least in specific regions of the world. Obesity is an important risk factor for UL. Up to 30% of paediatric patients with UL diagnosed between 2003 and 2005 were reported to be overweight (more than 90th percentile). Nonetheless, a genetic background is much more obvious in the younger population with a lot of genetic diseases having their onset already in childhood.
Bernd Hoppe
Abstract An increasing number of paediatric patients of all ages with renal calculi are being seen in outpatient clinics worldwide. This is attributed to changes in environmental factors like diet, fluid intake and obesity. In children however, genetic and/or metabolic disorders are still the main reason for kidney stones. Next to hypercalciuria, which is generally considered to be the most frequent risk factor, other lithogenic or stone-inhibitory disorders like hypocitraturia or hyperoxaluria and a variety of renal tubular diseases have to be evaluated by urine and/or blood analysis. Non-specific symptoms like growth retardation, intestinal malabsorption or bone demineralization are to be considered not only to avoid further complications, but for diagnostic purposes. In preterm infants a high incidence of nephrocalcinosis is observed. These infants often have a combination of immature kidney function or medication that leads to relative hypocitraturia. Concise evaluation to diagnose the underlying patho-mechanism as early as possible is mandatory in all paediatric patients. In more than three-quarters of children a metabolic basis of urolithiasis/nephrocalcinosis will be found. Early treatment by reducing urinary saturation index by increasing fluid intake, by providing crystallization inhibitors, but also by disease specific medication prevents recurrent kidney stones and/or progressive nephrocalcinosis and therefore deterioration of renal function.
Keywords diagnosis; hypercalciuria; hyperoxaluria; hypocitraturia; nephrocalcinosis; paediatric urolithiasis; treatment
Introduction A significant increase in incidence and prevalence rates of adult nephrolithiasis has been noted in the industrialized countries. This increase is believed to mostly relate to environmental factors like dietary habits, fluid intake and obesity (metabolic syndrome). Although this is gaining importance in the paediatric population, genetic, metabolic and anatomical causes are still the main culprits for childhood stone disease. Nonetheless, paediatric outpatient visits and subsequently hospitalization for kidney stone disease have also increased over recent years. Around 80% of kidney stones contain calcium. Most consist of calcium-oxalate and metabolic disorders including hypercalciuria, hyperoxaluria and hypocitraturia are the most prominent risk factors for both nephrocalcinosis and nephrolithiasis. Urolithiasis (UL) is defined as stones formed in the kidney, but localized anywhere in the urinary tract. The term nephrolithiasis (NL) is used for stones remaining in the kidneys. Nephrocalcinosis (NC) describes calcium salts deposited in the tubules, the tubular epithelium and/or the interstitial tissue of the kidneys. NC frequently is classified based on the anatomic area involved: the three subtypes of medullary NC are rated according the degree of increase in parenchymal echogenicity and
Lithogenic risk factors of stone disease Hypercalciuria Hypercalciuria is the most frequently found urinary risk factor for UL. Primary (or idiopathic) hypercalciuria, is traditionally divided into a renal and an absorptive subtype. Primary hypercalciuria is the most common cause of calcium-containing stones. In the renal subtype, an elevated fasting urinary calcium excretion is found. However, many paediatric patients cannot easily be classified. Idiopathic calcium NL is considered a multifactorial disease characterized by a complex interaction of environmental and individual, or genetic factors. Genetic factors undoubtedly contribute to stone formation. In up to 50% of patients with
Bernd Hoppe MD is a Consultant at the University Hospital, Department of Pediatrics, Division of Pediatric Nephrology, Bonn, Germany. Conflict of interest: none declared.
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SYMPOSIUM: NEPHROLOGY
idiopathic hypercalciuria a positive family history is found. Also, calcium excretion is positively correlated between parents and their progeny and between siblings, but not between spouses. Genetic-derived risks appear to be greater than diet-related risks. So far, genetic research has focused on monogenic disorders and autosomal dominant, recessive and X-linked inherited genetic disorders have been identified.
adrenal insufficiency and metastatic malignant bone disease. Acidebase disturbances associated with long-term ventilation and parenteral nutrition can lead to hypercalciuria. Conditions with elevated serum calcium Other clinical entities lead to hypercalcaemia and secondary hypercalciuria. Here, primary hyperparathyroidism, the most frequent cause of hypercalcemic hypercalciuria in adults, is rather rare in children. Hypervitaminosis D, e.g. based on the application of multivitamin preparations including vitamin D, or on vitamin D added to milk preparations, or even due to vitamin D prophylaxis in (preterm) infants, may induce hypercalcaemia and hypercalciuria (Table 1). An excessive intake of vitamin A, more than 10,000 units/day, may also lead to hypercalcaemia and can therefore induce hypercalciuria. Short-term immobilization reduces bone mass rapidly (w15e20%) and is also accompanied by hypercalciuria.
Conditions leading to elevated urinary calcium with normal serum calcium Medullary NC and calcium phosphate stones are frequently seen in patients with distal renal tubular acidosis (d-RTA, Figure 1). Here, a high urinary pH, hypercalciuria and hypocitraturia combine to predispose the child to renal calculi. Medullary NC with or without cortical NC is also described in tyrosinemia, a rare disease (1:100.000 live births) which often is combined with impaired renal function, aminoaciduria, hypercalciuria and tubular acidosis. In Dent’s disease I, a rare but extremely severe X-linked hypercalciuric nephropathy with tubular proteinuria, early progressive NC and renal failure occur. Hypercalciuria also occurs after long-term administration of furosemide, dexamethasone or ACTH. Hypercalciuria is also found in several syndromes ie Bartter’s syndrome, William’s syndrome or can occur secondary to renal tubular damage (Wilson’s disease, Dent II syndrome, Table 1). Other conditions known to lead to hypercalciuria are hyper- and hypothyroidism, Cushing syndrome,
Hyperoxaluria An increased urinary oxalate excretion (hyperoxaluria) is an important promoter of crystallization processes. Primary (endogenous oxalate overproduction) is distinguished from secondary causes (Table 1). Primary hyperoxaluria: currently, three forms of primary hyperoxaluria (PH), which are rare, autosomal-recessive
Figure 1 (a) Bladder stone in a 3-year-old girl with hypocitraturia, (b) kidney stones in a 20 months old girl with dystrophy and chronic urinary tract infections, (c) kidney stones in a patient with primary hyperoxaluria type III and (d) medullary nephrocalcinosis in a patient with renal tubular acidosis. Source: Images provided by Mark Born, MD, Department of Radiology, Division of Pediatric Radiology, University of Bonn, Germany.
PAEDIATRICS AND CHILD HEALTH --:-
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PAEDIATRICS AND CHILD HEALTH --:-
Non genetic reasons
Genetic reasons (monogenetic diseases) Hyperoxaluria
Most frequent reason of normo-calcemic hypercalciuria 9 PTHY = PTH[ big overlapping ; PTH[
C
C
Hypercalcemic hypercalciuria
C
C
Normo-calcemic hypercalciuria
Hyperparathyroidism, tumour/bone metastasis, hypervitaminosis D/A, hypophosphatasia, immobilization, hyperthyroidism, sarcoidosis, adrenal insufficiency, corticosteroid excess RTA, furosemide treatment, hyperalimentation, juvenile rheumatoid arthritis, hypophosphatemia, familial hypomagnesaemia hypercalciuria and nephrocalcinosis syndrome (FHHNC), high sodium intake
C
Mostly renal symptoms Fanconi syndrome (hypercalciuria, proteinuria, glycosuria, amino-aciduria, phosphaturia), NC, rickets, progress to early end stage renal failure Dent 2 disease (Lowe) Fanconi syndrome, rickets, cataract, mental retardation, chronic kidney disease Familial hypomagnesaemia and hyperHypercalciuria, hypomagnesaemia, medullary calciuria syndrome (FFHNC) NC, chronic kidney disease Dent 1 disease
C
CYP24A1 mutations
C
Bartter syndrome
Vitamin D sensitivity, hypercalciuria, early (infantile) nephrocalcinosis Hypokalemia with hypochloremic metabolic alkalosis, hypercalciuria and NC ¼ classic BS
In the context of systemic diseases C Tyrosinemia type 1 C Wilson’s disease C Glycogen-storage disease type 1a C WilliamseBeuren syndrome (WBS) Hyperoxaluria C
Enteric/diet
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Inflammatory bowel diseases (Crohn’s), malabsorption syndromes, e.g. cystic fibrosis, post bowel resections/short bowel syndrome, fat malabsorption, dietary calcium restrictions, lack of intestinal oxalate degrading bacteria (Oxalobacter formigenes)
C
Prim. hyperoxaluria type I (PH I)
In urine: oxalate þ glycolate [, in plasma: oxalate [ In infantile oxalosis: diffuse NC (“white kidney") and early end stage renal failure Childhood: rec. urolithiasis, kidney failure variable either in childhood, or as late as the 5th decade of life Vitamin B6 treatment leads to normalization of urinary oxalate excretion in some patients with missense mutations (continued on next page)
SYMPOSIUM: NEPHROLOGY
Idiopathic hypercalciuria Absorptive HC Renal (loss) HC Resorptive (bone) HC
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Reasons of urolithiasis (UL) or nephrocalcinosis (NC) in childhood. ADPKD [ autosomal dominant polycystic kidney disease, FHHNC [ familial hypomagnesaemia and hypercalciuria syndrome, HC [ Hypercalciuria, HOG [ hydroxyl-oxo-glutarate, PH [ primary hyperoxaluria, PTH [ parathyroid hormone, RTA [ renal tubular acidosis, UTI [ urinary tract infection
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Non genetic reasons
Genetic reasons (monogenetic diseases) Hyperoxaluria
C
Drugs/intoxications
Vitamin C overdosage, ethylene-glycolintoxication
C
Prim. hyperoxaluria II (PH II)
C
Prim. hyperoxaluria III (PH III)
In urine: oxalate þ L-glyceric acid [, in plasma: oxalate [ In comparison to PH type I more benign phenotype, with ESRD in about 20% of patients In urine: oxalate (þcalcium [ þ uric acid [) and HOG [, in plasma: oxalate [ Already in infancy severe recurrent kidney stone disease, less severe symptoms in further follow up, even stop of symptoms possible, no end stage renal failure reported yet
Hypocitraturia Preterm infants
Especially <1500 g birth weight and <30. Gestation age, NC persistent in 15e50% of cases
C
Transplantation/immunosuppressive medication Dietary
Medication induced hypocitraturia, e.g. calcineurine inhibitors Diet high in animal protein
C
Renal tubular acidosis
C
Distal RTA (type 1) with reduced urinary Hþexcretion and significant hypocitraturia and NC Proximal RTA (type 2) with urinary bicarbonate wasting þ less severe hypocitraturia and milder NC/UL Further subforms or secondary forms accompanying other systemic diseases
Other risk factors
C
Urinary tract infections Anatomic anomalies of kidney and urinary tract Hyperuricosuria
C
Drugs
C C
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Table 1
Infectious stones, e.g. Proteus mirabilis UTI Obstruction, ADPKD (uric acid stones), megacalicosis e.g. Tumor lysis syndrome, dietary (metabolic syndrome), Colitis ulcerosa Sulfonamide, Ceftriaxone, Amoxicilline, Magnesium silicates (antacida), Allopurinol (Xanthine), Indinavir, Triamterene
C
Hyperuricosuria
C
Cystinuria
C
Xanthinuria
LescheNyhan syndrome, with gout, UL, automutilation Type I, non-type I and mixed type high urinary cystine excretion, hexagonal cystine crystals in sediment, recurrent kidney stone formation Extremely rare, most often subclinical course, elevated urinary xanthine excretion, in 50% of patients UL in childhood
SYMPOSIUM: NEPHROLOGY
C
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Table 1 (continued )
SYMPOSIUM: NEPHROLOGY
Cystinuria The overall prevalence of the autosomal-recessive form of cystinuria is one in 7000. It is the cause of up to 10% of all urinary stones in children. More than half of the patients present with bilateral urolithiasis, most frequently during the first two decades of life. Without treatment frequent stone formation and passage is the case. Cystinuria is the result of a defective transport of cystine and the dibasic amino acids lysine, ornithine and arginine through the epithelial cells of the renal tubule and the intestinal tract. Only cystine however, is insoluble enough to form stones. At urine pH more than 8, cystine solubility is increased threefold. According to the disease specific genotype three types of cystinuria are now distinguished: type A with mutations on chromosome 2, type B on chromosome 19 and type AB with mutations on both. There is no obvious clinical difference based on the different genotype.
inherited defects of the glyoxylate metabolism, are known. Primary hyperoxaluria type I with low or absent activity of liver specific peroxisomal alanine:glyoxylate aminotransferase (AGT) is the most prevalent and the most disastrous form not only of PH, but also of urolithiasis per se. The encoding AGXT-gene is found on chromosome 2q36-37 and diagnosis is made by genetic mutation analysis. PH I is rare with a prevalence of approximately two patients per million population. Both urinary oxalate and glycolate excretion are highly increased, which causes recurrent calcium-oxalate calculi, medullary, or in infantile oxalosis generalized NC, or both (Figure 1). Inflammatory processes in the kidney induced by oxalate itself lead to rapid decline in renal function, which aggravates calcium-oxalate crystals accumulation and its deposition in the parenchyma of other organs, as well as in bones and retina. A very large clinical, biochemical and genetic heterogeneity is known, ranging from infantile oxalosis, prompt renal failure and all too often death to patients just having occasional passage of stones in adult life with preserved renal function. Therefore it is a disaster if the diagnosis of PH I is delayed for many years, and it should be excluded in all repeated calcium-oxalate stone formers. In primary hyperoxaluria type II (PH II), which is less frequently observed than PH I, urinary excretion of oxalate and Lglyceric acid is increased due to a defect of both liver specific Dglycerate dehydrogenase and hydroxypyruvate reductase (GRHPR). Its clinical course is much milder than in PH I, although symptoms are comparable. However, end stage renal failure is rather the exception (5e10% of patients). Mutation analysis of the GRHPR gene is the diagnostic gold standard. Primary hyperoxaluria type III is probably the second most common form of the PH’s. It starts in early childhood with severe urolithiasis and often stone removal procedures are necessary. In PH type III mutations of the hydroxy-oxo-glutarate gene HOGA1 lead to a loss of function of the encoded enzyme and hence to elevated urinary excretions of oxalate and hydroxy-oxoglutarate. The patho-mechanism leading to the elevated oxalate production is still a matter of debate. Currently, no patient with type III PH has developed chronic kidney failure and most reports show that the clinical situation improves over time. However, hyperoxaluria and sometimes even hypercalciuria may persist.
Purine stones Hyperuricosuria: uric acid stones are a seldom seen in the paediatric population. Hyperuricosuria is found in those with high-purine diets, myeloproliferative disorders, tumour lysis syndrome, or enzymatic defects. Drugs like probenecid, salicylates or contrast media also increase uric acid excretion. The strongest risk factors for uric acid stones are a low urine pH and low urine volume. Rare inherited deficiencies of the purine salvage enzymes hypoxanthine-phosphoribosyl-transferase (HPRT) and adeninePRT (APRT) induce primary purine overproduction. Complete HPRT deficiency leads to the X-linked LescheNyhan syndrome. This is characterized by mental retardation, automutilation, choreoathetosis, gout and uric acid NC, whereas partial deficiency of HPRT results in urolithiasis and renal failure alone. Gout and urolithiasis are also found in glycogen-storage disease type I. Rarer purine stones 2,8-Dihydroxyadeninuria: APRT deficiency has an autosomalrecessive inheritance. Here, serum uric acid is normal but there is an elevation of urinary 2,8-dihydroxyadenine which can also form stones. The stones are radiolucent and may be confused with uric acid stones. Urine microscopy reveals characteristic brownish round crystals, diagnosis will be confirmed by decreased APRT activity in red blood cells or from urinary excretion of dihydroxyadenine.
Secondary hyperoxaluria: it is frequently found in patients with chronic inflammatory bowel disease (e.g. Crohn’s), with malabsorption syndromes (cystic fibrosis, celiac disease, a-ß lipoproteinemia), or in patients with short bowel syndrome, e.g. after necrotizing enterocolitis. Normally, intestinal oxalate binds to calcium to form insoluble calcium-oxalate, which is not absorbed. In malabsorptive states calcium instead binds to fatty acids and more soluble oxalate is available for absorption, this leads to enteric hyperoxaluria. A lack of intestinal oxalate degrading bacteria, e.g. Oxalobacter formigenes, is another reason for increased oxalate absorption, e.g. in patients with cystic fibrosis. If intestinal oxalate degradation does not take place, more oxalate is again available for absorption. The prevalence of UL is reported to be as high as 17% in patients with Crohn’s disease. Up to 50% of our patients with cystic fibrosis have hyperoxaluria and about one in ten develop UL or NC. Enteric hyperoxaluria may also lead to severe NC and/or recurrent urolithiasis, even renal failure and systemic oxalosis.
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Xanthinuria: deficiency of xanthine-oxidase, which converts xanthine to uric acid, leads to xanthinuria, where serum uric acid concentration is very low. Characteristic findings in xanthinuria are an orange-brown urinary sediment or orange-stained nappies, but later xanthine stones. Hypocitraturia: urinary citrate will inhibit calcium stone formation. Hypocitraturia is a characteristic finding in the complete form of d-RTA, but is also observed in persistent mild or latent metabolic acidosis, in hypokalemia and in patients with malabsorption syndromes. Idiopathic hypocitraturia may be secondary to low intestinal alkali absorption. In some regions of the world, as well as in specific patient populations (e.g. preterm infants), hypocitraturia is the most important risk factor for stone disease (Table 1). Also, hypocitraturia was reported to be one of the major determinants of preterm nephrocalcinosis.
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Infectious stones Infectious stones are often only composed of struvite (magnesium ammonium phosphate), but can also contain carbonateapatite, which crystallizes at high urinary pH (more than 7.0). Urease-producing bacteria induce hydrolysation of urea to ammonium ions which in turn results in a high urinary pH. Many gram-positive and gram-negative bacteria produce urease, but Proteus species are the predominant organisms. Struvite stones are mostly found in the kidney, but they may also form in the bladder (Figure 1). Often, an additional primary anomaly of the urinary tract, like uretero-pelvic junction obstruction, primary mega-ureter, or more rarely ureterocele or urethral valves is found. Neurogenic bladder patients, particularly those based on a meningomyelocele, are particularly prone to struvite stones. Infectious stones may also form on a nidus of different composition and therefore it is important not to miss an underlying metabolic disorder.
substantial information on concomitant diseases, fluid intake, diet, medications, but also about possible genetic disorders (Figure 2). Clinical symptoms may be analogous to adults, as most children present with flank or abdominal pain. Atypical and nonspecific complaints are more likely in younger children especially in infants. Nausea and vomiting, the presence of flank pain, or haematuria are all positively associated with UL in children. Nephrocalcinosis, however, is mostly asymptomatic and often only diagnosed when ultrasound is performed in patients with haematuria. An approach to the evaluation of childhood UL is shown in Figure 2. The gold standard for diagnosis is an analysis of repeated 24-hour urine samples for lithogenic and stone-inhibitory parameters. In the smaller infant spot urine evaluations might only be possible (age related molar creatinine ratios, Table 2). The first-line imaging procedure is an ultrasound scan of the kidneys, ureters and bladder. Whilst unenhanced computed tomography (CT) will depict stones more accurately than ultrasound (ultrasound detects 90% of kidney stones, but only 38% of ureteral stones compared to CT). However, in infants and young children, ultrasound should always be the first choice to minimize radiation exposure and as there is no need for sedation.
Medication and intoxications Only a small proportion (1e2%) of renal stones in children is solely drug related. Poorly soluble drug components either form stones itself, e.g. indinavir, or provide a nidus for stone formation. Other medications precipitating in the urine but rarely causing stones include ceftriaxone, sulfonamides, ampicillin, amoxicillin, triamterene, acyclovir and oxypurine. Medication can increase the excretion of lithogenic substances (e.g. loop diuretics, calcium/vitamin D supplementation) or reduce the excretion of anti-lithogenic substances (carbonicanhydrase inhibitors, topiramate). Hypercalciuria induced by loop diuretics is known as one major risk factor in nephrocalcinosis of prematurity. Many patients with drug-induced nephrolithiasis, however, have additional metabolic abnormalities as risk factors. Nephrolithiasis due to melamine contamination of powdered milk formula was reported in 2008 with more than 50,000 children suffering from urolithiasis and acute or chronic kidney injury. Melamine is a synthetic chemical added to milk or animal feed to boost the protein because of its high nitrogen content. Children exposed to high-melamine formula display a 5.4e7.0 fold increased risk of urolithiasis. Ethylene glycol intoxication, usually observed after accidental ingestion of antifreeze or because of suicide attempts, leads to severe hyperoxaluria based on its conversion to glycolic acid, formalin and oxalic acid via alcohol dehydrogenase. An extreme anion-gap and abundant calcium-oxalate crystals in the urine are found, the latter inducing acute renal failure due to calciumoxalate crystal agglomeration in the renal parenchyma. For treatment administration of ethanol or 4-methylpyrazole is necessary to block the alcohol dehydrogenase, bicarbonate to treat the metabolic acidosis and haemodialysis to remove both ethylene glycol and its metabolites.
Treatment Acute stone passage Patients with acute renal colic present with severe pain and analgesia will be required (Figure 3). Stone passage can often be induced by a combination of high fluid intake plus medication like calcium channel blockers, alpha-blockers and/or corticosteroids. When obstruction is obvious, renal function is impaired or a urinary tract infection is present, prompt stone removal is indicated. Minimally invasive procedures for stone removal are the usual first choice (not lithotripsy). Initial urine drainage by a nephrostomy tube can be performed to facilitate urine excretion and to avoid further kidney damage. It is important to try to catch the stone for further analysis. Conservative, preventive measures Preventive management is mainly based on the reduction of the solute concentration in the urine. Independent of the underlying disorder, hyperhydration (more than 1.5e2 L/1.73 m2 body surface area/day) is the precondition for all further treatment. Fluid intake must be distributed over the whole day to provide peaks of high concentration levels of the soluble. Dietary recommendations should only carefully be given. Dietary restrictions, for example, a low calcium diet in any patient with calcium stones is obsolete, as it will lead to secondary hyperoxaluria. Also, a low oxalate diet in patients with secondary hyperoxaluria is restricted to food with a very high oxalate content. Crystallization inhibitors Crystallization inhibitors (mainly citrate and magnesium) are an effective treatment option to increase urinary solubility. Urinary citrate binds to calcium forming a soluble complex and thus reducing the precipitation of calcium with other substances. Also, urinary calcium excretion can be reduced by approximately 30%. Citrate treatment has been shown to decrease stone production and to reduce progression of nephrocalcinosis.
Clinical presentation and diagnostic pathway in children It is important to realize that nephrocalcinosis and urolithiasis are the symptom of underlying diseases and not the disease itself. Therefore, a thorough diagnostic evaluation is required in each child after the first stone event, or when nephrocalcinosis is detected. A thorough personal and family history provides
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SYMPOSIUM: NEPHROLOGY
Micro-/ macrohematuria
Recurrent flank pain
Known NL/NC
Tubulopathy
Recurrent UTI
Known genetic stone disease
Diagnostic algorithm History Prematurity? Intestinal diseases, malabsorption syndromes? Fluid intake? Vitamin supplementation, especially Vitamin D and/or A? Medication, especially steroids, immune suppressants, diuretics? Anatomic anomalies? Rec. UTI? (secondary) Enuresis → urine concentration defects?
Family history Known NC/NL Consanguinity? Cases of unclassified kidney failure or chronic renal insufficiencey?
Clinics Acute Symptoms Renal colic, flank pain? Hematuria? Dysuria, urine stasis? Stone passage?
Chronic symptoms Recurrent abdominal pain of unknown origin? (Secondary) enuresis? Micro-/Macrohematuria? Malabsortion/failure to thrive?
Labs Urine analysis Dipstick spot urine (pH, density, osmolarity, hematuria, proteinuria, glucosuria), cylinder? Non glomerular hematuria? Spot urine: Molar creatinine ratios for oxalate/calcium/citrate/uric acid Better: 24-h-urine with calcium, oxalate, citrate, uric acid excretion, pH, density, volume Specific diagnostics Amino acid screen (cystine)
Serum analysis Blood gas analysis, pH, bicarbonate elektrolytes, creatinine, (cystatine C), urea, uric acid, calcium, phosphate, iPTH, alkaline phosphatase Stone analysis Specific diagnostic evaluation Plasma oxalate Vitamin D, A FGF23 Genetic analysis Imaging
Ultrasound of kidneys and urinary tract
CT (low enhanced) to identify small stones, microcalculi
Figure 2 Diagnostic algorithm of evaluation of children with nephrocalcinosis or nephrolithiasis.
latter, the potassium-sparing diuretic amiloride may occasionally be given.
The recommended daily dosage is 0.1e0.2 g/kg body weight (0.3 e0.6 mmol/kg body weight) as sodiumepotassium or potassium citrate, but in patients with distal RTA, the dosage will be higher and should be adapted to the serum pH and serum potassium levels. The alkalinization of urine produced by oral citrate increases the solubility of cystine, uric acid and calcium-oxalate. However, urinary pH has to be monitored to avoid very high levels increasing the risk of calcium-phosphate precipitation.
Specific treatment in primary hyperoxaluria Patients with PH I are treated with pyridoxal-phosphate, the cofactor of the defective enzyme. Treatment in supra-physiological doses (5e20 mg/kg body weight per day), help to reduce the endogenous oxalate production and hence the urinary oxalate excretion in approximately a third of patients. Side effects are polyneuropathy, but sometimes also bullous skin eruptions, as well as acne. Future treatment options in primary, but also secondary hyperoxaluria might include the oral administration of intestinal oxalate degrading bacteria, e.g. O. formigenes, which already showed its efficacy in reducing urinary oxalate excretion in two pilot trials. No renal replacement therapy is capable of removing sufficient amounts of oxalate. Hence, patients with PH and renal
Thiazides in hypercalciuria In patients with severe hypercalciuria thiazides help to reduce the renal calcium excretion by increasing calcium uptake in the distal tubule and stimulation of calcium reabsorption in the proximal tubule. In patients with a reduced bone density due to hypercalciuria, thiazide treatment is indicated, as it may also improve bone density. A daily dosage of 0.5e1 mg per kg body weight is given twice daily but side effects like hypotension and hypokalemia should be monitored for. To avoid the
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PAEDIATRICS AND CHILD HEALTH --:-
Calcium
Citrate
Cystine
Oxalate
Urate
24 hours Urine excretion parameters <10 years <55 umol/1.73 m2/24 hours All age <0.5 mmol/1.73 m2/24 hours <1 year All age <0.1 mmol/kg/24 hours All age Boys: <70 umol/kg/24 hours 2 <13 mg/1.73 m2/24 hours groups <45 mg/1.73 m2/24 hours <1.3 mg/kg/24 hours groups <4 mg/kg/24 hours groups >1.9 mmol/1.73 m /24 hours >365 mg/1.73 m2/24 hours 1e5 years <65 umol/kg/24 hours Girls: >10 years <200 umol/1.73 m2/24 hours 2 <1.1 mg/kg/24 hours >1.6 mmol/1.73 m /24 hours <48 mg/1.73 m2/24 hours >310 mg/1.73 m2/24 hours >5 years <55 umol/kg/24 hours <0.9 mg/kg/24 hours Soluble/creatinine ratio (spot urine samples) mol/mol g/g <12 months 1e3 years 3e5 years 5e7 years >7 years Table 2
<2.2 <1.5 <1.1 <0.8 <0.6
<0.8 <0.53 <0.4 <0.3 <0.21
mol/mol
g/g
0-5 years
>0.12e0.25
>0.2e0.42
>5 years
>0.08e0.15
>0.14e0.25
mmol/mol
mg/g
<1 month
<85
<180
1e6 months
<53
<112
>6 months
<18
<38
0e6 months 7e24 months 2e5 years 5e14 years >14 years
mmol/mol
mg/g
<325e360 <132e174 <98e101 <70e82 <40
<260e88 <110e39 <80e81 <60e65 <32
<12 months 1e3 years 3e5 years 5e10 years >10 years
mol/mol
g/g
<1.5 <1.3 <1.0 <0.6 <0.4
<2.2 <1.9 <1.5 <0.9 <0.6
SYMPOSIUM: NEPHROLOGY
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Normal values for lithogenic and stone-inhibitory parameters in 24 hours urine samples (excretion), or spot urines (molar creatinine ratios). Urine samples are preserved with either thymol 5% in isopropanol, or 2 N HCl before start of collection. Repeated collections are necessary for verification of results. Adequate collection is checked by 24 hours urine volume and creatinine excretion (2 mg/kg 0.8 mg)
SYMPOSIUM: NEPHROLOGY
Acute colicky abdominal pain
Sonography Without evidence, but still clinical signs Nephrolithiasis with severe obstruction/ infection
Nephrolithiasis (non-obstructive)
Low enhanced CT
Without evidence
Other reasons for abdominal pain
Conservative measures: i.v.-hydration Analgesia + Spasmolytics Steroids and Calcium-channel-blockers
No clinical improvement
Stone passage
Prompt intervention by pediatric urologist
Stone analysis and further diagnostic evaluation
Figure 3 Therapeutic algorithm in acute colicky abdominal pain.
Specific treatment in purine stones In patients with uric acid stones urine alkalinization to keep a urinary pH above 6.5 is the main goal. In addition excess protein intake should be avoided. Allopurinol, an inhibitor of the xanthineoxidase, reduces serum uric acid and therefore its excretion. A careful dosing regimen is necessary, as it can lead to significant xanthinuria. Xanthine solubility does not increase in alkalinized urine, thus hyperhydration is the main means of therapy. In patients with dihydroxyadenine stones, urine dilution, allopurinol dietary restrictions of adenine and purine are all helpful measures.
failure should be transplanted as early as possible. Combined liverekidney transplantation is the method of choice in PH I to cure the liver specific enzyme defect. Isolated kidney transplantation is performed in PH type II and can be considered in the PH I patient being pyridoxine sensitive. Also, pre-emptive liver transplantation was performed in PH I, but timing of the procedure is difficult due to the clinical heterogeneity of the disease. Specific treatment in cystinuria A careful methionine (protein) restricted diet is recommended in patients with cystinuria, as it is metabolized to cysteine. Cystine is then formed by the oxidation of two cysteine molecules linked by a disulfide bond. Urine alkalinization is the main goal of pharmacotherapy as cystine has a higher solubility at urinary pH more than 8. Chelating agents cleave the disulfide bond of cystine to cysteine, a 50 times more soluble homodimer of cystine. D-Penicillamine and alpha-mercaptopropionyl-glycine (MPG) are equally effective (20e40 mg/kg body weight per day in two divided doses). Side effects include rash, arthralgia, exanthema, thrombocytopenia, polymyositis and nephritic syndrome, which limits treatment. ACE inhibitors act equivalent to MPG in increasing cystine solubility and may also be accompanied by less severe side effects. D-Penicillamine reduces the level of pyridoxine, which therefore has to be supplemented. Ascorbic acid can reduce cystine to cysteine when administered in very high doses, however, there is ongoing debate about the efficacy and it can induce hyperoxaluria.
PAEDIATRICS AND CHILD HEALTH --:-
Infectious stones For children with recurrent infectious stones, stone removal and surgical management of anatomic anomalies are the most important therapeutic steps. Failure to remove the stones increases the risk of further infection.
Conclusion In children with renal calculi or nephrocalcinosis prompt metabolic evaluation should be performed. The stone or the crystal deposition is not the disease itself, it is only its (first) symptom. In approximately 75% of children a metabolic or genetic background for UL/NC will be found and can be treated in most of the patients. In these cases recurrent kidney stones or progressive NC, or eventual renal failure, e.g. in the primary hyperoxalurias, can be prevented.
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SYMPOSIUM: NEPHROLOGY
Schell-Feith EA, Kist-van Holthe JE, Conneman N, et al. Etiology of nephrocalcinosis in preterm neonates: association of nutritional intake and urinary parameters. Kidney Int 2000; 58: 2102e10. Sternberg K, Greenfield SP, Williot P, Wan J. Pediatric stone disease: an evolving experience. J Urol 2005; 174: 1711e4. discussion 1714. Straub M, Strohmaier WL, Berg W, et al. Diagnosis and metaphylaxis of stone disease. Consensus concept of the National Working Committee on Stone Disease for the upcoming German Urolithiasis Guideline. World J Urol 2005 Nov; 23: 309e23. Thomas BG. Management of stones in childhood. Curr Opin Urol 2010; 20: 159e62. van’t Hoff WG. Aetiological factors in paediatric urolithiasis. Nephron Clin Pract 2004; 98: 45e8.
Only minimally invasive procedures for stone removal should be performed in children, silent stones may be left in place. Infectious stones, however, have to be removed to prevent recurrent urinary tract infections. It is, of course, always better to perform prophylactic treatment, which is cheaper and less harmful, than repeated stone removals. Conservative treatment is most efficient in the majority of patients. A FURTHER READING Beck BB, Baasner A, Buescher A, et al. Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies. Eur J Hum Genet 2013; 21: 162e72. Cameron MA, Sakhaee K, Moe OW. Nephrolithiasis in children. Pediatr Nephrol 2005; 20: 1587e92. Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med 2013; 369: 649 e58. Erratum in: N Engl J Med 2013;369(22):2168. Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and urolithiasis in children. Kidney Int 2011; 80: 1278e91. Hollingsworth JM, Rogers MAM, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006; 368: 1171e9. Hoppe B, Leumann A, Milliner DS. Urolithiasis and nephrocalcinosis in childhood. Philadelphia. In: Geary DF, Schaefer F, eds. Comprehensive pediatric nephrology 2008; 499e525. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol 2012; 8: 467e75. pez M, Hoppe B. History, epidemiology and regional diversities of Lo urolithiasis. Pediatr Nephrol 2010; 25: 49e59. Palmer JS, Donaher ER, O’Riordan MA, Dell KM. Diagnosis of pediatric urolithiasis: role of ultrasound and computerized tomography. J Urol 2005; 174: 1413e6.
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Practice points C
C
C
C
10
The first kidney stone and every nephrocalcinosis should lead to a thorough diagnostic evaluation in every child and should start with a thorough patient and family history Urine examinations and stone analysis are helpful in defining underlying lithogenic pathology and are followed by specific blood chemistry analysis and genetic testing Try to prevent stone recurrence to avoid kidney damage. Recurrent kidney stones and progressive nephrocalcinosis can lead to end stage renal failure, if the underlying pathology is not adequately diagnosed and treated High fluid intake, medication to increase urine solubility and disease specific therapy, e.g. pyridoxine in primary hyperoxaluria type I, can be successful when diagnosis is made early
Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Hoppe B, Renal calculi in children, Paediatrics and Child Health (2014), http://dx.doi.org/10.1016/ j.paed.2014.04.008