50: Urolithiasis—Medical Management
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Pediatric urolithiasis is on the raise with an annual increasing rate of approximately 5–10%.1 Various metabolic, genetic, anatomic, and environmental/dietary factors are responsible for this change. It is increasingly recognized that urolithiasis is a systemic condition with significant morbidity due to its association with various diseases such as cardio-vascular disease, diabetes mellitus, and metabolic syndrome.2,3,4,5,6,7,8 Urolithiasis has a high recurrence rate with potential for chronicity and for the development of renal insufficiency.9,10,11,12 Therefore, adequate management of pediatric urolithiasis is important to prevent recurrence and its associated complications, as well as to protect kidney function.
Initial Evaluation of a Child with Urolithiasis
An initial comprehensive diagnostic evaluation should be performed in every child who presents with a first episode of urolithiasis because it will guide treatment and will allow a better prevention strategy. Due to the multifactorial etiology of urolithiasis (metabolic, anatomic, genetic, dietary, environmental), children who have an obvious risk for kidney stone development should also undergo a detailed work-up. The initial evaluation includes a detailed history and physical examination, laboratory investigation, and radiologic imaging of the urine tract as presented in Figure 1. There is no consensus on what serum chemistry should be performed as part of the initial work-up, but calcium, phosphorus, magnesium, alkaline phosphatase, sodium, potassium, chloride, bicarbonate, uric acid, creatinine, and urea nitrogen are initial preferred tests sufficient to identify renal tubular acidosis, hypercalcemia, hypomagnesemia, and renal insufficiency. Qualitative cysteine testing is an important initial screening in cystinuria. Microscopy is additionally used to screen for various crystals in the urinary sediment.
Figure 1 Initial evaluation of a child with urolithiasis.
Spot urines for calcium, citrate, uric acid, oxalate and cystine can be obtained as the initial screening for a metabolic abnormality, and normal references by age and expressed units (mg/mg or mmol/mmol) are available in Table 1. Spot urines are particularly important in children who are not toilet trained. Whenever possible, urine solute concentrations and excretory rates in timed 24-hour urine collection should be obtained to confirm the results of initial screening with spot urine samples. The benefit of performing a 24-hour urine analysis has been proven in children who underwent at least one 24-hour urine collection because a significant reduction in the risk of their stone recurrence was found compared to those who did not have such a test.13 The timed 24 hour urine collection provides information on urine volume and saturation, as well as on 24 hour urinary excretion of calcium, phosphorus, oxalate, citrate, uric acid, sodium, potassium, and magnesium. There is ongoing debate on the benefit of a single urine collection compared to repeated 24-hour urine collections.14 Due to diurnal variation in diet and fluid intake, two initial 24-hour urine collections should be performed. Urine creatinine should be checked for the completeness of urine collection (urine creatinine of more than 15 mg/kg/day is desired). The timed collection should be performed without altering the child’s usual fluid intake, diet or activity in the absence of a urinary tract infection, and should be done at least a month after the spontaneous passage of stone or surgical intervention. Results can be interpreted with respect to weight, body surface area, and urine creatinine (Table 1). Patients should be asked to complete a dietary diary at the same time of the 24-hour urine collection. The diary should include the type and amount of each consumed food and drink.
Table 1 Normal Value for Urinary Excretion of Metabolites. * Same value for mg/mg and mmol/mmol; **A range for normal random citrate values is presented in the table to account for regional variations.
|Constituent||Age||Random in mg/mg (mmol/mmol)||Timed (all ages)|
|Calcium||0 to 6 months||<0.8*||<4 mg/kg per 24 hours (<0.1 mmol/kg per 24 hours)|
|7 to 12 months||<0.6*|
|Oxalate||0 to 6 months||<0.26*||<40 mg/1.73 m² per 24 hours (<0.5 mmol/1.73 m² per 24 hours)|
|7 to 24 months||<0.11*|
|2 to 5 years||<0.08*|
|5 to 14 years||<0.06*|
|Cystine||> 6 months||<0.075*||<60 mg/1.73 m² per 24 hours (<250 micromol/1.73 m² per 24 hours)|
|Uric acid||<1 year||<2.2 (<1.5)||<815 mg/1.73 m² per 24 hours (<486 mmol/1.73 m² per 24 hours)|
|1-3 years||<1.9 (<1.3)|
|3-5 years||<1.5 (<1.0)|
|5-10 years||<0.9 (<0.6)|
|>10 years||<0.6 (<0.4)|
|Citrate**||0 to 5 years||>0.2 to 0.42 (>0.12 to 0.25)||>310 mg/1.73 m² per 24 hours (>1.6 mmol/1.73 m² per 24 hours) in girls; >365 mg/1.73 m² per 24 hours (>1.9 mmol/1.73 m² per 24 hours) in boys|
|>5 years||>0.14 to 0.25 (>0.08 to 0.15)|
|Magnesium||> 2 years||>0.13*||>0.8mg/kg (>0.04 mmol/kg)|
Stone analysis is an important step in the initial evaluation of urolithiasis. The composition of all recovered stone fragments should be analyzed by either infrared spectroscopy or X-ray diffraction, and components exceeding 5% should be reported. This should be done with each passage of stone since composition may differ from the initial presentation. Most stones in the pediatric population are calcium-based.15
Metabolic evaluation is an important component of the overall management of pediatric urolithiasis since a metabolic abnormality is present in up to 90% of children with hypercalciuria and hypocitraturia being the most common etiologies.15,16,17,18 Compared to adults, a predisposing cause for stone formation is found in about 2/3 of children and includes metabolic (33–95%), anatomic (8–32%) and infectious factors (2–24%), alone or in combination.19,20,21,22,23
Initial diagnostic imaging is aimed at detecting the stone, estimating the stone size and its likelihood of passing, and at identifying whether it is obstructing the urinary flow (potential need for surgery). Additionally, imaging is important in diagnosing any structural abnormality of the urinary tract which might cause local urinary stasis, such as primary megaureter, medullary sponge disease, autosomal dominant polycystic kidney disease, ureteropelvic junction obstruction, ureterocele, horseshoe kidney, bladder exstrophy, neuropathic bladder, and surgically reconstructed or augmented bladders. Ultrasonography and a plain abdominal radiograph showing kidney/ureter/bladder (KUB) are the mainstay of initial radiological imaging in children.24,25 Ultrasonography (US) is an easy test with a high sensitivity of 77–90% and a specificity of 88–94%.26 It has the advantages of being a painless test without the risk of radiation or need of anesthesia. US reveals the anatomy of the kidneys and the urinary tract and is important in detecting hydronephrosis. Additionally, stones of all compositions should be visualized by US. The cost is low, and the study can be repeated as many times as needed. However, US is operator dependent, overestimates stone size, can miss ureteral calculi, papillary or calyceal stones, and small calculi (<5 mm), and stone visualization can be affected by the patient’s body habitus and bowel gas. Simultaneous KUB should be performed to identify ureteral stones and to appreciate the calcium content of the stone. Computed tomography (CT) scan without contrast is used sparingly in the initial evaluation of urolithiasis in children due to its high risk of radiation and the potential need for sedation. However, low radiation dose, non-contrast CT scan protocols have been developed for pediatric patients and are mainly indicated when the patient is symptomatic and when the stones are suspected but not seen by ultrasound. CT has high sensitivity and specificity 90–100%, and the advantages of providing anatomic details of the kidney and urinary tract, as well as of detecting small and radiolucent stones.
The immediate treatment goals during an acute stone episode are pain relief, nausea and vomiting control, rehydration, and treatment of associated infection. For most patients, this is usually managed as an outpatient. Pain control can be achieved with oral non-steroidal anti-inflammatory medications (if renal function and hydration are adequate) or with oral or intravenous narcotics (e.g., morphine 0.3 mg/kg PO every 3–4 hours or 0.05 mg/kg IV every 2–4 hours). The preferred antiemetic agent is ondansetron due to its minimal side effects; metoclopramide hydrochloride or prochlorperazine are acceptable options.
With adequate pain control, uncomplicated unilateral stones causing only minimal or partial obstruction can be managed conservatively for several weeks before surgical intervention is considered. Stones up to 5 mm have a high likelihood of spontaneous passage in children of all ages. Medical expulsive therapy (MET) for smaller ureteral stones has been used, especially in older children, with some success. The most used agent is tamsulosin, which causes relaxation of ureteral smooth muscle with inhibition of ureteral spasm and dilatation of the ureter. Alternatively, alpha blockers or calcium channel blockers can be used to facilitate the passage of ureteral stones under 10 mm in size.27,28,29,30,31 During an acute episode, all stone patients should be asked to filter urine through a sieve to capture stones for analysis.
The indications for hospitalization include urgent need for upper tract decompression (nephrostomy tube or an indwelling stent), severe vomiting requiring intravenous hydration, severe pain requiring intravenous analgesia, and urosepsis/acute pyelonephritis requiring intravenous antibiotic therapy.
Metabolic Work Up and Evaluation for Risk of Recurrent Urolithiasis
Following the initial presentation and acute management, children with urolithiasis should be referred to a specialized multidisciplinary stone clinic for treatment and further evaluation of the risk factors that might predispose to recurrence of stone. The prevention of recurrence is particularly important in pediatrics due to the high risk of recurrent renal stones in children that reaches up to 50% within 3 years from the first episode of urolithiasis.32 The rate of recurrence is higher in those with an identifiable metabolic abnormality and those with a positive family history of stones in first-degree relatives.22 Additionally, recurrent stone-formers have a two times higher risk of developing CKD and ESRD compared to non-stone formers.33 Ideally, a combined “stone clinic” should provide nephrologic and urologic expertise, genetic testing, dietary services, and appropriate metabolic laboratory investigation.
Basic metabolic panel testing and 24-hour urine analysis should be repeated. Blood levels of parathyroid hormone and 1,25-dihydroxyvitamin D are additional tests required in patients with calcium-based stones and when abnormal blood levels of calcium and/or phosphorus are identified. Primary hyperparathyroidism is rare in children, but evidence for suppression of PTH offers a clue to states of vitamin D excess. Moreover, uric acid stones work up should include serum uric acid levels and enzyme assays to check if hyperuricosuria is due to enzyme deficiencies.34 Measurement of blood level oxalate is important in hyperoxaluria to identify the primary types of the disease. The measurement of 24-hour urinary parameters is particularly vital in identifying children who will need pharmacological treatment following their initial stone event.
Genetic testing should be part of the work-up of pediatric patient presenting with urolithiasis in several circumstances: 1, young age at presentation and strong family history of stone disease, as well as consanguineous marriages; 2, failure to thrive and developmental delay, abnormal features, vision and hearing impairment, rickets; 3, high serum creatinine at presentation; 4, development of recurrent stones in spite of treatment; 5, presence of rare tubulopathies; 6, stone composition (cysteine, uric acid, dihydroadenine, xanthine). Early recognition of the monogenic forms of nephrolithiasis (such as primary hyperoxalurias, cystinuria, dRTA, Dent’s disease, Bartter syndrome, Adenine phosphoribosyl transferase deficiency) will allow early treatment and prevention of various complications including irreversible kidney damage.
Repeat metabolic assessment and renal ultrasound are needed to diagnose stone recurrence or increasing size of previous stones. The frequency of these tests depends on the presence and severity of the metabolic abnormality, the number of stones and recurrence rate. A child with a single stone and no evidence of an underlying metabolic abnormality will require less frequent monitoring than a child with multiple stones and a significant metabolic problem known to be at greater risk for recurrent nephrolithiasis (primary hyperoxaluria or cystinuria). Compliance with high fluid intake should be monitored by measuring the urine specific gravity. Children receiving drug therapy should be closely monitored for adverse effects.
In an asymptomatic child, repeat ultrasonography is usually performed six months after the initial episode. If the ultrasound shows no stone recurrence or change in residual stone size, the study can be performed yearly. Metabolic work-up is repeated four to six weeks after therapy has been initiated. If the metabolic abnormality was corrected, repeat studies should be done at six months, and then yearly. Re-evaluation is needed if metabolic abnormalities persist.
Treatment of urolithiasis includes dietary modification and pharmacological intervention.
General dietary recommendation in all children with urolithiasis regardless of etiology include high fluid consumption, salt restriction, and increased intake of vegetables and fruit (Table 2).35,36 Aggressive fluid intake that is evenly distributed throughout the day is aimed to prevent tubular precipitation of various salts. Adequate hydration can be estimated from the urine specific gravity and/or urine osmolality. Water should be encouraged because the fructose found in sweet beverages could cause an increase in the urinary excretion of calcium and oxalate enhancing the risk of stone. Furthermore, sugary drinks will cause weight gain, an undesired effect in overweight children. Fruit and vegetables represent a good source of potassium which facilitates urinary citrate excretion, and a good source of phytates which increase the solubility of calcium salt. High fiber diet facilitates binding of intestinal calcium.
Table 2 General dietary recommendation in pediatric urolithiasis.**
|Fluid intake||High at >2 L / 1.73 m²/day, mainly water|
|Salt intake||Low at <3 mEq/kg/day|
|Vegetables and fruit intake||High|
|Calcium intake||100% of the daily allowance|
|Protein intake||100% of the daily allowance|
|Vitamin D intake||Supplement if low|
|Vitamin C intake||Avoid excess|
Excessive salt intake causes increased excretion of urinary calcium, and sodium restriction is advised in all stone-formers. Patients should be advised to avoid adding salt or sodium-rich seasoning to food either during preparation or during consumption. Families should be educated to read food labels before purchasing, and to choose foods low in sodium (increased in ingredients such as sodium nitrate, monosodium glutamate, sodium bicarbonate and sodium phosphate). High-salt foods such as processed and canned food, fast food, pickles and olives, salt crackers and pizza, should be avoided.
Restriction of calcium and protein intake is not recommended in children because they are necessary for growth and bone health. Additionally, calcium binds to free oxalate in the digestive tract and prevents hyperoxaluria. Avoiding high oxalate foods (such as chocolate, spinach, nuts, cola) is particularly important in children with secondary hyperoxaluria, while patients with hyperuricosuria should be advised low intake of purine-containing food (such as red meat).23
Targeted pharmacological therapies based on the identified metabolic risk factor(s) is presented in Table 3.
Urinary alkalinization with oral potassium citrate to achieve a pH >7.0 is useful in patients with distal RTA /hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia, and cystinuria because it increases the solubility of these solutes.37,38,39 The recommended dose is 0.5 to 1 mmol/kg/day in divided doses which effectively and safely decreases urinary calcium without significant adverse effects. Potassium citrate therapy should be taken after a meal or with a snack and with a big glass of water to prevent stomach pain which could cause poor therapy adherence. Urinary pH should be closely monitored since a higher pH may decrease the solubility of phosphate leading to calcium phosphate urolithiasis. Additionally, serum K and bicarbonate should be measured periodically. Another treatment option for urinary alkalinization is high lemon extract intake (“Lemon Protocol”) but there are no studies to prove its efficiency in pediatrics and it may not be well tolerated in children leading to non-compliance.40
Thiazide diuretics (e.g., hydrochlorothiazide or chlorthalodine) have a good effect on reducing the urinary calcium excretion in children by causing volume contraction that increases calcium absorption in the proximal tubule.41,42 The starting dose is 0.5–1 mg/kg/day as a single dose, titrated to achieve maximum efficacy and good tolerance. Close laboratory monitoring is required since may cause hypokalemia, hyponatremia or hyperuricemia. Long-term non-adherence is reported in about one third of patients and hypercalciuria recurs in 44%.43
Children with cystinuria should undergo aggressive hydration, low salt intake, limited animal protein diet, and urinary alkalinization. In many cases these measures are insufficient and a cystine-binding thiol containing medication (d-penicillamine, tiopronin, and captopril) is needed. Both d-penicillamine and tiopronin act by cleaving the disulfide bond of cystine to produce two cysteine molecules. Both drugs are equally effective and have similar results. Due to potential significant adverse effects, each drug should be started at a lower dose and should be gradually increased based on urinary cystine concentration over several weeks. The targeted goal is a urinary cystine concentration of less than 1,250 micromol/l.44 Close dose monitoring for both efficacy and toxicity is required, with the goal of effectively reducing urinary cystine levels, while minimizing side effects.
Table 3 Pharmacologic intervention in pediatric urolithiasis. *Calcium supplements can be prescribed because calcium binds to oxalate in the intestinal tract forming calcium-oxalate complex that is excreted in the feces. However, calcium should be taken during a meal because otherwise can cause hypercalciuria. **Reserved for children with a known disorder of uric acid metabolism
|Condition||Pharmacologic treatments||Adverse effects|
|Hypercalciuria||hydrochlorothiazide (1–2 mg/kg per day, older children 25–100 mg/day)||Hypokalemia, hyponatremia or hyperuricemia|
|Hyperoxaluria||pyridoxine (5–10 mg/kg per day) for primary hyperoxaluria||Numbness and tingling, drowsiness, decreased sensation, sensory nerve damage, nausea, loss of appetite, decreased folic acid|
|magnesium (if hypomagnesuria is present)||Diarrhea, muscle weakness, fatigue|
|calcium supplements*||Constipation, bloating|
|treatment of secondary hyperoxaluria should be directed at the treatment of the underlying cause.|
|Hyperuricosuria||allopurinol (4–10 mg/kg/day, older children 300 mg per day) **||Nausea, diarrhea, stomach upset, skin rash, changes in liver function test.|
|Cystinuria||tiopronin (15 mg/kg/day divided in 3 doses)||Skin and mucosal eruption, arthralgias, zinc and copper deficiency, lupus-like drug reaction, myasthenia gravis like reaction, pemphigus.|
|D-penicillamine (30 mg/kg/day divided in 4 doses)||Hematological: aplastic anemia, neutropenia, thrombocytopenia, altered taste, renal: proteinuria, vitamin B deficiency|
|captopril (0.5–1.5 mg/kg/day divided in 4 doses)||Hyperkalemia, elevated serum creatinine, cough|
- Metabolic risk factors are commonly identified in pediatric urolithiasis;
- A complete metabolic work up should include a 24-hour urine collection and should be performed in all children with kidney stones;
- Stone fragment(s) should be obtained and send for analysis;
- Red flags for genetic causes should be identified;
- A high skilled multidisciplinary team and an experienced lab are the key to successful treatment and prevention;
- Treatment should be optimized to the highest efficiency and lowest risk of complications.
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