Stephen Schneider PA-c, Children’s hospital of Philadelphia The Advance Practice Provider’s Role in the Diagnosis and Management of Pediatric Kidney Stones Stephen Schneider PA-c, Children’s hospital of Philadelphia

Disclosures None

Objectives Discuss the different types of kidney stones and the physiology behind them Educate on how to manage and treat common types of pediatric kidney stones Review education strategies focused on the prevention of kidney stones in the pediatric patient

The Basics – What is a kidney stone? Hard Mass developed from crystals Various types of chemicals Accumulation of stone forming substances Pain Agony Misery Accumulation of stone forming substances Increase in concentration/Decrease in inhibitors = stone formation Super-saturation Urinary pH

The Basics – What is a kidney stone? Size Range from a grain of sand or golf ball sized Shape Smooth or jagged Color Yellow/brown/white

Pathophysiology Stone growth starts with the formation of crystals Crystals adhere to the urothelium Adherence creates the nidus for the later stone growth

Incidence Increasingly common among children Among adolescents, the incidence of nephrolithiasis has increased 6-10% annually over 20 years. Nephrolithiasis (kidney stones) affect 9% of the United States population.1 The prevalence of nephrolithiasis among adults has increased 70% over the last thirty years. The incidence of nephrolithiasis among children has risen even more rapidly and has increased by 6-10% per year over the last 20 years.2-4 The long term harms of nephrolithiasis are severe and include an increased risk of end-stage renal disease and coronary heart disease.1,5-8

Risk Factors Environment Non-modifiable Risk Factors Behavior Temperature Sunlight Behavior Diet Fluid intake Obesity Non-modifiable Risk Factors Age Gender Genetics Preexisting medical conditions The ecological model of human disease can be used to understand an individuals and a population risk of kidney stones. The risk of stones is comprised of the interaction between the environment, non-modifiable risk factors, and behaviors

Risk Factors Non-modifiable risk factors Age Gender Genetics Preexisting medical conditions Developmental anomalies of urinary tract Promote stasis/infection UPJO Neurogenic bladder

Risk Factors Environmental Behavioral Warmer climates/Stone belt Several days of heat may increase risk Behavioral To be discussed in more detail later High temperatures cause water loss, concentrate urine, low urine volume and pH

Risk Factors Current U.S. ‘stone-belt’ or high-risk kidney stone area in yellow. Computer model predicts expansion of stone-belt over time in orange (2050) and in red (2095). Currently, 41% of the population is within a high-risk zone. Computer model predicts 56% of the population will be in a high-risk zone by 2050 and 70% by 2095. Via PNAS 2008.

Different Types of Kidney Stones Calcium Stones Calcium oxalate Calcium phosphate Struvite Uric Acid Cystine Stones

Pediatric Stone Composition

Calcium Stones Most common type of stone made Two major forms 80% of all stones Two major forms Calcium Oxalate Calcium Phosphate

Calcium Oxalate Stones Oxalate is a type of acid with a plant origin Not essential to life Excreted through the urine unchanged Excess of vitamin C is converted to oxalate Foods high in oxalate Spinach, rhubarb, nuts, and wheat bran Calcium Oxalate Monohydrate Stones

Calcium Oxalate Stones Caused by high calcium and high oxalate excretion Associated with high levels of serum calcium Parathyroid disorders Dehydration Diet Refined Carbohydrates Protein 75 % of stones Refined Carbohydrates Sugar causes the pancreas to excrete insulin therefor causing the kidney to increase calcium excretion Protein Red meat/poultry increases uric acid, calcium, and oxalates in the urine and decreases citrate levels

Calcium Oxalate Stones Calcium intake should NOT be restricted Calcium binds to oxalate in the intestines therefor decreasing the amount of calcium oxalate that needs to be eliminated from the body in the urine preventing the formation of calcium oxalate stones in the kidneys

Calcium Phosphate Stones Caused by the combination of high urine calcium and alkaline urine Often associated with renal tubular acidosis and hyperparathyroidism Most often occurs in combination with calcium oxalate stones 5-10% of all stones Meaning the urine has a high pH – ph is greater than 7.2 The presence of an underlying condition should be considered n patients with pure calcium phosphate stones Calcium Phosphate Stone

Struvite (staghorn) Stone Infectious stone Produced by the bacterial waste products formed during the UTI Composed of magnesium, ammonium, phosphate Urea- Splitting Bacteria Bacteria splits urea into ammonia which decreases the acidity of the urine and forms struvite stones Proteus mirabilis, Klebsiella, Serratia Pseudomonas 10-20% An enzyme called urease is produced by the infection causing bacteria that causes chemical decomposition of urea into ammonium and hydroxyl ions.  In a situation where there is an increase in the above mentioned compounds and the urine is of a high alkaline quality, it provides the right environment for the formation of struvite stone.  This kidney stone type can grow rapidly and become quite large but with little or no symptoms. Struvite Stones

Uric Acid Stone The end product of purine metabolism which causes urate to crystallize in the kidney The urine is often excessively acidic Presence of an underlying condition should be considered in patients with uric acid stones gout Radiolucent stones Low PH 5-10% of stones Meat/fish/chicken High fructose intake Uric Acid Stones

Cystine Stones Autosomal recessive pattern of inheritance Cystinuria results in the excessive excretion of four basic amino acids Cystine, ornithine, lysine, arginine (COLA) Cystine is insoluble in acidic urine Inborn error of metabolism 1-2% of stones Cystine kidney stones are due to cystinuria, an inherited (genetic) disorder of the transport of an amino acid (a building block of protein) called cystine that results in an excess of cystine in the urine (cystinuria) and the formation of cystine stones. Amino acids are the building blocks of muscles and nerves Cystine Stones

Clinical Presentation Abdominal pain (often confused with appendicitis) Young children: generalized (abdominal pain) Adolescents: localized (flank pain) colicky Nausea Hematuria Dysuria Urinary frequency Flank pain in adolescents moves to the lower quadrant, penis or vagina as the stone travels down the ureter Macroscopic or microscopic hematuria can occur in up to 90% of children with urolithiasis

Physical exam CVA tenderness Patient can not get comfortable Absence of peritoneal signs

Pathway/ Algorithms

Pathway/ Algorithms www.chop.edu/pathways A clinical pathway is a task-oriented care plan that details essential steps in the care of patients with a specific clinical problem and describes the patients expected clinical course. www.chop.edu/pathways Goals of clinical pathway standardize care improve outcomes reduce cost

Pathway/ Algorithms 2 nephrolithiasis pathways at CHOP Nephrolithiasis, suspected, emergent care - http://www.chop.edu/clinical-pathway/suspected-nephrolithiasis- clinical-pathway Nephrolithiasis, outpatient specialty care - http://www.chop.edu/clinical-pathway/nephrolithiasis-clinical-pathway

Pathway/ Algorithms Kidney Stone Pathway Goals Metrics Reduce recurrence Reduce associated burden of the disease Set the international standard for care Metrics % of patients appropriately referred to nephrology from urology % of patients who keep clinic referral appointment Decrease in emergency department visits Recurrence of stones

Emergent stone pathway and work up Diagnostic imaging Only 10-25% of children with suspected nephrolithiasis actually have stones (Persaud et al., Pediatrics, 2009) 72% of children who underwent CT for suspected nephrolithiasis did not have stones. 9% had clinically important alternative diagnoses identified by CT Use ultrasound as the initial imaging study for children with suspected kidney stones American Urological Association (2012) European Association of Urology (2009) Limit radiation where possible Image Gently (2007)

Imaging Renal and bladder ultrasound Advantages: Limitations: Accessible Can detected obstruction by showing dilation - * Can also detect radiolucent stones that are frequently missed on plain abdominal x-ray Requires no ionizing radiating Limitations: Poor visualization of ureteral stones Measurement of stone size less reproducible by ultrasound than by CT Good test Sensitivity = 70% Specificity = 100% Most stones not visualized are not clinically important Secondary signs of obstruction usually present Hydronephrosis No ureteral jet

Imaging Renal ultrasound Good test Sensitivity = 70% Specificity = 100%

Imaging Renal ultrasound Good test Sensitivity = 70% Specificity = 100%

Imaging CT scan Advantages Disadvantages Most sensitive and specific radiology test Fast Definitive diagnosis Disadvantages Less accessible Relatively expensive Cancer risk Indicated in children with persistent symptoms of urolithiasis and a non-diagnostic ultrasound. Sensitivity: 95-100% Specificity: 94-96% Provides info on non-genitourinary conditions attributable risk of cancer from 1 CT ≅ 0.2-0.3% (Kuhns et al., Ped Emer Care, 2011) Higher risk for children Risk is cumulative (Smith-Bindman, Arch Int Med, 2009)

Imaging CT Scan

Imaging KUB Abdominal radiograph of the kidneys, ureter, and bladder Gives size, shape, location 90% or more of urinary-tract stones are radio-opaque 10% of stones there is not enough Ca to be seen Uric acid stones are radio-lucent The degree of opacity varies depending upon the composition of stone, size of the stone, position of the stone, and constipation

Imaging KUB

Emergent Stone Pathway Hydronephrosis Hydroureter Increase in renal size Uroepithelial thickening Significant pain Hematuria History of:Nephrolithiasis Hypercalcuria Hyperoxaluria Hyperuricosuria Cystinuria Multiple urinary tract infections Reassess patient Consider broader differential for abdominal pain May refer to possible appendicitis and abdominal pain in post pubertal females if indicated

Outpatient Stone Pathway To help evaluate, diagnose, treat, and prevent stone disease

Preparation for the Office Visit

Serum Labs BMP Magnesium, phosphate, and uric acid Urinalysis

Detailed H&P

Indications for Surgery

Medical Expulsion Therapy Dilate smooth muscle of the distal third of ureter Use on passing/ureteral stone

Medical Expulsion Therapy Alpha blockers (Tamsulosin) Advantages Increase spontaneous passage rates of ureteral stones Decrease time for stone passage Decrease analgesic requirements Cost effective Disadvantages Few studies have assessed the efficacy of MET for ureteral stones Decrease blood pressure which can lead to dizziness and orthostatic hypotension Take at night

Surgical treatments Shock wave lithotripsy Ureteroscopy Falling out of favor Ureteroscopy Percutaneous Nephrolithotomy Stones greater than 1.5 cm Lower pole stones >8 mm Infected stones Multiple stones Reason why ESWL is not great - Poor stone free rates High re-intervention rates Long term safety in children not demonstrated Still needs GA We have better interventions Advantage to PCNL – better stone free rates with one procedure, disadvantage – riskier operation, increased bleeding, inpatient procedure

Outpatient Stone Pathway

Metabolic Evaluation

24 hour urine test Analyzes urine to help determine the cause of the kidney stones Helps to guide the treatment Aids in prevention of kidney stones in the future 70% of children with nephrolithiasis will have abnormalities in the urine that increase the risk of stone formation targets for dietary and pharmacological interventions Patient obtains the 24 hour urine at home and then the coorelating blood work Determines How much urine is being produced The acidity (pH) of the urine The amount of certain substances in the urine, such as calcium, sodium, uric acid, oxalate, citrate, and creatinine

24 hour urine test

24 hour urine test Creatinine clearance – first thing to look at this helps to tell us if this was an adequate sample. Unfortunately the normal are values set are only for adults, but most teenagers will fit into these normal. Normal male is 18-24 and normal female is 15 – 20.

24 hour urine test This is the amount of urine that the patient is putting out. Ideally you want them to put out 2 liters of urine. A Low urine volume increases supersaturation of Ca, oxalate 50% reduction in recurrence with increased water

Treatment for low urine output The single most important determinant of stone formation is low fluid intake. A low fluid intake results in the production of concentrated urine causing a supersaturation and crystallization of stone forming compounds Low urine flow rates promote crystal deposition on the urothelium

Treatment for low urine output Tips: Ask the kids to look at the color of their urine. Most kids think their urine should be yellow, rather we want more clear urine. Encourage the parents to buy the kid a “cool” water bottle and remind the child to fill it often Keep a glass of water on your desk at school Keep another glass next to your bed. Many of us wake up dehydrated first thing in the morning Decrease sugary drinks as well Fructose increases calciuria

24 hour urine test Hypocitraturia Normal for males is greater than 450 and females is >550

hypocitraturia Citrate is a molecule that binds to calcium in the urine Citrate inhibits calcium stone formation Prevents calcium from binding to oxalate or phosphate Treatment Add Lemonade to the diet Potassium citrate Hypocitraturia Citrate is a molecule that binds to calcium in the urine

hypocitraturia Potassium Citrate Alkalinizing agent Start with 10mEq (1080mg) TID, max 100mEq daily Take with full glass water Relatively safe with minor GI side effects Nausea Long- term compliance with therapy and the effect on decreasing stone recurrence in children remain unknown

24 hour urine test Normal sodium level is considered 50-150 Normal calcium for males is <250 and females <200

High sodium level Industrialized countries (food processing) consume far more Na than our recommended daily allowance. Decrease sodium to <2 grams/day Direct link between increased sodium level and increasing calcium level DO NOT DECREASE CALCIUM INTAKE Low calcium diets INCREASE risk of kidney stones) children 1-3 yrs 1.0 g children 4-8 yrs 1.2 g children 9-13 yrs 1.5 g males 14-50 yrs 1.5 g females 14-50 yrs 1.5 g

Hypercalciuria Treatment Medication use to be considered after maximizing urine calcium reduction by limiting the dietary sodium intake. Thiazides – hydrochlorothiazide (not potassium sparing) Increase calcium absorption in the proximal tubule Decrease urine calcium

24 hour urine test Normal oxalate level is between 20-40

hyperoxaluria Only 10-20% of urinary oxalate excretion is derived from diet. Berries, Greens, Chocolate, Tea (Ice-), and nuts We used to restrict oxalate intake, but this has fallen out of favor because of the high Magnesium content of these food. Magnesium can also help prevent kidney stone formation Vitamin C supplements also associated with increased risk of CaOx stones, as oxalate is a byproduct of ascorbic acid metabolism

Metabolic Evaluation Recommendation if to follow up in either urology, nephrology , or joint uro/nephrology clinci based on metatbolic evaluation. Typical follow up in every 6 months wit ha repeat RBUS and 24 hour urine

Children are at Higher Risk Longer lifetime over which recurrent stones may occur Longer lifetime over which diseases associated with nephrolithiasis may develop

Associated Disease Loss of Kidney Function (Alexander et al., BMJ 2013) Women <50 years with ≥1 kidney stone had a 3.6 times greater risk of ESRD Increased but lesser risk present among men and older women Coronary Heart Disease (Ferraro et al., JAMA, 2013) Highest risk of MI observed among younger women Bone fracture (Denburg et al., CJASN, 2014) Among women in 30s, kidney stones were associated with a 55% increased risk of fracture Among boys 10-19 years old, kidney stones associated with a 13% increase risk of fracture

In Conclusion The incidence of kidney stones is increasing in children Ultrasound should be the first line study 24 hour urine test will help to target dietary and pharmacological intervention There are behavioral risk factors that can be modified to help reduce the risk of reoccurrence Increase water and lemonade Decrease sodium intake Risk of recurrence ~ 50% in 3 years

Questions?