ADVANCES IN THE MANAGEMENT OF NEPHROLITHIASIS Comprehensive Kidney Stone Center at Duke University Medical Center Durham, North Carolina Glenn M. Preminger, M.D.

NEPHROLITHIASIS EPIDEMIOLOGY Affects 1 - 3 % of adult population Annual incidence 1% in white males Life - time risk in adult males - 20% Recurrent stones in 63% after 8 years

NEPHROLITHIASIS ANATOMY

NATURAL HISTORY & RISK FACTORS NEPHROLITHIASIS NATURAL HISTORY & RISK FACTORS Peak incidence age 30 - 60 Gender (Male : Female) 3 : 1 Family history 3 - fold  risk Body size  risk with  weight Recurrence after first stone: Year 1 10 - 15% Year 5 50 - 60% Year 10 70 - 80%

STONE BELT

ECONOMIC IMPLICATIONS - 1993 DATA NEPHROLITHIASIS ECONOMIC IMPLICATIONS - 1993 DATA Inpatient Evaluation $155 million Hospitalization $848 million Professional $762 million Wages $140 million Outpatient Evaluation $358 million Wages $128 million Total $2.39 Billion Thompson, et al, 1995

ASYMPTOMATIC CALCULI TREATMENT Solitary kidney Occupation (pilot, business traveler Simultaneous contralateral treatment It’s difficult to make an asymptomatic patient feel any better !

SURGICAL STONE DEFINITION Intractable pain Significant obstruction Recurrent infection Severe bleeding Imminent threat

STONE MANAGEMENT OPTIONS Open surgery Percutaneous nephrolithotomy Ureteroscopy Shock wave lithotripsy Medical therapy

STONE MANAGEMENT OPEN NEPHROLITHOTOMY

SURGICAL STONE MANAGEMENT CONSIDERATIONS Residual stone rate Recurrence rate Number of procedures Hospitalization Convalescence Cost

SHOCK WAVE LITHOTRIPSY HISTORY 1972 - 1980 Preliminary research Feb, 1980 First human treated May, 1984 Clinical trials begin in USA Dec, 1984 FDA approval (Dornier)

SHOCK WAVE LITHOTRIPSY ORIGINAL DORNIER HM3

SHOCK WAVE LITHOTRIPSY SECOND GENERATION MACHINES

SHOCK WAVE LITHOTRIPSY STONE FRAGMENTATION

SHOCK WAVE LITHOTRIPSY STONE FRAGMENTATION

SHOCK WAVE LITHOTRIPSY INDICATIONS Surgical stone No obstruction Reasonable chance of expeditious removal

SHOCK WAVE LITHOTRIPSY RELATIVE CONTAINDICATIONS Large stones Calcium oxalate > 20 mm Struvite > 30 mm Cystine stones Distal obstruction Poorly informed patients

SHOCK WAVE LITHOTRIPSY CLINICAL SIDE-EFFECTS Hematuria Pain Obstruction (Steinstrasse)

SHOCK WAVE LITHOTRIPSY CLINICAL RENAL INJURY Mild contusion - Large hematoma Renal injury in 63 - 85% by MRI Little data on chronic injury Hypertension probably not a problem

SHOCK WAVE LITHOTRIPSY APPROPRIATE FOLLOW-UP Plain radiographs (KUB + tomograms) Renal scan Intravenous pyelogram Spiral CT

SHOCK WAVE LITHOTRIPSY REALITY <15mm 15-29mm >30mm Multiple SWL 5% 10% 15-30% Stone-free rate >80% 60% 50% Auxiliary procedures 2% 5-7% 15% Repeat procedures 1-2% 10-15% 15-20%

SHOCK WAVE LITHOTRIPSY REALITY Ideal for some Marginal in some Contraindicated in few THE KEY IS PROPER PATIENT SELECTION AND EDUCATION

SHOCK WAVE LITHOTRIPSY IDEAL CANDIDATES Small stone (< 1.5 cm) Mid or upper pole location Normal renal anatomy No distal obstruction

SURGICAL STONE MANAGEMENT MODIFIERS OF STONE-FREE RATE Stone size Stone location Stone composition

SHOCK WAVE LITHOTRIPSY LIMITATIONS Completeness of stone fragmentation Completeness of fragment elimination

SHOCK WAVE LITHOTRIPSY STONE FREE RATES % Stone Free Lingeman and Newman, 1990

PERCUTANEOUS NEPHROLITHOTOMY STONE MANAGEMENT PERCUTANEOUS NEPHROLITHOTOMY

PERCUTANEOUS NEPHROLITHOTOMY STONE MANAGEMENT PERCUTANEOUS NEPHROLITHOTOMY

STONE MANAGEMENT PNL IN THE AGE OF SWL Large stone mass Obstruction Anatomic abnormality SWL failure Horseshoe, divertic Certainty of results Cystine stones Obesity

SURGICAL STONE MANAGEMENT CURRENT ROLE OF PERCUTANEOUS STONE REMOVAL Stone volume 46% Obstruction 16% Cystine stones 16% Body habitus 12% SWL failures 10%

SURGICAL STONE MANAGEMENT CURRENT ROLE OF PNL

SURGICAL STONE MANAGEMENT CURRENT ROLE OF PERCUTANEOUS STONE REMOVAL Pre-op KUB Post-SWL KUB

SURGICAL STONE MANAGEMENT CURRENT ROLE OF PERCUTANEOUS STONE REMOVAL Post-PNL KUB Post-PNL IVP

SURGICAL STONE MANAGEMENT STAY OUT OF TROUBLE Pre-op KUB Pre-op IVP

SURGICAL STONE MANAGEMENT STAY OUT OF TROUBLE Post-op tomogram Post-op IVP

CRITERIA FOR EVALUATION STAGHORN CALCULI CRITERIA FOR EVALUATION Stone-free rates Primary procedures Secondary procedures Unexplained secondary procedures Hospital days AUA Guidelines Panel, 1994

STAGHORN CALCULI STONE FREE RATE % Stone Free AUA Guidelines Panel, 1994

PROCEDURES PER PATIENT (20) STAGHORN CALCULI PROCEDURES PER PATIENT (20) % 20 Procedures AUA Guidelines Panel, 1994

STAGHORN CALCULI SANDWICH THERAPY PNL SWL FLEX NEPHROCOPY

STAGHORN CALCULI SANDWICH THERAPY Allows debulking of large stones (Should push PNL "to the limit") SWL reserved for inaccessible fragments Flexible nephroscopy to insure stone-free status

STAGHORN CALCULI SANDWICH THERAPY

AGGRESSIVE PNL - SINGLE PROCEDURE STAGHORN CALCULI AGGRESSIVE PNL - SINGLE PROCEDURE Pre-op KUB Pre-op KUB

AGGRESSIVE PNL - SINGLE PROCEDURE STAGHORN CALCULI AGGRESSIVE PNL - SINGLE PROCEDURE Pre-op IVP Pre-op IVP

AGGRESSIVE PNL - SINGLE PROCEDURE STAGHORN CALCULI AGGRESSIVE PNL - SINGLE PROCEDURE 3 N-tracts Upper pole access

AGGRESSIVE PNL - SINGLE PROCEDURE STAGHORN CALCULI AGGRESSIVE PNL - SINGLE PROCEDURE 3 access sheaths Post-op N-tubes

URETERAL CALCULI

TREATMENT CONSIDERATIONS URETERAL CALCULI TREATMENT CONSIDERATIONS Location Size Chronicity Equipment Expertise

URETERAL CALCULI TREATMENT OPTIONS Observation Shock wave lithotripsy Ureteroscopy Blind basket extraction Percutaneous approach Open surgery

URETERAL CALCULI SPONTANEOUS PASSAGE

Of all stones that pass spontaneously, 95% will pass within 6 weeks URETERAL CALCULI SPONTANEOUS PASSAGE Of all stones that pass spontaneously, 95% will pass within 6 weeks Miller & Kane, 1999

URETERAL CALCULI MEDICAL MANAGEMENT Hollingsworth & Hollenbeck, 2006

URETERAL CALCULI MEDICAL MANAGEMENT Hollingsworth & Hollenbeck, 2006

URETERAL CALCULI 3RD GENERATION SWL

URETERAL CALCULI IN SITU SWL Minimal anesthesia requirements Non-invasive procedure No stenting / less complications Similar approach to ureteral calculi in all locations

SWL FOR URETERAL CALCULI

URETERAL CALCULI PARAMETERS FOR COMPARISON Stone-free is not everything !!

PARAMETERS FOR COMPARISON URETERAL CALCULI PARAMETERS FOR COMPARISON Effectiveness Morbidity Convalescence Cost

SWL FOR URETERAL CALCULI DORNIER HM-3 Upper Middle Lower N= 33 N=248 N=381 Success of 94.8% 85.9% 98.2% 1O procedure Re-tx rate 6.8% 15.7% 1.8% Complications 10% 15.3% 8.4% Lingeman, et al, 1993

DISTAL URETERAL CALCULI COMPARISON OF MONOTHERAPY STUDIES URS is 10 - 18% more effective than SWL (depending on type of SWL unit) Morbidity / convalescence reduced with SWL Need for stents 40-60% less with SWL Cost issues not addressed in monotherapy studies

DISTAL URETERAL CALCULI OVERVIEW OF HISTORICAL CONTROL STUDIES SWL URS Effectiveness Slightly better Morbidity Less Hospitalization Less Cost Slightly less

DISTAL URETERAL CALCULI PROSPECTIVE, RANDOMIZED TRIAL 80 patients randomized to receive SWL or URS 40 patients had stones > 5 mm 40 patients had stones < 5 mm SWL performed on Dornier MFL 5000 URS performed with 6.5F or 9.5F semi-rigid ureteroscopes (basket vs. pneumatic lithotripsy) Peschel & Bartsch, 1999

DISTAL URETERAL CALCULI PROSPECTIVE, RANDOMIZED TRIAL STONES < 5 MM URS SWL OR time (min) 19 63 Fluoro time (min) 0.8 5.1 Stone-free (days) 0.2 10.8 Stent (days) 7.2 0 Re-treatment rate 0 15% * * * * * Peschel & Bartsch, 1999

SWL OF DISTAL URETERAL CALCULI ADVERSE EFFECTS TO FEMALE REPRODUCTIVE TRACT? Initial animal studies suggest ovarian trauma Impaired fertility Mutagenesis Subsequent animal investigations demonstrate no impact on fertility or offspring Mice Rats Rabbits

SWL OF DISTAL URETERAL CALCULI ADVERSE EFFECTS TO FEMALE REPRODUCTIVE TRACT? Analyzed Rx data and radiation exposure in 84 women of reproductive age 7 children born to 6 patients with no malformations or chromosomal anomalies Miscarriages in 3 patients (but occurred at least 1 year after SWL) Viewig & Miller, 1992

URETEROSCOPY

FLEXIBLE URETEROSCOPY URETERAL CALCULI FLEXIBLE URETEROSCOPY

ANTEGRADE MANIPULATION OF URETERAL CALCULI INDICATIONS Large stone burden Body habitus Urinary diversion Transplant kidney

PERCUTANEOUS APPROACH URETERAL CALCULI PERCUTANEOUS APPROACH

URETERAL STONE MANAGEMENT IN SITU SWL Advantages Minimal anesthesia requirements Non-invasive procedure No stenting/less complications Similar approach for all ureteral calculi Disadvantages Lower success rate than URS Higher re-treatment rate

URETERAL STONE MANAGEMENT URETEROSCOPY Advantages Highest success rate Definitive Rx - No waiting for stone passage Disadvantages More invasive than SWL Higher complication rate Requires greater technical expertise

URETERAL CALCULI: CURRENT OPTIONS PROX AND MID URETERAL STONES Approach Invasive Stent S-F Rate Re-RxRate URS +++ 100% 75-90% 10-15% Push/Smash ++ Rarely 92% 9% SWL + Stent + 100% 75-80% 20-25% In situ SWL 0 No 75-80% 20-25% * Defined as complete stone removal with single procedure

URETERAL CALCULI: CURRENT OPTIONS DISTAL URETERAL STONES Approach Invasive Stent S-F Rate Re-RxRate URS +++ 100% 98-100% 0-2% Push/Smash ++ Rarely 92% 9% SWL + Stent + 100% 75-80% 20-25% In situ SWL 0 No 75-80% 20-25% * Defined as complete stone removal with single procedure

SURGICAL STONE MANAGEMENT CHANGING TREATMENT PHILOSOPHIES 1980’s 1990’s 2000’s 2010’s Shock wave lithotripsy 95% 85% 75% ??? Endoscopic procedures 5% 15% 25% ??? Open stone surgery < 1% < 1% < 1% 0

NATURAL HISTORY & RISK FACTORS NEPHROLITHIASIS NATURAL HISTORY & RISK FACTORS Peak incidence age 30 - 60 Gender (Male : Female) 3 : 1 Family history 3 - fold  risk Body size  risk with  weight Recurrence after first stone: Year 1 10 - 15% Year 5 50 - 60% Year 10 70 - 80%

SHOCK WAVE LITHOTRIPSY RECURRENT STONE FORMATION One Year Two Years Post SWL Post SWL Stone Free New stones 8% 10% Residual Stones Stone growth 22% 21% Lingeman, et al, 1989

SHOCK WAVE LITHOTRIPSY EFFECT ON STONE RISK FACTORS Urine Values Pre- 3 Mo Post- (mg/day) Lithotripsy Lithotripsy Calcium 254 261 Uric Acid 552 548 Citrate 249 257 Oxalate 42 41 Brown, et al, 1989

MEDICAL MANAGEMENT OF NEPHROLITHIASIS PROGRESS Elucidation Urinary environment conducive to stone formation Diagnosis Detection of underlying physiologic abnormalities Medical Therapy Development of new treatment strategies

STONE FORMATION MAJOR FORCES Concentration / solubility of stone-forming salts Promoters of crystallization and aggregation Inhibitors of crystallization and aggregation

IMPACT OF LOW CALCIUM DIET DIETARY CALCIUM IMPACT OF LOW CALCIUM DIET Early recommendations suggest that low calcium diet will decrease urinary Ca++ excretion, thereby reducing risk of stone formation Potential risk factors involving low calcium diet: Reduced bone mass Increased urinary oxalate

DIETARY CALCIUM RECOMMENDATIONS Moderate calcium restriction in patients with AH Limit dietary intake of oxalate Spinach, tea, chocolate, nuts Limit dietary sodium intake

PHYSIOLOGICAL EVIDENCE CALCIUM SUPPLEMENTS PHYSIOLOGICAL EVIDENCE Calciuric response to calcium supplementation Depends on duration of treatment and patient population

RECOMMENDATIONS: PREMENOPAUSAL WOMEN CALCIUM SUPPLEMENTS RECOMMENDATIONS: PREMENOPAUSAL WOMEN Give HCTZ during initial three months to prevent hypercalciuria, then discontinue for one month If urinary calcium up at 4 months, re-start HCTZ Alternative: Significantly increase fluid intake for first three months and then check 24-hour urinary calcium

RECOMMENDATIONS: POSTMENOPAUSAL WOMEN CALCIUM SUPPLEMENTS RECOMMENDATIONS: POSTMENOPAUSAL WOMEN Check 24-hour urinary calcium 4 months after starting calcium supplements Offer thiazide to hypercalciuric patients

CALCIUM SUPPLEMENTS CURRENT PREPARATIONS “Standard” Calcium Supplements Calcium carbonate Calcium phosphate

CALCIUM SUPPLEMENTS CURRENT PREPARATIONS Limitations Poorly absorbed from intestinal tract Increased urinary calcium excretion Promotes CaOx, CaPhos stone disease

CALCIUM SUPPLEMENTS CALCIUM CITRATE "Citracal" Over-the-counter preparation Calcium citrate 950 mg Elemental calcium 200 gm Provides increased intestinal calcium absorption Prevents supersaturation of stone-forming salts A more "stone-friendly" calcium supplement

CALCIUM SUPPLEMENTS CALCIUM CITRATE Long-term clinical trial in pre-menopausal women No significant change in urinary saturation of: Calcium oxalate Calcium phosphate (brushite) No increased propensity for crystallization of calcium salts Mainly due to "protective" effects of citrate Sakhaee & Pak, 1994

MEDICAL MANAGEMENT OF NEPHROLITHIASIS SELECTIVE TREATMENT APPROACH Reverse underlying physicochemical and physiologic abnormalities Inhibit new stone formation Overcome non-renal complications Bone disease in RTA Free of serious side effects

METABOLIC EVALUATION SELECTION OF PATIENTS Simplified evaluation Comprehensive evaluation Metabolically inactive Metabolically active Single stone, low risk Single stone, high risk Positive family history Early age of onset Nephrocalcinosis Associate medical conditions

“LOW RISK” STONE FORMER METABOLIC EVALUATION “LOW RISK” STONE FORMER Serum Ca, Phos 10 HPT Serum electrolytes RTA Serum uric acid Gout, HUCU Urinalysis Crystals, infection History (risk factors) Fluids, diet, meds X-rays Nehprocalcinosis RTA Radiolucent stones Uric acid, ? Cystine Staghorn stones Struvite Stone analysis Type of stone

METABOLIC EVALUATION URINARY CRYSTALS

AMBULATORY EVALUATION EVOLUTION 1971 1974 1986 2001 Hospitalization (days) 14 0 0 0 Outpatient visits 0 0 3 1-2 Duration (days) 14 21 21 14 # diagnostic categories 3 4 9 13 Unclassified etiology 43% 11% 11% 3%

AMBULATORY EVALUATION OUTLINE Blood Urine CBC SMA PTH TV pH Ca Ox UA Na Cit Creat Cyst Visit 1 x x x x x x x x x x x Visit 2 x x x x x x x x x Fast x x x Load x x x

METABOLIC EVALUATION CLASSIFICATION Calcareous calculi Non-calcareous calculi Hypercalciuria (40-75%) Low urinary pH Uric acid stones (5%) Hyperuricosuria (10-50%) Cystinuria Hyperoxaluria (<5%) Cystine stones (1%) Hypomagesuria (<5%) Infection (urea-splitting) Struvite stones (15%) Hypocitraturia (10-50%) * Expressed as percentage of total

METABOLIC EVALUATION CLASSIFICATION Sole Combined Occurrence Occurrence Absorptive hypercalciuria 20% 40% Type I, Type II Renal hypercalciuria 5% 8% Resorptive hypercalciuria 3% 5% Unclassified hypercalciuria 15% 25% Hyperuricosuric nephrolithiasis 10% 40% Hyperoxaluric nephrolithiasis 2% 15%

METABOLIC EVALUATION CLASSIFICATION Sole Combined Occurrence Occurrence Hypocitraturia 10% 50% Hypomagnesiuria 5% 10% Gouty diathesis 15% 30% Cystinuria <1% Infection stones 1% 5% Low urine volume 10% 50% No Dx / miscellaneous < 3%

MEDICAL MANAGEMENT OF NEPHROLITHIASIS SELECTIVE TREATMENT APPROACH Reverse underlying physicochemical and physiologic abnormalities Inhibit new stone formation Overcome non-renal complications Bone disease in RTA Free of serious side effects

MEDICAL MANAGEMENT OF NEPHROLITHIASIS SELECTIVE TREATMENT APPROACH First Line Second Line AHI Thiazide Cellulose phos RH Thiazide HUCU Allopurinol Citrate Enteric hyperox Ca++/ Mg++ Citrate Gouty diathesis Citrate Allopurinol Hypocit Citrate Bicarb Cystinuria Thiola d-Pen Struvite Remove stone Thiola

SELECTIVE MEDICAL THERAPY IMPACT OF MEDICAL RX SELECTIVE MEDICAL THERAPY Stone Formation Rate Pre-Rx On K-Citrate

MEDICAL MANAGEMENT OF NEPHROLITHIASIS SELECTIVE VS. CONSERVATIVE TREATMENT Placebo/ Potassium Conservative Citrate Stone formation 0.54 0.25 0.52 0.02 rate (no/pt/yr) Reduction in stone 54% 96% formation rate Remission rate 61% 96% * * Preminger & Pak, 1985

IMPACT OF MEDICAL THERAPY NEED FOR STONE REMOVAL Pre- On Treatment Treatment Duration (yr/pt) 3.0 3.7 Surgery rate (no/pt) 0.21 0.01 Patients requiring 58% 2% Surgery * * Preminger & Pak, 1985