NEPHROLITHIASIS / RENAL STONES

YOUR LECTURER :

NEPHROLITHIASIS
- Magnitude of Stone disease: 1 out of 5 will have urologic stone in a lifetime 7 to 10 of every 1000 hosp. admissions(USA) 4/5 cases are male; peak age 25 - 35 years (prime of life) 
Stones may injure kidneys, produce Renal Failure by infection or obstruction, cause severe pain or worrisome bleeding. More morbidity occurs than death or ESRD (accounts for 2-3% only of all-cause CKD) Majority of cases, stone dse will accelerate; complex etiology; overall hx is of chronicity and hope of waning as age progresses is for the majority, unrealistic.  Recurrence is the rule: one stone every 2-3 years Average recurrence: 50% within 5 yrs; 60% in 10 yrs

MANIFESTATIONS : ‡ Asymptomatic - as long as stone remains attached to renal papillae ‡ Hematuria - may be isolated or associated with pain ‡ Obstruction - typically produce pain from acute obstruction anywhere from ureteropelvic to ureterovesical junction called renal colic which gradually increases severity over 30 mins to a plateau. ‡ Stone passage - pain begins at flank then moves downward and laterally along anterior abdomen to loin, testis or vulva. Stone lodged in ureterovesical junction present as frequency, urgency or dysuria mistaken as UTI. ‡ Staghorn calcuili - can be struvite, cystine or uric acid stones grown too large, usually in the presence of urease + organisms ‡ Nephrocalcinosis - multiple papillary calcifications commonly seen in RTA and medullary sponge kidneys. ‡ Sludge - precipitate plug of uric acid or cystine crystals ‡ Infection ± flank pain, fever, chills, nausea/vomiting, hypogastric pain

Hydronephrosis causes tubular dilatation with cellular atrophy. · after 2-3 days,blunting of the renal papillae with gradual atrophy of renal tissue · in 7 days, atrophy is seen up to the distal nephron · by 14 days, progressive dilatation of the distal tubules with atrophy up to proximal tubules - at 28 days, 50% loss of the medulla with marked atrophy of proximal tubules and thinning of the cortex. Glomerular damage occurs after 28 days of obstruction

In one study of 75 patients with ureteral stones who were followed prospectively, the average time for stone passage in patients with stones that were 2 mm in diameter or smaller, 2 to 4 mm, and greater than 4 mm was 8, 12, and 22 days, respectively

Pain control ± Both NSAIDs and narcotics have traditionally been
used for pain control in patients with acute renal colic and in prospective studies are equally effective. One study compared indomethacin (100 mg) by rectal suppository or I.V. morphine (5 mg then up to two additional 2.5 mg doses if needed). There was no significant difference between the two. A second RCT found that I.V. Ketorolac (60 mg initial dose) had superior pain relief compared with I.V. meperidine (50 mg initial dose). Alternative opiates include tramadol and fentanyl , used alone or in conjunction with NSAIDs.

NSAIDs have advantage of decreased ureteral smooth muscle tone. On the other hand, in patients w/ preexisting renal disease, NSAIDs impair the kidney's autoregulatory response to acute obstruction and induce acute renal failure. Moreover, NSAIDs should be stopped 3 days before ESWL to minimize the risk of bleeding, owing to antiplatelet effect. Newer COX-2 inhibitors have promise in acute colic pain relief with less antiplatelet effect, but to date there are no good studies nor guideline recommendations.

50% of patients have only 1 stone. ‡ Waiting for a 2nd stone before metabolic workup is reasonable because of attitudinal behavior and low incidence of renal impairment; except a.) < 25 or > 60 yo b.) strong family history c.) preexisting renal disease ‡ Analysis of stones passed out spontaneously - may NOT be useful. 80% stones are Ca++ oxalate, no matter the primary d/o. This won¶t alter the workup in recurrent stone dse. Ex: hyperuricosuria causes calcareous stones 4x more than uric acid stones by enhancing Ca oxalate precipitation and adsorbing urinary stone inhibitors such as citrate However, as with crystalluria, will give a clue to the underlying metabolic d/o, such as with cystine and struvite stone formers.

Cystine ³hexagon´ crystals

MgNH4CaPO4 /struvite ³coffin lid´ crystals

STONE DISSOLUTION (Medical) OR SURGERY - 1924, Cromwell dissolved cystine stones in mercuchrome & alkali - 1940, Suby and Albright used ³chemolysis´ to dissolve phosphate calculi by nephrostomy tube irrigation - Percutaneous technics now allow stone extraction or disintegration so that only < 10% of cases require open stone surgery. - Advent of ESWL 1980 allowed stone disruption and elimination of surgery. Drawback: $ 5-9,000 although less than endourologic stone removal costing $ 6-10,000. Locally, ESWL = P 45,000 ; NL = P 30-60,000 - Presently, renal calculi is preventable with selective medical therapy designed to correct underlying metabolic disorders or derangements in urinary biochemistry.

Consensus Conference on Prevention and Treatment of Kidney Stones ± ³ Current medical therapy will NOT dissolve most stones. Rather, aimed at inhibiting stone growth and preventing formation of new stones.´ 

ESWL for stones < 2 cm dia; bigger stones and

lower pole stones > 1 cm require repeat procedures. Ureteral stones pass out spontaneously if < 5 mm. ESWL and invasive procedures may be delayed for 3-4 days w/o causing permanent damage to the kidneys even with complete obstruction. 

ESWL best for proximal ureteral stones while
endoscopic technics / ureterenoscopy better for lower ureteral stones. 

Lithotripsy CANNOT replace medical prevention.

Surgery & medical Rx complementary. Medical Rx effectively: 1. prevents recurrence 2. reduces need for surgery 3. avoids renal colic 4. correct extrarenal manifestations of a systemic disease 5. cost effective = $ 1,000 for comprehensive metabolic eval¶n and $ 300 per year for selective medical Rx

ECONOLITH 3000

The major indications for surgical intervention of urolithiasis are relief of pain, uncontrolled Infection, persistent gross hematuria or relief of significant obstruction that will destroy renal function.

IVP

The best studies to determine significant obstruction is the intravenous urogram / IVP to demonstrate calyceal clubbing and dilatation as well as renal function. Ultrasound can only define the anatomy and not functional impairment. A meta-analysis of four studies including 296 patients concluded that non-contrast helical CT is significantly better at diagnosing and ruling out stones than IVP. Thus, the new gold standard is now the use of Non-contrast helical CT or ³stonogram´ with a 98% sensitivity and 100% specificity.

TREATMENT Ureteroscopic removal of stone Pushing back stone with ESWL In situ ESWL

INDICATION Stone in distal ureter not progressing downward Stone in proximal ureter not progressing downward Stone in distal ureter not progressing downward Kidney stones 0.5 - < 2 cm

EFFICACY

98% 96-100% 78% if w/o stent 89% w/ stent 77-80% (20% add¶l procedure) 35-40% 54% (60% add¶l)

Kidney stones > 2 cm Kidney stones in lower pole >1cm PerCutaneous NephroLithotomy (PCNL)

Stone in proximal ureter 90% not progressing downward or failed push-back ESWL in 1-2% cases Kidney stones not best treated with ESWL alone 80-85% (30% add¶l) uric acid stones variable; poor if stone coated w/ oxalate or struvite variable; poor if stone coated w/ oxalate or struvite

Dissolution agents: Alkali

Water + penicillamine cystine stones or tiopronin

‡ Pathogenesis & Treatment of Kidney Stones- Coe and Parks; NEJM. Oct 92

Empiric Antibiotic Regimens for Complicated UTI 

Choice of Antibiotics:

14 day regimen

Oral regimen (mild cases): Ciprofloxacin 500 mg BID Norfloxacin 400 mg BID Ofloxacin 400 mg BID Cotrimoxazole 800 mg BID Parenteral regimen (mod.-severe cases) : (mod.Ampicillin 1 gm q 6h IV + Genta 3-5 mkd IV 3Ceftazidime 1-2 gm q 8h IV 1Ceftriaxone 1-2 gm OD IV 1Imipenem 250-500 mg q 6-8h IV 2506Ciprofloxacin 200-400 mg q 12h IV 200Ofloxacin 200-400mg q 12h IV 200Antibiotics should be modified according to urine CS result. Oral switch therapy done once afebrile or clinically improved after 48hrs

PATHOPHYSIOLOGY
Activity product ratio =

free ion activity product equilibrium solubility product

= measure of degree of saturation < 1 = undersaturation; > 1 = oversaturation Formation product = APR at which solid phase begins
UNSTABLE

stone

Urine of stone formers is supersaturated than normal. APR at the limit of metastability (FP) is lower in stone formers, suggesting facilitation of crystallization.

FP = upper limit of metastability METASTABLE Equilibrium solubility. product = free ionized Ca x oxalate conc.

Homogenous nucleation = spontaneous formation of new crystal nuclei in oversaturated urine.

STABLE

Heterogenous nucleation = any surface that serves as substrate for ions in solution to organize. Epitaxis = similarity of spacing of charged sites on preformed surface and on the lattice of crystal crystal growth Ex: monosodium urate or uric acid for Ca oxalate/phosphate

BRUSHITE WEDDELLITE WHEWELLITE CYSTINE

4 MAIN TYPES OF STONES:
1. Calcium 75% oxalate ( monohydrate/ whewellite or dihydrate/ weddellite ) 50% hydroxyapatite (CaPO4) Brushite (CaHPO4) Oxalate + Uric acid 20% Others (CO3 ; Orthophosphate) 2. Uric Acid 8% 3. Cystine 1% 4. Struvite (MgNH4PO4 amd CaCO3) 15%

STRUVITE

STONE DENSITY BASED ON DEGREE OF RADIOOPACITY Density Degree of Opacity Calcium phosphate 22.0 Very opaque Calcium oxalate 10.8 Opaque Mg-Ammonium phosphate 4.1 Moderately opaque Cystine 3.7 Slightly opaque Uric Acid 1.4 Nonopaque* Xanthine 1.4 Nonopaque
* 60% or more in composition

Limits of Normal for Excreted Materials in Urine: mg/24h Material Male Female Mg/kg/24hr Calcium 300 250 4 Uric Acid 800 750 Oxalate 50 50 0.73 Citrate 500 750 -

Calcium Stones: Idiopathic Hypercalciuria - said to be most impt determinant for stone form. - autosomal dom. pattern; 50% of stone formers Calcium reabsorption at the tubules is altered by high Na and protein diets. Hypercalciuria - oversat. and complexing of Ca oxalate and phosphates. MECHANISMS: 1. Idiopathic a. Renal Leak - defect in tub. Ca reabsorption with modest fall in serum Ca++ patients have high urine Ca levels despite Ca-restriction b. Absorptive Hypercalciuria - increased intestinal Ca reabsorption due to either duodenal absorptive defect, inc. Vit D3 action or passive absorption with inc. carbohydrate intake 2. Hyperuricosuria - high purine diets or highly acidic urine; acts as nidus 3. Primary Hyper PTH - 5% of stone formers; hypercalcemia and hypophos. 4. Hyperoxaluria - intestinal diseases, gut bypass, Vit C excess, dietary oxalate excess, or rarely,primary. - childhood onset and severity suggests primary type. - may be reduced with vit.B6 supplements >50mg/day 5. Hypocitraturia - 2nd most impt determinant of stone formation - 15 to 83% incidence; 61% in frequent stone formers (>2 per 3yrs) 6. Other rare causes (<5% of total): cystinuria, triamterene stones, RTA, xanthinuria, hypomagnesiuria

Schema for Metabolic Classification: U Ca Uca/GFR mg/24h mg% Renal Leak ______> 200 > 0.11 Absorptive Hc > 200 < 0.11 Hyperuricosuria < 200 < 0.11 Normal < 200 < 0.11

Uca/Ucr U Ua mg/24h > 0.2 < 700 > 0.2 < 700 < 0.2 > 700 < 0.2 < 700

Inhibitors of growth and nucleation: Citrate = provides 50% of inhibitory action for stone formation. 1. forms soluble complexes with Ca, reducing free ionic Ca++ 2. inhibits agglomeration of Ca++ oxalate 3. also impairs the urate-induced crystallization of Ca++ oxalate Magnesium= also potent inhibitor; 20% of urine¶s total CaPO4 crystallization inhibitory activity. Pyrophosphate = increases formation product and adsorbs calcium on its surface. Less potent at 7% of urine inhibitory action. Nephrocalcin = urine glycoprotein inhibitor Tamm Horsfall protein Acid mucopolysaccharide (AMPS) , acid peptides

SPECIFIC TREATMENT TO PREVENT OR DISSOLVE STONES
INDICATION TREATMENT EFFICACY Idiopathic Hypercal, Thiazides/diuretics Oral phosphates new stones 11-22% vs 40% controls ;up to 50% decreased risk new stones 9-25% new stones in 29-38% new stones in 27%

Low Ca++ diet (no bone dse) Sodium cellulose phosphate Primary PTH Hypocitraturia RTA type 1 Ileostomy or small bowel malabs. Hyperoxaluria ,all kinds Enteric hyperoxal. Hyperuricosuria w/ oxalate stones Uric stones, all parathyroid surgery Potassium alkali salts Potassium alkali salts Potassium alkali salts

100% new stones in 12% no data no data

Potassium alkali salts oral Ca supplements, cholestyramine, or low fat diet allopurinol Potassium alkali salts Diet ESWL or PCNL Acetohydroxamic acid

no data

no data

new stones 14% vs 35% controls new stones 12% men, 0% women

Struvite

30-40% stone free if < 2cm stone growth 0% vs 95% controls in 15-19 mos; 15% DeepVeinThr no data

Cystinuria

Penicillamine Tiopronin, Potassium alkali salts

Foods high in Oxalate
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Cocoa Chocolate Black Tea Green beans Beets Celery Green onions Leeks ‡ ‡ ‡ ‡ ‡ ‡ ‡ Leafy greens Berries Orange and lemon peel Dried figs Summer squash Nuts Peanut butter

Foods high in Purine
‡ Innards: liver, kidney, brains, heart ‡ Shell fish ‡ Meat: beef, pork, poultry, lamb ‡ Fish: anchovies, sardines, mackerel, herring, tuna, carp, halibut, cod ‡ Meat extracts: bouillon, broth, stock ‡ Gravies ‡ Vegetables: asparagus, cauliflower, spinach, peas, lentils ‡ Mushrooms ‡ Kidney beans

Beverage Use and Risk for Kidney Stones in Women*
‡ 81,093 women 40-65 y.o. ‡ Prospective cohort study with 8 year follow-up ‡ Self-administered food-frequency questionnaires to assess diet in 1986 and 1990 ‡ Outcome measure: incident symptomatic kidney stones ‡ 719 cases of kidney stones documented ‡ Relative Risk for Stone formation fluid 0.62 (95% CI 0.48-0.80) ‡ Multivariate analysis for beverages Water 0.98 (95%CI 0.94-1.02) Skim milk 0.98 (95%CI 0.86-1.12) Apple juice 0.67 (95%CI 0.36-1.25) Orange juice 1.00 (95%CI 0.80-1.26) Grapefruit juice 1.44 (95%CI 1.09-1.92) Coffee 0.90 (95%CI 0.85-0.95) Tea 0.92 (95%CI 0.85-0.99) Beer 0.88 (95%CI 0.71-1.08) Wine 0.41 (95%CI 0.25-0.68) Soda (sugared) 1.05 (95%CI 0.95-1.17) Soda (diet) 0.98 (95%CI 0.92-1.04)
* Ann Int Med 126:534-540, 1998

Comparison of Dietary Calcium with Supplemental Calcium and Other Nutrients as Risk for Kidney Stone Disease in Women*
‡ 91,731 women 34-59 y.o. ‡ Prospective cohort study with 12 year follow-up (1980-1992) ‡ Self-administered food-frequency questionnaires to assess diet in 1980, 1984, 1986 and 1990 ‡ Outcome measure: incident symptomatic kidney stones
‡ ‡ 864 cases of kidney stones documented Relative Risk for Stone formation fluid 0.61 (95% CI 0.48-0.78) dietary Ca intake 0.65 (95% CI 0.50-0.83) potassium 0.65 (95% CI 0.51-0.84) supplemental Ca 1.20 (95% CI 1.02-1.41) sodium 1.30 (95% CI 1.05-1.62) sucrose 1.52 (95% CI 1.18-1.96)

* Ann Int Med 126:497-504, 1997

Stone Formers¶ Diet
‡ Limit protein intake to < 1 gm/kg/day ‡ Limit sodium intake to < 100-130 meq/day ‡ Increase fluid intake to increase urine output to > 2 Liters/day ‡ Avoid calcium restriction NORMAL calcium diet, preferably using natural sources AND taken with meals ‡ Encourage potassium intake ‡ Low oxalate bran consumption of 15 gm/day

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