A. Introduction

1. Majority of stones form in the kidneys (rather than in the urinary bladder)
2. In USA and Europe, 0.1-0.4% of population has kidney stones (nephrolithiasis)
3. Also referred to as urinary tract stones (urolithiasis)
4. Lifetime risk in USA and Europe is ~12% for men, 6% for women
5. Some 50-75% of renal stones recur over 20 years
6. Stones are composed of inorganic and organic crystals amalgamated with proteins

B. Types of Stones

1. Calcium Stones
   1. Account for >75% of all renal stones (85% in men, 70% in women)
   2. Usually combined with oxalate (as monohydrate or dehydrate)
   3. Calcium phosphate (as apatite or brushite) stones are next most common
   4. Calcium oxalate or phosphate stones are black, grey or white
   5. Typically small (<1cm diameter)
   6. Opaque on radiography
2. Uric Acid Stones
   1. Represent ~8% of kidney stones
   2. Associated with hyperuricosuria ~25%: high urine uric acid and normal urine pH
   3. Gouty diathesis ~10%: normal urine uric acid and low urine pH<5.5
   4. Most persons with uric acid stones have acquired abnormalities
   5. In persons with gouty diathesis, calcium oxalate stones may also be present
   6. Stones are smooth, round, yellow-orange
   7. Nearly radiographically transparent unless mixed with struvite or calcium stones
   8. Types I and II primary hyperoxaluria are rare genetic defects that can cause urate stones
3. Stones Associated with Infection
   1. Urea-splitting organisms convert urea to ammonium and hydroxyl ions
   2. This leads to alkaline pH of urine, increasing formation of trivalent phosphate
   3. Struvite (magnesium-ammonium phosphate) and carbonate apatite stones form
   4. Proteus, Haemophilus, Ureaplasma urealyticum, and Klebsiella can split urea
   5. E. coli does not split urea
4. Cystine stones comprise about 1% of all kidney stoneste
5. Multiple metabolic abnormalities appear to be present in ~30% of patients
6. Drugs that precipitate to stones
   1. Indinavir
   2. Acyclovir can precipitate in renal ducts, form crystals, block urine drainage
   3. Triampterene
7. Indinavir [4]
   1. Nephrolithiasis occurs ~4% and is reduced by drinking >48 ounces of water daily
   2. Unique urinary indinavir crystals: plate-like rectangles, fan-shaped or starburst forms
   3. These crystals have been associated with stones, flank pain, and dysuria

C. Summary of Types of Kidney Stones

1. Promoters of Urinary Stones
   1. Minerals: calcium, sodium
   2. Acids: oxalate, urate, cystine
   3. Low urine pH
   4. Low urine flow
   5. Bacterial products
   6. Primary hyperparathyroidism
   7. Renal tubular acidosis
2. Other Risk Factors for Calcium Oxalate Stones [1]
   1. Elevated animal protein intake
   2. Family history
   3. Primary hyperoxaluria
   4. Gout
   5. Obesity
   6. Hypertension
   7. Inflammatory bowel disease, other malabsorption syndromes
3. Abnormal Calcium Metabolism
   1. Overall, etiologic in 65-80% of patients with stones
   2. Hypercalciuria - overall, present in ~50% of persons with stones
   3. Hyperparathyroidism
   4. Hypocitriuria calcium nephrolithiasis (abnormally low citric acid)
   5. Familial idiopathic hypercalciuria - increased stone risk with age, duration, increased urinary calcium and urate concentrations [6]
   6. Hyperoxaluria can also precipitate stone formation with normal calcium metabolism
4. Calcium Source and Stone Formation [5]
   1. High dietary calcium inversely associated with kidney stones
   2. High exogenous calcium intake positively associated with kidney stones
   3. However, low calcium diet does not reduce recurrent calcium oxalate stone formation [7]
   4. Restricted intake of animal protein and salt reduces recurrent calcium oxalate stone episodes in men [7]
   5. Likely that dietary calcium complexes with oxalate and reduces absorption of both
5. Tamm-Horsfall Protein (THP)
   1. Most abundant protein in human urine
   2. Synthesized and secreted by epithelial of Thick Ascending Limb (Loop of Henle)
   3. Mainly affects aggregation of preformed crystals
   4. Controversy exists as to whether THP is a promoter or inhibitor of renal stones
6. Inhibitors of Stones
   1. Magnesium
   2. Pyrophosphate
   3. Citrate
   4. Nephrocalcin
   5. Urinary prothrombin fragment 1
   6. Glycosaminoglycans
   7. High urine flow

E. Symptoms

1. Renal Colic
   1. Increasing, often severe pain, writhing, very uncomfortable
   2. Joint pain may be prominant
   3. Typically followed by nausea, vomiting
2. Obstruction
3. Increased frequency of urination
4. Dysuria
5. Hematuria - microscopic or macroscopic
6. Sudden Cessation of Pain (stone is passed)
7. Recurrence of Stones
   1. ~14% at 1 year
   2. ~35% at 5 years
   3. ~52% at 10 years
8. In women, the incidence of kidney stones is 1 per 1000 person-years [5]

F. Evaluation [3]

1. Urinalysis for crystals and pH
2. Abdominal radiographs detect ~80% for stones (most stones contain calcium)
3. Ultrasound: sensitivity 60%, specificity 100%
4. Helical computerized tomographic (CT)
   1. Preferred modality as is most sensitive and specific
   2. Sensitivity 96%, specificity 100%
   3. Improved localization of stone compared with other methods
5. Complete serum electrolytes including Ca2+, phosphate, uric acid
6. Urine collection, 24 hours
   1. Creatinine (for determining creatinine clearance and normal urine values)
   2. Calcium and Phosphorus
   3. Uric acid
   4. Citrate
   5. Oxalate
   6. Magnesium (for Struvite stones)
   7. Cysteine if indicated
7. Normal Values for urine
   1. Normal 24 hour urine creatinine 15-25 mg/kg
   2. Normal 24 hour calcium <200 mg/day
   3. Normal 24 hour citrate <320 mg/day
   4. Normal 24 hour cysteine <200 mg/day
   5. Normal 24 hour oxalate <44 mg/day
   6. Normal 24 hour uric acid <600 mg/day
   7. Normal volume 2-2.5 Liters
   8. pH 5.5-7.0

G. Passage of Ureteral Stones (Table 2, Ref [2])

1. Indications for Urgent Intervention
   1. Obstruction
   2. Infection - usually treated with ampicillin+gentamicin (or consider oral fluoroquinolone)
   3. Impending renal deterioration
   4. Intractable pain or vomiting
   5. Anuria
   6. Stone >6mm (relatively urgent)
2. Pain Control
   1. Goal is pain free and encouragement of good urine flow
   2. NSAIDs are very effective for pain relief, probably moreso than opioids [8]
   3. Opioids usually given, usually meperidine (Demerol®) with hydroxyzine IM
   4. Ketorolac (Toradol®) IV may be as effective as opiates
   5. Concern with use of high doses of NSAIDs in renal insufficiency
3. Nausea / Vomiting
   1. Commonly associated with renal pain
   2. Prochlorperazine (Compazine®) 5-10mg IV (or PO), or 25mg per rectum
   3. Promethazine (Phenergan®) - 25mg IV
   4. Serotonin 5HT3 Antagonists - several highly effective agents available
   5. Ondansetron (Zofran®) - 8-12mg IV q8-12 hours
   6. Granisetron (Kytril®) - 3mg IV q 24 hours
   7. Dolasetron (Anzemet®) - 100mg IV x 1; 100mg po x 1
4. Stone Removal
   1. Stones 5mm or smaller can usually pass on their own
   2. Extracorporeal Lithotripsy (see below)
   3. Cystoscopic Basketing or Fragmentation - can remove stones even in kidney
   4. Surgery - percutaneous nephrolithostomy, open ureterolithotomy or nephrolithotomy
   5. Stones should be removed if indication for urgent intervention needed
5. Extracorporeal Shock Wave Lithotripsy [1]
   1. Least invasive, uses shock wave to shatter stone
   2. Used for stones <2cm (20mm) located in renal pelvis
   3. Composed of calcium oxalate, apatite, uric acid or struvite
   4. Reduces morbidity associated with stone passage
6. Good Urine Flow
   1. Hydration to insure urine volume 2-3L per day
   2. Alkalinization of urine as Indicated (including for calcium oxalate stones)
7. Medical Therapy [9]
   1. Calcium blockers or alpha-adrenergic blockers increase stone passage
   2. Pooled analysis suggests that treated patients have 65% increased stone passage
   3. Consider use of these agents in patients with prolonged pain
8. Chronic Treatment / Prevention
   1. Hypercalciuria - potassium citrate ± thiazide diuretic; low salt/animal protein diet [7]
   2. Gouty Diathesis - potassium citrate
   3. Dietary Hyperoxaluria - restrict dietary oxalate; avoid severe calcium restriction
   4. Enteric Hyperoxaluria - potassium citrate, calcium or magnesium citrate
   5. Hypocitraturic Calcium - potassium citrate
   6. Infection stones - antibiotic and acetohydroxamic acid
   7. Mild Cystinuria - chelating agent, potassium citrate, high fluid intake
   8. Moderate to Severe Cystinuria - >500mg/day, potassium citrate and tiopronin
   9. Reduced calcium intake does not reduce calcium oxalate stone recurrence in men [7]

References

1. Curhan GC. 2005. JAMA. 293(9):1107
2. Teichman JMH. 2004. NEJM. 350(7):684
3. Moe OW. 2006. Lancet. 367(9507):333
4. Kopp JB, Miller KD, Mican JAM, et al. 1997. Ann Intern Med. 127(2):119
5. Curhan GC, Willett WC, Speizer FE, et al. 1997. Ann Intern Med. 126(7):497
6. Lerolle N, Lantz B, Paillard F, et al. 2002. Am J Med. 113(2):99
7. Borghi L, Schianchi T, Meschi T, et al. 2002. NEJM. 346(2):77
8. Holdgate A and Pollock T. 2004. Brit Med J. 328:1401
9. Hollingsworth JM, Rogers MA, Kaufman SR, et al. 2006. Lancet. 368(9542):1171