Urinary Calculi (Stones / Urolithiasis / Nephrolithiasis):

Links: PP & Risks | S/s | Lab | Tx | PV | W/u Recurrent | Underlying Etiology | Hypercalciuria | Hyperuricuria (Uric Acid Stones) | Hyperoxaluria | Hypocitruria | Struvite | Cystinuria | Calcium-Phosphate | Bladder Stones & References |

A relatively common problem, has a 5-15% lifetime risk worldwide, M: F, 3:1, most between ages 20-50, has a 50% recurrence rate within 5 years. The first episode in men tends to occur at an average age of 30 yo, where as women have a bimodal age of onset, with episodes peaking at 35 and 55 years. Peak incidence is the early AM due to hyperconcentration and low urine output.  55% have a FHx of stones. Kidney stones are solid deposits that form in the kidneys from substances excreted in urine. Children under 16 years of age constitute ~ 7% of all cases of renal stones with a 1:1 sex distribution. ~80% of pt’s with urolithiasis form calcium stones, most of which are composed primarily of calcium oxalate, and less often, calcium phosphate.

PP:  The precise cause of urinary stone formation is unknown. It requires three elements: supersaturation, lack of inhibitors, and stasis. The process of stone formation depends on urinary volume; concentrations of calcium, phosphate, oxalate, sodium, and uric acid ions; concentrations of natural calculus inhibitors (e.g., citrate, magnesium, Tamm-Horsfall mucoproteins, bikunin); and urinary pH.4 High ion levels, low urinary volume, low pH, and low citrate levels favor calculus formation. When waste materials in urine do not dissolve completely, microscopic particles begin to form and over time grow into kidney stones.  Supersaturation of urine --> crystallizes, and then aggregates.  May have dec amount of urinary stone inhibitors (primarily citrate).  Nanobacteria (small intracellular bacteria that from a Ca-phosphate shell) were present in the central nidus of 97% of kidney stones in ones study, but this was never replicated by others, thus likely was a contaminent (Kidney Int 1999;56:1893). A polymorphism of the vitamin D receptor gene (Fok-1) appears to be associated with some aspects of calcium urolithiasis (OR = 2.15) (BJU Int 2007;99:1534-1538)(higher first-void morning urinary calcium levels)...They were also significantly younger than the median age of 45 years at the onset of the first episode (OR = 3.23).

Risks: Bowel disease (chronic diarrheal states) promotes low urine volume, acidic urine (depletes available citrate) and hyperoxaluria. Excess dietary meat (including poultry) creates acidic urinary milieu, depletes available citrate; promotes hyperuricosuria. Excess dietary oxalate promotes hyperoxaluria. Excess dietary sodium promotes hypercalciuria.  Low urine volume allows stone constituents to supersaturate. Obesity may promote hypercalciuria; other results similar to excess dietary meat. Primary hyperparathyroidism creates persistent hypercalciuria. Prolonged immobilization leads to bone turnover, whick creates hypercalciuria. Renal tubular acidosis (type 1) give an alkaline urine promotes calcium phosphate supersaturation; loss of citrate.  FHx of stones (3-fold risk, J Am Soc Nephrol 1997;8:1568), prolonged immobilization, recurrent urinary infections, drugs (Indinavir, acetazolamide, triamterene, ephedrine, felbamate, topiramate and zonisamide, guaifenesin, calcium + Vit-D, or sulfadiazine). Systemic illnesses that may increase the risk for kidney stone formation or otherwise affect the clinical course include primary hyperparathyroidism, renal tubular acidosis, cystinuria, gout, diabetes mellitus, inflammatory bowel disease, renal insufficiency, sarcoidosis, and medullary sponge kidney. Insulin resistance leads to ammonia mishandling; alters pH of urine. Gout promotes hyperuricosuria.  Chronically sleeping on the side at risk of calculi formation can be seen in pt’s with unilateral stone dz (J Urol 2001;165:1085), consider attaching a tennis ball to sleep ware to break this habit.  HTN in 32.8% (Semin Nephrol 1995;5:519–525). Men who work in the steel industry and are exposed to high temperatures have an increased risk of developing urinary lithiasis (Urology 2005:65:858-861) (related to dehydration and hypocitraturia).

Urine pH: Calcium oxalate stones are not pH-dependent.  Most people excrete an acid urine which favors uric acid precipitation which may promote the formation of calcium stones. Calcium phosphate stones form in a relatively alkaline urine. 

    ICD-9 Codes:

592.0 Calculus of kidney - Nephrolithiasis NOS

592.1 Calculus of ureter

592.9 Urinary calculus, unspecified

594.1 Other calculus in bladder - bladder stone

594.9 Calculus of lower urinary tract, unspecified

788.0 Renal colic

S/s: Renal colic: a misnomer, aching flank pain that is usually constant, sometimes waxes and wanes.  No position of comfort (unlike Appy, diverticulosis, salpingitis/ peritoneal inflammation (makes pt want to lay still).   Pain starts as a colicky flank pain radiating to the groin / testicle or labia and can be accompanied by N/V and hematuria.  Character of the pain changes as is passes down the ureter and may diminish even if stuck as transition from a hyperperistaltic to an aperistaltic ureter.  At renal calyces is a deep, dull flank/back ache.  At the renal pelvis it is a sharp pain radiating to the ipsilateral abd quadrant.  At the upper-mid ureter it is sharp, bandlike radiating to the mid-low abd.  At the distal ureter it is boring that radiates to the ipsilateral groin.  Urgency and frequency can occur if stone is close to bladder.  In the bladder it may produce a suprapubic pain with stranguria, urgency, frequency and/or dysuria.  Pain resolves with passage of stone, may persist temporarily from ureteral edema.

Ddx:  appendicitis, PID, pyelonephritis, diverticulitis, dissecting AAA, cholecystitis, ovarian pathology and ectopic pregnancy.

Lab: U/A, BUN or Cr.  +CBC, lytes, Ca, P.  Gross of microscopic hematuria in 90%.

X-ray:   KUB:  Best study if PMHx of stones. 90% contain calcium and are radiopaque (yet only 30% seen in ER, up to 70% with IVP), if >2-3 mm should see on KUB. (r/o calcified mesenteric lymph node, phlebolith, fecalith, renal calcification, barium), misses 10% as uric acid, struvite calculi and cysteine are radiolucent or poorly visualized on plain film radiography.  

Spiral (helical) CT: without contrast (unenhanced) now considered best overall study to establish dx (96% sensitive), takes < 5 minutes, no risk of contrast reaction, detects all stone types, rules out other pathologic processes (r/o AAA if age >55yo).  Takes 0.5mm cuts from top of bladder to top of kidneys (nl abd CT take 1cm cuts).   Noncontrast helical CT consistently has outperformed IVP in studies of pt’s with suspected ureteral stones. Because helical CT has other advantages in this setting (no use of contrast material, visualization of other intra-abd causes of sx’s), it is becoming the imaging procedure of choice for these pt’s (Ann Emerg Med 2002;40:280-6).  An unenhanced low-dose abd CT (LDCT) protocol should replace the initial abd plain film in pt's with a clinical suspicion of renal colic (Urology. 2006;67:64-68) (sensitivity of 95-100% with a 2.1-mSv radiation dose to women and 1.6 mSv to men) (the mean effective dose [all testing done] was 3.5 mSv in group 1 and 6.9 mSv in group 2).

IVP:  Delayed images required if high-grade obstruction (delayed “blush” if obstructed). 

Ultrasound: has a lower sens/spec, but it is the preferred imaging modality in pregnant women.

Three places stones get caught: ureteropelvic junction (UPJ), midureteral (at iliac vessels), ureterovesical junction.

Stone Types seen in the USA:

Mixed Ca-oxalate and Ca-phosphate@37%.

Calcium oxalate@26%.

Calcium phosphate@7%.

Uric acid@5%.

Struvite@22%.

Cystine@2%.

(Kelly's Textbook of Medicine. New York, Lippincott Williams & Wilkins, 2006, pp 1243-1248).

Tx:  Link: Consult Indications & Surgical Options | No urgent intervention needed unless the upper urinary tract is obstructed and infected, the renal function is compromised, or there is intractable pain or vomiting.  Most pt's can be managed expectantly with analgesics...NSAIDs like Motrin 600-800mg TID, adequeat hydration, strain urine, local heat with an electric blanket at lateral abd & lower back.  Takes an average of 8 days to pass, if not passed by then or fever or increased pain etc, need to monitor serum Cr. For acute pain IV Toradol better than morphine.  Pt's treated with NSAIDs for renal colic report better pain relief and are less likely to need further analgesia than those treated with opioids (and less N/V) (BMJ 2004;328:1401-4), based on a pooled analysis of 10 trials. Hydration (no benefit to stone passage), strain urine, NSAIDs, Abx if evidence of infection.  Local heat with an electric blanket at lateral abd & lower back (42 C) decreases the pain, anxiety and nausea of renal colic (J Urol 2003;170:741-44). A combination of IV morphine 5mg + Ketorolac 15 mg (both repeated in 20min) was superior to either drug alone for tx of acute renal colic (Ann Emerg Med 2006;48:173-81).

Stone size:  The likelihood of spontaneous stone passage is directly related to the size of the stone and the time needed for passage.

If stone <5 mm:  98% of proximal and distal stones pass spontaneously (J Urol 1997;158:1915–1921) (within 4 weeks, may take up to 40 days).    

If 5-10mm: ~53% pass spontaneously. Observation and periodic intervention for pt’s with newly diagnosed stones <10 mm in diameter and controlled sx’s, with drugs offered when necessary to facilitate stone passage, is an appropriate tx option (AUA 2007 Annual Meeting: AUA/EAU Guidelines Update: Ureteral Stone Management. Presented May 21, 2007).

>10mm: ~20% pass and thus pt will likely need an intervention. 

Time: Takes an average of 8 days to pass if <2mm, 12 days if 2-4mm and 22 days if >4mm (Time to stone passage. J Urol 1999;162:688-91).   If no stone movement has occurred after a 4-6 weeks, intervention is warranted because the incidence of complications (renal deterioration, sepsis, ureteral stricture) is increased.

Medical Expulsive Therapy (MET):  Indicated in most pt’s with ureteral stones measuring <1 cm who are candidates for observation, especially those with stones in the distal ureter.  Medical tx costs just a fraction of the average cost of ureteroscopy ($2,645) or shock wave lithotripsy ($4,225). The estimated cost for medical tx ranges from $10 to $74 for a 28-day course of Cardura (doxazosin) to $104 to $141 for a 42-day course of Flomax.  The likelihood of spontaneous urinary stone passage can be increased significantly by tx with calcium channel blockers or alpha-blockers, according to meta-analysis of 9 RCT’s with nearly 700 pt’s with urinary calculi (Lancet 2006; 368:1171-79) (chance of expulsion is 65% greater) (Risk Ratio:  CCB or alpha blockers @ 1.65.  Alpha blockers @ 1.54.  CCB @ 1.51.  CCB + steroids @ 1.90).  There are large numbers of alpha-1 adrenoceptors in the distal ureter, these blockers inhibit basal ureteral tone and peristaltic frequency and decrease the intensity of ureteral contractions.

Tamsulosin (Flomax):  0.4 mg qd x 5-7 days.   Instead of immediately performing cystoscopy or lithotripsy, new research suggests that pt’s with distal ureteral stones should be given a trial of MET (J Urol 2005;174:167-172)....210 pt's were randomized to receive home tx with tamsulosin, phloroglucinol, or nifedipine + oral corticosteroid + Abx prophylaxis. Injectable diclofenac was given on an as-needed basis. All were encouraged to drink 2 L of water daily.  The expulsion rate for tamsulosin was 97.1%, whereas phloroglucinol and nifedipine had rates of 64.3% and 77.1%, respectively.  Pt's treated with tamsulosin achieved stone passage in a shorter period of time and were less likely to be hospitalized and has less renal colic than pt's treated with the other agents.  In another study, stone expulsion was noted in 80%, 85%, and 43%, in the nifedipine, tamsulosin, and control groups, respectively.  With lower ureteral stones < 1cm in diameter, tx with nifedipine or tamsulosin increases the rate of ureteral stone expulsion and decreases the need for analgesic therapy (J Urol 2004;172:568-571). Stone expulsion in 80% on nifedipine (ave 9.3 days) and 85% with tamsulosin (ave 7.9 days) Vs 43% of controls (ave 12 days) after 4 weeks. The authors conclude that for lower ureteral stones nearest to the bladder the most effective tx is tamsulosin with cortisone, Nifedipine plus cortisone is useful for stones which are lower-ureteral but further away from the bladder (Nifedipine versus tamsulosin for the management of lower ureteral stones. J Urol 2004;172:568-71). Adjunctive tx with tamsulosin after ureteroscopic laser lithotripsy for large renal and ureteric calculi improves the stone-free rate as well as pt’s' quality of life (AUA annual meeting. Abstract 1707. May 26, 2006)(4.3% experienced ureteric colic episodes VS 23.4% of controls and 94.6% were stone-free Vs 83.1%).

Calcium channel blockers (Nifedipine SR 30mg qd = Procardia XL or Adalat CC):  x 7-28 days, and oral steroids can facilitate stone passage, both may inc the success rate & also dec the pain after ESWL (Urology 2002;59:835-38).   Nifedipine 40mg qd + oral methylprednisolone 16 mg qd x 45 days lead to stone passage in 87% of pt’s Vs 65% who received methylprednisolone alone. Stone passage occurred at 11.2 +7.5 days in the pt’s treated with combo tx Vs 16.4 +11.0 days in pt’s treated with methylprednisolone alone (J Urol 1994;152:1095-98).   A RCT with an oral corticosteroid and nifedipine compared with corticosteroid alone found an improved stone expulsion rate (79% Vs 35%), faster expulsion time (7 Vs 20 days) as well as a decreased requirement for analgesia (Urology 2000; 56:579–583).

F/u: If fail to pass stone in 5-7 days, fever, unrelenting pain, vomiting.   Check radiograph of kidney and upper bladder (KUB), UA and serum Cr.

Urine strainer:  can use a coffee filter or place a small square cut from a pair of nylon panty hose (rinse & re-use) over the urethra while voiding to catch the stone for analysis.  Send passed or removed stone for analysis.  (Acute renal colic from ureteral calculus. NEJM 2004;350:684-93)

Consult Urology: if stone >5-7 mm diameter, severe persistent pain, not passed spontaneously in 1-2 wks (depending on size), an upcoming away trip from home, persistent hydronephrosis, infection/sepsis, staghorn calculus, solitary or transplant kidney, occupation (pilot or bus driver), anuria or renal failure.    Urgent intervention is indicated in a pt with an obstructed, infected upper urinary tract, impending renal deterioration, intractable pain or vomiting, anuria, or high-grade obstruction of a solitary or transplanted kidney.  Women who develop nephrolithiasis during pregnancy have nearly double the risk of preterm delivery as pregnant women who do not (Obstet Gynecol 2007;109:1099-1104).

Tx Options for Urologist:  

For treating urolithiasis, shock wave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy have replaced open surgery (BMJ. 2007;334:468-472).....Shock wave lithotripsy is effective in approximately 80% to 85% of simple renal calculi. For complex renal calculi, percutaneous nephrolithotomy is the tx of choice. Staghorn calculi should be treated, preferably with percutaneous nephrolithotomy in most pt’s. For pt’s who are pregnant, morbidly obese, or have coagulopathy, ureteroscopy is the preferred tx.

1. Emergent Decompression:  With either a nephrostomy tube (percutaneous nephrolitholapaxy = PCNL) or ureteral stent. Septic pt’s with obstruction should have nephrostomy tube placed (can be done with local anesthesia), drainage can be monitored as opposed to internal stent that might not be draining properly.

2. Extracorporeal Shock Wave Lithotripsy (ESWL): Usually under mild IV sedation although some machines require general or regional anesthesia Shock waves break up the stone into small fragments that pass out on own.   Best choice for renal, proximal and mid ureteral stones <1-2 cm.  85% overall success rate.  Occasionally a fragment can obstruct the ureter and require intervention.  Repeat tx required 10-20%. Lower-pole stones have been consistently associated with decreased stone-free rates following SWL when compared with upper and middle-pole stones.  Cystine, brushite and calcium oxalate monohydrate stones have demonstrated a high degree of resistance to fragmentation by SWL owing to their high density, whereas less dense stones (calcium oxalate dihydrate, hydroxyapatite and uric acid) are more susceptible to SWL (Prediction of shockwave failure in pt’s with urinary tract stones. Curr Opin Urol 2006;16:88-92).  Can gait the shocks to the pt’s ECG (heart rate) such that arrhythmia potential is lowered… R-wave triggered mode, where ESWL can trigger the atrial output pulse and the subsequent inhibition of the following ventricular pulse if pt has a dual pacemakers to the VVI or VOO mode prior to ESWL to prevent this occurrence. The rate of clearance of renal stones after ESWL is lower in elderly pt’s than in younger pt’s (BJU Int 2007;100:392-395)(stone-free rate after ESWL: in the >60 year age group at 37.6% Vs in the 40-and-under at 54% and 41-60 at 43%)....suggest that "more endoscopic procedures should be offered to the elderly population."

Pneumatic lithotripter: Can generate contact pressures of up to 2.9 MPa at the tip of the probe. The device is powered by a carbon dioxide cartridge that can deliver at least 80 shocks via a spring-loaded hammer that drives a projectile into contact with the probe. The "StoneBreaker" is a rapid and effective means of fragmenting urinary stones (BJU Internat 2007;100:629-631)...Hand-held portable, appears to offer much faster intracorporeal lithotripsy compared with other ballistic lithotripters.

3. Ureteroscopy / ureterorenoscopy (URS) Stone Removal:  Stone fragments are removed using suction, graspers, or basket extraction.   Endoscopic (laser) lithotripsy can be successful in up to 95% for distal stones.  Tx of choice for distal stones or proximal stones > 1-2cm. Indicated for ESWL failures.  Ureteroscopy traditionally requires the placement of a stent in order to minimize the risk of flank pain secondary to ureteric edema and facilitate the passage of residual fragments. The presence of a ureteric stent, however, has been shown to reduce quality of life in up to 80% of pt’s and thus many authors have shown that it is not necessary on a routine basis (The management of ureteric colic. Curr Opin Urol 2006;16:71-76)….risk factors for complication included renal pelvic stone location, bilateral procedure, lithotripsy, history of urolithiasis, diabetes mellitus, recurrent/recent infection, operative time of 45 min or more plus lithotripsy and operative time of 45 min or more plus ureteral dilatation.

4. Percutaneous Lithotripsy:  Best for large/staghorn renal calculi, can be followed by ESWL for residual fragments. Conventional PCNL is recommended in this situation only when there is a significant stone burden or when external shock-wave lithotripsy fails.  Minimally invasive percutaneous nephrolithotomy (mPCNL) is an effective and safe strategy for dealing with upper urinary tract calculi in transplanted kidneys (BJU International 2007;99:1467-1471)....should be the initial approach for most cases of upper urinary tract stones in transplanted kidneys, except for simple and small stones in the middle or lower calyx

Complications of Urolithiasis:  renal failure, ureteral stricture, infection/ sepsis, urine extravasation, perinephric abscess, xanthogranulomatous pyelonephritis.  Stone bulk, dilated pelvicalyceal systems, and previous UTI have strong associations with UTI after kidney stone surgery, while infected stones, pelvic urine, and cloudy urine are predictors of urosepsis after percutaneous nephrolithotomy (EAU 22nd Annual Congress: Abstract 876. Presented March 23, 2007).

Retained Stones:  likely no problems if in the renal pelvis.  Consider annual KUB to monitor for size changes.  Non-obstructing ureteral stones need annual monitoring of renal US.

Prevention of Ca stones:  

Normalization of body weight (BMI) and cardiovascular risk factors, sufficient physical activity, balanced nutrition and sufficient circadian fluid intake would be the appropriate measures to avoid new calculus formation.   Up to 85% of all stone pt’s could anticipate lower risk of stone recurrence with basic changes in lifestyle and dietary habits, ~15% of pt’s require additional specific pharmacological prevention (Curr Opin Urology. 2005;15:119–126). 

Diet: A low urinary volume increases urinary supersaturation, thus fluid therapy is safe, cheap and effective: Increased water (8-10 cups a day) will dec recurrence by 55%.  Try to maintain 2L urine output a day or try to maintain a clear-colored urine rather than yellow urine.  Lemon juice/ lemonade increases citrate excretion, particularly in the hypocitraturic stone former (4 ounces a day in divided doses).  Can add lemon juice or diluted potassium citrate to just plain water. The type of fluid consumed may be important; grapefruit juice may enhance the risk of stone formation (Ann Intern Med 1998;128:534), whereas pt’s who ingest one bottle of beer a day may reduce the risk of stone formation by 40% (Am J Epidemiol 1999;150:187).   Higher sucrose intake is associated with an increased risk of stone formation in younger and older women (Arch Intern Med 2004; 164:885).

Calcium: A normal-calcium, low animal protein and low-salt diet reduce the risk of recurrence (NEJM 2002;346:77-84).  Avoid soft drinks (promotes natriuresis and hypercalcuria).  Dietary calcium and supplemental calcium are not associated with increased risk of kidney stones and may even be protective in younger (27-44 yo) women (Arch Intern Med 2004;164:885-891). Recommendation for calcium intake cannot be generalized since the effect of calcium intake on stone formation depends on the type of stone, oxalate intake, presence of stones and the efficiency of calcium absorption from the bowel.  Calcium restriction recommended in pt’s who have moderately to severely elevated intestinal calcium absorption and urinary calcium levels.  Pt’s with calcium phosphate stones may need to carefully monitor their calcium dietary intake.    Except for absorptive hypercalciuria, calcium restriction in nephrolithiasis pt’s is not recommended (Curr Opin Urology. 2005;15:119–126). 

Phytates (myoinositol hexaphosphate): High intake better.  Found in cold cereal, dark bread, wheat fiber, bran, rice, nuts and beans.  Dietary phytate (the most abundant form of phosphate in plants) binds tightly to double charged ions such as calcium (and zinc, iron, magnesium and manganese) in the GI tract to reduce absorption and enhance urinary excretion, which may reduce stone formation (37%) (Arch Intern Med 2004;164:885-891).   Calcium oxalate crystal formation is strongly inhibited in vitro by phytate.

Avoid excess:  Protein (restrict to 1g/kg/d or ~<52g/d), salt (restrict to 2-3g/d by avoiding processed foods), oxalates (if have Ca-oxalate stones, particularly if have hyperoxaluria on testing – not the same as oxalate stones), prevent recurrent infections.  Obesity and weight gain increase the risk of kidney stones (JAMA. 2005;293:455-462) as a larger body size may result in increased urinary excretion of calcium, oxalate, and uric acid.

W/u: All pt’s should have stone analysis. Detailed metabolic evaluation should be postponed until after the acute stone event has resolved.

Limited evaluation if first stone:  — Because the rate of recurrence is variable, most recommend only a limited evaluation after a first stone. Ck routine blood chemistries, including multiple measurements of serum calcium (at least two and more in pt’s with high-normal values to r/o hyperparathyroidism).   A low serum phosphorus warrants further eval as well.  A low plasma bicarbonate concentration is suggestive of type 1 renal tubular acidosis or chronic diarrhea.

Furthier eval indicated if Recurrent, multiple stones, younger, FHx or pt requests eval.   Pt’s with stones composed of cystine, uric acid, calcium phosphate or struvite.   A 2-day food diary may be helpful.   

24-hour urine collections: urine volume, pH, and excretion of calcium, uric acid, citrate, oxalate, sodium, creatinine, urinary supersaturation. 2 or 3 separate collections may required to obtain all of this information.  

Normal values:

Calcium:  For a pt with a history of renal stone formation, urinary calcium results will be more meaningful if the pt’s usual diet is followed for 3 days before specimen collection. Do not stop medications.  If the urine calcium test is done because of a metabolic disorder, the pt should eat a low-calcium diet and calcium medications should be restricted for 1 to 3 days before specimen collection.

Normal diet:  Men  <300 (7.5 mmol/day).  Women <250 (6.25 mmol/day). Child <4mg/kg.

Low-calcium diet: 50–150 mg/24 h or 1.25–3.75 mmol/d.  The bulk of calcium excreted is eliminated in the stool. Increased calcium in urine results from an increase in intestinal calcium absorption, a lack of renal tubule reabsorption of calcium, resorption or loss of calcium from bone, or a combination of these mechanisms.

Ddx increased urine Ca:  Hyperparathyroidism (30% to 50% of cases).  Sarcoidosis.  Primary cancers of breast and bladder.  Osteolytic bone metastases.  Multiple myeloma.  Paget’s disease.  Renal tubular acidosis.  Fanconi’s syndrome.  Vit-D intoxication. Idiopathic hypercalcuria.  Diabetes mellitus.  Crohn’s disease and some cases of ulcerative colitis.  Thyrotoxicosis.  Increased urinary calcium almost always accompanies increased blood calcium levels.  Ca excretion levels > calcium intake levels are always excessive; urine excretion values >450 mg/24 hours are reliably abnormal.   Increased Ca excretion occurs whenever Ca is mobilized from the bone, as in metastatic cancer or prolonged skeletal immobilization.  When Ca is excreted in increasing amounts, the situation creates the potential for nephrolithiasis or nephrocalcinosis, especially with high protein intake.

Falsely elevated Ca levels:  drugs (calcitonin, vitamins A, K, and C, corticosteroids), meals high in Ca (milk), increased exposure to sunlight, immobilization (especially in children).

Ddx decreased urine Ca:  Hypoparathyroidism.  Familial hypocalciuria hypercalcemia. Vit-D def. Preeclampsia. Acute nephrosis, nephritis, renal failure. Renal osteodystrophy. Vit D–resistant rickets.  Metastatic carcinoma of prostate. Malabsorption syndrome—celiac-sprue disease, steatorrhea. Urine calcium decreases in late normal pregnancy. 

Falsely decreased Ca levels: increased ingestion of phosphate, bicarbonate, antacids. Alkaline urine. Thiazide diuretics. Oral contraceptives, estrogens. Lithium.

Uric acid:  Men <800 (4.8 mmol/day).  Women <750 (4.5 mmol/day).

Oxalate:  Men <45 (0.5 mmol/day).  Women <45 (0.5 mmol/day).

Citrate: normal is 320-1300mg for men and women.

Phosphorus (360-1600mg).

Na (52-380mEq).

Mg (28-180mg/d).

Urinary Creatinine excretion:  permits assessment of the completeness of the 24-hour collection. Low level suggest an incomplete collection (need repeat) except for older subjects or malnourished pt’s with decreased muscle mass.

Normal in <50 yo:  20-25 mg/kg (177-221 µmol/kg) lean body weight in men and 15-20 mg/kg (133-177 µmol/kg) in women.  

Normal in >50yo: 10-12 mg/kg/d for men. 8-10mg/kg/d in women.

If normal, calculate the ratio of “measured-to-estimated creatinine clearance”.  If <0.75 then repeat as inaccurate.

If 0.75-0.9 the inaccurate, but still may be useful. If 0.9-1.1 then accurate urine collection.  

If 1.1-1.25 then inaccurate, but still may be useful. If >1.25 then inaccurate, needs repeat.

Sodium excretion:  increased sodium intake can contribute to hypercalciuria.

24hr Urine (commercial kits are available) initially while pt on a random diet.  Evaluate for volume (>2L), pH (Ca-phos stones form if pH  >7, may be due to distal RTA if low urinary citrate, vegetarian diet if high citrate.  If pH >7.5 suspect infection.  If pH <5.5 suspect uric acid, cysteine, chronic diarrhea or strenuous physical exercise). Can repeat 24hr Ur after modified diets (Ca restriction to see if hypercalcuria is dependent on dietary intake), acid load test or on meds.  

Check serum for:  Ca, P, uric acid, creatinine, alkaline phosphatase, intact PTH.  A recent study found no significant association between stone recurrence and initial phosphate levels in serum or urine, thus may not be necessary to check (Scan J Urol 2002;36:368-72).    In pt's with first-time kidney stones, conservative therapy (dietary modification only) is the most cost-effective strategy, but for pt's with recurrent kidney stones, empiric therapy (dietary modification and potassium citrate) and a modified simple metabolic evaluation (a single 24-hour urine collection for renal stone risk factors, with potassium citrate and HCTZ for pt's with hypercalciuria and potassium citrate alone for pt’s with normocalciuria) are equally cost-effective (J Urol 2004;172(6 pt 1):2275-81).

UroRisk & StoneRisk diagnostic profiles: measures 10 urine risk factors for stone formation (Calcium oxalate - Brushite - Sodium urate - Uric acid). It offers a urine collection and preservation system and is recommended for initial and recurrent stone formers who test positive for a UTI.  Calculates the "relative supersaturation.  Give a choice of three customized profiles.  (800) 330-6565, ext. 7308

Underlying Causes of Stones:

Links: Hypercalciuria | Hyperuricuria (Uric Acid Stones) | Hyperoxaluria | Hypocitruria | Struvite | Cystinuria | Calcium-Phosphate |

Urine pH: Uric acid and cystine stones associated with acid urine.   Renal tubular acidosis (type I), and infection related stones associated with alkaline urine.  Tx of uric acid and cystine stones includes alkalinization of urine, limit proteins

Hypercalciuria:

(50%) (>300mg/d in M, >250 in F), causes 45% of Ca stones. Idiopathic hypercalciuria (IH) is the most common cause of calcium-containing kidney stones. IH is defined as excessive urinary calcium excretion (hypercalciuria) in the setting of normocalcemia and in the absence of secondary causes of hypercalciuria.  Determining the specific etiology of hypercalciuria with special diets often not that helpful since it makes little difference in tx.  The disorder is familial, was initially thought to exhibit an autosomal dominant pattern of inheritance, but may be polygenetic.      

May be due to: IH consists of a spectrum of these disorders, with considerable overlap among these potential mechanisms.

1. Absorptive hypercalciuria: Excessive intestinal calcium absorption. Inc intestinal absorption causes inc serum Ca (high normal), which suppresses PTH, dec P. 

2. Renal Hypercalciuria: Decreased renal tubular calcium reabsorption. Defective resorption of Ca in kidney, have dec serum Ca and inc PTH, no change with fasting state.  Due to Ca leaking from distal tubules.

3. Primary Hyperparathyroidism: Enhanced bone demineralization. Inc PTH --> inc bone resorption of Ca and inc 1,25(OH)2D to stimulate intestinal absorption.   More common in women.  R/o if high-normal serum Ca.   The intact hormone assay is the best choice for proving subtle HPT. This need to be treated with Alendronate, Calcitonin of Mithramycin.

4. Unclassified Hypercalciuria: normal PTH and serum Ca with inc urinary Ca and no change with fasting. 

Other --> RTA, Addison’s, sarcoid, hyperthyroid, V-D intoxication, milk-alkali syndrome.   Only 5% have associated dz (RTA or hyperparathyroidism).

Tx of Hypercalciuria: Limit dietary protein, oxalate and Na (<2g/d).  High calcium diet (low intake increases the risk of stones).  A low-sodium, low-protein diet in place of a traditional low-calcium diet is best for hypercalciuric men who form calcium oxalate stone (NEJM 2002;346-84).

Thiazide diuretic:  Start HCTZ  @25-50mg qd, increase up to 50mg BID as dictated by 24hr urine. Adding K-citrate 20-30mEq BID will inc excretion of citrate (a stone inhibitor) as well as prevent dec K.  Can also add a K-sparing diuretic.   1/3 of females with Ca stone have medullary sponge kidney.   Inc risk of osteoporosis in hypercalciuria: thiazides are beneficial.  Ca-citrate is the preferred Ca supplement in postmenopausal females with stones. Can also use Bendroflumethiazide 2.5 mg BID, Trichlormethiazide 2-4mg qd, Na-cellulose phosphate 2.5-5g TID or Orthophosphate 500mg BID.   A high calcium diet, if not accompanied by higher intake of fluids, potassium, magnesium and phosphate, may increase the risk for calcium oxalate stones, results of a metabolic investigation suggest, the risk is increased further if calcium is increased by using supplements rather than by diet based on urinary Ca excretion (J Urol 2003;169:470-474).  (J Urol 1997;158) (Am J Clin Nutr 1994;60).

ICD-9 Code:  275.4 Hypercalcinuria

Hyperuricuria:

(15% of stones)(>800mg/d M, >750mg F) Uric-acid stones are more difficult to diagnose than other types of kidney calculi because they are radiolucent and therefore don't show up on standard abdominal x-rays. Can be seen in chronic diarrheal states that cause loss of water and bicarb., hypermetabolic states, myeloproliferative d/o’s, medications such as thiazides.  Uric acid can serve as a nidus for Ca-oxalate stones (12% of pt’s).  Uric acid stones may be suspected on the basis of a history of uric acid stones or of gout (present in ~20% of pt’s with uric acid stones). The typical pt has normal amounts of uric acid in an acidic urine; this condition increases the likelihood of uric acid crystallization. Pure uric acid calculi are radiolucent on plain imaging but visible on U/S or CT. Other radiolucent stones that should be considered in appropriate clinical settings include matrix stones (which are made of organic material and are occasionally seen in pt’s with urease-producing bacteria) and indinavir stones. Pure uric acid stones primarily occur in pt’s in whom a persistently acid urine (pH <5.5) promotes uric acid precipitation.   That the incidence of nephrolithiasis is increasing, both in the US and worldwide, particularly for those composed of uric acid (Am J Kidney Dis 2006;48:897-904)....HTN, obesity and diabetes are significantly associated with a dx of urate nephrolithiasis (OR = 1.22). Hyperoxaluria is often seen in pt’s with kidney stones who have undergone bariatric surgery using currently accepted methods (J Urol 2007;177:565-569). Pt’s with elements of metabolic syndrome are more likely to develop highly acidic urine, increasing their risk of forming uric-acid kidney stones (Clin j Am Soc Nephrol 2007;2:883-888).

Tx:  Uric acid stones are unique in that they can be managed medically. Increase fluid intake.  Avoid Purine rich foods, restrict animal protein to 5-7oz of meat/ fish per day) + Allopurinol (Zyloprim) @100-300  mg/d to dec uric acid production(especially if hyperuricemia) .   Alkalinizing the urine (inc Ur pH) with bicarb or potassium citrate 10-30 mEq (~20 mmol) TID to inc solubility of uric acid and dissolves pure uric acid stones (goal is pH of 6.5-7, pt can measure with Nitrazine paper, higher than 7 may cause CaP to precipitate). At a urinary pH below 5.5, uric acid is poorly soluble; solubility increases at a pH above 6.5.   Can dissolve them at a rate of 1cm/mo, imaging can be repeated at one month to determine whether dissolution has occurred. Unless a stone is pure uric acid, however, oral dissolution therapy is not possible. If oral dissolution therapy fails, tx should proceed as for a radiopaque stone.

Purine Content of Foods:

Very-very high: herring & roe, mussels, sardines, yeast.   

Very high: anchovies, crab, lobster, trout, salmon, turkey, veal, beef, bacon, pheasant, venison.  

High: bass, halibut, oysters, tuna, chicken, pork, ham, duck, asparagus, cauliflower, kidney/ lima beans, spinach, whole grains, mushrooms, peas.  

Low: non whole grains (breads, cereals), cheese, eggs, nuts, fruits, peanut butter, tea/ coffee, chocolate, butter, soft drinks.

ICD-9 Code: 274.11  Uric acid nephrolithiasis

Hyperoxaluria:

(15%) (>40mg/d of oxalate). Hyperoxaluria which may be present in up to 40% of male and 15% of female stone formers and is typically only slightly elevated; in comparison, marked hyperoxaluria is usually associated with inflammatory bowel disease and/or malabsorption or primary hyperoxaluria.   75% of all stones are composed of some CaOxalate, Mixed Ca-Oxalate-P in 34%. 15% is related to dietary consumption of oxalate or inc Vit-C.  Also seen in Crohn’s, chronic pancreatitis, celiac sprue, Ca restriction, primary hyperoxaluria or other ileal dz because of inc absorption as Ca is bound to free fatty acids.    Recurrence rate for untreated Ca-Oxalate stones --> 10% at 1 year, 35% in 5yr, 50% recur in 10yr.  If inc urine output to >2L/d will cut in ½ the recurrence rate.   If serum Ca>10.3 --> check PTH.  

Tx: avoid excess oxalates (spinach/ leafy dark greens, nuts, rhubarb, instant coffee, tea, chocolate, berries, purple grapes, Tofu, wheat germ), Ca or Mg-oxide 200-400mg BID supplements + Pyridoxine 25-100 mg qd (as many deficient) with meals to bind oxalates in the gut.  

K-Mg-Citrate: for recurrent Ca-Oxalate stones, less GI SE’s than K-citrate (10-30 mEq qd).  Dose of 42mEq K + 21mEq Mg + 63mEq citrate qd (J Uro 1997:158).  Other less efficacious: Cholestyramine 4g TID, Mg-citrate 10 mEq BID.  Probiotics with Oxalobacter formigenes may reduce the ocalate exretion (J Urol 2001;166:1487-91).

Oxalate Content of Foods:

High content:  beets, black tea, chocolate, cocoa, dried figs, ground pepper, lamb, lime peel, nuts, parsley, poppy seeds, rhubarb, sorrel, spinach, swiss chard.  

Moderately high: beans, all types of berries, carrots, cashews, celery, coffee, concord grapes, okra, green onions, oranges, green peppers, sweet potatoes, tomatoes. Strawberries, cranberries, raspberries, plums, and apples. This is somewhat confusing, however, because several of these have been shown to decrease incidence of kidney stones even though they contain significant amounts of oxalate! In addition, some studies have shown that eating oxalate- and calcium-containing foods together may actually decrease stone risk (The influence of diet on kidney stone disease. J Urol 1996;155:432–440). A large cohort study of more than 85,000 women showed that those who consumed black tea had an 8% decreased risk of developing kidney stones (Arch Intern Med 1998;128:534–540).

Hypocitruria:

(20%)(<450-600mg/d M, <650-800 in F) citrate is a stone inhibitor.   Hypocitraturia can be marked in pt’s with chronic metabolic acidosis; however, mild hypocitraturia occurs in a significant proportion of stone formers in the absence of academia.  

Tx: K-citrate (Urocit-K) [5, 10 mEq tab] start @ 5mEq BID with food, titrate to 10-20 mEq TID-QID (0.5-1mEq/kg/d).  Contra: hyperkalemia or renal insufficiency is present, monitor serum K and Cr.  Avoid Na-citrate unless K-citrate not tolerated. The dosage should be adjusted to maintain a urine pH 6.5-7, it usually needs to be continued indefinitely.   

Causes: Often idiopathic, may be RTA, met acidosis, high protein/ salt diet, dec K or Mg, UTI, carbonic anhydrase inhibitors, renal insufficiency, dehydration, thiazides, diarrhea.    People subject to recurrent calcium renal stones tend to excrete low amounts of citrate in their urine (Am J Kidney Dis 2006;48:546-554)…..Their analysis showed that hypocitraturia is associated with urinary potassium level, and may reflect low levels of potassium in the diet, the chief source of which is fruit.

Struvite:

(8%): (Mg-P-NH₃). Also known as infection or triple-phosphate stones, consist of magnesium, ammonium, and calcium phosphate. Infection of the urinary tract with organisms that secrete the ectoenzyme urease can greatly increase the urinary ammonia concentration and pH. From urea splitting organisms (Proteus, Pseudomonas, Providencia, U. urealyticum). Struvite stones only form in pt’s with a chronic UTI due to a urease producing organism such as Proteus or Klebsiella. Affected pt’s often have multiple magnesium ammonium phosphate crystals in the urine sediment. The stone may grow rapidly over a period of weeks to mo’s and, if not adequately treated, can develop into a staghorn or branched calculus involving the entire renal collecting system. They occur more often in women than in men and are the leading cause of staghorn calculi.

Tx: removal of entire stone. If the pt is febrile or presents with signs of systemic infection, surgical manipulation should be delayed until Abx tx has been administered and the pt has been afebrile for at least 48 hours. After surgical intervention, medical therapy should focus on preventing recurrent UTIs. Retained residual fragments increase the risk of recurrent UTI and future calculi. Acetohydroxamic acid (Lithostat, 250mg TID) is an irreversible inhibitor of urease and can prevent the crystallization of struvite stones, however, because of side effects (including deep venous thrombosis), it generally is reserved for use in pt’s who cannot tolerate surgical intervention. Consider Amoxicillin suppressive therapy 250mg PO qd.

Cystinuria:

(3%): consists of two cystine molecules linked with a disulfide bond.  Cystinuria is an autosomal recessive d/o in which excessive urinary excretion of the dicarboxylic amino acids (cystine, ornithine, lysine, and arginine) results from impaired transport.  Cystine stones develop in pt’s with cystinuria due to the insolubility of cystine in the urine.  Only homozygote pt’s form cystine calculi and often present with stones during childhood.

Dx: The normal rate of cystine excretion is 30 mg/day (1.3 mmol/day). In contrast, pt’s with cystinuria excrete >400 mg/day and sometimes up to 3,600 mg/day.  The dx of cystinuria is made by identification of the pathognomonic hexagonal cystine crystals on urinalysis (which can be seen in the initial urinalysis in about 25% of pt’), and by measurement of urinary cystine excretion of >250 mg/liter.

Tx: Stones can form rapidly increase fluids to 4-5L/d (round the clock).  Alkalinize the uring to pH>7-7.5 with K-citrate 10-30mEq TID, Pyridoxine 50mg/d.  If these measures are not effective, administration of cystine binders such as penicillamine (Cuprimine) and tiopronin (Thiola) can help prevent cystine calculi.  Bind sulfhydryl groups to other molecules (chelation) by adding: D-Penicillamine 250mg QID, Captopril 50mg BID or Mercapto-propionylglycine 250mg TID to interfere with disulfide bond formation.   Dietary manipulation with a low-methionine diet is difficult and rarely successful.

Calcium Phosphate (CaP):

(7%): often have an acidification disorder such as Distal RTA, giving an alkaline urine. Can also be due to primary hyperparathyroidism, excessive alkalinization, and sarcoidosis. F>M. Same risks as Ca-Oxalate stones (other than hyperoxaluria and hyperuricosuria)… one exception is that calcium phosphate stones are more typical of Type I (distal) renal tubular acidosis in which the urine pH is persistently >5.3, even after an acid load.

Tx: K-citrate to increase the inhibitor level to normal to correct the hypercalciuria.  Care must be taken to avoid excessive alkalinization, because high urinary pH can increase the urinary supersaturation of calcium phosphate salts. If hypercalciuria persists, addition of a thiazide diuretic is indicated.

HypoMg-uria: <50mg/d and no diarrhea d/o.  Triamterene: found in diuretics and Indinavir.

Bladder Stone:

Vesical calculi affect men predominantly and account for 5% of urinary calculi in the Western world(Schwartz, 2000).  Most occur in men older than 50 years and are often associated with bladder outlet obstruction.  The majority of bladder calculi are struvite, but calcium oxalate and uric acid stones are also encountered.

Risk factors:  bladder outlet obstruction; neurogenic bladder; chronic bacteriuria (urea-splitting organisms); foreign bodies; bladder diverticula; and, rarely, upper tract stones.  Children at risk for ammonium urate bladder stones in underdeveloped nations where a low-protein, high-carbohydrate diet and chronic dehydration predispose to endemic stones.

S/s: Bladder calculi are often found incidentally during evaluation of pt’s with obstructive or irritative voiding sx’s. Recurrent UTIs are common and are an identified risk factor.  Bladder stones may be voided spontaneously, with larger calculi precipitating acute urinary retention. Dysuria, gross hematuria, and suprapubic pain may occur. Interruption of the urinary stream from impaction of the stone at the bladder neck or urethra is not uncommon.  Bladder calculi are often radiolucent, may be single or multiple, and can be diagnosed as filling defects on the cystogram phase of an IV urogram or as an incidental finding on CT scan. On U/S, a hyperechoic, mobile bladder mass with shadowing is suspicious.

Tx: Cystoscopy is essential to evaluate the bladder and the bladder outlet, both to determine the etiology of the stone and to plan the most appropriate tx approach. Percutaneous suprapubic cystolithotripsy to remove bladder calculi can be safely accomplished under local anesthesia (Urology 2006;68:38-41) (2% lignocaine (lidocaine) injected 3 to 4 cm above the symphysis pubis. Lignocaine gel was also used for urethral lubrication).

**Ref:(Campbell’s Urology, 7^th ed., 1998, WB Saunders) (Urologic Clin NA 1997;24:1, pp50-122) (NEJM 1992;327:1141-52) (Prevention of recurrent nephrolithiasis. Am Fam Physician. 1999;60:2269-76) (Nephrolithiasis. Semin Nephrol. 1999;19:381-8) (Urolithiasis.  Uro Clin North Am 2000;27:2) (Acute Renal Colic from Ureteral Calculus. NEJM 2004;350:684-93) (An evidence-based literature review of the management of urolithiasis. BMJ. 2007;334:468-472)

Male Anatomy: