Friday, June 13, 2014

Medical Expulsive Therapy for Kidney Stones

It is estimated that 5% of women and 10% of men in the US have nephrolithiasis (or kidney stones).[1,2]  Most people do not know they have kidney stones until they obstruct one of the ureters, connecting the kidney to the bladder.  These symptoms may include flank pain, nausea and vomiting, hematuria (blood in the urine) or high fever.  There are a number of treatments ranging from observation and medications to temporary drainage (stenting) and lithrotripsy (breaking up the stone through ultrasound or laser technologies).

In this blog we will review medical expulsive therapy (MET), or the use of medications to promote passage of a kidney stone without surgery.

CAUSES OF "STONE PAIN"

The painful symptoms of an obstructing kidney stone can range from the flank to the genitals, can cause nausea, vomiting or even gastrointestinal symptoms.  While the exact cause of this pain is not well understood, the pain is believed to stem from:

  • obstruction - which causes distention of renal capsule, collecting system and ureter activating pain-sensing nerves in the body
  • irritation - the hard, sharp stone itself can activate pain sensors
  • spasm - sometimes referred to "renal colic," describes spasm of the ureter and renal collecting system that can cause contractile, episodic pain
To alleviate these symptoms and promote passage of the blocking stone, a number of strategies have been developed and examined.  These strategies and their efficacy are reviewed below.

Increasing Proximal Pressure: Hydration

Increasing the fluid and pressure behind the kidney stone is theorized to "push" the stone further down the ureter.  Two randomized trials were reviewed in a Cochrane Meta-analysis and failed to demonstrate any benefit to intense intravenous hydration or diuresis as compared to standard-of-care hydration.[3] 

Decreasing Ureteral Swelling: Anti-inflammatories

The potential benefits of non-steroidal anti-inflammatory drugs (NSAIDs) are reduced inflammation and treatment of pain and, by doing so, facilitate stone passage.  In two studies, one of which was a double-blind, placebo-controlled randomized study, NSAIDs failed to improve the proportion of stones passed or the time to passage.[4,5]

Decreasing Ureteral Contractions: Anti-spasmodics

A number of medications have been used in order to decrease ureteral spasm, improve pain and facilitate stone passage.  Antimuscarinics, phosphodiesterase inhibitors and steroids have failed to demonstrate a benefit in stone passage.  However, alpha-blockers (AB) and calcium-channel blockers (CCB) do improve stone passage rates and time to passage.  Through direct interactions with the alpha-adrenergic receptor, AB inhibit ureteral contraction, reduce basal tone of the ureter, decrease peristaltic frequency and therefore decrease the colicky pain associated with obstruction.  CCB inhibit endogenous prostaglandin synthesis and reduce spontaneous contractions of distal ureter.

Calcium Channel Blockers (CCB)

The landmark clinical trial in CCB therapy was by Borghi and colleagues in 1994.[6] Since then, nine studies including 686 demonstrate a 50% improvement in stone passage rates, and six of those studies demonstrated an improvement in time to expulsion (2.7 versus 12 days).[7]
Recommended Rx: Nifedipine XL 30mg daily for 2-4 weeks or stone passed or active treatment

Alpha-Blockers (AB)

The landmark study in AB therapy was by Pedro and colleagues in 2008.[8] Since then, 29 studies involving over 2,000 patients have examined the role of AB for MET.  A variety of AB have been used including tamsulosin, doxazosin and terazosin.  The benefit for each medication ranges from a 28-56% improvement in expulsion rates.  The benefit of MET with AB is significantly related to ureteral stone size.  Only 4 of 9 studies with stones <5mm demonstrated a benefit in expulsion rates.  However 19 of 20 studies with stones >5mm demonstrated a benefit to MET with AB.  This is likely related to the very-high rate of spontaneous passage for obstructing stones <5mm without any treatment.  (Interestingly, this size-to-benefit ratio is not seen in CCB, likely because fewer studies have been performed to parse out this difference).[7]
Recommended Rx: Tamsulosin 0.4mg PO daily for 2-4 weeks or stone passed or active treatment

Side Effects of MET

The most common side-effect of CCB or AB is hypotension (low blood pressure) which occurs in 0-10% of patients.  However, very few patients (3-4%) stop taking the medication due to side effects and it appears that CCB are tolerated slightly better than AB for patients who develop hypotension.[7]  Importantly, these side effects are reversible with immediate discontinuation of the medication.

Benefits and Cost-Effectiveness of MET

There are many proposed benefits to MET including:

  • Reduced Hospitalization Rates (0-10% vs. 7-34%)
    • Emergency room visits reduced (2.9 vs. 11.4)
    • Work days lost reduced (2 vs. 5)
  • Reduced analgesic requirements (85% studies)
  • Reduced number of colic episodes (0-8% vs. 1-20%) [7]
A number of studies have attempted to quantify the benefits of MET through cost-effectiveness models that compare the costs of invasive procedures (like ureteroscopy and laser lithotripsy) to costs of MET medications, pain killers, days of work lost and hospitalization rates.[8]  In addition, it is estimated that MET could save over 250,000 operations per year if used more broadly as primary therapy for an obstructing ureteral stone.[9]


Summary

  • Medical Expulsion Therapy, MET can facilitate the passage of obstructing renal or ureteral stones by:
    • Increasing proximal pressure
    • Decreasing ureteral inflammation
    • Decreasing ureteral contraction
  • The best and most widely used medications include:
    • Calcium-Channel Blockers 
    • α-blockers
  • Clinical trials demonstrate a benefit to MET:
    • Increased rate of expulsion
    • Decreased time to expulsion
    • Low rates of side effects
    • Decreased hospitalization
    • Decreased narcotic requirements




1. Johnson, C. M., Wilson, D. M., O'Fallon, W. M., Malek, R. S. & Kurland, L. T. Renal stone epidemiology: a 25-year study in Rochester, Minnesota. Kidney Int. 16, 624–631 (1979).
2. Hiatt, R. A., Dales, L. G., Friedman, G. D. & Hunkeler, E. M. Frequency of urolithiasis in a prepaid medical care program. Am. J. Epidemiol. 115, 255–265 (1982).
3. Worster AS1, Bhanich Supapol W.Fluids and diuretics for acute ureteric colic.  Cochrane Database Syst Rev. 2012 Feb 15;2:CD004926. doi: 10.1002/14651858.CD004926.pub3.
4. Al-Waili NS. Prostaglandin synthetase inhibition with indomethacin rectal suppositories in the treatment of acute and chronic urinary calculus obstruction. Clin Exp Phamacol Physiol 1986.
5. Laerum E et al. Oral diclofenac in the prophylactic treatment of recurrent renal colic: a double-blind comparison with placebo. Eur Urol 1995.
6. L. Borghi, T. Meschi, F. Amato et al.  Nifedipine and methylprednisolone in facilitating ureteral stone passage: a randomized, double-blind, placebo-controlled study.  J Urol, 152 (1994), pp. 1095–1098
7. Seitz C1, Liatsikos E, Porpiglia F, Tiselius HG, Zwergel U.  Medical therapy to facilitate the passage of stones: what is the evidence?  Eur Urol. 2009 Sep;56(3):455-71. doi: 10.1016/j.eururo.2009.06.012. Epub 2009 Jun 21.
8.  Bensalah K, Pearle M, Lotan Y.Cost-effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones.  Eur Urol. 2008 Feb;53(2):411-8. Epub 2007 Sep 18.
9.  Hollingsworth JM, Davis MM, West BT, Wolf JS Jr, Hollenbeck BK.Trends in medical expulsive therapy use for urinary stone disease in U.S. emergency departments.  Urology. 2009 Dec;74(6):1206-9. doi: 10.1016/j.urology.2009.03.050. Epub 2009 Oct 7.


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