Urolithiasis: Basic Science and Clinical Practice

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Part of the hypocalciuric effect of thiazide is due to mere volume contraction-induced increased proximal tubule calcium absorption. If this were true, the thiazide effect can be achieved equally well with dietary sodium restriction without exposure to the risk of glucose intolerance.

A summary of drug used in the treatment of hypercalciuric nephrolithiasis is detailed in Table 3. In a short term trial, bisphosphonates were shown to lower urinary calcium excretion. Three randomized trials were performed in recurrent calcium-stone formers. This effect is compatible with results from non-randomized studies. In hypocitraturic calcium or uric acid urolithiasis, potassium citrate 1—4. A summary of these trials is illustrated in Table 2. Alkali treatment is relatively safe with minor gastrointestinal side effects.

One potential concern is that the overtreatment with alkali may increase the risk of calcium-phosphate-stone formation by increasing the abundance of monohydrogen phosphate. Although this pathophysiological link has been proposed, it has never been studied. It is interesting that the potassium citrate treatment in patients with distal renal tubular acidosis and pre-existing high urinary pH has been shown to considerably lower rather than increase kidney stone recurrence rate.

Although both sodium and potassium alkali treatment are equally effective in raising urinary pH, potassium citrate is more effective in preventing the formation of calcium stones by attenuating urinary calcium excretion. As acidic urine pH is the most predominant factor in the development of uric acid stones, alkalinization of the urine is the most effective way to treat patients with uric acid nephrolithiasis.

Although it has not been tested in long-term randomized trials, sodium bicarbonate may also offer the same alkalinizing effect although this treatment may confer an increased risk of calcium stone formation due to sodium-induced hypercalciuria, promotion of monosodium urate-induced calcium oxalate crystallization, and high pH-induced calcium phosphate precipitation.

Pharmacotherapy of urolithiasis: evidence from clinical trials

Although urinary alkalinization does not get at the root of the pathophysiology of aciduria in uric acid stones, it is a pragmatic and effective therapy. A common practice is to frequently measure h urine pH and to titrate the alkaline dose to maintain a urine pH above 6. However, urine pH from a h urine collection may not adequately reflect the diurnal variation in urine pH during periods of extreme acidity. Although direct urinary pH measurements throughout the day would be impractical, pH measurements may be performed by urinary dip-stick analysis.

This treatment should be invariably considered in patients with hyperuricemia, including primary gout, those with inborn errors in metabolism, myeloproliferative disorders, hemolytic anemia, and in tumor lysis syndrome. Although hyperuricosura is not usually the cause of uric acid stones in the absence of aciduria, there is the condition of hyperuricosuric calcium oxalate urolithiasis in which sodium urate or uric acid contributes to the formation of calcium oxalate stones. Two studies have shown that for hyperuricosuric calcium oxalate stone-formers without other metabolic abnormalities, allopurinol is effective in reducing urinary uric acid and stone recurrence compared with no treatment Table 2.

A non-purine analog xanthine oxidase inhibitor was recently approved for treating hyperuricemia associated with gouty arthritis.

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Although shown to be effective in reducing hyperuricemia and arthritis attacks, the effect on uricosuria was not reported. On the basis of its mechanism of action, one would expect hypouricosuric effects, so for patients who cannot tolerate allopurinol, febuxostat is a plausible consideration without supportive data.

The use of recombinant uricase has no proven role in the chronic management of hyperuricosuria.

As the pH dependency of urinary cystine solubility was shown over half a century ago, alkali treatment has been widely used in the management of cystinuric subjects. However, alkali therapy alone has limited effectiveness, as a large dose is necessary because of the high pKa of cystine 8. Such highly alkaline urine can predispose the patient to calcium phosphate stone formation thus a urinary pH of 6. However, to date no RCTs have been performed demonstrating the superiority of medical treatment over placebo in this population.

The thiol-containing compound captopril has been suggested to function similarly to reduce urinary cystine excretion, 54 , 55 but this finding was not reproduced by others. Hyperoxaluria is an equally important contributor to calcium oxalate supersaturation as hypercalciuria. Hyperoxaluria can result from rare monogenetic causes primary hyperoxaluria type 1: Type 1 patients can be managed with pyridoxine.

In one study over patient-years, pyridoxine reduced hyperoxaluria, but effect on stone events were not reported. The probiotic approach of Oxalobacter formigenes or direct administration of recombinant oxalate decarboxylase is still in the experimental phase with mixed results in both humans and rodents. Although luminal oxalate degradation will certainly lower stool oxalate, it is still unclear whether this will lower urinary oxalate. In another short-term study, patients with enteric hyperoxaluria were treated with increasing dosages of a lactic acid bacteria mixture. This study demonstrated lowered calcium oxalate supersaturation during this treatment, mainly due to decreased urinary oxalate excretion.

However, the degree of change was not statistically significant. Despite some clear and encouraging successes we have witnessed over the last few decades, we are poised at a juncture where there is a dire need for development of novel medical pharmacotherapeutics in urolithiasis both in depth and in lateral scope.

The approach of developing a universal treatment protocol regardless of underlying pathophysiology or even urinary chemical parameters, may have its pragmatic attractions because of sheer simplicity, obviation of investigations, and initial cost reduction. This really is not in the best interest of the patient as potential for ineffective or even harmful therapy is substantial.

Future efforts should be directed to refine therapy based on underlying etiology and pathophysiology so eventually therapy can be tailored for the individual stone former rather than population of stone formers. This will require coordinated and simultaneous investigations at the levels of the laboratory bench, human metabolic investigations, and population-based clinical research. The majority of breakthrough discoveries will no doubt originate from the former two categories.

At the present moment and with the current database, certain clinical trials can be very informative and will clearly improve our existing treatment protocols. These efforts should be multi-center-based to ensure power and shorten the duration to completion. For such a common disease, this really should be an achievable goal provided support is available. As indicated above, one can systematically test therapy targeted to known underlying pathophysiology using individualized regimens vs non-selective blanket treatment for stone formers.

Although targeted therapy is intuitively correct, its practical utility has not been definitively documented in the form of a trial. One would predict that the results will favor tailored therapy but this needs to be shown at the population level. Such clinical evidence will provide the justification and motivation for metabolic evaluation of all patients with urolithiasis.

Sometimes when the ideal is not possible and realizing that there may be circumstances in some practices in which metabolic evaluation is not realistic, which empiric pharmacological agent s should one use for calcareous stones-alkali, thiazides, or both? There is a need for comparison between pharmacotherapy vs dietary therapy vs both. As discussed earlier, the hypocalciuric effect of thiazides alone needs to be compared with dietary sodium restriction alone, and to both salt restriction plus thiazide. If the effect of thiazides is really due solely to volume contraction, one may consider using it as an alternative or adjuncts to dietary sodium restriction.

The long-term side effects of thiazides, particular regarding glucose intolerance, in stone formers should also be prospectively evaluated. It is not known whether thiazides have a direct effect on glucose metabolism or potassium deficiency may be the mediating culprit. One may find comparable efficacy of pharmacological and dietary therapy in a strictly controlled clinical trial, but adherence may be difficult to achieve with chronic dietary changes leaving potassium alkali as the preferred choice.

Protein restriction may also be quite different from acid neutralization because there may be non-acid components of protein that are lithogenic.

Another study will be to test single vs combination therapy. An empirical approach used by practitioners is that when one therapy does not suffice, often a second drug is tried or added. Are two drugs better than one? The intuitive answer appears to be yes, but we really do not have clinical data to support whether combination therapy is indeed superior.

As none of the current regimens are completely effective, there is clearly room for further reduction of stone events. A combination therapy of thiazide and potassium citrate is logical from a pathophysiological viewpoint and not necessarily contrived. Another kind of study will be to prospectively examine the response of stone formers who have never undergone procedures vs those who have.

Retrospective data seem to indicate much better result with medical treatment in patients post lithotripsy or percutaneous procedures than those without medical treatment following non-invasive surgical intervention. This is a most intriguing finding lending one to wonder whether there is a fundamental difference in the pathobiology after surgical intervention or simply patients become much more compliant and motivated to avoid further procedures.

As urolithiasis is a systemic disease, there is a dire need to understand the long-term effects of pharmacotherapy on parameters other than urinary chemistry and stone events, such as bone health. As current markers of kidney stone formation relies on computer-based analysis of urine chemistry as surrogates or stones events as long-term gold standard outcomes.

One may consider an intermediate form of physical chemical surrogate such as crystal agglomeration and growth as an additional read-out to improve prediction. Finally, as urolithiasis is a systemic disease, outcomes such as insulin resistance, and hypertension should also be targeted and examined in the course of intervention. There is no doubt that these efforts are costly as with all multi-center clinical trials and should be prioritized when resources are limiting. It is also apparent that we need further multi-level efforts at the basic science bench, metabolic research units, and population studies to unravel and discover pathophysiology-directed intervention strategies.

Although urolithiasis rarely carries the grave curse of mortality of end stage renal failure, cardiovascular disease, or neoplasm, it does have profound impact on quality of life and unlike the aforementioned conditions; cure of urolithiasis is not too far in the horizon if the proper efforts are executed. We are grateful to Dr Charles Pak for reading the manuscript and valuable suggestions. We also wish to acknowledge Ms.

Hadley Armstrong in her assistance in the preparation of this manuscript. All the authors declared no competing interests. National Center for Biotechnology Information , U. Author manuscript; available in PMC Aug 1. Moe , 1, 2, 3 Margaret S. Pearle , 1, 4 and Khashayar Sakhaee 1, 2. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Kidney Int.

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See other articles in PMC that cite the published article. Abstract Urolithiasis is a worldwide problem with significant health and economic burdens. Medical Expulsive Therapy Met One area in which medical therapy alters the natural history of stone disease is on the spontaneous passage of ureteral calculi. Table 1 Commonly used drugs in medical expulsive therapy. Open in a separate window.

Hypercalciuria At present, the only medical therapy directed at reducing urinary calcium is thiazide diuretics. Table 2 Major clinical trial in pharmacotherapy of urolithiasis. Hypocitraturia Barcelo et al. Table 3 Commonly used drugs in the treatment of hypercalciuric calcium nephrolithiasis. Because of its long action, this treatment may cause hypokalemia and hypocitraturia. Hypocitraturia Three randomized trials were performed in recurrent calcium-stone formers.

Uric Acid Stones As acidic urine pH is the most predominant factor in the development of uric acid stones, alkalinization of the urine is the most effective way to treat patients with uric acid nephrolithiasis. Hyperuricosuric Calcium Nephrolithiasis Although hyperuricosura is not usually the cause of uric acid stones in the absence of aciduria, there is the condition of hyperuricosuric calcium oxalate urolithiasis in which sodium urate or uric acid contributes to the formation of calcium oxalate stones.

Cystinuria As the pH dependency of urinary cystine solubility was shown over half a century ago, alkali treatment has been widely used in the management of cystinuric subjects. Hyperoxaluria Hyperoxaluria is an equally important contributor to calcium oxalate supersaturation as hypercalciuria.

Current Status and Direction of Further Clinical Studies Despite some clear and encouraging successes we have witnessed over the last few decades, we are poised at a juncture where there is a dire need for development of novel medical pharmacotherapeutics in urolithiasis both in depth and in lateral scope. Acknowledgments We are grateful to Dr Charles Pak for reading the manuscript and valuable suggestions. Cost-effectiveness of medical management strategies for nephrolithiasis. Evidence for durable kidney stone prevention over several decades.

Natural history and current concepts for the treatment of small ureteral calculi. Evidence for the presence of alpha1 adrenoceptor subtypes in the human ureter. Medical therapy to facilitate urinary stone passage: Medical-expulsive therapy for distal ureterolithiasis: The E-mail Address es field is required.

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Urolithiasis : basic science and clinical practice

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Please enter the message. Please verify that you are not a robot. Would you also like to submit a review for this item? You already recently rated this item. Your rating has been recorded. Write a review Rate this item: Preview this item Preview this item. Jamsheer Talati ; Farhat Abbas Publisher: English View all editions and formats Summary: Basic Science and Clinical Practice is a comprehensive text that assists urologists in defining the best choice of treatment for each case through a balanced presentation of underlying science, diagnostic methods and practical tips, with additional discussions on educational issues, costs and management of resources.

This user-friendly practical resource is replete with full-color illustrations and radiographs, covering all aspects of stone disease, and offering perspectives from Europe, the Americas, China, South Asia, Africa, and Australia. Topics include the biochemical and physiological basis of stone formation, treatment options, complications, assessment of techniques and technologies available, and guidelines on the prevention of stone recurrence.

Basic Science and Clinical Practice is the definitive text on stone disease and is a must read for young consultants starting a new practice, and urologists in residence and training. Allow this favorite library to be seen by others Keep this favorite library private. Find a copy in the library Finding libraries that hold this item Electronic books Additional Physical Format: Document, Internet resource Document Type: Jamsheer Talati ; Farhat Abbas Find more information about: Jamsheer Talati Farhat Abbas.

Featuring a wealth of illustrations and videos, this publication offers comprehensive assistance to urologists in defining the best choice of treatment for each case, through a balanced presentation of underlying science, diagnostic methods and practical tips. Reviews User-contributed reviews Add a review and share your thoughts with other readers. Add a review and share your thoughts with other readers. Similar Items Related Subjects: Linked Data More info about Linked Data. Home About Help Search. Privacy Policy Terms and Conditions.

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