Systematic screening of herbal remedies is needed to validate their efficacy

Herbal remedies for renal stone disease have a long and ancient history, and this form of treatment remains popular with the general public and is often publicized in the media and on the Internet, but with little supporting information much of which is anedoctal.

Despite our scientific progress in understanding drug design, formulation, and drug action, we still do not know which herbal medicines or mixtures actually work in clinical practice, what their mode of action is and whether it is novel; if there is one or more active ingredient and what it is, or if all such remedies are universally safe to prescribe. This subject warrants more serious attention and there is still a lot of work that needs to be done to properly exploit these traditional ‘cures’.

Exactly how renal stones form continues to be a subject of ongoing speculation, despite the significant advances we have made in our understanding of many of the urinary components and external factors, including diet and lifestyle, and even genetics, that are strongly associated with the risk of stone formation and stone type, which are: low urine volume, increased excretion of calcium and oxalate, increased or decreased urine pH, decreased excretion of citrate and magnesium. However, as doctors (physicians or surgeons), we have very few, if any, medical treatments, preventive or otherwise, other than oral citrate, in the often forlorn hope that our patients will take it and that we can give sufficient to boost its excretion; thiazide diuretics to reduce calcium excretion, which is also ‘hit and miss’, if their dose-related metabolic and electrolyte side effects are to be avoided; xanthine oxidase inhibitors such as allopurinol or febuxostat for uric acid stones; and the more specific thiol-based chelators for those with cystinuria and cystine stones.

Therefore, it is not surprising that many (desperate) patients ask about the value of various ‘herbal remedies’ that have been touted in the media or on the Internet as a ‘cure’ for kidney stones; but is there any evidence that they are of benefit and if so, what might the active ingredient(s) be?

Systematic investigation

A more systematic exploration and investigation of herbal remedies for treating renal stones not only has potential clinical value as preventive or adjunct medication, but also as a scientific endeavour to identify novel targets and pathways involved in the pathogenesis of stone formation. An innovative and relatively ‘high throughput’ screening approach has already been described in the fruit fly for calcium oxalate stone formation1, which could be followed up by isolating the active ingredient(s) and progressing to a clinical trial to show efficacy.

Using the search terms ‘kidney stones’ and ‘herbal’ or ‘herbs’ in PubMed you will get a return of between 10 and 60 publications, respectively; however, the actual number is surprisingly variable and uncertain, and seems relatively small, confused by what is defined as ‘herbal’, rather than a dietary component such as fruit or vegetables containing alkali, citrate and magnesium, and both the (changing) composition and indications for use of various herbal extracts, making it difficult to determine what might be of benefit and how. Many are so-called ‘natural remedies’ with scant information on their mode of action (See Table 1). However, it seems likely that many of these remedies may achieve their apparent success and popularity from a mild diuretic effect, for example, from caffeine (an adenosine receptor antagonist)2, or smooth muscle relaxation (also a potential effect of caffeine), similar to α-blockade, or provide alkali as citrate, or even act as mild urinary antiseptics.

Table 1: Proposed ‘natural remedies’ for treating renal stones and their possible actions:

Moreover, as a warning, many ‘over-the-counter’ health tonics or stimulants contain ‘ephedra’ or ephedrine, which can be a cause of renal stones4. That said almost all reports are based on in vitro assays of stone formation (crystal formation in artificial urine)5 or in animal models3,5, and almost exclusively for use in treating calcium oxalate stones, rather than any human data from the ‘gold-standard’ of a prospective double blind randomized controlled trial (RCT).

RCTs have always been challenging to do for the treatment of nephrolithiasis, because its natural history is often unpredictable, compliance with treatment is generally poor (anything given more than once a day over the long-term), as well as the difficulty in blinding any medication; all this makes the choice of outcome and end-point, other than short-term changes in urine composition or long-term rates of stone recurrence, uncertain and costly.

Indeed, Butterweck & Khan3, in their comprehensive review of herbal treatments for nephrolithiasis a few years ago, could find only 21 human trials, but all in healthy volunteers, and many testing citrus or cranberry juices that can affect citrate excretion and/ or urine pH. In fact, there are very few RCTs for medical treatment of renal stones, apart from thiazide diuretics, including indapamide, oral citrate, and allopurinol.

I could find four published and accessible randomized clinical trials, only one of which was double-blind. These looked at stone-free interval after lithotripsy7 and effect on urinary calcium excretion8 with Uriston; urine composition at six weeks and stone-free interval at one year with Cystone (See Table 2)9, and another lithotripsy study using biomarkers of oxidative damage to study the ‘protective’ effect of a popular Chinese herbal mixture for renal stones. All except the Cystone study, the only double-blind study, claimed to show some benefit, but the numbers are small and duration short. Interestingly, Cystone has shown a positive effect in vitro to reduce calcium oxalate crystallization5, but this did not translate to any clinical efficacy in vivo.

Table 2: Herbal preparations used to treat renal stones in published clinical trials:

Systematic approach to screening

In summary and (this author’s) conclusion, looking through the published literature, which is often not in mainstream nephrological or urological journals, it is very difficult to chart a course and find any potentially useful herbal remedies that have been validated and properly tested in clinical trials, and at the same time be confident of avoiding any risk of toxicity from non-standardized or fully analyzed herbal preparations. We have a limited therapeutic armamentarium for renal stone disease and so it is not unreasonable to turn to herbal remedies as a potential source of new and additional treatments.

However, until we adopt a more systematic approach to screening these herbal remedies, identifying their active ingredients, understanding their mechanisms of action, and demonstrating efficacy in rigorously conducted clinical trials, any benefit will remain little more than hearsay, and we risk misleading our patients. How to encourage wider academic interest in understanding the pathophysiology of renal stone disease, as well as pharmaceutical interest in its treatment, is a key challenge for us.

Author:
Prof. Robert Unwin, Centre for Nephrology University College London, London (UK)