One hundred fifty-three Egyptian patients who had a kidney stone of 4 to 10 mm in size in the distal ureter were randomly assigned to receive (without blinding) L-arginine (1 gram once a day), tamsulosin (0.4 mg once a day; a treatment that is known to be effective for promoting stone passage) or placebo for 4 weeks. The proportion of patients who passed (expelled) their stone during the study was 11.8% in the placebo group, 31.4% in the tamsulosin group, and 94.1% in the L-arginine group.

Comment: If this modest dosage of L-arginine is as effective as this study suggests for promoting the passage of kidney stones, it would represent a major advance in the treatment of kidney stones. However, I have doubts that this study is real.

As readers of the Townsend Letter know, over the past 10 years or so, I have been concerned about the large and growing number of published papers that left me wondering whether the research was fabricated; that is, whether people were writing papers about research that had not actually been conducted. Most of the questionable papers have come from Iran, but there have also been concerns about papers from China, Egypt, Japan, India, Italy, and a few other countries. A careful review of the present study revealed a number of concerns. I outlined these concerns in an email sent on June 19 and again on June 26 to the editor in chief of the journal that published this paper. To date there has been no acknowledgement that the emails were received. Below are the various concerns that led me to question the integrity of the paper.

1. Implausible patient enrollment: One hundred sixty-two patients were assessed for eligibility, of which 9 were excluded prior to randomization because they were “lost to follow-up.” It is logical to assume that assessment for eligibility and enrollment in the study took place at the time the patients presented with acute renal colic. It is difficult to understand how 9 patients could have been lost to follow-up, since there would not have been any follow-up visits at the time of first presentation.

All of the remaining 153 patients enrolled in the study and were randomized. It is difficult to believe that all 153 patients fulfilled all of the inclusion criteria. For example, none of the patients had a stone smaller than 4 mm or larger than 10 mm in size; all of the stones were in the distal ureter (statistically, one would expect one-third of stones not to be distal); none of the patients had a symptomatic urinary tract infection (in fact, according to Table 1 in the paper, 4 patients had a positive urine culture), and none of the patients had multiple or bilateral stones.

Even if all 153 patients did fulfil the inclusion criteria, it is difficult to imagine that 100% of the patients would have agreed to participate in a randomized trial. Such a high participation rate almost never occurs in clinical trials, particularly a trial that requires someone in pain to attend weekly follow-up visits for 4 weeks. Moreover, the “informed consent” form would have informed the patients that tamsulosin is known to be effective for promoting passage of ureteral stones, and that two-thirds of the patients in the study would receive either a placebo or a treatment (L-arginine) that has not been demonstrated to be effective. It is difficult to imagine that anyone (let alone 100 percent of patients) would agree to participate in such a trial.

The study authors lived in two separate cities in Egypt (Sohag and Aswan), which are separated by about 5.5 hours by car. There is no mention in the paper about where patient enrollment took place or over what time period the study was conducted. The omission of that information is unusual.

2. Ethical issues: According to the paper, the study was approved by “the local ethics committee.” There is no mention of the name of the ethics committee or what city the ethics committee resided in. The omission of that information is unusual.

One might also question the ethics of giving a placebo to one-third of the patients in the study, when there is a treatment that is known to be effective (tamsulosin). It is doubtful that a knowledgeable ethics committee would have allowed such a study to take place.

3. Issues related to blinding: The paper stated that the study was “non-blinded,” and yet, one-third of the patients were given a placebo. It does not seem possible to have a placebo group in a study where there is no blinding.

4. Issues related to follow-up: The paper stated that none of the patients in the study missed follow-up, implying that all 153 patients attended all 4 of their weekly follow-up visits. Such a high compliance rate is extremely unusual for a clinical trial.

5. Mathematically impossible data: In calculating the time before stone expulsion, patients were assigned a fixed time of 28 days if the stone was not expelled during the study. According to Table 4, the mean time to stone expulsion in the control group was 19.6 days. However, also according to Table 4, either 45 or 46 of the 51 patients in the control group would have been assigned a stone expulsion time of 28 days, since they did not pass their stone during the study. Even if the remaining 5 or 6 patients in the control group had expelled their stone as early as one day after randomization, it would be mathematically impossible for the mean time to stone expulsion to be lower than 24.8 days.

6. Implausibly large effect size of L-arginine: The dosage of L-arginine in this study was relatively low (1 gram per day). For comparison, the mean dietary intake of L-arginine in Egypt has been reported to be 4.05 grams per day. Most clinical trials of L-arginine for the treatment of conditions such as heart failure, angina pectoris, or erectile dysfunction have used L-arginine dosages of 4 to 9 grams per day. It is difficult to believe that a dosage as low as 1 gram per day could provide significant benefit, let alone being dramatically more effective than tamsulosin.

7. Issues related to funding: The only funding listed was “Open access funding,” which apparently refers to the fee paid to have the paper published. There does not appear to have been any additional funding for this large clinical trial, which included many hundreds of ultrasound studies and PUT (plain urinary tract) imaging studies. It is not plausible that the study could have been conducted without funding.

8. Issues related to the study authors: The only information provided about the six authors is that they are affiliated either with Sohag University or Aswan University in Egypt. There is no mention of whether they are students or professors, what department they are in, or whether they have any training in urology. A Pub Med search of each of the six authors revealed that none of them have published any other paper than the one being reviewed here. It is difficult to believe that a group of people with no apparent research experience and no funding could have conducted this trial.

Reference

Mahmoud Mohammed Ahmed Elsherief A, et al. L-arginine role for stone lower ureter: A randomized controlled trial.  Urolithiasis. 2025;53:109.