Cystinuria
Conditions
Keywords
Cystinuria, Kidney stone, Alpha lipoic acid
Brief summary
This study evaluates how daily alpha lipoic acid supplementation affects cystine kidney stone recurrence. Half of the subjects will receive 1200 mg alpha lipoic acid orally daily for three years, while the other half will receive a placebo. The funding source for this clinical trial is FDA OOPD.
Detailed description
Cystinuria is a rare inherited autosomal recessive disorder of the kidney that is the result of a defect in the dibasic amino acid transporter in the renal proximal tubule and small intestine. Supersaturation of cystine in the urine produces crystals that precipitate and form calculi, which can be a cause of obstruction, infection, and chronic kidney disease (Chillarón 2010). One potential therapeutic is a thiol-containing compound alpha-lipoic acid (thioctic acid, 5-(1,2-dithiolan-3- yl) pentanoic acid, ALA). It is an over-the-counter supplement with antioxidant property. Once ALA is transported into the cell, it is reduced to dihydrolipoic acid (DHLA). Both ALA and DHLA have direct antioxidant activity (Scholich 1989), and they can regenerate endogenous antioxidants including ascorbic acid and vitamin E. It can also increase intracellular coenzyme Q10 and glutathione levels. ALA and DHLA also have additional biochemical effects as metal chelators, reactive oxygen species scavengers, and modulators of signaling transduction of several pathways (Gomes 2014). While the potential therapeutic effects of ALA have been studied in a number of diseases including, for example, Alzheimer's disease, obesity, cardiovascular disease, hypertension, and several cancers (Gomes 2014), the efficacy of ALA has been best studied in type 2 diabetic peripheral neuropathy (Ziegler 2011). In our lab, results from a mouse model of cystinuria show that ALA markedly slows the initiation of cystine stone formation as well as the growth of existing stones. Given this history in clinical medicine and, most importantly, based upon our positive findings of ALA effectiveness in a mouse model of cystinuria, we propose a pilot study on the use of this molecule in cystinuric patients.
Interventions
DIETARY_SUPPLEMENTAlpha lipoic acid
Already mentioned in arm/group descriptions.
DRUGPlacebo
Already mentioned in arm/group descriptions.
Sponsors
Thomas Chi, MD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented cystinuria on prior 24-hour urine collection and/or stone analysis; history of previous cystine kidney stones. * Being able and willing to provide consent.
Exclusion criteria
* Poorly controlled diabetes mellitus (hemoglobin A1C \> 8.0% for more than 1 year). * Current alpha-lipoic acid administration at the time of screening or within the last year prior to screening. * Vulnerable populations including incarceration status. * Unable to give informed consent. * Non-English primary language. * Pregnancy, lactation, or child-bearing age without birth control devices. * Anticipation of pregnancy during the study period. * Serious illness likely to cause death within the next 5 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cystine Stone Recurrence | 3 years | The primary efficacy endpoint will be assessed in two ways: 1. symptomatic stone recurrences, defined as renal colic, stone passage, or surgical removal of a stone; 2. silent stone recurrences, classified as stone growth or new stones, diagnosed on the basis of renal ultrasound, plain KUB x-ray, or if clinically indicated, computed tomography. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urinary Cystine Level | 3 years | The secondary endpoints will be quantitative urinary cystine level determined by 24-hour urine collection. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORThomas Chi, MD
University of California, San Francisco
Participant flow
Recruitment details
Potential participants were screened by their Primary Urologist outside of UCSF or from the UCSF urology clinic under the care of Drs. Stoller and Chi. Eligibility was determined by the following inclusion criteria: age 18 or older; documented cystinuria on prior 24-hour urine collection or stone analysis; and being able and willing to provide consent. This information was present at the time of the clinic visit for new participants or at follow-up visits for current patients of study PIs.
Pre-assignment details
Participants were computer sequence-randomized to receive either oral daily dosing of 1200 mg ALA or placebo for three years.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants |
| baseline non-contrast CT scan | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 48 Participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 25 | 0 / 25 |
| other Total, other adverse events | 4 / 25 | 0 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 |
Outcome results
None listed