Nephrolithiasis Prevention by Lemon Juice
Condition: Nephrolithiasis
MeSH terms: Nephrolithiasis; Kidney Calculi
Study type: Interventional
Phase: Phase 2

Summary: 
      Calcium oxalate nephrolithiasis is a relatively common disease. The prevalence in the general
      population may range from 10 to 12 percent, and 0.4 to 1 percent of new cases are reported
      every year according to different series. Without specific pharmacological therapy, the
      recurrence rate in patient with established diagnosis of nephrolithiasis is extremely high
      and may range from 15 to 20 percent per year, with a cumulative incidence at five years
      ranging from 27 to 50 percent.Although genetic factors play an important role in the
      development of nephrolithiasis, environmental factors such as diet also appear to affect
      stone formation. Potassium citrate is also effective in preventing stone recurrence in
      patients with calcium oxalate nephrolithiasis. Low tolerability, however, may remarkably
      limit the use of these medication. Citrus fruits are a natural rich source of citrate and
      diet supplementation with juice of citrus fruits may represent a valuable alternative option
      to supply citrate without exposing the patients to the adverse effects of citrate containing
      medications. Among the most commonly consumed citrus fruits, lemons contain the greatest
      concentrations of citric acid (49,2 g/Kg);a half cup of pure lemon juice can provide a daily
      amount of citrate comparable to that of a standard daily dose of alkali citrate medications.

      A few studies tried to evaluate the effects of lemon juice supplementation in patients with
      calcium oxalate nephrolithiasis, but the findings were flawed by the retrospective,
      observational design of the study or by the too small sample size that limited the power of
      statistical analyses and the reliability of the results. This study will be primarily aimed
      at evaluating whether lemon juice added to standard diet recommendations compared to diet
      recommendations alone may reduce the risk of new stone formation in patients with recurrent
      idiopathic calcium oxalate nephrolithiasis. Secondarily, the study will evaluate the effects
      of lemon juice supplementation on complications of nephrolithiasis such as urinary tract
      infections, colic symptoms, and hospitalizations for stone disruption or removal, as well as
      the effects on urinary factors (such as urinary citrate, oxalate, calcium excretion or pH)
      that may favor or limit stone formations and the relationships between these effects and the
      risk of stone recurrence.
    

Detailed description: 
      BACKGROUND Calcium oxalate nephrolithiasis is a relatively common disease. The prevalence in
      the general population may range from 10 to 12 percent, and 0.4 to 1 percent of new cases are
      reported every year according to different series. Without specific pharmacological therapy,
      the recurrence rate in patient with established diagnosis of nephrolithiasis is extremely
      high and may range from 15 to 20 percent per year, with a cumulative incidence at five years
      ranging from 27 to 50 percent.

      Although genetic factors play an important role in the development of nephrolithiasis,
      environmental factors such as diet also appear to affect stone formation. Diet based on
      restricted intake of animal proteins and salt, combined with a normal calcium intake, may
      reduce the risk of stone formation. However, the efficacy in preventing stone recurrences is
      limited, in particular in repeated stone formers.

      Potassium citrate is also effective in preventing stone recurrence in patients with calcium
      oxalate nephrolithiasis. Low tolerability, however, may remarkably limit the use of these
      medication.

      Citrus fruits are a natural rich source of citrate and diet supplementation with juice of
      citrus fruits may represent a valuable alternative option to supply citrate without exposing
      the patients to the adverse effects of citrate containing medications.

      Among the most commonly consumed citrus fruits, lemons contain the greatest concentrations of
      citric acid (49,2 g/Kg), nearly 5 times the concentrations in the orange. A half cup of pure
      lemon juice can provide a daily amount of citrate comparable to that of a standard daily dose
      of alkali citrate medications. The citrate supplied with the juice that escapes metabolic
      degradation in vivo is excreted unchanged in the urine where may prevent the tendency of
      calcium oxalate salts to precipitate. Lemon juice supplementation may also have the
      additional advantage of reducing urinary calcium excretion without affecting oxalate
      excretion, while orange juice does not affect urinary calcium and may increase urinary
      oxalate.

      A few studies tried to evaluate the effects of lemon juice supplementation in patients with
      calcium oxalate nephrolithiasis, but the findings were flawed by the retrospective,
      observational design of the study or by the too small sample size that limited the power of
      statistical analyses and the reliability of the results. Thus, the protective effect of lemon
      juice supplementation against recurrence of stones in patients with calcium oxalate
      nephrolithiasis is worth investigating in adequately powered and designed trials.

      AIM The study will be primarily aimed at evaluating whether lemon juice added to standard
      diet recommendations compared to diet recommendations alone may reduce the risk of new stone
      formation in patients with recurrent idiopathic calcium oxalate nephrolithiasis. Secondarily,
      the study will evaluate the effects of lemon juice supplementation on complications of
      nephrolithiasis such as urinary tract infections, colic symptoms, and hospitalizations for
      stone disruption or removal, as well as the effects on urinary factors (such as urinary
      citrate, oxalate, calcium excretion or pH) that may favor or limit stone formations and the
      relationships between these effects and the risk of stone recurrence.

      DESIGN

      According to urinary citrate excretion at baseline evaluation patients satisfying the
      selection criteria will be stratified into two strata:

      Stratum 1: Hypocitraturia (urinary citrate excretion >320 mg/24 h) Stratum 2: Normocitraturia
      (urinary citrate excretion <320 mg/24 h) Within each stratum, patients will be randomized on
      a 1:1 basis to two-year treatment with lemon juice supplemented to standard recommended diet
      or to standard diet alone. All patients in the hypocitraturic stratum will also be prescribed
      potassium citrate 2g twice daily. Due to the Prospective, Randomized, Open, Blind Endpoint
      (PROBE) design of the study, patients and physicians in charge of patient care and monitoring
      will be aware of patient treatment, while all the Investigators involved in data handling and
      analyses will be blinded to patient treatment allocation.

      101 patients per group will have to be included. Thus, a total of 202 patients will have to
      be randomized.
    

Intervention name(s): Lemon supplementation
Intervention type(s): Dietary Supplement
Intervention description(s): 60 ml of lemon juice twice daily (an amount expected to provide 6 grams or 92 mEq of citric acid per day)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Recurrent idiopathic calcium oxalate nephrolithiasis.