Genetic Study of Nephrolithiasis in Gouty Diathesis
Genetic Study of Nephrolithiasis in Gouty Diathesis
Gouty diathesis describes uric acid or calcium oxalate nephrolithiasis and low urinary pH
 (<5.5). A hereditary component has been outlined for several forms of nephrolithiasis (such
 as hypercalciuria, hyperoxaluria, cystinuria, renal tubular acidosis), leading to the
 hypothesis of a genetic predisposition to nephrolithiasis. At the Unit of Nephrology,
 Ospedali Riuniti di Bergamo, more than 100 patients affected by gouty diathesis are followed.
 Fifty percent of them has a familiarity for kidney stones formation. The aim of our study is
 to identify the genetic factors that predispose to the development of nephrolithiasis in
 patients with gouty diathesis.
INTRODUCTION Nephrolithiasis is a common disorder with a reported incidence of 12% in
 industrialized countries. The peak incidence is in ages 20s to 40s. Men are affected two to
 three times more often than women. Gouty diathesis describes uric acid or calcium oxalate
 nephrolithiasis and low urinary pH (<5.5) in the absence of excessive gastrointestinal alkali
 loses or dietary animal protein excess. Hyperuricemia, hypertriglyceridemia, and a history of
 gouty arthritis may be present. Subjects with gout are singularly predisposed to stone
 formation. Persistent acidity of the urine is a common manifestation of primary gout, that
 may be accompanied by uric acid nephrolithiasis. In the presence of an increase in the
 concentration of uric acid in the urine, the formation of uric acid stones is further
 facilitated.

 In the primary forms of nephrolithiasis the most important predisposing factors for kidney
 stones are: hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia, hypomagnesuria,
 high urinary sulfate, low urine volume, high urinary sodium, cystinuria, infection,
 persistently high or low urinary pH. A hereditary component has been outlined for several of
 these abnormalities, leading to the hypothesis of a genetic predisposition to
 nephrolithiasis. Pirastu and co-workers took advantage from a small, isolated population from
 Sardinia, characterized by a high prevalence of Uric Acid Nephrolithiasis (UAN). The disease
 shows familial clustering, although the transmission of UAN does not follow a simple
 mendelian inheritance pattern, suggesting that hereditary factors could play an important
 role in susceptibility to UAN. They found an association of UAN to a new gene, called ZNF365,
 and in particular to its variant Ala62Thr, making it a strong candidate predisposing factor.

 At the Unit of Nephrology, Ospedali Riuniti di Bergamo, we follow at the moment 560 patients
 with nephrolithiasis of which more than 100 are affected by gouty diathesis. 50% of all
 patients with gouty diathesis has a familiarity for kidney stones formation.

 Understanding of the genetic factors that contribute to the development of this disorder may
 lead to earlier diagnosis, thus allowing to identify, within a family, subjects that are at
 risk to develop nephrolithiasis before manifestation of the disease. These subjects may have
 access to counseling aimed at modifying their dietetic and sanitary attitudes and/or to
 pharmacological treatments in order to prevent the manifestation of the renal disease or to
 slow its progression.

 AIM The study is aimed at identifying the genetic factors that predispose to the development
 of nephrolithiasis in patients with gouty diathesis.

 DESIGN Fifteen consecutive unrelated patients with familial form of nephrolithiasis
 associated with gouty diathesis (at least two affected subjects within a family) will be
 recruited, within 3 years, through the stone clinic ambulatory of the Unit of Nephrology,
 Ospedali Riuniti di Bergamo.

 All patients affected by gouty diathesis and their selected relatives will undergo to the
 following evaluations:

 -  clinical history collection;

 -  renal ultrasound examination, to confirm previous diagnoses and identify asymptomatic
 cases;

 -  metabolic analyses, including:

 -  blood collection in order to evaluate: urate, urea triglycerides, calcium, phosphate,
 creatinine, bicarbonate, sodium, potassium, chloride, glucose;

 -  24 hours urine collection in order to evaluate urate, calcium, phosphate, oxalate,
 citrate, urea, magnesium, sodium, chloride, creatinine, sulphate, ammonium;
 determination of urinary pH and titrable acidity; calculation of acid net excretion;

 -  morning urine spot in order to evaluate volume, pH, calcium, uric acid, creatinine;

 -  genetic analyses: 10 ml blood on EDTA to obtain DNA and 3 ml without anticoagulant to
 obtain serum from each subject will be collected.
Inclusion Criteria:

 -  male and female, ≥ 10 years of age

 -  uric acid or calcium oxalate nephrolithiasis

 -  urinary 24 h pH < 5.5 in absence of high animal protein intake (urinary sulphate
 excretion <25 mM/24 h after one week of low animal protein intake)

 -  familial history of kidney stones (at least two first or second degree family members
 affected)

 -  written informed consent according to the Declaration of Helsinki guidelines

 Exclusion Criteria:

 -  renal colic in the 4 weeks preceding evaluations

 -  excessive gastrointestinal alkali loses

 -  inability to fully understand the purposes of the study or to provide a written
 informed consent