Hypocitraturia as a risk factor for nephrocalcinosis after kidney transplantation

Calcium-oxalate crystal deposition in kidney transplant biopsy specimen led us to investigate the impact of calcineurin inhibitor treatment on urinary excretion of lithogenic and stone inhibitory substances in 53 children after successful kidney transplantation (KTx) receiving cyclosporine A (CsA) or tacrolimus. We compared the values obtained with those of 12 patients with recurrent nephrotic syndrome under CsA and of 6 patients with Rasmussen encephalitis (RE) under tacrolimus therapy. Renal ultrasound examinations were repeatedly performed. Hypocitraturia was found in 69% of patients, with KTx patients having a significantly lower urinary citrate excretion than those receiving calcineurin inhibitors for other reasons. Secondly, we found hyperoxaluria in 35% of patients, again especially in those after KTx. No significant difference in urinary substances was seen comparing CsA with tacrolimus treatment. Urolithiasis was found in one and calcium-oxalate crystal deposition in biopsy specimen of three KTx patients. Calcineurin inhibitor treatment can lead to significant hypocitraturia, especially in patients after KTx receiving the highest dose of medication. Hyperoxaluria is primarily the result of a removal of significant body oxalate stores, deposited during dialysis, but may not be suspected as a specific side effect of calcineurin inhibitor therapy. Both findings can increase the risk for urolithiasis or nephrocalcinosis.     

Insulin resistance and low urinary citrate excretion in calcium stone formers.

Epidemiological data suggest an association between kidney stones and some features of metabolic syndrome such as an overweight condition, arterial hypertension or glucose intolerance. However, mechanisms remain to be elucidated. This study aimed to evaluate insulin resistance, as assessed by homeostasis model assessment (HOMA-IR), and urine composition analysis in patients affected by calcium nephrolithiasis. A cohort of 61 (38 male, 29-57 years of age) non-diabetic calcium stone formers was studied. Data about body mass index, arterial blood pressure, serum biochemistry including parathyroid hormone and calcitriol were recorded in all the patients; fasting glucose and insulin were determined to calculate HOMA-IR value and accordingly the patients were grouped into tertiles. Urine pH and urinary excretion of calcium, citrate, phosphate, oxalate, uric acid, urea and creatinine were measured on 24h urine samples. Patients of the highest HOMA-IR tertile showed lower urine citrate levels than patients of the lowest HOMA-IR tertile (475+/-243 vs. 630+/-187 mg/24h, p<0.05), whereas no difference was detected as far as urinary oxalate, calcium, uric acid, phosphate, and urine pH and urine volume output were concerned. HOMA-IR values were positively related to uric acid serum levels (r=0.31, p<0.05) and negatively to urinary citrate excretion (r=-0.26, p<0.05). Hypocitraturic patients showed higher levels of HOMA-IR than normocitraturic ones (3.03+/-0.92 vs. 2.25+/-1.19, p<0.05). This study shows that a higher level of insulin resistance is associated with lower urinary citrate excretion, and that hypocitraturic patients show a greater insulin resistance than normocitraturic calcium stone formers. This may be related to changes in citrate, Na(+)-K(+) and H(+) renal tubule transports, which have been described in insulin resistance. In conclusion, insulin resistance may contribute to an increased risk of calcium stone formation by lowering urinary citrate excretion. This finding suggests the need for a careful metabolic assessment in patients known to form calcium stones in order to ensure stone recurrence prevention and cardiovascular protection.     

Determination of Clara cell protein urinary elimination as a marker of tubular dysfunction

Clara cell 16-kDa protein (CC16) is a protein expressed primarily by the bronchial cells. It is rapidly eliminated by glomerular filtration, reabsorbed almost entirely, and catabolized in proximal tubule cells. To date, normal values for urinary CC16 in healthy children have not been determined. We have studied 63 pediatric patients (mean age 8.17 ± 3.91 years) and 31 healthy children (control group; mean age 8.83 ± 3.65 years). In the control group, the CC16/creatinine ratio was 1.22 ± 1.52 μg/g. In 16 out of 31 control children, the value of the ratio was zero. Fourteen patients (22.2%) showed a high CC16/creatinine ratio; in contrast, among these same patients, the ratio N-acetyl-β-d-glucosaminidase (NAG)/creatinine was elevated in seven cases (11.1%) and the ratio β2-microglobulin/creatinine was elevated in seven cases (11.1%). The three parameters were in agreement in 51 patients (80.9%). Among the patients, the CC16/creatinine ratio was correlated with both the β2-microglobulin/creatinina ratio (r = 0.76, P < 0.001) and the NAG/creatinine ratio (r = 0.6, P < 0.001). Our findings indicate that CC16 is a good marker of proximal tubular function in childhood. The highest observed values were in children with proximal tubulopathies, in children with chronic renal failure, and in those treated with cyclosporine.     

The SLC13 gene family of sodium sulphate/carboxylate cotransporters

The SLC13 gene family consist of five sequence-related members that have been identified in a variety of animals, plants, yeast and bacteria. Proteins encoded by these genes are divided into two functionally unrelated groups: the Na⁺-sulphate (NaS) cotransporters and the Na⁺-carboxylate (NaC) cotransporters. Members of this family include the renal Na⁺-dependent inorganic sulphate transporter-1 (NaSi-1, SLC13A1), the Na⁺-dependent dicarboxylate transporters NaDC-1/SDCT1 (SLC13A2), NaDC-3/SDCT2 (SLC13A3), the sulphate transporter-1 (SUT-1, SLC13A4) and the Na⁺-coupled citrate transporter (NaCT, SLC13A5). The general characteristics of the SLC13 proteins are that they encode multi-spanning proteins with 8–13 transmembrane domains, have a wide tissue distribution with most being expressed in the epithelial cells of the kidney and the gastrointestinal tract. They are Na⁺-coupled symporters, DIDS-insensitive, with strong cation preference for Na⁺, with a Na⁺:anion coupling ratio of around 3:1 and have a substrate preference for divalent anions, which include tetraoxyanions (for the NaS cotransporters) or Krebs cycle intermediates, including mono-, di-, and tri-carboxylates (for the NaC cotransporters). The purpose of this review is to provide an update on the most recent advances and to summarize the biochemical, physiological and structural aspects of the vertebrate SLC13 gene family.     

Pediatric urolithiasis in a non-endemic country: A single center experience from The Netherlands

ObjectiveTo provide insight in causative factors of pediatric urolithiasis in The Netherlands, a non-endemic country.Patients and methodsData from 71 children with urolithiasis and stone analyses between 1996 and 2010 in the Radboud University Nijmegen Medical Centre were studied retrospectively. Patients (48 boys, 23 girls, ratio 2.1:1) were aged 0.5–18.3 years (mean 8.8, SD 5.6). All stone analyses were performed with FTIR spectroscopy.ResultsOf the 49 patients with metabolic analysis, 78% showed one (n = 15) or more (n = 23) metabolic abnormalities. Forty-seven percent had hypercalciuria (n = 23), 31% had hyperoxaluria (n = 15), 29% hypocitraturia (n = 14), 10% hyperuricosuria (n = 5), 10% cystinuria (n = 5), and 6% had hypomagnesiuria (n = 3).Sixty-one percent of the stones were composed of calcium phosphate, calcium oxalate, or a combination of those. Twenty-six percent consisted of pure or mixed magnesium ammonium phosphate, 8.3% pure or mixed urate, and 8.3% cystine.ConclusionChildren with urolithiasis in The Netherlands show stone composition similar to other Western European countries. However, a high percentage of metabolic abnormalities (78%) was found, indicating the need for extensive evaluation of pediatric urolithiasis to find underlying causes and thereby prevent stone recurrences. A close collaboration between a pediatric nephrologist and urologist is mandatory for optimal surgical and medical treatment.     

Medical and alternative therapies in urinary tract stone disease

Nephrolithiasis is a serious problem for both patients and the health system. Recurrence stands out as a significant problem in urinary system stone disease, the prevalence of which is increasing gradually. If recurrence is not prevented, patients may go through recurrent operations due to nephrolithiasis. While classical therapeutic options are available for all stone types, the number of randomized controlled studies and extensive meta-analyses focusing on their efficiency are inadequate. Various alternative therapeutic options to these medical therapies also stand out in recent years. The etiology of urolithiasis is multifactorial and not always related to nutritional factors. Nutrition therapy seems to be useful, either along with pharmacological therapy or as a monotherapy. General nutrition guidelines are useful in promoting public health and developing nutrition plans that reduce the risk or attenuate the effects of diseases affected by nutrition. Nutrition therapy involves the evaluation of a patient's nutritional state and intake, the diagnosis of nutrition risk factors, and the organization and application of a nutrition program. The main target is the reduction or prevention of calculus formation and growth via decreasing lithogenic risk factors and increasing lithogenic inhibitors in urine. This review focuses briefly on classical medical therapy, along with alternative options, related diets, and medical expulsive therapy.     

Risk factors of calcium stone formation in patients with primary Sjögren's syndrome

Distal renal tubular acidosis (dRTA), which occurs in patients with primary Sjögren's syndrome (SS), is a risk factor for the development of urolithiasis. Twenty-seven patients with SS were evaluated with respect to biochemical risk factors of calcium stone formation. Sixteen had no history of urolithiasis (group 1) whereas 11 had such a history (group 2). The stone composition was known for seven of the patients, and calcium phosphate was the major stone constituent in all of them. dRTA was present in all patients in group 2, and in 7 of the 16 patients in group 1. Hypocitraturia was common inboth groups, and the urinary excretion of citrate did not differ between the two groups. There was a higher urinary excretion of calcium and urate in group 2 and this group also had a higher urine volume. The risk of forming a urine supersaturated with calcium oxalate (CaOx) expressed in terms of AP(CaOx)index(s), which is an approximate estimate of the ion-activity product of CaOx calculated for a 24-h urine volume of 1500 ml, was higher in stone formers. A similarly derived estimate of the ion-activity product of calcium phosphate, AP(CaP)index(s), was calculated for a urine pH of 7. Although AP(CaP)index(s) was not significantly higher in group 2, there was a good correlation between AP(CaP)index(s) and AP(CaOx)index(s). We conclude that the urine composition in patients with SS, dRTA and urolithiasis is similar to that of other stone-forming patients with dRTA, and recurrence preventive therapy can be designed as for these patients.     

Genetic basis of renal cellular dysfunction and the formation of kidney stones

Nephrolithiasis is a result of formation and retention of crystals within the kidneys. The driving force behind crystal formation is urinary supersaturation with respect to the stone-forming salts, which means that crystals form when the concentrations of participating ions are higher than the thermodynamic solubility for that salt. Levels of supersaturation are kept low and under control by proper functioning of a variety of cells including those that line the renal tubules. It is our hypothesis that crystal deposition, i.e., formation and retention in the kidneys, is a result of impaired cellular function, which may be intrinsic and inherent or triggered by external stimuli and challenges. Cellular impairment or dysfunction affects the supersaturation, by influencing the excretion of participating ions such as calcium, oxalate and citrate and causing hypercalciuria, hyperoxaluria or hypocitraturia. The production and excretion of macromolecular promoters and inhibitors of crystallization is also dependent upon proper functioning of the renal epithelial cells. Insufficient or ineffective crystallization modulators such as osteopontin, Tamm-Horsfall protein, bikunin, etc. are most likely produced by the impaired cells.