Kelley-Seegmiller Syndrome: Urolithiasis, Renal Uric Acid Deposits, and Gout: What is the Role of the Urologist?

Kelley-Seegmiller syndrome (KSS) is a disorder that occurs when there is a partial deficiency of the enzyme hypoxanthine guanine phosphoribosyl transferase. It is involved in the metabolism of purines, clinically manifesting as hyperuricemia, hyperuricosuria, gout arthritis, and urolithiasis. The aim of this article is to present the case of a 33-year-old male with KSS, with left ureteral colic, and a 5-mm, 323-HU ureteral calculi, successfully managed with conservative management. It is critical to recognize that most urologists are not familiar with this inborn metabolic error and 75% of these patients will be affected by urolithiasis, thus making it a very critical and significant disease in our practice.

A role of the endothelial nitric oxide system in acute renal colic caused by ureteral stone.

BACKGROUND AND AIMS: Endothelial nitric oxide synthase gene polymorphisms play a role in some pathophysiological processes. In this study, the possible effects of endothelial nitric oxide synthase gene polymorphisms on ureteral stone disease in patients who were admitted to the emergency department with severe pain due to renal colic are examined. MATERIALS AND METHODS: The study groups were designed as controls and patients. The control group was formed from the healthy volunteers who applied to the blood center next to the emergency service. The patient group comprised patients who were diagnosed with ureteral stone disease with severe pain. All of the genetic studies were based on extracted peripheral blood samples using the necessary procedures from the Genome and Stem Cell Center at Erciyes University (GENKOK). The data were analyzed with SPSS (IBM, ver 20, United Sate). RESULTS: The study group comprised 62 females and 138 males, and the control group comprised 64 females and 136 males. All of the stones that caused renal colic were found to be localized in the ureters and the ureterovesical junction. The genotypes of the intron 4 polymorphism were found to be as follows: 4a/4a in 10 people, 4b/4a in 115, and 4b/4b in 275 people. The GG genotype of the eNOS-G894T polymorphism was found in 108 patients in the study group and in117 of the healthy individuals. There was no statistically significant difference between the two groups regarding these data. CONCLUSION: Although this study is the first in the literature to examine the relationship between renal colic and endothelial nitric oxide synthase gene polymorphisms, our study demonstrated that no relation was found.

Familial risks in urolithiasis in the population of Sweden.

OBJECTIVE: To assess detailed familial risks for medically diagnosed urolithiasis (UL, urinary tract stone disease) based on nationwide hospital and population records. PATIENTS/SUBJECTS AND METHODS: Subjects were identified from the Swedish Multigeneration Register in which there were 211 718 patients with UL. Standardised incidence ratios (SIRs) were calculated by comparison to individuals without a family history of UL. RESULTS: The highest familial SIRs were invariably found for the same (concordant) type of UL: 2.18 for kidney, 2.20 for ureter, and 1.93 for bladder. SIRs increased from 1.84, when one parent was affected, to 3.54 when both parents were affected, which was a multiplicative interaction. The SIR was 1.79 when one sibling was affected but it increased to 24.91 when two siblings were affected. Such excessive risks (5.2% of familial cases) are probably explained by high-penetrant genes. A low SIR of 1.29 between spouses suggested a minor contribution by shared environmental factors on the familial risk. CONCLUSIONS: The results point to underlying genetic causes for the observed familial clustering and establish the genetic landscape of UL. Family histories should be taken in UL diagnostics and prevention could follow guidelines recommended for recurrent UL.

Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis.

Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP)/phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a) the sex-specific PDE5 distribution in the rat ureter; b) the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c) the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats' ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of "ureteral crises" and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain.

[2,8-dihydroxyadenine urolithiasis: case report and literature review]. / Calcolosi di 2,8-diidrossiadenina. Descrizione di un caso clinico e revisione della letteratura.

INTRODUCTION: 2,8-Dihydroxyadenine (DHA) urolithiasis is a rare type of urinary stone disease secondary to deficiency of adenine phosphoribosyltransferase (APRT) activity, a rare, inherited autosomal recessive disease with an incidental rate from 0.4 to 1.2%. The prevalence is higher among Japanese than other ethnic groups. APRT normally catalyzes the conversion of adenine to adenosine monophosphate and its deficiency results in 2,8-dihydroxyadenine (2,8-DHA) accumulation. This compound is extremely insoluble and its crystallization can lead to stone formation and renal failure. We report the case of 2,8-dihydroxyadenine (DHA) urolithiasis in a 52-year-old male patient. MATERIAL AND METHODS: In December 2008 a 52-year-old Caucasian man was admitted to our hospital with sudden pain in the left lumbar region. Abdominal X-ray did not show any radiopaque urinary stone. I.V. pielography showed a radiolucent left lumbar ureteral (0.6 mm) and renal (1.5 cm) stone. After therapy with tamsulosin, the ureteral stone was excreted. Successful ESWL treatment was performed for renal stone. He presented a clinical history of several episodes of bilateral renal colic and two prior ESWL treatment for radiolucent stones. Chemolitholysis was never successful. RESULTS. Stone analysis by infrared spectroscopy and microscopic examination of urine reveal typical 2,8-DHA crystals. APRT deficiency was detected in the hemolysate of erythrocyte. Partial deficiency of APRT in the patient's relatives showed heterozygosity of the enzyme defect. Allopurinol therapy successfully prevented further stone formation. 20 months later the patient remains stone free. CONCLUSION: Two types of deficit are commonly distinguished, depending on the level of residual APRT activity. Type I is complete enzyme deficiency. Type II shows residual activity in cell lysates, but enzyme activity is not demonstrable in intact cells. About 78% of the Japanese patients belong to type II. The diagnosis of the disease is based on stone analysis by infrared spectroscopy or microscopic examination of urine, which may reveal typical 2,8-DHA crystals. Molecular approach can identify mutations, which are responsible of this inherited disease. Excessive water intake, restriction of foods with high adenine contents and administration of allopurinol are useful treatments. APRT deficiency is a rare disease but we can consider this pathology in case of recurrent radiolucent stones after chemolitolysis.

Evidence suggesting a genetic contribution to kidney stone in northeastern Thai population.

Genetic factor may play a role in the pathogenesis of kidney stone that is found in the northeastern (NE) Thai population. Herein, we report initial evidence suggesting genetic contribution to the disease in this population. We examined 1,034 subjects including 135 patients with kidney stone, 551 family members, and 348 villagers by radiography of kidney-ureter-bladder (KUB) and other methods, and also analyzed stones removed by surgical operations. One hundred and sixteen of 551 family members (21.05%) and 23 of the 348 villagers (6.61%) were affected with kidney stone. The relative risk (lambda(R)) of the disease among family members was 3.18. Calcium stones (whewellite, dahllite, and weddellite) were observed in about 88% of stones analyzed. Our data indicate familial aggregation of kidney stone in this population supporting that genetic factor should play some role in its pathogenesis. Genetic and genomic studies will be conducted to identify the genes associated with the disease.

Family history and age at the onset of upper urinary tract calculi.

INTRODUCTION: The aim of this study was to evaluate the effect of family history on the age of urinary calculus formation and its relation with characteristics of the calculi and patients. MATERIALS AND METHODS: In a cross-sectional study in Tabriz, a total of 210 patients with upper urinary tract calculi were evaluated. Their demographics and clinical characteristics and detailed information on their family history were recorded. RESULTS: Of the patients, 28.6% had a positive family history for urinary calculi. Siblings were the majority of the affected family members (71.1%). The rate of a positive family history was slightly higher in women than in men (30.0% versus 28.1%; P = .20). The mean age at the disease onset of the men with and without a positive family history was 37.2 years versus 39.3 years, respectively (P = .20). Such a difference was not detected in the female patients, either (P = .63). In general, the calculi were more detected on the left renal unit, but more prevalent on the right side in patients with a positive family history (P = .008). No relation was found between the number and size of the calculi and the family history. CONCLUSION: About one-third of the patients with urinary calculi had a positive family history too. Men with affected family members are slightly more susceptible to the disease at younger ages. There might be differences in the side of the calculi and family members with a history of disease that warrants further studies.

Microsatellite instability in urothelial carcinoma of the upper urinary tract.

PURPOSE: Transitional cell carcinoma (TCC) of the upper urinary tract (TCC-UUT) may develop with high frequency in patients with hereditary nonpolyposis colorectal cancer syndrome. Tumors in patients with this syndrome show genomic lesions in DNA mismatch repair genes that are detectable as microsatellite instability (MSI). Because little is known about genetic lesions in TCC-UUT compared with bladder TCC, we determined the genetic profiles (MSI and allelic loss) in a series of 26 upper urinary tract tumors using 5 informative microsatellite markers. MATERIALS AND METHODS: A total of 26 paraffin embedded samples from 24 patients with clinically diagnosed TCC-UUT (renal pelvis and/or ureter) were tested for loss of heterozygosity (LOH) and MSI with the dinucleotide markers D9S171 (9p21) and D5S346 (5q22), and the mononucleotide repeats BAT25 (4q12), BAT26 (2p16) and BAT40 (1p13.1). RESULTS: MSI was detected at 1 or more microsatellite loci in 12 of the 26 tumors (46%). The markers BAT40, BAT25, BAT26, D9S171 and D5S346 showed instability in 7, 4, 4, 2 and 3 tumor samples, respectively. LOH at D9S171 was detected in 58% of the cases and 10 of the 14 tumors showing LOH were superficial. LOH at D5S346 occurred in 27% of the cases and it was a feature of invasive high grade TCC-UUT. CONCLUSIONS: Frequent LOH at D9S171 in TCC-UUT confirms that LOH at 9p21 is not only observed in bladder TCC, but rather in whole urinary tract TCC. Furthermore, our study indicates a high level of MSI in TCC-UUT, although it is a rare event in bladder cancer. The establishment of distinct genetic profiles between upper and lower urinary tract tumors could provide an additional tool to improve diagnosis, disease monitoring and prediction of prognosis.

Primary hyperoxaluria (glycolic acid variant): a clinical and genetical investigation of eight cases.

The clinical features of eight cases of primary hyperoxaluria have been summarized. The possibility of different phenotypes is discussed. A reduction, but no normalization, of the oxalate formation during pyridoxine therapy was found. A renal transplantation performed in one of the patients failed because of the formation of nephrocalcinosis.