Uric Acid nephrolithiasis: recent progress and future directions

The prevalence of urolithiasis has been increasing for the past few decades in industrialized nations. Uric acid calculi account for a significant percentage of urinary stones. Certain risk factors may be involved in the pathogenesis of uric acid nephrolithiasis, including hyperuricosuria, low urinary volume, and persistently low urinary pH. Patients with medical conditions that promote profound hyperuricosuria are at high risk of developing uric acid calculi. These conditions include chronic diarrheal states; myeloproliferative disorders; insulin resistance, including diabetes mellitus; and monogenic metabolic disorders, such as Lesch-Nyhan syndrome. Computed tomography can provide a definitive diagnosis. Except in cases in which there is severe obstruction, progressive azotemia, serious infection, or unremitting pain, the initial treatment of patients with uric acid nephrolithiasis should be medical dissolution therapy because this approach is successful in the majority of cases. A thorough review of the epidemiology and pathophysiology of uric acid nephrolithiasis is crucial for the diagnosis, treatment, and prevention of stones in patients with this condition.     

Microcalcifications,calcium-sensing receptor,and cancer

Calcium stones and calculi are observed in numerous human tissues. They are the result of deposition of calcium salts and are due to high local calcium concentrations. Prostatic calculi are usually classified as endogenous or extrinsic stones. Endogenous stones are commonly caused by obstruction of the prostatic ducts around an enlarged prostate resulting from benign prostatic hyperplasia or from chronic inflammation. The latter occurs mainly around the urethra and is generally caused by reflux of urine into the prostate. Calcium concentrations higher than in the plasma at sites of infection may induce the chemotactic response that eventually leads to recruitment of inflammatory cells. The calcium sensing receptor (CaSR) may be crucial for this recruitment as its expression and activity are increased by cytokines such as IL-6 and high extracellular calcium concentrations, respectively. The links between calcium calculi, inflammation, calcium supplementation, and CaSR functions in prostate cancer patients will be discussed in this review.     

Plasma levels and urinary excretion of amino acids by subjects with renal calculi

Plasma levels and urinary amino acid excretions were estimated by high-performance liquid chromatography in 15 control subjects and 36 stone formers (SFs) classified according to the stone type: (1) 22 cases with calcium oxalate stones; (2) four cases with pure uric acid stones; (3) 10 cases with magnesium-ammonium phosphate stones, either pure or mixed with apatite. Some types of stones (namely oxalate and uric acid calculi) are mainly formed as a result of a metabolic deficiency that may affect the amino acid metabolism, and thus may be reflected in the urinary amino acid pattern. Data demonstrated clearly that there is a general tendency towards decreased amino acid excretions in all SFs with all types of stones. As a whole, one can observe a higher percentage of patients with calcium oxalate and phosphate calculosis, who have low urine excretions of amino acids; about 50% are the SFs with lower urine excretion of serine, glycine, taurine and i-leucine; the high percentage of patients with CaOX calculi shows lower urine excretions of tyrosine and ornithine.     

Experimental oxalate urolith formation in rats.

Urinary calculi composed of calcium oxalate were produced in male hooded Wistar rats fed a vitamin B6 deficient diet over 16 weeks. This basic diet was modified by doubling the phosphate content or loading with vitamin C or D3 in three treatment groups. The number of rats developing oxalate stones was not altered by the addition of vitamin D3 or phosphate, but there was a significant increase in total weight of stone formed and histological evidence of extensive renal damage in rats on the high vitamin D3 diet. The addition of vitamin C to the vitamin B6 deficient rats resulted in a reduction in the number of rats with uroliths and a fall in urinary oxalate excretion, while similarly loaded vitamin B6 supplemented controls were free of oxalate calculi. It is concluded that the oxalate urolithiasis induced by vitamin B6 deficiency was exacerbated by added vitamin D3 and reduced by vitamin C.     

The Prevention of Residual Biliary Calculi

Residual calculi following cholecystectomy may be expected in approximately seven percent of cases. The vast majority of these are overlooked during operation; truly re-formed stones are rare.Calculi are missed during cholecystectomy because of failure to explore the common bile duct. This is due to (1) the presence of silent choledochal stones, and (2) reliance on negative cystic duct cholangiograms in the presence of indications for common duct exploration.Overlooking of silent stones during cholecystectomy may be prevented by routine operative cholangiography. Ideally, false-negative cystic duct cholangiograms should be eliminated by the use of fluoroscopic cholangiography.Retained calculi following duct exploration may be prevented by (a) routine biliary endoscopy and (b) completion fluoroscopic cholangiography.Re-formation of ductal calculi can probably be prevented by appropriate biliary drainage procedures performed during the initial choledochotomy. Selection of patients for primary biliary decompression remains an experimental problem.     

Struvite Urolithiasis in Long–Evans Rats

Struvite urinary calculi, which are composed of magnesium, ammonium, and phosphate, can cause complications including sepsis and renal failure. Struvite calculi were identified within the urinary bladder and renal pelvis of 2 Long-Evans rats that died within days after arrival from a commercial vendor. The remaining rats in the shipment were screened by physical examination, radiography, and ultrasonography, revealing an additional 2 animals that were clinically affected. These rats were euthanized, necropsied, and yielded similar findings to those from the first 2 rats. In addition, urine samples had an alkaline pH and contained numerous bacteria (predominantly Proteus mirabilis), leukocytes, and crystals. All calculi were composed completely of struvite. Another 7 rats in the shipment had alkaline urine with the presence of blood cells; 6 of these rats also had abundant struvite crystals, and P. mirabilis was cultured from the urine of 3 rats. Further investigation by the vendor identified 2 of 100 rats with struvite calculi from the same colony. Although no specific cause could be implicated, the fact that all the affected rats came from the same breeding area suggests a genetic or environmental triggering event; a contribution due to diet cannot be ruled out. Our findings suggest that the affected rats had metabolic disturbances coupled with bacterial infection that predisposed them to develop struvite calculi. During sudden increases of struvite urinary calculi cases in rats, urine cultures followed by appropriate surgical intervention and antibiotic therapy is warranted. Additional factors, including diet, merit attention as well.Struvite, also known as triple phosphate, is a crystalline substance composed of magnesium ammonium phosphate (MgNH₄PO₄• 6 H₂0)¹⁰ that was first identified in the 18th century. This mineral is what consolidates into urinary calculi, or stones, both in humans and animals. Other frequently encountered types of urinary stones include calcium oxalate, calcium phosphate, uric acid, and cysteine.¹⁷ Although only 2% to 3% of stones from humans are composed of struvite,⁴³ struvite calculi are important clinically because they can lead to sepsis and renal failure.⁴³In both humans and animals, stones in the urinary tract can obstruct the urine outflow, with subsequent extreme pain, hydronephrosis, and (possibly) rupture of the urinary bladder. In addition, disruption of kidney function can lead to metabolic imbalances, such as uremia, seizures, depression, anorexia, dehydration, even coma and death.^1,8 Here we present a case study describing the spontaneous presentation of struvite urolithiasis in a recently imported cohort of rats and related significant clinical findings.     

Salivary calculi microbiota: new insights into microbial networks and pathogens reservoir

Sialolithiasis represents the most common disorders of salivary glands in middle-aged patients. It has been hypothesized that the retrograde migration of bacteria from the oral cavity to gland ducts may facilitate the formation of stones. Thus, in the present study, a microbiome characterization of salivary calculi was performed to evaluate the abundance and the potential correlations between microorganisms constituting the salivary calculi microbiota. Our data supported the presence of a core microbiota of sialoliths constituted principally by Streptococcus spp., Fusobacterium spp. and Eikenella spp., along with the presence of important pathogens commonly involved in infective sialoadenitis.     

Urinary Pyrophosphate in Normal Subjects and in Stone Formers

The urinary excretion of inorganic pyrophosphate was determined in nine normal subjects and also in eight patients with recurrent calcium-containing renal stones during varied levels of phosphate intake. The excretion of pyrophosphate and orthophosphate is virtually the same in the two groups at all levels of phosphate intake. It appears unlikely that a consistently reduced urinary excretion of pyrophosphate is a factor in the formation of urinary calculi. Pyrophosphate excretion rose and calcium excretion fell with increasing phosphate intake; this might be expected to have a beneficial effect in patients with recurrent calcium stones.     

Clastogenic activity of seven endodontic medications used in dental practice in human dental pulp cells

Numerous and varied chemical agents are used for endodontic treatments in dental practice. Endodontic medications are administered directly to the teeth in relatively high concentrations and chemical agents applied to enamel or dentin can penetrate the dental pulp tissue and circulate through the body in the bloodstream. In the present study, to assess safety regarding mutagenicity, we investigated the ability of seven endodontic medications to induce chromosome aberrations in human dental pulp cells. Chromosome aberrations were induced in cells treated with each of six endodontic medications, eugenol, guaiacol, modified phenol, phenol, thymol, and zinc oxide. The other endodontic medication, zinc chloride, failed to induce chromosome aberrations in the presence or absence of exogenous metabolic activation. The percentages of cells with polyploid or endoreduplication were not enhanced by any of the endodontic medications tested. Our results indicate that the endodontic medications that exhibited a positive response are potentially mutagenic to human cells.     

Heavy Metal Components in Blood and Urinary Stones of Urolithiasis Patients

Lifestyle, food intake, and exposure to chemicals are potential risk factors for the development of calcium urolithiasis. Pb, Cd, and Hg have been proved to cause renal illness, and urinary tract stones might be caused by exposure to metals. Therefore, this study aimed to measure the concentration of metals in urinary tract stones and blood simultaneously in urolithiasis patients. Moreover, we intended to determine whether urinary tract stones can be regarded as a biomarker of exposure or an effect marker in a population with environmental exposure to metals. Thirty-five urolithiasis patients (case) and 34 healthy inhabitants (control) were recruited in this study. The contents of Pb, Cd, Cr, Cu, Ni, As, Zn, and Hg were determined in urinary stones and blood in the case and control groups. The most abundant metals were Zn and Cu in blood and Zn and Ni in urinary stones. Significantly higher levels of Zn, Ni, and As were found in calcium phosphate stones than in calcium oxalate or uric acid stones. The majority of metals were not present at consistent levels in both blood and urinary stones, except for Zn. Urinary stones might be explained as providing another metabolic pathway for metal contamination. Moreover, as the metals with the highest content in urinary stones were Ni and Zn, and Ni content was very much higher than in other countries, contamination by Ni should be further taken into consideration if there is any serious contamination in Taiwan.     

Microsome- and hepatocyte-mediated mutagenicity of hydroxyurea and related aliphatic hydroxamic acids in V79 Chinese hamster cells

The potential of N-hydroxyurea to induce gene mutations in V79 Chinese hamster cells was investigated. Upon metabolic activation by liver microsomes from phenobarbital-treated rats or by isolated rat hepatocytes co-cultured with the V79 cells, hydroxyurea caused a concentration-dependent increase in the frequency of HGPRT-deficient mutants. Hydroxyurea was not mutagenic in the absence of metabolic activation. Addition of catalase inhibited microsome-mediated mutagenicity, indicating that hydrogen peroxide was involved in the formation of the mutagenic DNA lesion. Acetohydroxamic acid and N-hydroxyurethane also induced hepatocyte-mediated mutagenicity, suggesting that the potential to elicit metabolism-dependent mutagenicity may be a common property of aliphatic hydroxamic acids.     

Potential role of new therapies in modifying cardiovascular risk in overweight patients with metabolic risk factors

The serotonin, norepinephrine, dopamine, and endocannabinoid systems, as well as a host of other systems, mediate hunger and satiety signals. Weight loss agents that modulate appetite through pure central nervous system pathways (e.g., APD356, a selective serotonin receptor agonist) and peripheral signals to central nervous system pathways (e.g., cholecystokinin receptor agonists and ghrelin receptor antagonists) are in preclinical or early phase studies. Both devices and pharmacological compounds that facilitate weight loss and/or target multiple components of metabolic risk also are in development. One of the medications that has completed extensive phase III clinical trials and may become available in the foreseeable future is rimonabant, a selective cannabinoid 1-receptor antagonist. Drugs that improve adipose tissue function or fatty acid metabolism (e.g., AOD9604) also are in clinical trials. Some currently available medications may reduce metabolic complications without treating obesity per se (e.g., acipimox, pioglitazone). Surgically implanted gastric pacemaker systems that modulate vagus nerve activity and delay gastric emptying are under study.     

Percutaneous cholecystolithotomy

A percutaneous method was used to remove stones from otherwise normal gall bladders, as assessed by cholecystography and ultrasonography. The procedure was performed in a single stage under general anaesthesia, adopting the method and instruments used for one stage percutaneous nephrolithotomy. A Foley catheter was left in the gall bladder and the system checked with contrast at 10 days to ensure free drainage and exclude residual calculi. Seven out of eight patients had a successful percutaneous cholecystolithotomy. An adequate track could not be secured in one man; he had an uneventful cholecystectomy under the same anaesthetic. Follow up at three months of the seven patients showed no calculi and no complications.Percutaneous cholecystolithotomy may prove complementary to extracorporeal shockwave lithotripsy in patients in whom there is difficulty focusing the shock waves on the gall bladder or who have had incomplete disintegration of stones.     

Urinary Calculi and Ulcerative Colitis

A survey of 458 patients treated for ulcerative colitis either medically or surgically by colectomy and the establishment of an ileostomy has provided further evidence that in Australia at least there is a significant association between ulcerative colitis and urinary calculi. The actual risk to the unoperated patient is not particularly high but is in the vicinity of 4%. The survey further confirms that the risk continues after colectomy and ileostomy, when the overall incidence of stones is roughly doubled. Finally, suggestive though admittedly somewhat inconclusive evidence supports the proposition that uric acid stones are more common in this group of patients.     

胆道镜结合微爆破碎石治疗复杂性胆道结石

目的:探讨微爆破碎石用于治疗复杂胆道结石的治疗体会。方法:在胆道镜直视下,分别在术中和术后对158例复杂的胆道结石患者进行微爆破碎石,然后用取石网取出碎石,泥沙状结石随液体流出或让其自行流入肠道。结果:158例患者156例取石成功。取石成功率98.73%。明显提高了胆道取石的成功率。无1例出现胆道穿孔、瘘道穿孔及胆道出血等严重并发症。结论:在胆道镜下,采用微爆破碎石术治疗复杂的胆道结石是一种安全、可靠、高效的方法,可以明显提高结石的取净率。     

THE TREATMENT OF URINARY TRACT CALCULI

From review of recent information relative to calculus formation in the kidney, the conclusion reached that we do not yet understand, despite much effort, the basic physicochemical mechanisms involved. Since this is so, it has seemed best to the author for the present to rely, in treating patients with renal stones, on simple therapeutic concepts, which, if carefully and conscientiously applied, produce good results. The concepts are the elimination of known causes such as parathyroid adenomas and obstructive lesions, elimination or at least treatment of infections, diminution of urinary components which form the basis of calculi by limiting the oral intake or absorption from the gastrointestinal tract and maintenance of a dilute urine of desired pH.A plan for preoperative study is suggested to allow planned therapy. Indications for operative removal of calculi as well as some points of technique are discussed. It is emphasized that surgical removal of a calculus is but an incident in the care of patients with calculi and that treatment during the postoperative period and followup therapy is most important if success is to be achieved. Reports of cases to illustrate the application of these concepts are presented.     

胆道镜结合微爆破碎石治疗复杂性胆道结石

目的：探讨微爆破碎石用于治疗复杂胆道结石的治疗体会。方法：在胆道镜直视下,分别在术中和术后对158例复杂的胆道结石患者进行微爆破碎石,然后用取石网取出碎石,泥沙状结石随液体流出或让其自行流入肠道。结果：158例患者156例取石成功。取石成功率98.73%。明显提高了胆道取石的成功率。无1例出现胆道穿孔、瘘道穿孔及胆道出血等严重并发症。结论：在胆道镜下,采用微爆破碎石术治疗复杂的胆道结石是一种安全、可靠、高效的方法,可以明显提高结石的取净率。     

Photoinduced conidiation inTrichoderma viride

Trichoderma viride is a deuteromycete in which conidiations is photo-inducible. Conidiation results when colonies grow in the day-night regime or when colonies grown in the dark are exposed to short pulses of near UV or blue light. Conidiation was induced by light pulses at intervals of 8, 16, 24, 48 or 72 hours. Several membrane-damaging agents, DNA-intercalating drugs and inhibitors of RNA or protein synthesis prevent photo-conidiation. A hypothetical scheme of photo-induced conidiation, based on the results with metabolic inhibitors, is presented. A sudden increase of intracellular ATP was observed as an immediate photo-response. The ATP level is dose-dependent, with a maximum at 1.2 klx. Drugs interfering with various signalling pathways were tested in an attempt to analyze the signal pathways whereby light pulses induce conidiation. Nonconidiating and color mutants have been obtained and used in complementation studied by means of heterokaryosis and protoplast fusion. In a color mutant with brown conidia, conidiation is accompanied by high production and excretion of anthraquinone metabolites. Modified version of a lecture given at the7th International Congress of IUMS Mycology Division, Prague, July 3rd–8th, 1994.     

2,8-Dihydroxyadenine Urolithiasis: A Not So Rare Inborn Error of Purine Metabolism

Adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation and formation of urinary crystals and kidney stones. The disease can be present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available, including stone analysis, crystalluria, and APRT activity in red blood cells, make the diagnosis easy to confirm when APRT deficiency is suspected. However, the lack of recognition of this metabolic disorder frequently resulted in a delay in diagnosis and treatment with grave consequences. The early recognition and treatment of APRT deficiency are of crucial importance to prevent irreversible loss of renal function. This review summarizes the genetic and metabolic mechanisms underlying DHA stones formation and chronic kidney disease, along with the issues of diagnosis and management of APRT deficiency. Moreover, we report the mutations in the APRT gene responsible for APRT deficiency in 51 French patients (43 families) including 22 pediatric cases (18 families) among the 64 patients identified in the biochemistry laboratories of Necker Hospital, Paris (1978–2013).