MEDICAL MANAGEMENT OF RENAL LITHIASIS—Increasing the Protective Urinary Colloids with Hyaluronidase

Urine is a highly saturated solution due to the presence of certain colloids. The protective action of urinary colloids is of major importance in preventing precipitation, agglomeration and conglomeration of crystalloids from a super-saturated solution.If the concentration of such protective colloids is insufficient, stone formation begins or is accelerated. In 680 human subjects, the incidence of stone was found to be almost inversely proportional to the degree of protective urinary colloids present. Urine specimens were subjected to ultramicroscopic examination, determination of electric charge carried by the colloidal particles, determination of the surface tension, and photo-ultramicrographic studies.Subcutaneous injection of hyaluronidase mixed with physiologic saline solution greatly increases the content of protective colloids in the urine. The colloids are caused to set up to a gel, thereby preventing electrolytes present from crystallizing. They act as excellent dispersing agents and prevent the formation of stone.Hyaluronidase therapy, using 150 turbidity reducing units every 24 to 72 hours, was effective in preventing calculous formation or reformation during a period of 11 to 14 months in 18 of 20 patients in whom, previously, stones formed rapidly. In a second series of ten patients in whom stones formed rapidly, larger doses of hyaluronidase, averaging 300 turbidity reducing units every 24 to 48 hours, were given. The period of observation at the time of report was from six to ten months. In this group, there was no new stone formation or enlargement of existing stones as evidenced by x-ray studies at 30- to 60-day intervals.     

Inhibition of hyaluronidase by fully O-sulfonated glycosaminoglycans.

We report a new flow injection assay (FIA) method for determining hyaluronidase activity and the inhibitory effects of chemical fully O-sulfonated glycosaminoglycans on this enzyme. The products of enzymatic action on hyaluronidase can be detected by FIA using fluorometric detection with the fluorogenic reagent 2-cyanoacetamide. The major products derived from hyaluronan by the action of mammalian testicular hyaluronidase (a hydrolyase) were confirmed by (1)H NMR spectroscopy and capillary electrophoresis. The FIA method was next applied to the assay of hyman urinary hyaluronidase activity and the screening of hyaluronidase inhibitors. The human urinary hyaluronidase activity measured ranged from 46 to 59 turbidity reducing units/mg protein. Among the glycosaminoglycans only heparin showed hyaluronidase inhibition. Chemically O-sulfonated glycosaminoglycans showed IC(50) values of hyaluronidase inhibition that correlated with the degree of O-sulfonation. Heparin was found to inhibit hyaluronidase activity noncompetitively, while chemically O-sulfonated HA strongly inhibited hyaluronidase through both competitive and noncompetitive effects.     

细菌影响泌尿系结石形成的作用机制及其化学基础

人体内影响泌尿系结石形成的细菌有2类：一类诱发尿石形成,主要是通过分解尿素使尿液pH升高、加重尿路感染、降低尿石抑制剂浓度、破坏尿路粘膜酸性粘多糖保护层从而促进晶体滞留;另一类抑制尿石的形成,这些细菌（主要为食草酸杆菌、乳酸杆菌和粪肠球菌等草酸分解菌）参与外源性草酸代谢,降低尿草酸浓度。探讨了该领域所面临的问题和将来的发展方向。     

Biochemical mechanisms and effects of Mimosa pudica (Linn) on experimental urolithiasis in rats

Urolithiasis, following implantation of Zn discs in urinary bladder (foreign body insertion technique), was examined in albino rats of either sex. Marked variation was observed between sex, regarding the formation of bladder stones. Ethylene glycol (1%) mixed in drinking water for 4 weeks, was unable to augment Zn disc-induced stone deposition. Chemical nature of stones was identified as of magnesium ammonium phosphate type. Neither urinary pH nor infection in the urinary bladder/tract affected chemical nature and quantity of stone formed. There was no significant influence of electrolytes or metabolic products on the uroliths. No correlation could be drawn between the quality and quantity of uroliths formed and the urinary electrolytes concentration. M. Pudica was not effective in either preventing stone deposition or dissolving preformed stones.     

The use of Thiazides in the Prevention of Renal Calculi

The efficacy of hydrochlorothiazide, in a usual dosage of 50 mg. twice daily, in preventing further stone formation was evaluated in 67 patients with recurrent calcium stones. Fifty-three of these patients had idiopathic hypercalciuria (11 with associated urinary infection), one had medullary sponge kidneys and urinary infection, and two had urinary infection only; no cause for stone formation was detected in 11 patients. Urinary infection was also treated when present. Thirty-three patients (Group 1) were stone-free and 34 patients (Group 2) had stones in the urinary tract when treatment was started. In Group 1 during a total of 343 patient years (py) between the onset of stone symptoms and the institution of thiazide therapy there were 194 episodes (.57 per py) including 83 stones passed spontaneously and 30 major operations, but during 72 py on treatment there were only two episodes (.03 per py), both of which resulted in spontaneous passage of stones. The 34 patients in Group 2 had 365 episodes (1.1 per py) during the 343 py before thiazide therapy but only 34 episodes (.53 per py) during the 64 py on treatment. Many episodes in the Group 2 patients were related to previous stones, and in only four of these patients was there clear-cut evidence of new stone formation. Side effects, usually mild, were experienced by 25 patients; in three patients treatment was discontinued because of side effects.     

MANAGEMENT OF PATIENTS WITH URETERAL STONE

Immediate steps in the treatment of ureteral stone, beginning with the often acute onset, are relief of pain, urinalysis (including Gram stain), forcing fluids, examination of urine for the stone and urography at the earliest feasible time. If the stone causes continual pain or appears unlikely to be passed safely, it should be removed—with a cystoscope if possible; if not, by operation which may be done while the patient is still under anesthesia.To combat further stone formation a large fluid intake should be maintained, the extracted stone analyzed, an acid ash diet prescribed, serum calcium and phosphorus measured, urinary stasis corrected and urinary infection and distant foci of infection cured. Vitamin A, aluminum gels and particularly hyaluronidase appear promising as preventives to stone formation.     

Sialylation of urinary prothrombin fragment 1 is implicated as a contributory factor in the risk of calcium oxalate kidney stone formation

Urinary glycoproteins are important inhibitors of calcium oxalate crystallization and adhesion of crystals to renal cells, both of which are key mechanisms in kidney stone formation. This has been attributed to glycosylation of the proteins. In South Africa, the black population rarely form stones (incidence < 1%) compared with the white population (incidence 12-15%). A previous study involving urinary prothrombin fragment 1 from both populations demonstrated superior inhibitory activity associated with the protein from the black group. In the present study, we compared N-linked and O-linked oligosaccharides released from urinary prothrombin fragment 1 isolated from the urine of healthy and stone-forming subjects in both populations to elucidate the relationship between glycosylation and calcium oxalate stone pathogenesis. The O-glycans of both control groups and the N-glycans of the black control samples were significantly more sialylated than those of the white stone-formers. This demonstrates a possible association between low-percentage sialylation and kidney stone disease and provides a potential diagnostic method for a predisposition to kidney stones that could lead to the implementation of a preventative regimen. These results indicate that sialylated glycoforms of urinary prothrombin fragment 1 afford protection against calcium oxalate stone formation, possibly by coating the surface of calcium oxalate crystals. This provides a rationale for the established roles of urinary prothrombin fragment 1, namely reducing the potential for crystal aggregation and inhibiting crystal-cell adhesion by masking the interaction of the calcium ions on the crystal surface with the renal cell surface along the nephron.     

Percutaneous Renal Stone Manipulation—A Nonoperative Alternative

Nephrostomy tube tracts, established operatively or percutaneously, can provide access to stones in the upper urinary tract. A variety of rigid or flexible urologic instruments can be used to percutaneously disintegrate or extract calculi, thus sparing a patient an operative procedure. This is most important in the case of high-risk patients, those previously operated upon or those who have active nephrolithiasis, in whom recurrent stones are prone to form. Our early experience in percutaneous renal stone disintegration and stone manipulation enabled us to remove most (in four patients) or all (again in four patients) calculi in nine patients. The procedure offers lower morbidity, shorter hospital stay and earlier return to employment than conventional operative stone procedures.     

Determinants of Brushite Stone Formation: A Case-Control Study

Purpose

The occurrence of brushite stones has increased during recent years. However, the pathogenic factors driving the development of brushite stones remain unclear.

Methods

Twenty-eight brushite stone formers and 28 age-, sex- and BMI-matched healthy individuals were enrolled in this case-control study. Anthropometric, clinical, 24 h urinary parameters and dietary intake from 7-day weighed food records were assessed.

Results

Pure brushite stones were present in 46% of patients, while calcium oxalate was the major secondary stone component. Urinary pH and oxalate excretion were significantly higher, whereas urinary citrate was lower in patients as compared to healthy controls. Despite lower dietary intake, urinary calcium excretion was significantly higher in brushite stone patients. Binary logistic regression analysis revealed pH>6.50 (OR 7.296; p = 0.035), calcium>6.40 mmol/24 h (OR 25.213; p = 0.001) and citrate excretion <2.600 mmol/24 h (OR 15.352; p = 0.005) as urinary risk factors for brushite stone formation. A total of 56% of patients exhibited distal renal tubular acidosis (dRTA). Urinary pH, calcium and citrate excretion did not significantly differ between patients with or without dRTA.

Conclusions

Hypercalciuria, a diminished citrate excretion and an elevated pH turned out to be the major urinary determinants of brushite stone formation. Interestingly, urinary phosphate was not associated with urolithiasis. The increased urinary oxalate excretion, possibly due to decreased calcium intake, promotes the risk of mixed stone formation with calcium oxalate. Neither dietary factors nor dRTA can account as cause for hypercalciuria, higher urinary pH and diminished citrate excretion. Further research is needed to define the role of dRTA in brushite stone formation and to evaluate the hypothesis of an acquired acidification defect.     

Urinary Stone Analysis in a Patient with Hyperuricemia to Determine the Mechanism of Stone Formation

In order to determine the mechanism of urinary stone formation in patients with hyperuricemia, we analyzed the crystal components and matrix proteins in a urinary stone from such a patient. Micro-area X-ray spectrometry and infrared (IR) spectroscopy suggested that the outside of the stone was composed of calcium oxalate monohydrate (COM) and the inside of uric acid (UA). Proteomic analysis identified 37 and 14 proteins from the inside and outside of the stone, respectively, as matrix proteins. The proteins that were identified in an ethylenediaminetetraacetic acid (EDTA) fraction were able to bind calcium ions. Thus, calcium-binding proteins may play a significant role in the formation of urinary stones in patients with hyperuricemia.     

Urinary stone analysis in a patient with hyperuricemia to determine the mechanism of stone formation

In order to determine the mechanism of urinary stone formation in patients with hyperuricemia, we analyzed the crystal components and matrix proteins in a urinary stone from such a patient. Micro-area X-ray spectrometry and infrared (IR) spectroscopy suggested that the outside of the stone was composed of calcium oxalate monohydrate (COM) and the inside of uric acid (UA). Proteomic analysis identified 37 and 14 proteins from the inside and outside of the stone, respectively, as matrix proteins. The proteins that were identified in an ethylenediaminetetraacetic acid (EDTA) fraction were able to bind calcium ions. Thus, calcium-binding proteins may play a significant role in the formation of urinary stones in patients with hyperuricemia.     

Oral contraceptives,pregnancy, and endogenous oestrogen in gall stone disease--a case-control study.

A case-control study of gall stone disease in women in relation to use of contraceptives, reproductive history, and concentrations of endogenous hormones was undertaken. The study population comprised 200 hospital patients with newly diagnosed gall stone disease, 182 individually matched controls selected from the community, and 234 controls who were patients in hospital. Use of oral contraceptives was associated with an increased risk of developing gall stones among young subjects but a decreased risk among older subjects. The risk of developing gall stone disease increased in association with increasing parity, particularly among younger women. The risk fell with increasing age at first pregnancy, independent of parity. Mean urinary excretion over 24 hours of oestrone, but not of pregnanediol, was significantly (p less than 0.05) greater for postmenopausal patients than controls. The age dependence of the relative risk associated with exposure to oral contraceptives and pregnancy suggests that there are subpopulations of women susceptible to early formation of gall stones after exposure to either oral contraceptives or pregnancy.     

侧卧体位下经皮肾穿刺取石术联合经尿道输尿管镜取石术治疗复杂上尿路结石的临床应用价值

目的：探讨侧卧体位下经皮肾穿刺取石术联合经尿道输尿管镜取石术治疗复杂上尿路结石的可行性及临床应用价值。方法：回顾性分析2009年8月至2011年9月我院采用侧卧体住下经皮肾穿刺取石术联合经尿道输尿管镜取石术治疗复杂上尿路结石患者52例的临床资料：患者同时存在肾脏铸型结石或多发结石和或输尿管上段结石,单个结石最大径8-30mm。结果：平均手术时间60分钟（50—120分钟）;术前血红蛋白116±30g／L,术后第一天复查105±26g／L,无大出血需要输血病例;一次结石取净率为86．5％（45／52）,总取净率为92．3％（48／52）。结论：侧卧体位下经皮肾穿刺取石术及经尿道输尿管镜取石术两种术式联合应用具有可行性及互补性,在预防及减少术中出血、获得清晰的手术视野、减少灌注液外渗、增加结石清除速度及碎石成功率、缩短手术时间、减少术后发热等方面疗效显著,为治疗复杂上尿路结石提供了一个可行的新方法。     

Effect of Cystone on urinary composition and stone formation over a one year period

Kidney stones are a common problem for which inadequate prevention exists. We recruited ten recurrent kidney stone formers with documented calcium oxalate stones into a two phased study to assess safety and effectiveness of Cystone^®, an herbal treatment for prevention of kidney stones. The first phase was a randomized double-blinded 12 week cross over study assessing the effect of Cystone^® vs. placebo on urinary supersaturation. The second phase was an open label one year study of Cystone^® to determine if renal stone burden decreased, as assessed by quantitative and subjective assessment of CT. Results revealed no statistically significant effect of Cystone^® on urinary composition short (6 weeks) or long (52 weeks) term. Average renal stone burden increased rather than decreased on Cystone^®. Therefore, this study does not support the efficacy of Cystone^® to treat calcium oxalate stone formers. Future studies will be needed to assess effects on stone passage, or on other stone types.     

A SIMPLE CASE OF SALT ANTAGONISM IN STARFISH EGGS

The jelly surrounding the eggs of the starfish, Asterias forbesi, is insoluble in normal sea water, but rapidly swells and dissolves when the eggs are washed in a pure isotonic solution of NaCl. In the presence of a small proportion of CaCl₂ this solvent and disintegrative action of the NaCl solution is entirely prevented, and in the mixed solution the jelly exhibits the same insolubility and other properties as in normal sea water. 2. This action of CaCl₂ in preventing the dissolution of the jelly runs parallel with its action in preventing certain definite effects of the pure NaCl solution on the living egg (agglutination, cytolytic action, membrane formation, prevention of maturation). 3. The inference is that the essential factor in these and similar antagonistic and protective actions is the formation of solid water-insoluble colloidal salts (e.g., soaps and proteinates) of calcium (or other metal) with the structural colloids of the protoplasm. Apparently the presence of a certain proportion of such compounds is necessary to the structural stability of the living protoplasm, and especially to the water-insolubility and semipermeability of its external layer or plasma membrane. When the cell is immersed in the pure NaCl solution, water-soluble Na compounds are substituted for the insoluble Ca compounds which normally provide the necessary insolubility and coherence, and disintegration results.     

Diet and calcium stones.

OBJECTIVE: To review the current literature on the dietary modification of urinary risk factors as a means of reducing the likelihood of recurrent stone formation and to develop practical dietary recommendations that might be useful to this end. DATA SOURCES: MEDLINE was searched for English-language articles published from 1983 to 1990. Additional references were selected from the bibliographies of identified articles. STUDY SELECTION: Nonrandomized trials and retrospective reviews were included because of a paucity of randomized controlled trials. DATA SYNTHESIS: Information on the dietary intake of calcium, oxalate, protein, sodium and fibre and on alcohol and fluid intake was used to develop practical guidelines on dietary modification. CONCLUSION: Dietary modification plays an important role in the reduction of urinary risk factors in patients with calcium stone disease of the urinary tract. As an initial form of prevention attention should be directed toward moderating the intake of calcium, oxalate, protein, sodium and alcohol and increasing the intake of fibre and water. Future research should include an assessment of the long-term reduction of dietary and urinary risk factors and the rates of recurrence of calcium stones.     

Kidney Stones in Primary Hyperoxaluria: New Lessons Learnt

To investigate potential differences in stone composition with regard to the type of Primary Hyperoxaluria (PH), and in relation to the patient’s medical therapy (treatment naïve patients versus those on preventive medication) we examined twelve kidney stones from ten PH I and six stones from four PH III patients. Unfortunately, no PH II stones were available for analysis. The study on this set of stones indicates a more diverse composition of PH stones than previously reported and a potential dynamic response of morphology and composition of calculi to treatment with crystallization inhibitors (citrate, magnesium) in PH I. Stones formed by PH I patients under treatment are more compact and consist predominantly of calcium-oxalate monohydrate (COM, whewellite), while calcium-oxalate dihydrate (COD, weddellite) is only rarely present. In contrast, the single stone available from a treatment naïve PH I patient as well as stones from PH III patients prior to and under treatment with alkali citrate contained a wide size range of aggregated COD crystals. No significant effects of the treatment were noted in PH III stones. In disagreement with findings from previous studies, stones from patients with primary hyperoxaluria did not exclusively consist of COM. Progressive replacement of COD by small COM crystals could be caused by prolonged stone growth and residence times in the urinary tract, eventually resulting in complete replacement of calcium-oxalate dihydrate by the monohydrate form. The noted difference to the naïve PH I stone may reflect a reduced growth rate in response to treatment. This pilot study highlights the importance of detailed stone diagnostics and could be of therapeutic relevance in calcium-oxalates urolithiasis, provided that the effects of treatment can be reproduced in subsequent larger studies.     

Influence of pore structure on the effectiveness of a biogenic carbonate surface treatment for limestone conservation

A ureolytic biodeposition treatment was applied to five types of limestone in order to investigate the effect of pore structure on the protective performance of a biogenic carbonate surface treatment. Protective performance was assessed by means of transport and degradation processes, and the penetration depth of the treatment was visualized by microtomography. Pore size governs bacterial adsorption and hence the location and amount of carbonate precipitated. This study indicated that in macroporous stone, biogenic carbonate formation occurred to a larger extent and at greater depths than in microporous stone. As a consequence, the biodeposition treatment exhibited the greatest protective performance on macroporous stone. While precipitation was limited to the outer surface of microporous stone, biogenic carbonate formation occurred at depths of greater than 2 mm for Savonnières and Euville. For Savonnières, the presence of biogenic carbonate resulted in a 20-fold decreased rate of water absorption, which resulted in increased resistance to sodium sulfate attack and to freezing and thawing. While untreated samples were completely degraded after 15 cycles of salt attack, no damage was observed in biodeposition-treated Savonnières. From this study, it is clear that biodeposition is very effective and more feasible for macroporous stones than for microporous stones.     

Management of Patients with Urinary Calculi

A retrospective survey was made of 305 patients with proved urinary calculi. When those patients with a solitary stone were compared with those with multiple stones no diagnostically helpful difference was noted in the prevalence of abnormal serum or urine biochemistry, urinary infection, or anatomical abnormality of the urinary tract. The same was true of the stone composition and the need for surgery. It seems that neither routine radiological examination nor regular follow-up is likely to help identify patients whose stones are going to recur.     

A Drosophila Model Identifies a Critical Role for Zinc in Mineralization for Kidney Stone Disease

Ectopic calcification is a driving force for a variety of diseases, including kidney stones and atherosclerosis, but initiating factors remain largely unknown. Given its importance in seemingly divergent disease processes, identifying fundamental principal actors for ectopic calcification may have broad translational significance. Here we establish a Drosophila melanogaster model for ectopic calcification by inhibiting xanthine dehydrogenase whose deficiency leads to kidney stones in humans and dogs. Micro X-ray absorption near edge spectroscopy (μXANES) synchrotron analyses revealed high enrichment of zinc in the Drosophila equivalent of kidney stones, which was also observed in human kidney stones and Randall’s plaques (early calcifications seen in human kidneys thought to be the precursor for renal stones). To further test the role of zinc in driving mineralization, we inhibited zinc transporter genes in the ZnT family and observed suppression of Drosophila stone formation. Taken together, genetic, dietary, and pharmacologic interventions to lower zinc confirm a critical role for zinc in driving the process of heterogeneous nucleation that eventually leads to stone formation. Our findings open a novel perspective on the etiology of urinary stones and related diseases, which may lead to the identification of new preventive and therapeutic approaches.