Dietary recommendations and treatment of patients with recurrent idiopathic calcium stone disease.

This review describes the various dietary regimens that have been used to advise patients on how to prevent the recurrence of their calcium-containing kidney stones. The conclusion is that although there is some general advice that may be useful to many patients, it is more efficacious to screen each patient individually to identify his/her main urinary, metabolic, nutritional, environmental, and lifestyle risk factors for stone-formation and then tailor specific advice for that particular patient based on the findings from these investigations. If the patient can be motivated to adhere strictly to this conservative approach to the prophylactic management of their stone problem over a long time period, then it is possible to prevent them from forming further stones. This approach to stone management is considerably less expensive than any of the procedures currently available for stone removal or disintegration. In the UK, for each new stone episode prevented by this conservative approach to prophylaxis it is calculated to save the Health Authority concerned around £2000 for every patient treated successfully. In the long term, this accumulates to a major saving within each hospital budget if most stone patients can be prevented from forming further stones and when the savings are totalled up country-wide saves the National Exchequer considerable sums in unclaimed Sick Pay and industry a significant number of manpower days which would otherwise be lost from work. It is also of immense relief and benefit to the patients not to have to suffer the discomfort and inconvenience of further stone episodes.

Potential role of fluctuations in the composition of renal tubular fluid through the nephron in the initiation of Randall's plugs and calcium oxalate crystalluria in a computer model of renal function.

This article describes an updated computer model which attempts to simulate known renal reabsorption and secretion activity through the nephron (NEPHROSIM) and its possible relevance to the initiation of calcium-containing renal stones. The model shows that, under certain conditions of plasma composition, de novo nucleation of both calcium oxalate (CaOx) and calcium phosphate (CaP) can take place at the end of the descending limb of the Loop of Henle (DLH), particularly in untreated, recurrent idiopathic CaOx stone-formers (RSF). The model incorporates a number of hydrodynamic factors that may influence the subsequent growth of crystals nucleated at the end of the DLH as they progress down the renal tubules. These include the fact that (a) crystals of either CaOx or CaP nucleated at the end of the DLH and travelling close to the walls of the tubule travel at slower velocities than the fluid flowing at the central axis of the tubule, (b) the transit of CaOx crystals travelling close to the tubule walls may be delayed for up to at least 25 min, during which time the crystals may continue to grow if the relative supersaturation with respect to CaOx (RSS CaOx) is high enough and (c) such CaOx crystals may stop moving or even fall back in upward-draining collecting ducts (CD) owing to the Stokes gravitational effect. The model predicts, firstly, that for small, transient increases in plasma oxalate concentration, crystallisation only takes place in the CD and leads to the formation of small crystals which are comfortably passed in the urine and, secondly, that for slightly greater increases in the filtered load of oxalate, spontaneous and/or heterogeneous nucleation of CaOx may occur both at the end of the DLH and in the CD. This latter situation leads to the passage in the final urine of a mixture of large crystals of CaOx (arising from nucleation at the end of the DLH) and small crystals of CaOx (as a result of nucleation originating in the CD). As a result of the higher calcium and oxalate concentrations in the urine of RSF, these patients have an increased probability of initiating CaOx crystallisation in the DLH and so of going on to form the large crystals and aggregates found in their fresh urines, but not in the fresh urines from normal subjects (N). These predictions are supported by evidence from clinical studies on six RSF and six normal controls (NC) who were maintained for 4 days on a fixed basal diet. Their patterns of CaOx crystalluria were measured on the second day of the basal diet and after a small dose of sodium oxalate was given before breakfast on the fourth day of the study. The model also shows that the tubular fluid of RSF is more likely than that of N to reach the conditions necessary for de novo nucleation of CaP at the end of the DLH. This may occur following either a small increase in ultrafiltrable phosphate, as a result of ingestion of a high phosphate-containing meal, or a small decrease in the proximal tubular reabsorption of phosphate resulting, for example, from increased parathyroid activity. CaP crystals initiated at this point may heterogeneously nucleate the crystallisation of CaOx under the high metastable conditions of RSS CaOx which frequently exist in the urines of RSF. Under certain conditions, it is predicted that CaP crystals, initiated at the end of the DLH and travelling close to the tubular walls where their transit time is increased, might also be able to grow and agglomerate sufficiently to become trapped at some point in the CD and lead to the formation of Randall's Plugs in the Ducts of Bellini. Currently, work is under way to incorporate data on the growth and aggregation of crystals of CaP into NEPHROSIM to confirm the likelihood of this phenomenon occurring. The model shows that an increase in plasma calcium is unlikely to lead to spontaneous nucleation of either CaOx or CaP at the end of the DLH unless the concentration of plasma calcium reaches values usually associated with the cases of primary hyperparathyroidism. The most likely cause of spontaneous CaOx crystal formation at the end of the DLH is a small increase in plasma oxalate; the most likely cause of spontaneous CaP crystal formation at the end of the DLH is either an increase in plasma phosphate or a decrease in the fractional reabsorption of phosphate in the proximal tubule. The model predicts that the maximum volume of CaOx crystalluria that is likely to occur in a given urine is a function of both the RSS CaOx and the oxalate/calcium ratio in the final urine. These data explain why the volume of CaOx crystalluria is in the order UK normals < UK recurrent stone-formers < Saudi Arabian recurrent stone-formers which, in turn, probably accounts for the very high incidence of CaOx-containing stones found in Saudi Arabia compared with that in the UK.

A London experience 1995-2012: demographic, dietary and biochemical characteristics of a large adult cohort of patients with renal stone disease.

BACKGROUND: Kidney stone disease has an estimated prevalence of around 10%. Genetic as well as environmental factors are thought to play an important role in the pathogenesis of renal stones. AIM: The aim of our study was to analyse and report the main characteristics of patients with kidney stones attending a large UK metabolic stone clinic in London between 1995 and 2012. DESIGN: A cross-sectional study. METHODS: Analysis of data from stone formers attending the University College and Royal Free Hospitals' metabolic stone clinic from 1995 to 2012. Demographic, clinical, dietary and biochemical characteristics have been summarized and analysed for men and women separately; trends over time have also been analysed. RESULTS: Of the 2861 patients included in the analysis, 2016 (70%) were men with an average age of 47 years (range 18-87 years) and median duration of disease of 6 years (range 0-60 years). The prevalence of low urine volume, hypercalciuria, hyperoxaluria, hyperuricosuria and hypocitraturia was 5.6%, 38%, 7.9%, 18% and 23%, respectively. The prevalence of several risk factors for stones increased over time. The majority of stones were mixed, with around 90% composed of calcium salts in varying proportion. CONCLUSION: Our findings in a large cohort of patients attending a London-based stone clinic over the past 20 years show differences in distributions of risk factors for stones for men and women, as well as metabolic profiles and stone composition. The impact of most risk factors for stones appeared to change over time.

Metabolic factors in the causation of urinary tract stones in patients with enterocystoplasties.

Stones are a common complication of the storage of urine in intestinal reservoirs. Previous studies have identified predisposing physical characteristics in the reservoirs. Biochemical and dietary factors have been little investigated. Fifteen patients (6 males and 9 females) who had undergone various enterocystoplasty operations and who had subsequently formed either upper or lower urinary tract stones were investigated. The programme has been previously described and included stone, blood and urine analysis and dietary review. Comparison was made with 15 age- and sex-matched idiopathic stone formers with normal bladders. Stones were infective in origin in 86% of cases, and 14% were sterile. Metabolic screen showed that 80% of enterocystoplasty patients had risk factors for at least three different types of stone. All patients had raised pH (mean 6.93) and hypocitraturia. Five had a raised alkaline phosphatase. Raised serum and urinary calcium, hyperoxaluria and hyperuricosuria were found in 33% of patients. Five had a 24-h urine volume below 1.6 l/day. All patients had a high risk index (PSF) for phosphatic stones and 12 also for calcium oxalate stones. Compared to age-and sex-matched idiopathic stone-formers, the urine had a higher pH, sodium and protein excretion and a lower calcium and citrate excretion. Although the patients were already selected as stone-formers, the data show that metabolic and dietary factors are present. They may be as important in the aetiology of the stones, as the already recognised factors of infection and poor reservoir drainage. Investigation should include such factors, the presence of which may be taken into account in a prophylactic regime.

Is prevention of stone recurrence financially worthwhile?

This review shows that the cost of relying solely on minimally-invasive urological procedures for removing stones when patients return with recurrent stones is considerable and is significantly greater that that incurred by screening already proven recurrent stone-formers to identify the risk factors that are causing their stones and then instituting prophylactic measures to prevent stone recurrence. In the UK, at 1998 prices (when the original survey was carried out) for every stone episode prevented, there is a potential saving of almost 2,000 pound to the local Health Authority concerned. In spite of this, many Health Authorities have taken the liberty to discontinue comprehensive stone screening within the past 20 years under the mistaken supposition that minimally-invasive techniques for removing stones have "solved the stone problem". At UCLH in London where such a comprehensive scheme has been in place for the past 8 years, savings of up to 250,000 pound per year can be made by identifying the particular lifestyle as well as the epidemiological, metabolic and nutritional risk factors involved in a given patient and then instituting appropriate measures to prevent further stones.

Uric acid and the kidney: urate transport, stone disease and progressive renal failure.

In this brief review and update, we try to cover recent developments in our understanding of uric acid transport by the kidney, the contribution of uric acid to renal stone disease, its potential role in progressive renal failure and, most recently, the novel and as yet unexplained link between the urinary glycoprotein Tamm-Horsfall protein (uromodulin) and hyperuricaemia and two inherited forms of renal disease with chronic renal failure.

Kidney models of calcium oxalate stone formation.

This review compares and contrasts three mathematical models used to describe the flow of urine through the renal tubule and the composition of tubular fluid throughout the length of the nephron. From these data the relative supersaturation of tubular fluid with respect to calcium oxalate (CaOx) is calculated at various points along the tubule. This shows that glomerular filtrate is well undersaturated with respect to CaOx and is still undersaturated at the end of the proximal tubule. By the end of the descending limb of the loop of Henle, it is highly supersaturated as a result of water reabsorption and CaOx may nucleate in this region, particularly when the tubular concentration of oxalate is increased. Supersaturation falls slightly by the end of the ascending limb and becomes briefly undersaturated again in the short distal tubule. The final water adjustment in the collecting tubules causes the supersaturation to rise to a very high value by the end of the collecting duct and spontaneous CaOx crystalluria is likely to occur. The review also examines the probability of these crystals growing large enough to be trapped at some point in the nephron within the transit time of tubular fluid from glomerular capsule to ducts of Bellini. All three models agree that, under normal conditions, the likelihood of individual crystals growing large enough to be trapped within the measured urine transit time of 3-4 min is very small. It is concluded that either there has to be aggregation of crystals or some other factor that delays the passage of crystals for them to grow large enough to become lodged at some point in the nephron. Three new hydrodynamic factors are introduced that may lead to delay of crystal passage: (a) fluid drag close to the tubule walls; (b) the drag effect of tubular walls on particles travelling close to the tubule walls, and (c) the effect of gravity on particles travelling in upward-draining sections of tubule. When these factors are introduced into the mathematical model of urine flow and tubular concentration, it is shown that any crystals that form at the end of the descending limb of the loop of Henle and which travel close to the tubular walls may be delayed long enough to grow large enough to become trapped further down the nephron, particularly in upward-draining sections of the nephron. This possibility becomes increasingly significant as urinary oxalate concentration increases. Crystals that nucleate in the late collecting duct, however, are readily passed as small crystals and are at no risk of being trapped in the tubular system. These predictions are used to explain data on the effects of oxalate loading on CaOx crystalluria in stone formers and normal controls. The data are interpreted as showing that if the additional hydrodynamic factors are added to the mathematical model of nephron function, then the 'free-particle' model of calcium stone formation is still possible. This possibility will be further enhanced if crystal aggregation also takes place during the period when crystal passage is delayed by these factors.

Role of dietary intake and intestinal absorption of oxalate in calcium stone formation.

The factors affecting the urinary excretion of oxalate are critical to the risk of forming calcium oxalate stones. This article reviews the role of dietary and intestinal oxalate in determining the level of oxalate excreted in urine. The amount of oxalate available for absorption throughout the intestine is highly dependent on the state of oxalate (a) in the food ingested, and (b) in the intestinal contents at each section of the intestinal tract since only the soluble form of oxalate can be absorbed. In this respect, the solubility of calcium oxalate (CaOx) under the prevailing conditions is paramount in determining the amount of oxalate available for absorption at any particular site. In turn, the main factors that control how much oxalate is in the soluble form are pH and the concentrations of calcium, magnesium and (indirectly) phosphate. Based on these parameters, a model of the intestine has been constructed which brings together the available evidence on the prevailing concentrations of these various factors at different sites in the intestine after allowing for dietary intake and the concentration of the above ions in intestinal secretions. The model then calculates the likely concentration of oxalate that is in the soluble form at each site and therefore available for passive absorption at that site. The model shows that oxalate is likely to be absorbed in the stomach, although it can be also absorbed in the small intestine, particularly at the distal end (after the absorption of calcium), and in the colon, since, on a normal intake of calcium and phosphate, most of the calcium in the large bowel would be anticipated to be precipitated as calcium phosphate under the prevailing alkaline conditions and high concentration of phosphate. The amount of free oxalate in the colon is also controlled by the presence or absence of Oxalobacter formigenes, an anaerobe that has an obligate requirement for oxalate as a source of energy and cellular carbon.

Risk factor analysis and relative supersaturation as tools for identifying calcium oxalate stone-forming dogs.

Twenty-four hour urine samples were collected from 17 calcium oxalate (CaOx) stone-forming (SF) dogs and 17 normal (N), age-, breed- and sex-matched dogs. Urinary CaOx relative supersaturation (RSS) was calculated and found to be significantly higher in the SF group than the N group. RSS measurement is not readily applicable to veterinary practice; thus, alternatives were explored. Discriminant analysis failed to identify key factors differentiating most SF from N dogs. Urinary calcium, oxalate and uric acid, which differed between the SF and N animals, were combined into a measure of relative probability of CaOx stone formation (PSF) to establish whether this approach could be used to assess the risk of CaOx stone formation in dogs. Although there was good correlation between the techniques, RSS more clearly discriminated between SF and N dogs. These data suggest that neither PSF nor discriminant analysis is preferable to RSS for assessing the risk of CaOx stone formation in dogs.

Mitochondrial superoxide production during oxalate-mediated oxidative stress in renal epithelial cells.

Crystals of calcium oxalate monohydrate (COM) in the renal tubule form the basis of most kidney stones. Tubular dysfunction resulting from COM-cell interactions occurs by mechanism(s) that are incompletely understood. We examined the production of reactive oxygen intermediates (ROI) by proximal (LLC-PK1) and distal (MDCK) tubular epithelial cells after treatment with COM (25-250 microg/ml) to determine whether ROI, specifically superoxide (O(2)(*-)), production was activated, and whether it was sufficient to induce oxidative stress. Employing inhibitors of cytosolic and mitochondrial systems, the source of ROI production was investigated. In addition, intracellular glutathione (total and oxidized), energy status (ATP), and NADH were measured. COM treatment for 1-24 h increased O(2)(*-) production 3-6-fold as measured by both lucigenin chemiluminescence in permeabilized cells and dihydrorhodamine fluorescence in intact cells. Using selective inhibitors we found no evidence of cytosolic production. The use of mitochondrial probes, substrates, and inhibitors indicated that increased O(2)(*-) production originated from mitochondria. Treatment with COM decreased glutathione (total and redox state), indicating a sustained oxidative insult. An increase in NADH in COM-treated cells suggested this cofactor could be responsible for elevating O(2)(*-) generation. In conclusion, COM increased mitochondrial O(2)(*-) production by epithelial cells, with a subsequent depletion of antioxidant status. These changes may contribute to the reported cellular transformations during the development of renal calculi.

Cutaneous advancement flap closure: alternative method for treatment of complicated anal fistulas.

PURPOSE: A retrospective chart review of 20 consecutive patients with 23 anal fistulas treated with cutaneous advancement flap closure was undertaken to ascertain the efficacy of this previously unreported technique. METHODS: The so-called "diamond" and "house" flaps are commonly used to treat anal stenosis, and mucosal advancement flaps are successfully used to close fistulas. The authors began, in 1994, to close selected fistulas with skin advancement flaps after suture closure of the internal opening and adequate drainage of the external opening. Fourteen patients (4 females; average age, 42 years; a total of 14 fistulas) without inflammatory bowel disease and 6 patients (3 females; average age, 35 years) with inflammatory bowel disease (5 with Crohn's disease; 1 with chronic ulcerative colitis; a total of 8 fistulas) were treated. Indications were low internal opening with transsphincteric fistula in both groups. Mucosal advancement was relatively contraindicated, either because of fear of ectropion or, in the inflammatory bowel disease patients, diseased mucosa. No one in the noninflammatory bowel disease group was diverted or kept without anything by mouth, and all were treated as outpatients or with overnight observation. The inflammatory bowel disease group was either diverted (1 patient) or kept on home total parenteral nutrition (5 patients) for three to six weeks. Cyclosporine, antibiotics, 5-acetylsalicylic acid, and other medications were used judiciously in the inflammatory bowel disease group. RESULTS: In the noninflammatory bowel disease group, complete healing of all wounds occurred in 11 patients in an average of 6.5 weeks (average follow-up, 18 months). Complications included donor site separation in two patients and minor incontinence of flatus in one patient. In the inflammatory bowel disease group, five fistulas healed, two failed, and one patient developed a new fistula during an average follow-up of 16 months. Deep venous thrombosis and catheter sepsis occurred in one patient in this group. There were no fatalities in either group. CONCLUSIONS: Although the numbers, especially in the inflammatory bowel disease group, are very small, the results are encouraging. This technique appears to have a place in the armamentarium of the surgeon repairing anal fistulas.

Uric acid stone formation in a patient after kidney transplantation--metabolic and therapeutic considerations.

The formation of urinary calculi following renal transplantation is a rare event with a frequency of less than 1% (4). Although 133 cases were described up to 1988, only 5 of these had pure uric acid stones (3). We report a case in which an excessive purine-rich diet probably caused the stone formation. Three modalities of treatment were used, percutaneous nephrolithotripsy, shock wave lithotripsy (ESWL) and chemolysis.

Zeta potential distribution on calcium oxalate crystal and Tamm-Horsfall protein surface analyzed with Doppler electrophoretic light scattering.

The zeta potential distribution (ZPD) and particle size of Tamm-Horsfall protein (THP) and of calcium oxalate monohydrate (COM) crystals were measured using a Doppler Electrophoretic Light Scattering Analysis Instrument. The studies showed differences in the ZPD pattern between THP derived from normal subjects (nTHP) and from stone patients (pTHP). Both nTHP and pTHP can shift the zeta potential of calcium oxalate crystals towards more negative values; nTHP is significantly more potent than pTHP. The zeta potential of both nTHP and pTHP becomes less negative with decreasing pH and with increasing calcium concentration or ionic strength. Tamm-Horsfall protein particle size measurements showed that nTHP particles are significantly smaller than pTHP particles. The size of both nTHP and pTHP increases with increasing calcium concentration or increasing ionic strength and with decreasing pH. The differences between nTHP and pTHP in surface charge and particle size may be based on differences in molecular structure and may cause functional differences in their ability to inhibit calcium oxalate crystal aggregation.

A review of new concepts in renal stone research.

Clinical and basic research in the field of urolithiasis has developed rapidly in recent years. Progress in extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrolithotomy (PNL) has brought about a revolution in the surgical treatment of urolithiasis and research at the cellular and molecular level is now expanding. In spite of these advances, however, clinical treatment of urolithiasis remains far from satisfactory. Stone recurrence in many patients cannot be predicted and is beyond control of urologists mainly because the mechanisms of stone formation are still not fully understood. It is necessary to study the process of stone-formation more intensely at the cellular and molecular level, and to strengthen the links between basic and clinical research in the field. In this review, the processes involved in the formation of stones are compared with those involved in normal bio-mineralization and a model of urolithiasis is put forward based on modern systems science. Attention is concentrated on: (a) Directions of research based on physico-chemical theories of stone formation; (b) The role of renal tubular defects in urolithiasis; (c) The role of free radical reactions in stone formation; and (d) Macromolecular abnormalities and their correction.

Importance of mild hyperoxaluria in the pathogenesis of urolithiasis--new evidence from studies in the Arabian peninsula.

The hypothesis that mild hyperoxaluria is more important than hypercalciuria in the pathogenesis of urolithiasis is re-examined in the light of new evidence. Small increments in urinary oxalate in the normal to high-normal range are much more critical than similar rises in urinary calcium for increasing the relative supersaturation of urine with respect to calcium oxalate, the oxalate/calcium ratio in urine, the total volume of calcium oxalate crystals excreted, the proportion of abnormally large crystals and aggregates of calcium oxalate and the severity of the disorder as defined by the recurrence rate of stone-formation. Data from the Arabian Peninsula, where the prevalence of calcium-containing stones is considerably higher than in the West, have shown that this occurs in spite of the almost complete absence of hypercalciuria. On the other hand, there is a strong association between stone-formation and the occurrence of mild hyperoxaluria. The life-time expectancy of stone-formation in men from various countries is strongly correlated with the average daily excretion of oxalate in the urine of the normal men in these countries. This relationship extends to include patients with enteric and hereditary hyperoxaluria. There is no such relationship, however, between the life-time expectancy of stones and urinary calcium excretion in the same populations. Studies on the regulation of urinary oxalate indicate that it is largely controlled by the quantity of "free" dietary oxalate available for absorption in the lower intestine. This can be calculated from the intakes of calcium and oxalate and the urinary excretion of calcium.