Is there a role for uric acid in an animal model of calcium phosphate nephrocalcinosis and calcium phosphate crystallization in urine of patients with idiopathic calcium urolithiasis? An orientational study

Uric acid (UA), a waste product of purine metabolism, may be involved in calcium phosphate crystallization and deposition. Rats, which develop nephrocalcinosis on high-fat or magnesium-deficient diets, and patients with idiopathic calcium urolithiasis have hyperproteinuria, especially of nonalbumin protein, and a shift toward elevated serum UA. In rats, an increase in UA precursors and renal UA suggests hypoxemia, which stimulates xanthine oxidase. In patients, a primary increase in renal xanthine oxidase would explain the low urine UA in the presence of an elevated serum concentration. For calcium phosphate deposition (rats) or incorporation into stones (humans) to occur, a crucial factor may be xanthine oxidase-mediated overproduction of free radical species and subsequent tissue damage. Another factor may be whether sufficient UA is synthesized to neutralize these free radicals. Allopurinol use, which inhibits xanthine oxidase and has long been favored for the treatment of idiopathic calcium urolithiasis, may not prevent stones, because it also diminishes the availability of UA. An investigation of the factors that control serum UA homeostasis may be rewarding in research into the etiology of idiopathic calcium urolithiasis.     

Methods for measuring crystallization in urolithiasis research: why, how and when?

Whereas crystalluria does not distinguish between kidney stone formers and healthy people and thus can be considered a physiologic event, kidney stone formation is a pathologic incident and reflects a specific form of biomineralization. Both single urinary crystals as well as whole kidney stones form under exquisite control of organic macromolecules. Simple crystal formation in the urinary tract is distinguished from stone formation in the kidney by the process of particle retention. The latter occurs either because nucleated crystals strongly aggregate to particles too large to pass freely through the tubules ('free particle' theory), or because crystals become abnormally adherent to tubular cell surfaces ('fixed particle' theory). Since it is impossible to mimic all the processes involved in stone formation in vitro, it is highly important to carefully chose a specific crystallization process for in vitro studies, and to select the most appropriate experimental conditions for measuring the chosen process as reliably as possible. This overview aims at critically reviewing the principles of currently available assay systems for studying crystallization processes involved in stone formation. Consensus is reached by the experts that no in vitro system really mimics what happens in renal stone formation, but that carefully designed in vitro studies will always play an important part in urolithiasis research. For such studies, it is highly important to exactly control the appropriate experimental conditions that are relevant to a specific crystallization process under investigation. Practical guidelines for researchers working with crystallization systems are provided, and it is concluded that international efforts should be made to standardize the terminology, to agree on a set of basic experimental parameters (temperature, pH, artificial urine composition), and to adopt simple tests or conditions are reference points for quality and comparative control.     

Rituximab in idiopathic nephrotic syndrome: does it make sense?

Idiopathic nephrotic syndrome (INS) includes three different entities: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and mesangial proliferative glomerulonephritis. Historically, this condition has been attributed to a T-cell disorder resulting in the secretion of a circulating factor that increases glomerular permeability to plasma proteins. The therapeutic approach to control the proteinuria of INS remains the use of drugs that have been considered to suppress the production of the “circulating factor” secreted by T cells. Recently, rituximab (RTX), a chimeric monoclonal antibody directed against the CD20 cell surface receptor expressed on B cells, has emerged as potential therapeutic agent. The number of publications reporting clinical experience with RTX in the treatment of nephrotic syndrome has greatly increased in the last few years. However, there is currently no good evidence from clinical or experimental studies that support a role of RTX in the treatment of MCD and FSGS proteinuria. In summary, there is the need for a better understanding of the pathogenesis of the proteinuria in INS and the potential role of RTX in this condition.     

Genetic and dietary factors in idiopathic calcium nephrolithiasis. What do we have, what do we need?

Nephrolithiasis is a complex, multifactorial disease resulting from an interaction between environmental and genetic factors, even if the actual contributions of these factors to stone disease are not yet quantifiable. The lack of convincing findings on genetic factors and genes responsible for nephrolithiasis is due to our still inadequate understanding of the pathogenesis.The hypothesis of an anomaly in cell membrane lipid composition might conceivably be the defect which links genetic and dietary factors and renal stone disease.     

Immune complex: does it have a role in pathogenesis of renal failure in dengue infection?

Dengue infection is a major public health problem. When acute renal failure complicates dengue infection, it is usually associated with severe disease as in dengue hemorrhagic fever or dengue shock syndrome. The role of immune complex in development of renal failure in dengue infection is still unclear. Here, the author used a computational medicine technology to study the property of the dengue virus-immunoglobulin complex. According to this study, the diameter of derived complex is much smaller, compared with the diameter of glomerulus. Entrapment of the immune complex is believed to occur when a previous glomerular lesion causes narrowing of the glomerulus's diameter. Therefore, the immune complex should not have a significant role in pathogenesis of renal failure in dengue infection.     

An evidence-based approach to hypercalciuria: is it really necessary for the study of the role of calcium in urolithiasis?

An abnormally raised 24-h urinary excretion of calcium has long been regarded as a common feature of calcium stone disease. However, hypercalciuria can be defined only by reference to a range of values measured in a representative population of individuals who have never suffered from stone disease. To date, there have been significant flaws in all published studies reporting normal ranges for daily urinary calcium excretion. There is no doubt that additional, carefully performed and documented investigations need to be undertaken to establish what is truly abnormal for a given population; the persistent use of arbitrarily defined limits may be hindering rather than helping to unravel the role of calcium in the pathogenesis of calcium stones.     

Is there a role for pentosan polysulfate in the prevention of calcium oxalate stones?

The clinical role for pentosan polysulfate (PPS) in the prevention of calcium oxalate urolithiasis is not known. Crystallization and aggregation are important steps in calcium oxalate stone formation, and PPS has been shown to inhibit these steps, both in vitro and in vivo. In addition, PPS has a role in repairing injured urothelium and inhibiting adhesion to epithelial defects. A randomized double-blind placebo-controlled study appears warranted to assess the utility of PPS in the prevention of recurrent calcium oxalate stones.     

The reappraisal of nephrocalcin – its role in the inhibition of calcium oxalate crystal growth and interaction with divalent metal ions

Nephrocalcin (NC) is a potent crystal growth inhibitor of calcium oxalate monohydrate. However, the sequence is undefined owing to its multiple glycosylations. Although there have been many biochemical studies of the binding capacity of calcium, the study of the function of the domain is still deferred. By using S-200 gel filtration and Mono Q ion-exchange chromatographic procedures, NC can be purified without further treatment for the removal of urobilirubin. The kinetic study of crystal growth in calcium oxalate monohydrate is performed using a seed slurry system. NC was cut into two peptides through interaction with copper ion and ascorbic acid. The interaction site of the copper ion is presumed to be located between 8 and 6 kDa of molecular weight in NC. The data suggest that divalent metal ions may be involved in the calcium oxalate crystallization through interaction with NC. The role of ascorbic acid in the formation of urinary stones should be reappraised for its association in the redox reaction, with resultant protein digestion in the presence of copper ions. Received: 20 June 2000 / Accepted: 16 November 2000     

Does uric acid have a pathogenetic role in graft dysfunction and hypertension in renal transplant recipients?

BACKGROUND: Uric acid (UA) may play a pathogenetic role in hypertension and kidney disease. We explored the prevalence of hyperuricemia and the relationship of UA to graft function and hypertension in prevalent renal transplant recipients (RTR). METHODS: Baseline and follow-up data were collected on 90 RTR (mean age 51 yrs, 53% male, median transplant duration 7 years). Graft function was estimated using MDRD Study Equation 7. RESULTS: At baseline, 70% RTR had hyperuricemia (UA >7.0 mg/dl (0.42 mmol/L) in men and >6.0 mg/dl (0.36 mmol/L) in women) compared to 80% after 2.2 years (P=0.06). UA was not associated with blood pressure (BP) level but was higher in RTR with a history of hypertension compared to those without (8.6+/-1.8 vs. 7.3+/-2.2 mg/dl, [0.51+/-0.11 vs. 0.43+/-0.13 mmol/L], P=0.003) and in RTR on > or =3 antihypertensive medications compared to those taking less (9.1+/-1.6 vs. 7.6+/-1.8 mg/dL, [0.54+/-0.1 vs. 0.45+/-0.11 mmol/L], P<0.001). A history of hypertension was independently predictive of UA (beta 0.06, [95% CI 0.02 to 0.10], P=0.007) in addition to sex, cyclosporine dose, prednisolone dose, estimated glomerular filtration rate (eGFRMDRD) and beta-blocker therapy. UA was independently predictive of follow-up eGFRMDRD (beta -22.2 [95% CI -41.2 to -3.2], P=0.02) but did not predict change in eGFRMDRD over time. UA was independently associated with requirement for antihypertensive therapy (beta 0.34, [95% CI 1.05 to 1.90], P=0.02). CONCLUSIONS: Hyperuricemia is common in RTR and is associated with need for antihypertensive therapy and level of graft function.     

Why does the Bonn Risk Index discriminate between calcium oxalate stone formers and healthy controls?

PURPOSE: The BRI has been shown to discriminate between calcium oxalate stone formers and controls. BRI is the ratio of the concentration of ionized calcium and the amount of oxalate that must be added to 200 ml urine to initiate crystallization. Higher BRI values are predictive of being a stone former and a value of 1.0 has been found to be the cutoff value to distinguish stone formers and controls. It is not easy to present a consistent argument based on the thermodynamics of calcium oxalate crystallization to account for the success of this index. For instance, why should 2 samples sharing the same BRI but with different ionized calcium and oxalate values have the same likelihood of being obtained from a stone former? MATERIALS AND METHODS: Using data on 195 samples the distribution and interrelationships of measured variables were examined. They were used to calculate illustrative data with which it was possible to examine the effects of varying the parameters and their relationships. RESULTS: Data simulations identified 3 necessary and sufficient conditions that must be met for BRI to be an effective discriminator between stone former and nonstone former urine samples. CONCLUSIONS: The success of BRI can be explained as the natural outcome of there being significantly different distributions (stone formers vs nonstone formers) of the concentration of ionized calcium and the formation product minus activity product difference as well as the correlation between these 2 variables.     

Citric acid or citrates in urine: which should we focus on in the prevention of calcium oxalate crystals and stones?

In order to distinguish between normocitraturia and hypocitraturia, the 24 h urine excretion value of citric acid is evaluated in relation to the established limit value of 2.5 mmol/day. We propose changing this widely-used excretion value to a "minimum contribution" of citric acid to the total urine's ionic strength, since the inhibitory effect of citric acid on crystallization depends on citrate anions being available to complex calcium ions or to associate with the crystal surface. A total of 71424 h-urine samples, taken from 74 healthy persons and 58 calcium stone formers, were investigated for pH, citric acid concentration ([CA]), and related relative calcium oxalate supersaturation (RS). Based on the Henderson-Hasselbalch-equation, the individual concentrations of the differently charged citrate anion species in each of the urines were calculated from the urinary pH and [CA]. From the anion concentrations determined, the contribution of the urine's citric acid to the total urine's ionic strength, ISCA, was calculated. Referring to the limit value of 2.5 mmol/day and assuming an average urine volume of 1.5 l/day, a hypothetical concentration limit of 1.67 mmol/l can be obtained. Grouping the samples into "stone-formers" and "non-stone-formers" as well as into three different ranges of RS revealed: (1). that the groups' median [CA]-values were below 1.67 mmol/l, and (2). that [CA] was not inversely associated with the risk of stone formation. Within the pH-range of 5 and 7, the ISCA-values which are related to, for example, [CA]=1.67 mmol/l, vary considerably by a factor of nearly three between 2.48 mmol/l and 6.64 mmol/l. The use of a fixed citric acid excretion level for the distinction of normocitraturia from hypocitraturia does not take into account the different citrate species which actually modify the urine's crystallization behaviour. The proposed ISCA approach takes this fact into consideration. From this parameter, a desirable "minimum impact of citric acid" can be derived. In a first approach, a potential ISCA-limit value, which currently distinguishes between urines indicated by a "normo-protective" impact and those indicated by a "hypo-protective" impact with respect to calcium oxalate precipitation, may be set at 2.48 mmol/l.     

Transrectal ultrasound biopsy of the prostate: does it still have a role in prostate cancer diagnosis?

Transrectal ultrasound (TRUS) guided biopsy of the prostate has been a standard diagnostic approach for prostate cancer over the past thirty years. Today, the role of TRUS biopsy is being challenged by transperineal (TP) prostate biopsy due to concerns over the safety and diagnostic yield of TRUS biopsy. TRUS biopsy still offers a convenient, reliable and accessible tool for diagnosing prostate cancer in the majority of patients. It continues to play a role in prostate cancer diagnosis, especially where hospital resource allocation is limited, including the public sector. TRUS biopsy has low rates of severe complications, although there remains room for improvement in current practice to improve the tolerability and reduce the incidence of post-biopsy infection.     

Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion

Hypercalciuria is one of the early manifestations of diabetic nephropathy. We explored here the role of α-Klotho, a protein expressed predominantly in distal convoluted tubules that has a role in calcium reabsorption. We studied 31 patients with early diabetic nephropathy and compared them with 31 patients with IgA nephropathy and 7 with minimal change disease. Renal α-Klotho expression was significantly lower and urinary calcium excretion (UCa/UCr) significantly higher in diabetic nephropathy than in IgA nephropathy or minimal change disease. Multiple regression analyses indicated that α-Klotho mRNA was inversely correlated with calcium excretion. We next measured these parameters in a mouse model of streptozotocin (STZ)-induced diabetic nephropathy, characterized by glomerular hyperfiltration, as seen in early diabetic nephropathy. We also confirmed a reduction of renal α-Klotho mRNA down to almost 50% and enhanced calcium excretion in mice with STZ-induced diabetic nephropathy in comparison with nondiabetic mice. Hypercalciuria was exacerbated in heterozygous α-Klotho knockout mice in comparison with wild-type mice, each with STZ-induced diabetic nephropathy. Thus, α-Klotho expression was decreased in distal convoluted tubules in diabetic nephropathy in humans and mice. Renal loss of α-Klotho may affect urinary calcium excretion in early diabetic nephropathy.     

Gallbladder rupture during laparoscopic cholecystectomy: does it have an effect on postoperative morbidity?

Gallbladder rupture during laparoscopic cholecystectomy is a common event that may lead to increased postoperative morbidity. To evaluate this event, we reviewed 300 cases of laparoscopic cholecystectomy. Duration of surgery and hospitalization, postoperative symptoms, wound infection, and late complications were analyzed by comparing two groups of patients, one without gallbladder rupture (A) and one with rupture (B). Gallbladder rupture was found in 40 cases (13.9%). Duration of surgery averaged 81 min for group A and 96.5 min for group B. Postoperative symptoms in the first 24 hours were present in approximately 10% of patients in both groups. Within the first 24 hours, 92.3% of patients in group A were discharged compared with 85% in group B. One patient (0.4%) in group A developed wound infection compared with 2 patients (5%) in group B (p = 0.05). To date, no patients have developed late abdominal complications associated with the procedure. Although this was a retrospective and uncontrolled study, gallbladder rupture during laparoscopic cholecystectomy was found to be associated with increased wound infections. No other significant effects on postoperative morbidity were detected.