Metabolic Syndrome and Nephrolithiasis Risk: Should the Medical Management of Nephrolithiasis Include the Treatment of Metabolic Syndrome?

This article reviews the relationship between metabolic syndrome (MetS) and nephrolithiasis, as well as the clinical implications for patients with this dual diagnosis. MetS, estimated to affect 25% of adults in the United States, is associated with a fivefold increase in the risk of developing diabetes, a doubling of the risk of acquiring cardiovascular disease, and an increase in overall mortality. Defined as a syndrome, MetS is recognized clinically by numerous constitutive traits, including abdominal obesity, hypertension, dyslipidemia (elevated triglycerides, low high-density lipoprotein cholesterol), and hyperglycemia. Urologic complications of MetS include a 30% higher risk of nephrolithiasis, with an increased percentage of uric acid nephrolithiasis in the setting of hyperuricemia, hyperuricosuria, low urine pH, and low urinary volume. Current American Urological Association and European Association of Urology guidelines suggest investigating the etiology of nephrolithiasis in affected individuals; however, there is no specific goal of treating MetS as part of the medical management. Weight loss and exercise, the main lifestyle treatments of MetS, counter abdominal obesity and insulin resistance and reduce the incidence of cardiovascular events and the development of diabetes. These recommendations may offer a beneficial adjunctive treatment option for nephrolithiasis complicated by MetS. Although definitive therapeutic recommendations must await further studies, it seems both reasonable and justifiable for the urologist, as part of a multidisciplinary team, to recommend these important lifestyle changes to patients with both conditions. These recommendations should accompany the currently accepted management of nephrolithiasis.Key words: Nephrolithiasis, Metabolic syndrome, Uric acid nephrolithiasisMetabolic syndrome (MetS), as defined by the National Cholesterol Education Program and the Adult Treatment Panel III in 2001 (and updated in 2005), represents a growing medical problem affecting more than 22% of US adults.^1–4 It is associated with an almost fivefold increase in the risk of developing diabetes and a doubling of the risk of acquiring cardiovascular disease.⁵ MetS is a clinical disorder defined by the presence of at least three of the following criteria: central obesity (abdominal girth > 102 cm [40 in] men and > 88 cm [35 in] women), low high-density lipoprotein (HDL) cholesterol (< 40 mg/dL in men and < 50 mg/dL in women), hypertriglyceridemia (> 150 mg/dL), hypertension (blood pressure > 130/85 mm Hg), and elevated fasting glucose (> 100 mg/dL).^2,4 The development of MetS appears to result from a complex interaction of genetics, phenotypic visceral fat accumulation (central obesity), insulin resistance, and sedentary behavior.^5,6 Beyond cardiometabolic risks, MetS has a wide range of long-term complications, including nonalcoholic fatty liver disease, polycystic ovarian syndrome, obstructive sleep apnea, hypogonadism, lipodystrophy, microvascular disease, and chronic renal disease.⁶ An important urologic complication of MetS, not routinely cited, is nephrolithiasis.^6–8Nephrolithiasis continues to be a major cause of morbidity and healthcare spending.⁹ A history of kidney stones is approximately twice as common in individuals with three criteria for MetS and three times as common in those with five criteria for MetS, as compared with those with none.¹⁰ These trends were confirmed in a large-scale, nationwide study of 30,448 Japanese patients with urolithiasis, who demonstrated that MetS was associated with a significantly increased risk of hypercalciuria, hyperuricosuria, hyperoxaluria, and hypocitraturia, independent of age and sex.¹¹ Additionally, patients with a history of nephrolithiasis are significantly more likely to have multiple risk factors for cardiovascular disease, premature atherosclerosis, and cardiovascular events.^10,12,13 It is unknown whether this is primarily a reflection of factors associated with nephrolithiasis, such as obesity, hypertension, or glucose intolerance/diabetes, or due to components of MetS, such as insulin resistance.¹⁴ The current American Urological Association (AUA) guidelines on the medical management of kidney stones suggests a need for future research on advising patients to exercise and lose weight, but does not make definitive recommendations on these lifestyle changes.¹⁵     

Metabolic pathways: does the actual Gibbs free-energy change affect the flux rate?

Energy dissipation fulfils an important function in metabolism driving the flux of matter through metabolic pathways. The flux rate is a multivariable function. One of such variables affecting the flux is the actual free energy change. A particular case of metabolic pathway is analysed to illustrate this fact, using only general enzymic and thermodynamic concepts.     

Turnover Rate of the γ-Aminobutyric Acid Transporter GAT1

We combined electrophysiological and freeze-fracture methods to estimate the unitary turnover rate of the γ-aminobutyric acid (GABA) transporter GAT1. Human GAT1 was expressed in Xenopus laevis oocytes, and individual cells were used to measure and correlate the macroscopic rate of GABA transport and the total number of transporters in the plasma membrane. The two-electrode voltage-clamp method was used to measure the transporter-mediated macroscopic current evoked by GABA ( ), macroscopic charge movements (Q _NaCl) evoked by voltage pulses and whole-cell capacitance. The same cells were then examined by freeze-fracture and electron microscopy in order to estimate the total number of GAT1 copies in the plasma membrane. GAT1 expression in the plasma membrane led to the appearance of a distinct population of 9-nm freeze-fracture particles which represented GAT1 dimers. There was a direct correlation between Q _NaCl and the total number of transporters in the plasma membrane. This relationship yielded an apparent valence of 8 ± 1 elementary charges per GAT1 particle. Assuming that the monomer is the functional unit, we obtained 4 ± 1 elementary charges per GAT1 monomer. This information and the relationship between and Q _NaCl were used to estimate a GAT1 unitary turnover rate of 15 ± 2 s⁻¹ (21°C, −50 mV). The temperature and voltage dependence of GAT1 were used to estimate the physiological turnover rate to be 79–93 s⁻¹ (37°C, −50 to −90 mV).     

A Slow ATP-induced Conformational Change Limits the Rate of DNA Binding but Not the Rate of �� Clamp Binding by the Escherichia coli �� Complex Clamp Loader

In Escherichia coli, the γ complex clamp loader loads the β-sliding clamp onto DNA. The β clamp tethers DNA polymerase III to DNA and enhances the efficiency of replication by increasing the processivity of DNA synthesis. In the presence of ATP, γ complex binds β and DNA to form a ternary complex. Binding to primed template DNA triggers γ complex to hydrolyze ATP and release the clamp onto DNA. Here, we investigated the kinetics of forming a ternary complex by measuring rates of γ complex binding β and DNA. A fluorescence intensity-based β binding assay was developed in which the fluorescence of pyrene covalently attached to β increases when bound by γ complex. Using this assay, an association rate constant of 2.3 × 10⁷ m⁻¹ s⁻¹ for γ complex binding β was determined. The rate of β binding was the same in experiments in which γ complex was preincubated with ATP before adding β or added directly to β and ATP. In contrast, when γ complex is preincubated with ATP, DNA binding is faster than when γ complex is added to DNA and ATP at the same time. Slow DNA binding in the absence of ATP preincubation is the result of a rate-limiting ATP-induced conformational change. Our results strongly suggest that the ATP-induced conformational changes that promote β binding and DNA binding differ. The slow ATP-induced conformational change that precedes DNA binding may provide a kinetic preference for γ complex to bind β before DNA during the clamp loading reaction cycle.     

Metabolic flexibility: the key to long-term evolutionary success in Bryozoa?

Oxygen consumption (MO2) and activity were evaluated in Antarctic Bryozoa. Three species representing two different morphologies, flat sheet, laminar forms, Isoseculiflustra tenuis and Kymella polaris, and the bush form Camptoplites bicornis were used. In Bryozoa, activity is measured as the proportion of colony zooids with their lophophores extended. In I. tenuis and K. polaris, residual analysis showed that the percentage of zooids with extended lophophores was not correlated with colony MO2. Lophophore extension is, therefore, a poor measure of activity, and other costs (e.g. growth, reproduction, storage) probably form the major metabolic costs. MO2 per unit of ash-free dry mass (AFDM) in the laminar forms was low compared with other Antarctic marine invertebrates, but not lower than brachiopods and echinoderms. However, the lowest rate here, 16.8 microg O2 g AFDM(-1) h(-1) for a K. polaris colony, is (to our knowledge) the lowest for any animal so far reported. MO2 per unit of AFDM for C. bicornis, however, is among the highest reported for sessile or slow moving Antarctic marine ectotherms, with values similar to those for bivalve and gastropod molluscs. The highest rate, 527 microg O2 g AFDM(-1) h(-1) for one colony is (to our knowledge) the highest reported for polar animals of this type. Extreme diversity in metabolic strategy may explain the bryozoan long evolutionary record and great success in shallow marine environments worldwide.     

Is there "Metabolic" DNA in the Mouse Seminal Vesicle?

This study was designed to answer the question: Is H³-thymidine uptake by nuclei of the mouse seminal vesicle evidence for DNA synthesis and mitosis, or does it signify some "metabolic" function of DNA unrelated to chromosome duplication? Mice were given an intraperitoneal injection of H³-thymidine. Six hours later Feulgen squashes of the seminal vesicle epithelium were made and covered with autoradiographic stripping film. The silver grains above labeled nuclei were counted, and the Feulgen dye contents of these same nuclei were determined photometrically after removal of the grains from the emulsion. Unlabeled nuclei were also measured. The dye contents of non-radioactive nuclei form a unimodal distribution, indicating that polyploidy is absent from this tissue. The radioactive nuclei fall into two groups. In the first, the average dye content is the same as that of the cold nuclei (2C). In the second, the values range from 2C to 4C. In the 2C to 4C group the grain count is proportional to the dye content, showing that incorporation is correlated with synthesis. The radioactive 2C nuclei arose by mitosis during the course of the experiment. This is shown by the following facts: (1) They frequently occur in pairs. (2) They average smaller than unlabeled 2C nuclei. (3) Their average grain count is approximately half that of the 4C nuclei. (4) Labeled division figures are found. (5) A mitotic rate estimated from the number of labeled 2C nuclei accords reasonably well with one based on the number of observed mitoses. Since the incorporation of thymidine accompanies DNA synthesis and precedes mitosis, there is no reason to postulate a special "metabolic" DNA in this tissue.     

Effect of Antihypertensive Drugs on the “Intrinsic” Heart Rate

“Intrinsic” heart rate in man was measured by giving simultaneous atropine and propranolol and used to study the direct effect of antihypertensive drugs on the heart. Though the intrinsic and control heart rates decreased significantly following the administration of reserpine, there was no significant difference between high and low doses. No similar effects were observed with debrisoquine sulphate and methyldopa, though in high doses the latter produced a decrease which was of some statistical significance.     

Metabolic and hedonic drives in the neural control of appetite: who is the boss?

Obesity is on the rise in all developed countries, and a large part of this epidemic has been attributed to excess caloric intake, induced by ever present food cues and the easy availability of energy dense foods in an environment of plenty. Clearly, there are strong homeostatic regulatory mechanisms keeping body weight of many individuals exposed to this environment remarkably stable over their adult life. Other individuals, however, seem to eat not only because of metabolic need, but also because of excessive hedonic drive to make them feel better and relieve stress. In the extreme, some individuals exhibit addiction-like behavior toward food, and parallels have been drawn to drug and alcohol addiction. However, there is an important distinction in that, unlike drugs and alcohol, food is a daily necessity. Considerable advances have been made recently in the identification of neural circuits that represent the interface between the metabolic and hedonic drives of eating. We will cover these new findings by focusing first on the capacity of metabolic signals to modulate processing of cognitive and reward functions in cortico-limbic systems (bottom-up) and then on pathways by which the cognitive and emotional brain may override homeostatic regulation (top-down).     

Mutation in the M1 Domain of the Acetylcholine Receptor α Subunit Decreases the Rate of Agonist Dissociation

We describe the kinetic consequences of the mutation N217K in the M1 domain of the acetylcholine receptor (AChR) α subunit that causes a slow channel congenital myasthenic syndrome (SCCMS). We previously showed that receptors containing αN217K expressed in 293 HEK cells open in prolonged activation episodes strikingly similar to those observed at the SCCMS end plates. Here we use single channel kinetic analysis to show that the prolonged activation episodes result primarily from slowing of the rate of acetylcholine (ACh) dissociation from the binding site. Rate constants for channel opening and closing are also slowed but to much smaller extents. The rate constants derived from kinetic analysis also describe the concentration dependence of receptor activation, revealing a 20-fold shift in the EC₅₀ to lower agonist concentrations for αN217K. The apparent affinity of ACh binding, measured by competition against the rate of ¹²⁵I-α-bungarotoxin binding, is also enhanced 20-fold by αN217K. Both the slowing of ACh dissociation and enhanced apparent affinity are specific to the lysine substitution, as the glutamine and glutamate substitutions have no effect. Substituting lysine for the equivalent asparagine in the β, ε, or δ subunits does not affect the kinetics of receptor activation or apparent agonist affinity. The results show that a mutation in the amino-terminal portion of the M1 domain produces a localized perturbation that stabilizes agonist bound to the resting state of the AChR.     

Interpreting the γ Statistic in Phylogenetic Diversification Rate Studies: A Rate Decrease Does Not Necessarily Indicate an Early Burst

Background

Phylogenetic hypotheses are increasingly being used to elucidate historical patterns of diversification rate-variation. Hypothesis testing is often conducted by comparing the observed vector of branching times to a null, pure-birth expectation. A popular method for inferring a decrease in speciation rate, which might suggest an early burst of diversification followed by a decrease in diversification rate is the γ statistic.

Methodology

Using simulations under varying conditions, I examine the sensitivity of γ to the distribution of the most recent branching times. Using an exploratory data analysis tool for lineages through time plots, tree deviation, I identified trees with a significant γ statistic that do not appear to have the characteristic early accumulation of lineages consistent with an early, rapid rate of cladogenesis. I further investigated the sensitivity of the γ statistic to recent diversification by examining the consequences of failing to simulate the full time interval following the most recent cladogenic event. The power of γ to detect rate decrease at varying times was assessed for simulated trees with an initial high rate of diversification followed by a relatively low rate.

Conclusions

The γ statistic is extraordinarily sensitive to recent diversification rates, and does not necessarily detect early bursts of diversification. This was true for trees of various sizes and completeness of taxon sampling. The γ statistic had greater power to detect recent diversification rate decreases compared to early bursts of diversification. Caution should be exercised when interpreting the γ statistic as an indication of early, rapid diversification.     

Perturbation Theory in the Catalytic Rate Constant of the Henri–Michaelis–Menten Enzymatic Reaction

The Henry–Michaelis–Menten (HMM) mechanism of enzymatic reaction is studied by means of perturbation theory in the reaction rate constant k ₂ of product formation. We present analytical solutions that provide the concentrations of the enzyme (E), the substrate (S), as well as those of the enzyme-substrate complex (C), and the product (P) as functions of time. For k ₂ small compared to k _?1, we properly describe the entire enzymatic activity from the beginning of the reaction up to longer times without imposing extra conditions on the initial concentrations E _o and?S _o , which can be comparable or much different.     

Obstetricians’ Opinions of the Optimal Caesarean Rate: A Global Survey

Background

The debate surrounding the optimal caesarean rate has been ongoing for several decades, with the WHO recommending an “acceptable” rate of 5–15% since 1997, despite a weak evidence base. Global expert opinion from obstetric care providers on the optimal caesarean rate has not been documented. The objective of this study was to examine providers’ opinions of the optimal caesarean rate worldwide, among all deliveries and within specific sub-groups of deliveries.

Methods

A global online survey of medical doctors who had performed at least one caesarean in the last five years was conducted between August 2013 and January 2014. Respondents were asked to report their opinion of the optimal caesarean rate—defined as the caesarean rate that would minimise poor maternal and perinatal outcomes—at the population level and within specific sub-groups of deliveries (including women with demographic and clinical risk factors for caesareans). Median reported optimal rates and corresponding inter-quartile ranges (IQRs) were calculated for the sample, and stratified according to national caesarean rate, institutional caesarean rate, facility level, and respondent characteristics.

Results

Responses were collected from 1,057 medical doctors from 96 countries. The median reported optimal caesarean rate was 20% (IQR: 15–30%) for all deliveries. Providers in private for-profit facilities and in facilities with high institutional rates reported optimal rates of 30% or above, while those in Europe, in public facilities and in facilities with low institutional rates reported rates of 15% or less. Reported optimal rates were lowest among low-risk deliveries and highest for Absolute Maternal Indications (AMIs), with wide IQRs observed for most categories other than AMIs.

Conclusions

Three-quarters of respondents reported an optimal caesarean rate above the WHO 15% upper threshold. There was substantial variation in responses, highlighting a lack of consensus around which women are in need of a caesarean among obstetric care providers worldwide.