Klotho in pregnancy and intrauterine development - Potential clinical implications: a review from the European Renal Association CKD-MBD Working Group.

Intrauterine development is crucial for life-long health; therefore, elucidation of its key regulators is of interest for their potential prognostic and therapeutic implications. Originally described as a membrane-bound anti-aging protein, Klotho has evolved as a regulator of numerous functions in different organ systems. Circulating Klotho is generated by alternative splicing or active shedding from cell membranes. Recently, Klotho was identified as a regulator of placental function, and while Klotho does not cross the placental barrier, increased levels of circulating α-Klotho have been identified in umbilical cord blood compared to maternal blood, indicating that Klotho may also play a role in intrauterine development. In this narrative review, we discuss novel insights into the specific functions of the Klotho proteins in the placenta and in intrauterine development, while summarizing up-to-date knowledge about their structures and functions. Klotho plays a role in stem cell functioning, organogenesis, and haematopoiesis. Low circulating maternal and foetal levels of Klotho are associated with preeclampsia, intra-uterine growth restriction, and an increased perinatal risk for newborns, indicating a potential used of Klotho as biomarker and therapeutic target. Experimental administration of Klotho protein indicates a neuro- and nephroprotective potential, suggesting a possible future role of Klotho as a therapeutic agent. However, the use of Klotho as intervention during pregnancy is yet unproven. Here, we summarize novel evidence, suggesting Klotho as a key regulator for healthy pregnancies and intrauterine development with promising potential for clinical use.

Glomerular hyperfiltration as a therapeutic target for CKD.

The global burden of chronic kidney disease (CKD) is high and increasing. Early diagnosis and intervention are key to improve outcomes. Single nephron glomerular hyperfiltration is an early pathophysiologic manifestation of CKD that may result in absolute glomerular hyperfiltration, i.e. a high glomerular filtration rate (GFR) or be associated with normal or low GFR because of nephron loss (relative glomerular hyperfiltration). Even though compensatory glomerular hyperfiltration may contribute to maintain kidney function after loss of kidney mass, the associated increased glomerular capillary pressure and glomerular and podocyte size drive podocyte loss, albuminuria and proximal tubular overload, contributing to CKD progression. In this regard, all kidney protective drugs in clinical use so far, from renin-angiotensin system blockers to mineralocorticoid receptor blockers to sodium-glucose cotransporter-2 inhibitors to tolvaptan, induced an early dip in glomerular filtration that is thought to represent reversal of hyperfiltration. As glomerular hyperfiltration may be present early in the course of kidney disease, its recognition may provide an effective intervention window that may predates current criteria based on high albuminuria or loss of GFR. Nevertheless, there is no diagnostic method with high sensitivity and specificity to identify single nephron glomerular hyperfiltration, except when it leads to obvious absolute glomerular hyperfiltration, as observed in the early stages of diabetic kidney disease when nephron mass is still preserved. We now review the concept of glomerular hyperfiltration as an indicator of CKD risk, including definitions, challenges in diagnosis and evaluation, underlying pathophysiological mechanisms, potential therapeutic approaches and unanswered questions.

Management of de novo nephrolithiasis after kidney transplantation: a comprehensive review from the European Renal Association CKD-MBD working group.

The lifetime incidence of kidney stones is 6%-12% in the general population. Nephrolithiasis is a known cause of acute and chronic kidney injury, mediated via obstructive uropathy or crystal-induced nephropathy, and several modifiable and non-modifiable genetic and lifestyle causes have been described. Evidence for epidemiology and management of nephrolithiasis after kidney transplantation is limited by a low number of publications, small study sizes and short observational periods. Denervation of the kidney and ureter graft greatly reduces symptomatology of kidney stones in transplant recipients, which may contribute to a considerable underdiagnosis. Thus, reported prevalence rates of 1%-2% after kidney transplantation and the lack of adverse effects on allograft function and survival should be interpreted with caution. In this narrative review we summarize current state-of-the-art knowledge regarding epidemiology, clinical presentation, diagnosis, prevention and therapy of nephrolithiasis after kidney transplantation, including management of asymptomatic stone disease in kidney donors. Our aim is to strengthen clinical nephrologists who treat kidney transplant recipients in informed decision-making regarding management of kidney stones. Available evidence, supporting both surgical and medical treatment and prevention of kidney stones, is presented and critically discussed. The specific anatomy of the transplanted kidney and urinary tract requires deviation from established interventional approaches for nephrolithiasis in native kidneys. Also, pharmacological and lifestyle changes may need adaptation to the specific situation of kidney transplant recipients. Finally, we point out current knowledge gaps and the need for additional evidence from future studies.

Comparative analysis of the WISC-IV in a clinical setting: ADHD vs. non-ADHD.

BACKGROUND: The Wechsler Intelligence Scale for Children, 4th edition (WISC-IV) is a useful tool for revealing differences in cognitive ability. Using the WISC-IV, the study investigated the intelligence profile of Turkish children diagnosed with ADHD and compared their profile with that of a non-ADHD clinical sample. METHOD: On the basis of the records of 257 drug-naïve patients (6-12years of age), ADHD (n=154) and non-ADHD (n=103) clinical groups were compared with respect to sociodemographic variables and WISC-IV scores. RESULTS: The non-ADHD clinical group had higher full scale, index, and subtest scores, except for their scores in the Comprehension subtest. The scores on Working Memory, Processing Speed Indices, Similarities, and Matrix Reasoning subtests were especially lower in the ADHD group than in the non-ADHD group. The Similarities, Matrix Reasoning, and Digit Span subtests classified 83% of the children as having ADHD and identified 43.7% of the non-ADHD clinical controls. CONCLUSION: In our study, we found differences in the WISC-IV profiles of the Turkish patients with ADHD. Moreover, the WISC-IV profile of the non-ADHD clinical group was different than that of the ADHD group. More prospective studies with larger groups of ADHD patients and further evaluations of executive function deficits can help clinicians better understand the differences in WISC-IV profiles.

Dehydroepiandrosterone supplementation improves predictive markers for diminished ovarian reserve: serum AMH, inhibin B and antral follicle count.

OBJECTIVE: To evaluate the effect of dehydroepiandrosterone (DHEA) supplementation on ovarian reserve by measuring markers such as antral follicle count, serum anti-Müllerian hormone (AMH) and inhibin B in patients with diminished ovarian reserve. STUDY DESIGN: This prospective study was undertaken at Dr. Zekai Tahir Burak Women's Health Research and Education Hospital, Ankara, Turkey. Forty-one patients with diminished ovarian reserve were included in the study and received supplementation with DHEA 25mg, t.i.d., for at least 6 weeks. Serum AMH, inhibin B, follicle-stimulating hormone (FSH) and oestradiol, and antral follicle count were determined before and after DHEA supplementation. Baseline ovarian reserve parameters such as antral follicle count, FSH, oestradiol, AMH, inhibin B, clinical and laboratory IVF outcomes, and pregnancy rates were studied. RESULTS: There were significant differences in day 3 FSH, oestradiol, antral follicle count, AMH and inhibin B levels before and after DHEA supplementation in all patients (p=0.001, 0.001, 0.002, 0.001 and 0.001, respectively). The study population was divided into two age groups (<35 and ≥35 years) to determine whether there was a difference in the effect of DHEA supplementation between younger and older patients with diminished ovarian reserve. Significant differences were found in all of the parameters in both study groups (p<0.05). CONCLUSIONS: DHEA supplementation is an effective option for patients with diminished ovarian reserve. Prior to assisted reproductive technology, patients with diminished ovarian reserve should be offered DHEA supplementation as an alternative to oocyte donation.

Removal mechanisms of 17ß-estradiol and 17α-ethinylestradiol in membrane bioreactors.

The fate and behavior of natural and synthetic estrogens in wastewater treatment processes is currently of increasing concern all over the world. In this study, the removal mechanisms of a natural estrogen, 17ß-estradiol (E2), and a synthetic estrogen, 17α-ethinylestradiol (EE2) were investigated in membrane bioreactors (MBRs) with and without powdered activated carbon (PAC) addition. The experimental results showed that the average removal rates of E2 and EE2 by the MBR without PAC addition were 89.0 and 70.9%; PAC addition in the MBR increased the removal rate of E2 and EE2 by 3.4 and 15.8%, respectively. The greater impact of PAC dosing on EE2 removal was due to its greater hydrophobic property. Adsorption played a more important role in the removal mechanisms of EE2 than E2. Biodegradation was the dominant mechanism for the removal of E2 and EE2 in MBRs. Unlike their adsorption behavior, the biodegradation rates of both E2 and EE2 were not significantly different between the MBRs with and without PAC addition.

Impact of free ammonia on anammox rates (anoxic ammonium oxidation) in a moving bed biofilm reactor.

Using a bench scale moving bed bioreactor (MBBR), the effect of free ammonia (FA, NH(3), the un-ionized form of ammonium NH(4)(+)) concentration on anoxic ammonium oxidation (anammox) was evaluated based on the volumetric nitrogen removal rate (NRR). Although, a detailed microbial analysis was not conducted, the major NRR observed was assumed to be by anammox, based on the nitrogen conversion ratios of nitrite to ammonium and nitrate to ammonium. Since the concentration of free ammonia as a proportion of the total ammonia concentration is pH-dependent, the impact of changing the operating pH from 6.9 to 8.2, was investigated under constant nitrogen loading conditions during continuous reactor operation. Furthermore, the effect of sudden nitrogen load changes was investigated under constant pH conditions. Batch tests were conducted to determine the immediate response of the anammox consortium to shifts in pH and FA concentrations. It was found that FA was inhibiting NRR at concentrations exceeding 2 mg N L(-1). In the pH range 7-8, the decrease in anammox activity was independent of pH and related only to the concentration of FA. Nitrite concentrations of up to 120 mg N L(-1) did not negatively affect NRR for up to 3.5 h. It was concluded that a stable NRR in a moving bed biofilm reactor depended on maintaining FA concentrations below 2 mg N L(-1) when the pH was maintained between 7 and 8.

Ethinylestradiol removal in a conventional and a simultaneous nitrification-denitrification membrane bioreactor.

The removal of a synthetic estrogen 17α-ethinylestradiol (EE2) was investigated in submerged membrane bioreactors (MBRs) with simultaneous nitrification-denitrification (SND) and conventional nitrification. The influent EE2 concentration was 500 ng/L as EE2. Using a yeast estrogen screen test, the conventional-MBR (C-MBR) and SND MBR (SND-MBR) removed 57 and 58% of the estrogenic activity (EA) respectively; there was no significant difference in their removal efficiencies. Biodegradation was the dominant removal mechanism for both reactors with K(BIO) coefficients of 1.5 ± 0.6 and 1.6 ± 0.4 day(-1) for the C-MBR and the SND-MBR respectively. Sorption to solid particles removed approximately 1% of influent EA in each reactor; the particle partitioning coefficient, K(D), was calculated to be 0.21 ± 0.07 L/(g MLSS) for the C-MBR and 0.27 ± 0.1 L/(g MLSS) for the SND-MBR. These findings suggest that conditions favoring SND in MBRs have no significant impact on EA reduction.

Importance of the operating pH in maintaining the stability of anoxic ammonium oxidation (anammox) activity in moving bed biofilm reactors.

Two bench-scale parallel moving bed biofilm reactors (MBBR) were operated to assess pH-associated anammox activity changes during long term treatment of anaerobically digested sludge centrate pre-treated in a suspended growth partial nitrification reactor. The pH was maintained at 6.5 in reactor R1, while it was allowed to vary naturally between 7.5 and 8.1 in reactor R2. At high nitrogen loads reactor R2 had a 61% lower volumetric specific nitrogen removal rate than reactor R1. The low pH and the associated low free ammonia (FA) concentrations were found to be critical to stable anammox activity in the MBBR. Nitrite enhanced the nitrogen removal rate in the conditions of low pH, all the way up to the investigated level of 50mg NO(2)-N/L. At low FA levels nitrite concentrations up to 250 mg NO(2)-N/L did not cause inactivation of anammox consortia over a 2-days exposure time.

Improving the performance of membrane bioreactors by powdered activated carbon dosing with cost considerations.

Effects of powdered activated carbon (PAC) dosing on the overall performance of membrane bioreactors (MBR) were investigated in two bench-scale submerged MBRs. Positive impacts of PAC dosing on membrane fouling and the removal of 17beta-estradiol (E2) and 17alpha-ethyinylestradiol (EE2) were demonstrated over a six-month stable operational period. PAC dosing in the MBR increased the removal rates of E2 and EE2 by 3.4% and 15.8%, respectively. The average soluble extracellular polymeric substances (EPS) and colloidal total organic carbon (TOC) concentrations in the PAC-MBR sludge was 60.1% and 61.8% lower than the control MBR sludge, respectively. Lower soluble EPS and colloidal TOC concentrations in the PAC-MBR sludge resulted in a slower rate of trans-membrane pressure (TMP) increase during MBRs operation, which could prolong the lifespan of membranes. Cost assessment showed that PAC dosing could reduce the operating cost for membrane cleaning and/or membrane replacement by about 25%. The operating cost for PAC dosing could be offset by the benefit from its reducing the cost for membrane maintenance.

Phosphorus removal from anaerobically digested swine wastewater through struvite precipitation.

Phosphorus removal from agricultural wastewater streams is an important aspect of managing surface water quality, due to the contribution of phosphorus to eutrophication. Removal of phosphorus through struvite precipitation allows for its recovery as a potential fertilizer, and by determining the best conditions for struvite precipitation the removal process can be optimized. The effects of pH, Mg:P ratio, and time on struvite precipitation from anaerobically digested swine manure effluent were investigated. Effluent with Mg:P ratios from 1.0:1 to 1.6:1 were adjusted to pH values between 7.5 and 9.5 and left to equilibrate for 24 h. Results indicate that phosphorus removal increased with increasing pH and Mg:P ratio; the maximum phosphorus removal achieved was 80% at pH 9.0 and a Mg:P ratio of 1.6:1. The purest struvite precipitate was found at pH 7.5, with calcium carbonate and struvite precipitating at higher pH values. A continuously stirred batch of centrate was adjusted to pH 8.4 to determine the struvite formation rate constant. The rate constant was found to be 1.55 h(-1), with 17% phosphorus removal during the first 20 min. The results indicate that struvite precipitation could be a viable method of phosphorus removal from anaerobically digested swine manure.

Effects of powdered activated carbon dosing on sludge characteristics and estrogen removal in membrane bioreactors.

Sludge characteristics associated with filterability as well as the removal of a natural estrogen 17beta-estradiol (E2) and a synthetic estrogen 17alpha-ethyinylestradiol (EE2) were investigated in submerged membrane bioreactors (MBR) with and without the addition of powdered activated carbon (PAC) under the same experimental conditions. Positive impacts of PAC dosing on membrane fouling and the removal of E2 and EE2 were demonstrated over a six months stable operational period. Experimental results showed that PAC dosing resulted in lower concentrations of soluble extracellular polymeric substances (EPS) and colloidal total organic carbon (TOC) in the PAC-MBR sludge. The average soluble EPS and colloidal TOC concentrations in the PAC-MBR sludge was 60.1% and 61.8% lower than the control MBR sludge, respectively. Regardless of PAC dosing, concentrations of colloidal TOC were strongly related to concentrations of soluble EPS and soluble carbohydrates in the sludge. In addition, the mean flocs size of the sludge with PAC dosing was shifted from 49.4 microm to 60.3 microm. PAC dosing in the MBR increased the removal rates of E2 and EE2 by 3.4% and 15.8%, respectively.

Long-term operation of membrane biofilm reactors for nitrogen removal with autotrophic bacteria.

Efficient gas delivery and biofilm development on membrane fibers in a membrane biofilm reactor (MBfR) would be well suited to autotrophic nitrification and denitrification using hydrogen. Total nitrogen removal in a two-step MBfR system incorporating sequential nitrification and hydrogen-driven autotrophic denitrification was investigated in order to achieve nitrogen removal by autotrophic bacteria alone. This study also aimed at the long-term stable operation, which proved difficult in previous studies due to excessive biofilm accumulation in autotrophic denitrification systems. Consecutive operation of nitrification and autotrophic denitrification lasted 230 days. Average specific nitrification rate of 1.87 g N/m(2) d was achieved and the performance was very stable throughout the experimental periods. Nitrification performance from this study showed comparable rates to previous studies although this work was conducted at slightly lower temperature. Batch tests confirmed the presence of nitrifiers from the effluent of the nitrification reactor, which reattached to the biofilm in the denitrification reactor leading to further nitrification. Performance of autotrophic denitrification was maintained stably throughout the experimental periods, however biofilm control by nitrogen sparging was required for process stability. Average specific denitrification rate of 1.41 g N/m(2) d and a maximum specific denitrification rate of 2.04 g N/m(2) d was maintained. This study showed that, with an appropriate biofilm control plan, stable long-term operation of a fully autotrophic MBfR system for total nitrogen removal was possible without major membrane cleaning procedures.

Aerobic treatment of landfill leachate using a submerged membrane bioreactor--prospects for on-site use.

Submerged membrane bioreactor (MBR) technology for aerobic treatment of landfill leachate was studied in laboratory scale to evaluate its potential for on-site use. Three combinations of solid retention time (SRT) - hydraulic retention time (HRT) of 60 days - 3.5 days, 60 days - 2 days and 30 days - 1 day, were examined to evaluate reactor performance under varying loading and biomass conditions. Chemical Oxygen Demand (COD) removal ranged from 54 to 78%, depending on the influent leachate source and loading conditions. The MBR showed excellent Biological Oxygen Demand (BOD5) removal of 97% and higher, even at HRT as low as 1 day. Complete suspended solids retention and full nitrification of the incoming ammonia was observed despite highly variable loading. Significant removal of iron, lead, manganese, cadmium and aluminum was observed. No significant changes in the removal efficiency of metals, ammonia, and BOD5 were observed at different SRT-HRT. Toxicity removal decreased with increasing HRT. The produced effluent met current water quality guidelines for discharge into natural streams in Manitoba.

Impact of shear force on the biofilm structure and performance of a membrane biofilm reactor for tertiary hydrogen-driven denitrification of municipal wastewater.

Hydrogen-driven denitrification using a hollow-fiber membrane biofilm reactor (MBfR) was evaluated for operation in tertiary wastewater treatment. Specific objectives were to evaluate the impact of different levels of shearing stress caused by mixing and nitrogen sparging on the biofilm structure and denitrification rates. Applying high shear force proved to be effective in improving denitrification rates by reducing the thickness of the biofilm. With intensive mixing a biofilm thickness of approximately 800 microm was maintained, while additional nitrogen sparging could further reduce the biofilm thickness to approximately 300 microm. The highest denitrification rates of 0.93 gN/m(2)d were obtained when biofilm thickness was lower than 500 microm. Lower extracellular polymeric substances (EPS) accumulation and carbohydrates to protein ratio observed in thinner biofilms allowed for higher nitrate removal in the system. No significant sloughing of biomass or change in total and soluble COD in the final effluent was observed under steady-state conditions.

Hydrogen-dependent denitrification of water in an anaerobic submerged membrane bioreactor coupled with a novel hydrogen delivery system.

Hydrogen-dependent denitrification has gained significant attention due to its potential economic advantage over heterotrophic denitrification. However, effective hydrogen delivery and biomass retention under anaerobic conditions are significant challenges to implementation of this process. An innovative hydrogenotrophic denitrification system, that addresses these challenges, consisting of an anaerobic submerged membrane bioreactor (MBR) and a novel hydrogen delivery unit, was evaluated for removal of nitrate from a synthetic groundwater feed. The hydrogen delivery unit was designed to release hydrogen-supersaturated water to the reactor and was efficient in hydrogen delivery, providing complete mass transfer. The anaerobic submerged MBR was successful in both reducing nitrate from 25 mg NO(3)-Nl(-1) to below detection and separating biomass from treated water to produce effluent free of suspended solids. Nitrogen gas produced during denitrification was internally recycled to effectively achieve membrane scouring and reactor mixing. The total organic carbon was similar to that of the incoming feed water, averaging approximately 6 mgl(-1).

Hydrogen limitation--a method for controlling the performance of membrane biofilm reactor for autotrophic denitrification of wastewater.

Hydrogen-driven denitrification using the fiber membrane biofilm reactor (MBfR) was evaluated for consistent operation in tertiary wastewater treatment. The possibility of controlling the process rates, as well as biofilm parameters by supplying limited amounts of electron donor (hydrogen), was tested. Limiting the hydrogen supply proved to be efficient in controlling the biofilm growth and performance of the MBfR. Denitrification rates remained unchanged for both synthetic wastewater (SWW) and real municipal wastewater (MWW) effluent as well through the fluctuations in the substrate (NO3-N) concentration. The average denitrification rates were 0.50 (+/- 0.02) g NO3-N per day per m2 for SWW and 0.59 (+/- 0.04) g NO3-N per day per m2 for MWW. Biofilm density rather than thickness was the determining factor in substrate diffusion and biofilm sloughing, ultimately determining operating stability. Limited hydrogen supply assured constant volatile solids (VS) concentration in the biofilm. It was determined that VS/TS ratio higher than 0.25 assured stable biofilm operation. Decrease of VS/TS ratio below 0.25 led to shearing of the nonbiological outer layers of the biofilm. The values of chemical oxygen demand (COD), volatile suspended solids (VSS) and total suspended solids (TSS) in the final effluent were stable and well below wastewater effluent guidelines. Substitutions of bicarbonate with gaseous carbon dioxide as the carbon source did not affect denitrification rates despite lower than optimum pH conditions.

Hydrogen-driven denitrification of wastewater in an anaerobic submerged membrane bioreactor: potential for water reuse.

An anaerobic submerged membrane bioreactor was coupled with a novel hydrogen delivery system for hydrogenotrophic denitrification of municipal final effluent containing nitrate. The biological treatment unit and hydrogen delivery unit were proven successful in removing nitrate and delivering hydrogen, respectively. Complete hydrogen transfer resulted in reducing nitrate below detectable levels at a loading of 0.14 kg Nm(-3) d(-1). The produced water met all drinking water guidelines except for color and organic carbon. However, the organic carbon was removed by 72% mostly by membrane rejection. To reduce the organic carbon and color of the effluent, post treatment of the produced water is required.

An approach to the measurement of decay, active fraction of biomass and extracellular polymeric substances: applied to hydrogen-driven denitrification.

A general method for measurement of active biomass and decay coefficient and Extracellular polymeric substances (EPS) concentration in steady-state biomass was developed. The model was applied to the process of hydrogenotrophic denitrification in order to measure biomass constituents and decay and yield coefficients. It was found that steady-state biomass obtained after operation at 20 day solids retention time (SRT) was composed of 41% active biomass, 25.6% cell debris and 33.4% extracellular polymeric substance. The value of 0.041 d(-1), and 0.27 mg active biomass per mg NO3-N were obtained for decay coefficient and true yield, respectively.

Kinetics of hydrogen-dependent denitrification under varying pH and temperature conditions.

It is important to determine the effect of changing environmental conditions on the microbial kinetics for design and modeling of biological treatment processes. In this research, the kinetics of nitrate and nitrite reduction by autotrophic hydrogen-dependent denitrifying bacteria and the possible role of acetogens were studied in two sequencing batch reactors (SBR) under varying pH and temperature conditions. A zero order kinetic model was proposed for nitrate and nitrite reduction and kinetic coefficients were obtained at two temperatures (25 +/- 1 and 12 +/- 1 degrees C), and pH ranging from 7 to 9.5. Nitrate and nitrite reduction was inhibited at pH of 7 at both temperatures of 12 +/- 1 and 25 +/- 1 degrees C. The optimum pH conditions for nitrate and nitrite reduction were 9.5 at 25 +/- 1 degrees C and 8.5 at 12 +/- 1 degrees C. Nitrate and nitrite reduction rates were compared, when they were used separately as the sole electron acceptor. It was shown that nitrite reduction rates consistently exceeded nitrate reduction rates, regardless of temperature and pH. The observed transitional accumulation of nitrite, when nitrate was used as an electron acceptor, indicated that nitrite reduction was slowed down by the presence of nitrate. No activity of acetogenic bacteria was observed in the hydrogenotrophic biomass and no residual acetate was detected, verifying that the kinetic parameters obtained were not influenced by heterotrophic denitrification and accurately represented autotrophic activity.