2009 CKD-EPI glomerular filtration rate estimation in Black individuals outside the United States: a systematic review and meta-analysis.

Background: The 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is the most used equation to estimate glomerular filtration rate (GFR), with race being a factor thereof, increasing GFR by 16% in self-identified Black persons compared with non-Black persons. However, recent publications indicate that it might overestimate GFR for Black adults outside the USA. In this meta-analysis, we assessed the accuracy, evaluated by the percentage of estimated GFR within 30% of measured GFR (P30), of the 2009 CKD-EPI equation in estimating GFR with and without the race coefficient in Black individuals outside the United States of America (USA). Methods: We searched MEDLINE and Embase from inception to 9 July 2022, with no language restriction, supplemented by manual reference searches. Studies that assessed the CKD-EPI P30 accuracy with or without the race coefficient in Black adults outside the USA with an adequate method of GFR measurement were included. Data were extracted by independent pairs of reviewers and were pooled using a random-effects model. Results: We included 11 studies, with a total of 1834 Black adults from South America, Africa and Europe. The race coefficient in the 2009 CKD-EPI equation significantly decreased P30 accuracy {61.9% [95% confidence interval (CI) 53-70%] versus 72.9% [95% CI 66.7-78.3%]; P = .03}. Conclusions: Outside the USA, the 2009 CKD-EPI equation should not be used with the race coefficient, even though the 2009 CKD-EPI equation is not sufficiently accurate either way (<75%). Thus we endorse the Kidney Disease: Improving Global Outcomes guidelines to use exogenous filtration markers when this may impact clinical conduct.

Accuracy evaluation of 2021 Chronic Kidney Disease Epidemiology Collaboration, Full Age Spectrum and European Kidney Function Consortium equations for estimating glomerular filtration rate in type 2 diabetes mellitus and healthy adults.

BACKGROUND AND AIMS: Estimated glomerular filtration rate (eGFR) equations accuracy has been questioned in diabetes mellitus (DM). We aimed to evaluate the performance of three equations - European Kidney Function Consortium (EKFC), Full Age Spectrum (FAS), and 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) - in healthy and type 2 DM participants. MATERIAL AND METHODS: This cross-sectional studycompared eGFR equations withareference method: measured GFR (mGFR) by 51Cr-EDTA. The equations performance was assessed usingBland-Altman plot,concordance correlation coefficient (CCC), bias,P30 andP15 accuracy. RESULTS: In the 100 healthy adults included (aged 39 ± 15 years, 67% women, mean mGFR 107 ± 15, 2021 CKD-EPI 109 ± 14, FAS 107 ± 18 and EKFC 101 ± 12 mL/min/1.73 m2), all equations reached P30 accuracy above the desirable benchmark of 90%. In the 122 patients with type 2 DM (aged 61 ± 10 years, 55% women, mGFR97 ± 22, 2021 CKD-EPI 86 ± 20, FAS 83 ± 25 and EKFC 79 ± 18 mL/min/1.73 m2), the equations presented larger biases, worst agreement with mGFR and inferior accuracy, with 2021 CKD-EPI (83%) and EKFC (82%) presenting greater P30 than FAS (77%). CONCLUSION: In healthy Brazilian adults, 2021 CKD-EPI, FAS and EKFC are suitable to estimate GFR. However, all equations underperform in people with type 2 DM.

The 2021-2022 position of Brazilian Diabetes Society on diabetic kidney disease (DKD) management: an evidence-based guideline to clinical practice. Screening and treatment of hyperglycemia, arterial hypertension, and dyslipidemia in the patient with DKD.

BACKGROUND: Diabetic kidney disease is the leading cause of end-stage renal disease and is associated with increased morbidity and mortality. This review is an authorized literal translation of part of the Brazilian Diabetes Society (SBD) Guidelines 2021-2022. This evidence-based guideline provides guidance on the correct management of Diabetic Kidney Disease (DKD) in clinical practice. METHODS: The methodology was published elsewhere in previous SBD guidelines and was approved by the internal institutional Steering Committee for publication. Briefly, the Brazilian Diabetes Society indicated 14 experts to constitute the Central Committee, designed to regulate methodology, review the manuscripts, and make judgments on degrees of recommendations and levels of evidence. SBD Renal Disease Department drafted the manuscript selecting key clinical questions to make a narrative review using MEDLINE via PubMed, with the best evidence available including high-quality clinical trials, metanalysis, and large observational studies related to DKD diagnosis and treatment, by using the MeSH terms [diabetes], [type 2 diabetes], [type 1 diabetes] and [chronic kidney disease]. RESULTS: The extensive review of the literature made by the 14 members of the Central Committee defined 24 recommendations. Three levels of evidence were considered: A. Data from more than 1 randomized clinical trial or 1 metanalysis of randomized clinical trials with low heterogeneity (I2 < 40%). B. Data from metanalysis, including large observational studies, a single randomized clinical trial, or a pre-specified subgroup analysis. C: Data from small or non-randomized studies, exploratory analyses, or consensus of expert opinion. The degree of recommendation was obtained based on a poll sent to the panelists, using the following criteria: Grade I: when more than 90% of agreement; Grade IIa 75-89% of agreement; IIb 50-74% of agreement, and III, when most of the panelist recommends against a defined treatment. CONCLUSIONS: To prevent or at least postpone the advanced stages of DKD with the associated cardiovascular complications, intensive glycemic and blood pressure control are required, as well as the use of renin-angiotensin-aldosterone system blocker agents such as ARB, ACEI, and MRA. Recently, SGLT2 inhibitors and GLP1 receptor agonists have been added to the therapeutic arsenal, with well-proven benefits regarding kidney protection and patients' survival.

Telephone calls and glycemic control in type 2 diabetes: A PRISMA-compliant systematic review and meta-analysis of randomized clinical trials.

AIMS: In-depth and updated systematic reviews evaluating telephone calls in type 2 diabetes (T2DM) management are missing. This study aimed to assess the effect of this intervention on glycemic control in T2DM patients when compared with usual care. METHODS: We systematically searched for randomized controlled trials (RCT) on T2DM using Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and LILACS, up to March 2021. The Risk of Bias 2.0 (Rob 2.0) tool and GRADE were used for the quality evaluation. The intervention effect was estimated by the change in glycated hemoglobin (HbA1c). PROSPERO registry CRD42020204519. RESULTS: 3545 references were reviewed and 32 were included (8598 patients). Telephone calls, all approaching education, improved HbA1c by 0.33% [95% CI, -0.48% to -0.18%; I2 = 78%; p < 0.0001] compared to usual care. A greater improvement was found when the intervention included pharmacologic modification (-0.82%, 95% CI, -1.42% to -0.22%; I2 = 92%) and when it was applied by nurses (-0.53%, 95% CI, -0.86% to -0.2%; I2 = 87%). Meta-regression showed no relationship between DM duration and HbA1c changes. CONCLUSION: The telephone call intervention provided a benefit regarding T2DM glycemic control, especially if provided by nurses, or if associated with patient education and pharmacological treatment modification.

Accuracy of Doppler assessment of the uterine arteries in healthy girls for the diagnosis of pubertal onset.

PURPOSE: To evaluate the accuracy of the uterine artery pulsatility index (PI) for the diagnosis of pubertal onset in girls. METHODS: Cross-sectional study of girls with normal pubertal development. Puberty was diagnosed by the presence of Tanner breast development score ≥2. All girls underwent pelvic ultrasound and Doppler imaging of the uterine arteries. We evaluated the uterine artery PI and uterine, endometrial, and ovarian measurements. We used ROC curves with cutoffs determined by Youden index for data analysis. RESULTS: We included 169 girls aged 5-16 years who underwent 202 pelvic ultrasound examinations. Prepubertal girls had a significantly higher mean PI (6.70 ± 2.15) than girls in initial puberty (4.14 ± 1.55) and in late puberty (2.81 ± 1.05) (P < 0.001 for all comparisons), which reflects a progressive increase in blood flow to the uterus with the progression of puberty. ROC curve analysis showed that the PI was able to identify the onset of puberty with a mean area under the curve of 0.838 ± 0.04 (P < 0.001), and the PI cutoff point of 5.05 had a sensitivity of 77%, specificity of 85%, positive predictive value (PPV) of 92%, and accuracy of 79%. The combination of PI < 5.05 plus uterine volume >3.75 cm³ had a sensitivity of 73%, specificity of 95%, PPV of 97%, and accuracy of 79% to detect initial puberty. CONCLUSIONS: We found a significant reduction in the PI during pubertal development, which can possibly be a valuable noninvasive tool in the evaluation of pubertal disorders, alone or in combination with uterine and ovarian volumes.

Monitoring and management of hyperglycemia in patients with advanced diabetic kidney disease.

Diabetes mellitus is the leading cause of end-stage renal disease, and uncontrolled hyperglycemia is directly related to the increased mortality in this setting. As kidney function decreases, it becomes more challenging to control blood glucose since the risk of hypoglycemia increases. Decreased appetite, changes in glycaemia homeostasis, along with reduced renal excretion of anti-hyperglycemic drugs tend to facilitate the occurrence of hypoglycemia, despite the paradoxical occurrence of insulin resistance in advanced kidney disease. Thus, in patients using insulin and/or oral anti-hyperglycemic agents, dynamic adjustments with drug dose reduction or drug switching are often necessary. Furthermore, in addition to consider these pharmacokinetics alterations, it is of utmost importance to choose drugs with proven cardio-renal benefits in this setting, such as sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists. In this review, we summarize the indications and contraindications, titration of doses and side effects of the available anti-hyperglycemic agents in the presence of advanced diabetic kidney disease (DKD) and dialysis, highlighting the risks and benefits of the different agents. Additionally, basic renal function assessment and monitoring of glycemic control in DKD will be evaluated in order to guide the use of drugs and define the glycemic targets to be achieved.

Role of non-classical effects of testosterone and epitestosterone on AMH balance and testicular development parameters.

Testosterone (T) and its 17-α epimer, epitestosterone (EpiT), are described as having non-classical effects in addition to their classical androgen actions via the intracellular androgen receptor (iAR). The actions of these androgens play an essential role in triggering factors that shift Sertoli cells from the proliferation phase to the maturation phase. This process is essential for successful spermatogenesis and normal fertility. The aim of this work was to investigate the difference between T and EpiT effects in normal and in chemically castrated Wistar rats. We also tested the effects of these hormones when the iAR-dependent pathways were inhibited by the antiandrogen flutamide. Rats were chemically castrated on postnatal day (pnd) 5 using EDS, a cytotoxic agent that promotes apoptosis of Leydig cells, reducing androgen levels. Then, animals received replacement with T or EpiT and were treated or not with flutamide from pnd 6 to pnd 13 or 20 and were euthanized on pnd 14 and 21. Animals treated with EpiT and flutamide had lower body weight overall. Epididymis weight was also reduced in animals treated with EpiT and flutamide. Flutamide per se reduced epididymis weight at both ages (pnd 14 and 21). Testicular weight and the testicular/body weight ratio were reduced in EDS animals, and flutamide further reduced this weight in animals which received T replacement. EDS administration reduced mRNA levels of both AMH (anti-Müllerian hormone) and its receptor, AMHR2, at pnd 14. In the testes of flutamide-treated animals, EpiT reduced AMH, and both T and EpiT replacement diminished AMHR2 mRNA expression also on pnd 14. EDS decreased iAR expression, and androgen replacement did not change this effect on pnd 21. In rats receiving flutamide, only those also receiving T and EpiT replacement exhibited decreased iAR expression. An increase in connexin 43 expression was observed in animals treated with EpiT without flutamide, whereas in rats treated with flutamide, both hormones were ineffective to increase connexin 43 expression reduced by EDS. Our results suggest that EpiT has an antiandrogen effect on androgen-sensitive tissues such as the epididymis. Nonetheless, the effects of T and EpiT on testicular development parameters are similar. Both hormones may act through their iAR-independent non-classical pathway, regulating AMH and AMHR2, as well as iAR expression.

Epitestosterone- and testosterone-replacement in immature castrated rats changes main testicular developmental characteristics.

Epitestosterone is the 17α-epimer of testosterone and has been described as an anti-androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the nuclear androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca2+ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR-immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells.

Non-classical effects of androgens on testes from neonatal rats.

The intratesticular testosterone concentration is high during the early postnatal period although the intracellular androgen receptor expression (iAR) is still absent in Sertoli cells (SCs). This study aimed to evaluate the non-classical effects of testosterone and epitestosterone on calcium uptake and the electrophysiological effects of testosterone (1µM) on SCs from rats on postnatal day (pnd) 3 and 4 with lack of expression of the iAR. In addition, crosstalk on the electrophysiological effects of testosterone and epitestosterone with follicle stimulating hormone (FSH) in SCs from 15-day-old rats was evaluated. The isotope (45)Ca(2+) was utilized to evaluate the effects of testosterone and epitestosterone in calcium uptake. The membrane potential of SCs was recorded using a standard single microelectrode technique. No immunoreaction concerning the iAR was observed in SCs on pnd 3 and 4. At this age, both testosterone and epitestosterone increased the (45)Ca(2+) uptake. Testosterone promoted membrane potential depolarization of SCs on pnd 4. FSH application followed by testosterone and epitestosterone reduced the depolarization of the two hormones. Application of epitestosterone 5 min after FSH resulted in a delay of epitestosterone-promoted depolarization. The cell resistance was also reduced. Thus, in SCs from neonatal Wistar rats, both testosterone and epitestosterone act through a non-classical mechanism stimulating calcium uptake in whole testes, and testosterone produces a depolarizing effect on SC membranes. Testosterone and epitestosterone stimulates non-classical actions via a membrane mechanism, which is independent of iAR. FSH and testosterone/epitestosterone affect each other's electrophysiological responses suggesting crosstalk between the intracellular signaling pathways.

Insulin and IGF-I actions on IGF-I receptor in seminiferous tubules from immature rats.

Insulin and insulin-like growth factor 1 (IGF-I) are capable of activating similar intracellular pathways. Insulin acts mainly through its own receptor, but can also activate the IGF-I receptor (IGF-IR). The aim of this study was to investigate the involvement of the IGF-IR in the effects of insulin and IGF-I on the membrane potential of immature Sertoli cells in whole seminiferous tubules, as well as on calcium, amino acid, and glucose uptake in testicular tissue of immature rats. The membrane potential of the Sertoli cells was recorded using a standard single microelectrode technique. In calcium uptake experiments, the testes were pre-incubated with (45)Ca(2+), with or without JB1 (1 µg/mL), and then incubated with insulin (100 nM) or IGF-I (15 nM). In amino acid and glucose uptake experiments, the gonads were pre-incubated with or without JB1 (1 µg/mL) and then incubated with radiolabeled amino acid or glucose analogues in the presence of insulin (100 nM) or IGF-I (15 nM). The blockade of IGF-IR with JB1 prevented the depolarising effects of both insulin and IGF-I on membrane potential, as well as the effect of insulin on calcium uptake. JB1 also inhibited the effects of insulin and IGF-I on glucose uptake. The effect of IGF-I on amino acid transport was inhibited in the presence of JB1, whereas the effect of insulin was not. We concluded that while IGF-I seems to act mainly through its cognate receptor to induce membrane depolarisation and calcium, amino acid and glucose uptake, insulin appears to be able to elicit its effects through IGF-IR, in seminiferous tubules from immature rats.

PI3K-dependent actions of insulin and IGF-I on seminiferous tubules from immature rats.

There is clear evidence that insulin and insulin-like growth factor I (IGF-I) are crucial for the normal metabolism and development of Sertoli cells. However, the mechanisms of insulin regulatory signaling remain unknown in these cells, especially during the immature period. The aim of this study was to investigate the electrophysiological effects of insulin and the effects of insulin and IGF-I on calcium uptake, amino acid, and glucose transport in whole seminiferous tubules from 12-day-old rats, as well as the involvement of PI3K/Akt signaling pathway in these effects. Insulin produces a depolarizing effect on the membrane potential of Sertoli cells in seminiferous tubules within 180 s. This effect was nullified by verapamil, an L-type voltage-dependent calcium channel blocker, therefore demonstrating a calcium-dependent depolarizing effect. Both insulin and IGF-I stimulate calcium uptake, amino acid, and glucose transport in whole testes from 12-day-old rats. These stimulatory effects of insulin and IGF-I on calcium uptake and amino acid and glucose transport on testicular tissue were nullified by wortmannin, which demonstrates the involvement of the PI3K/Akt signaling pathway in these hormonal effects.