Pitfalls when comparing COVID-19-related outcomes across studies-lessons learnt from the ERACODA collaboration

Reported outcomes, such as incidence rates of mortality and intensive care unit admission, vary widely across epidemiological coronavirus disease 2019 (COVID-19) studies, including in the nephrology field. This variation can in part be explained by differences in patient characteristics, but also methodological aspects must be considered. In this review, we reflect on the methodological factors that contribute to the observed variation in COVID-19-related outcomes and their risk factors that are identified in the various studies. We focus on issues that arose during the design and analysis phase of the European Renal Association COVID-19 Database (ERACODA), and use examples from recently published reports on COVID-19 to illustrate these issues

Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study

Uncertainty exists regarding the necessity of continuing triple therapy consisting of mycophenolate mofetil (MMF), cyclosporine (CsA), and prednisone (Pred) after kidney transplantation (RTx). At 6 mo after RTx, 212 patients were randomized to stop CsA (n = 63), stop Pred (n = 76), or continue triple drug therapy (n = 73). The MMF dose was 1000 mg twice daily, target CsA trough levels were 150 ng/ml, and Pred dose was 0.10 mg/kg per d. Follow-up was until 24 mo after RTx. Biopsy-proven acute rejection occurred in 14 (22%) of 63 patients after CsA withdrawal compared with 3 (4%) of 76 in the Pred withdrawal group (P = 0.001) and 1 (1.4%) of 73 in the control group (P = 0.0001). Biopsy-proven chronic rejection was present in one patient in the control group, in nine patients after CsA withdrawal (P = 0.006 versus control group); and in four patients after discontinuation of Pred (NS). Graft loss occurred in two versus one patient after CsA or Pred withdrawal, respectively, and in two patients in the control group (NS). Patients who successfully withdrew CsA had a significantly lower serum creatinine during follow-up. Pred withdrawal resulted in a reduction in mean arterial pressure, and the total cholesterol/HDL ratio increased. In conclusion, rapid CsA withdrawal at 6 mo after RTx results in a significantly increased incidence of biopsy-proven acute and chronic rejection. Pred withdrawal was safe and resulted in a reduction in mean arterial pressure. However, patient and graft survival and renal function 2 yr after RTx were not different among groups

Wfs1-deficient mice display altered function of serotonergic system and increased behavioral response to antidepressants

It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT) and noradrenaline (NA) reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioral despair. The tail suspension test (TST) and forced swimming test (FST) were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT) were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 min to brightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states

Corneal Pachymetry by AS-OCT after Descemet's Membrane Endothelial Keratoplasty

Corneal thickness (pachymetry) maps can be used to monitor restoration of corneal endothelial function, for example after Descemet's membrane endothelial keratoplasty (DMEK). Automated delineation of the corneal interfaces in anterior segment optical coherence tomography (AS-OCT) can be challenging for corneas that are irregularly shaped due to pathology, or as a consequence of surgery, leading to incorrect thickness measurements. In this research, deep learning is used to automatically delineate the corneal interfaces and measure corneal thickness with high accuracy in post-DMEK AS-OCT B-scans. Three different deep learning strategies were developed based on 960 B-scans from 50 patients. On an independent test set of 320 B-scans, corneal thickness could be measured with an error of 13.98 to 15.50 micrometer for the central 9 mm range, which is less than 3% of the average corneal thickness. The accurate thickness measurements were used to construct detailed pachymetry maps. Moreover, follow-up scans could be registered based on anatomical landmarks to obtain differential pachymetry maps. These maps may enable a more comprehensive understanding of the restoration of the endothelial function after DMEK, where thickness often varies throughout different regions of the cornea, and subsequently contribute to a standardized postoperative regime.Comment: Fixed typo in abstract: The development set consists of 960 B-scans from 50 patients (instead of 68). The B-scans from the other 18 patients were used for testing onl

Compensation comparison method for assessment of retinal straylight,”

PURPOSE. Presently, no instrument or method exists that is generally accepted for routine clinical assessment of (functional) retinal straylight. Yet retinal straylight is the cause of major patient complaints, such as hindrance from glare and loss of contrast. It results from disturbances in the optical media that increase light-scattering over angles of 1°to 90°. Its assessment would help to decide whether to perform surgery for (early) cataract and would help in the evaluation of corneal or vitreal turbidity. METHODS. The psychophysical technique of the "direct compensation" method was adapted to make it suitable for routine clinical assessment. In the new approach, called "compensation comparison, " the central test field is subdivided into two half fields: one with and one without counterphase compensation light. The subject's task is a forced-choice comparison between the two half fields, to decide which half flickers more strongly. A theoretical form for the respective psychometric function was defined and experimentally verified in a laboratory experiment involving seven subjects, with and without artificially increased light scattering. The method was applied in a separate multicenter study. Its reliability was additionally tested with a commercial implement (C-Quant; Oculus Optikgeräte, Wetzlar-Dutenhofen, Germany). RESULTS. A repeated-measures SD of 0.07 log units was achieved, to be compared with differences in the young normal population of 0.4 log units and an increase with healthy aging by 0.5 log units at 80 years and by 1.0 or more log units with (early) cataract or corneal disturbances. Reliability was further found to be high when using the commercial version of the method. CONCLUSIONS. The compensation comparison method for measuring retinal straylight is suited for clinical use to diagnose patients with complaints caused by large angle light scattering in the eye such as early cataract. (Invest Ophthalmol Vis Sci

Pioglitazone Decreases Plasma Cholesteryl Ester Transfer Protein Mass, Associated With a Decrease in Hepatic Triglyceride Content, in Patients With Type 2 Diabetes

Thiazolidinediones reduce hepatic steatosis and increase HDL cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in hepatic triglyceride content is associated with a decrease in plasma cholesteryl ester transfer protein (CETP) mass and an increase in HDL levels. Therefore, the aim of the present study was to assess the effects of pioglitazone on CETP mass in patients with type 2 diabetes. We included 78 men with type 2 diabetes (aged 56.5 +/- 0.6 years; HbA1c 7.1 +/- 0.1%) who were randomly assigned to treatment with pioglitazone (30 mg/day) or metformin (2000 mg/day) and matching placebo, in addition to glimepiride. At baseline and after 24 weeks of treatment plasma HDL cholesterol levels and CETP mass were measured, and hepatic triglyceride content was assessed by proton magnetic resonance spectroscopy. RESULTS Pioglitazone decreased hepatic triglyceride content (5.9 [interquartile range 2.6-17.4] versus 4.1 [1.9-12.3]%, P <0.05), decreased plasma CETP mass (2.33 +/- 0.10 vs. 2.06 +/- 0.10 microg/ml, P <0.05), and increased plasma HDL cholesterol level (1.22 +/- 0.05 vs. 1.34 +/- 0.05 mmol/l, P <0.05). Metformin did not significantly change any of these parameters. A decrease in hepatic triglyceride content by pioglitazone is accompanied by a decrease in plasma CETP mass and associated with an increase in HDL cholesterol levels. These results in patients with type 2 diabetes fully confirm recent findings in mic

Predictors of Nonseroconversion to SARS-CoV-2 Vaccination in Kidney Transplant Recipients

Kidney transplant recipients (KTRs) are still at risk of severe COVID-19 disease after SARS‑CoV‑2 vaccination, especially when they have limited antibody formation. Our aim was to understand the factors that may limit their humoral response. METHODS. Our data are derived from KTRs who were enrolled in the Dutch Renal Patients COVID-19 Vaccination consortium, using a discovery cohort and 2 external validation cohorts. Included in the discovery (N = 1804) and first validation (N = 288) cohorts were participants who received 2 doses of the mRNA-1273 vaccine. The second validation cohort consisted of KTRs who subsequently received a third dose of any SARS-CoV-2 vaccine (N = 1401). All participants had no history of SARS-CoV-2 infection. A multivariable logistic prediction model was built using stepwise backward regression analysis with nonseroconversion as the outcome. RESULTS. The discovery cohort comprised 836 (46.3%) KTRs, the first validation cohort 124 (43.1%) KTRs, and the second validation cohort 358 (25.6%) KTRs who did not seroconvert. In the final multivariable model‚ 12 factors remained predictive for nonseroconversion: use of mycophenolate mofetil/mycophenolic acid (MMF/MPA); chronic lung disease, heart failure, and diabetes; increased age; shorter time after transplantation; lower body mass index; lower kidney function; no alcohol consumption; ≥2 transplantations; and no use of mammalian target of rapamycin inhibitors or calcineurin inhibitors. The area under the curve was 0.77 (95% confidence interval [CI], 0.74-0.79) in the discovery cohort after adjustment for optimism, 0.81 (95% CI, 0.76-0.86) in the first validation cohort, and 0.67 (95% CI, 0.64-0.71) in the second validation cohort. The strongest predictor was the use of MMF/MPA, with a dose-dependent unfavorable effect, which remained after 3 vaccinations. CONCLUSIONS. In a large sample of KTRs, we identify a selection of KTRs at high risk of nonseroconversion after SARS-CoV-2 vaccination. Modulation of MMF/MPA treatment before vaccination may help to optimize vaccine response in these KTRs. This model contributes to future considerations on alternative vaccination strategies

Employment and ability to work after kidney transplantation in the Netherlands:The impact of preemptive versus non-preemptive kidney transplantation

Background: Work can have a major positive impact on health and wellbeing. Employment of kidney transplant recipients (KTR) of working age is much lower than in the general population. The first aim of this study was to examine the impact of a preemptive kidney transplantation (PKT) on employment, in addition to other possible influencing factors. The second aim was to explore differences in work ability, absenteeism and work performance among employed KTR with different types of transplantations. Methods: A cross-sectional survey study was conducted between 2018 and 2019 in nine Dutch hospitals. PKT as potential predictor of employment was examined. Furthermore, work ability, absenteeism and loss of work performance were compared between employed preemptive recipients with a living donor (L-PKT) and non-preemptive recipients with a living donor (L-nPKT) and with a deceased donor (D-nPKT). Results: Two hundred and twenty four KTR participated; 71% reported having paid work. Paid work was more common among PKT recipients (82% vs. 65% in L-nPKT and 55% in D-nPKT) and recipients who were younger (OR .950, 95%CI .913-.989), had no comorbidities (1 comorbidity: OR .397, 95%CI .167-.942; 2 comorbidities: OR .347, 95%CI .142-.844), had less fatigue (OR .974, 95%CI .962-.987) and had mentally demanding work tasks (only in comparison with physically demanding tasks, OR .342, 95%CI .145-.806). If recipients were employed, D-nPKT recipients worked fewer hours (mean 24.6 +/- 11.3 vs. PKT 31.1 +/- 9.6, L-nPKT 30.1 +/- 9.5) and D-nPKT and L-nPKT recipients received more often supplemental disability benefits (32 and 33.3%, respectively) compared to PKT recipients (9.9%). No differences were found for self-reported ability to work, sick leave (absenteeism) and loss of work performance with the exception of limitations in functioning at work. Conclusions: Preemptive kidney transplantation recipients with a kidney from a living donor are employed more often, work more hours per week (only in comparison with D-nPKT) and have a partial disability benefit less often than nPKT recipients. More knowledge regarding treatments supporting sustainable participation in the labor force is needed as work has a positive impact on recipients' health and wellbeing and is also beneficial for society as a whole