Dialysis Patient Experiences During the COVID-19 Pandemic: A Survey Study.

Rationale & Objective: The coronavirus disease 2019 (COVID-19) pandemic imposed several changes in the care of patients with kidney failure receiving dialysis. We explored patient care experiences during the pandemic. Study Design: The study team verbally administered surveys including Likert scale multiple-choice questions and open-ended questions and recorded responses. Setting & Participants: Surveys were administered to adults receiving dialysis through an academic nephrology practice after the first wave of the COVID-19 pandemic. Exposure: Outpatient dialysis treatment during the COVID-19 pandemic. Outcomes: Perceptions of care and changes in health. Analytical Approach: Multiple-choice responses were quantified using descriptive statistics. Thematic analysis was used to code open-ended responses and derive themes surrounding patient experiences. Results: A total of 172 patients receiving dialysis were surveyed. Most patients reported feeling "very connected" to the care teams. Seventeen percent of participants reported transportation issues, 6% reported difficulty obtaining medications, and 9% reported difficulty getting groceries. Four themes emerged as influencing patient experiences during the pandemic: 1) the COVID-19 pandemic did not significantly affect participants' experience of dialysis care; 2) the COVID-19 pandemic significantly impacted other aspects of participants' lives, which in turn were felt to affect mental and physical health; 3) regarding dialysis care experience more generally, participants valued consistency, dependability, and personal connection to staff; and 4) the COVID-19 pandemic highlighted the importance of external social support. Limitations: Surveys were administered early in the COVID-19 pandemic, and patient perspectives have not been reassessed. Further qualitative analysis using semi-structured interviews was not performed. Survey distribution in additional practice settings, using validated questionnaires, would increase generalizability of the study. The study was not powered for statistical analysis. Conclusions: Early in the COVID-19 pandemic, perceptions of dialysis care were unchanged for most patients. Other aspects of participants' lives were impacted, which affected their health. Subpopulations of patients receiving dialysis may be more vulnerable during the pandemic: those with histories of mental health conditions, non-White patients, and patients treated by in-center hemodialysis. Plain-language summary: Patients with kidney failure continue to receive life-sustaining dialysis treatments during the coronavirus disease 2019 (COVID-19) pandemic. We sought to understand perceived changes in care and mental health during this challenging time. We administered surveys to patients receiving dialysis after the initial wave of COVID-19, asking questions on topics including access to care, ability to reach care teams, and depression. Most participants did not feel that their dialysis care experiences had changed, but some reported difficulties in other aspects of living such as nutrition and social interactions. Participants highlighted the importance of consistent dialysis care teams and the availability of external support. We found that patients who are treated with in-center hemodialysis, are non-White, or have mental health conditions may have been more vulnerable during the pandemic.

Clinically adjudicated deceased donor acute kidney injury and graft outcomes.

BACKGROUND: Acute kidney injury (AKI) in deceased donors is not associated with graft failure (GF). We hypothesize that hemodynamic AKI (hAKI) comprises the majority of donor AKI and may explain this lack of association. METHODS: In this ancillary analysis of the Deceased Donor Study, 428 donors with available charts were selected to identify those with and without AKI. AKI cases were classified as hAKI, intrinsic (iAKI), or mixed (mAKI) based on majority adjudication by three nephrologists. We evaluated the associations between AKI phenotypes and delayed graft function (DGF), 1-year eGFR and GF. We also evaluated differences in urine biomarkers among AKI phenotypes. RESULTS: Of the 291 (68%) donors with AKI, 106 (36%) were adjudicated as hAKI, 84 (29%) as iAKI and 101 (35%) as mAKI. Of the 856 potential kidneys, 669 were transplanted with 32% developing DGF and 5% experiencing GF. Median 1-year eGFR was 53 (IQR: 41-70) ml/min/1.73m2. Compared to non-AKI, donors with iAKI had higher odds DGF [aOR (95%CI); 4.83 (2.29, 10.22)] and had lower 1-year eGFR [adjusted B coefficient (95% CI): -11 (-19, -3) mL/min/1.73 m2]. hAKI and mAKI were not associated with DGF or 1-year eGFR. Rates of GF were not different among AKI phenotypes and non-AKI. Urine biomarkers such as NGAL, LFABP, MCP-1, YKL-40, cystatin-C and albumin were higher in iAKI. CONCLUSION: iAKI was associated with higher DGF and lower 1-year eGFR but not with GF. Clinically phenotyped donor AKI is biologically different based on biomarkers and may help inform decisions regarding organ utilization.

Association of AKI-D with Urinary Findings and Baseline eGFR in Hospitalized COVID-19 Patients.

Background: AKI is common in patients hospitalized with coronavirus disease 2019 (COVID-19). Risk factors for AKI requiring dialysis (AKI-D) are not fully understood. We aimed to identify risk factors associated with AKI-D and AKI not requiring dialysis (AKI-ND). Methods: We reviewed electronic health records of 3186 patients aged ≥18 years old who were hospitalized with COVID-19 across six hospitals. Patient characteristics, urinalysis findings, and inflammatory markers were analyzed for association with in-hospital AKI status (AKI-D, AKI-ND, or no AKI), and we subsequently evaluated mortality. Results: After adjustment for multiple covariates, higher baseline eGFR was associated with 30% lower odds of AKI-D and 11% lower odds of AKI-ND (for AKI-D, OR, 0.70; 95% CI, 0.64 to 0.77; for AKI-ND, OR, 0.89; 95% CI, 0.85 to 0.92). Patients with obesity and those who were Latino had increased odds of AKI-D, whereas patients with congestive heart failure or diabetes with complications had increased odds of AKI-ND. Females had lower odds of in-hospital AKI (for AKI-D, OR, 0.28; 95% CI, 0.17 to 0.46; for AKI-ND, OR, 0.83; 95% CI, 0.70 to 0.99). After adjustment for covariates and baseline eGFR, 1-4+ protein on initial urinalysis was associated with a nine-fold increase in odds of AKI-D (OR, 9.00; 95% CI, 2.16 to 37.38) and more than two-fold higher odds of AKI-ND (OR, 2.28; 95% CI, 1.66 to 3.13). Findings of 1-3+ blood and trace glucose on initial urinalysis were also associated with increased odds of both AKI-D and AKI-ND. AKI-D and AKI-ND were associated with in-hospital death (for AKI-D, OR, 2.64; 95% CI, 1.13 to 6.17; for AKI-ND, OR, 2.44; 95% CI, 1.77 to 3.35). Conclusions: Active urine sediments, even after adjustment for baseline kidney function, and reduced baseline eGFR are significantly associated with increased odds of AKI-D and AKI-ND. In-hospital AKI was associated with in-hospital death. These findings may help prognosticate patients hospitalized with COVID-19.

Management of COVID-19 in an Outpatient Dialysis Program.

In March 2020, the COVID-19 pandemic became an increasingly urgent issue of public health concern in the United States. Patients on dialysis are considered to be at increased risk for infection due to their medical comorbidities and need for continued face-to-face encounters in dialysis units. In our outpatient dialysis practice, 42 out of 269 patients (15.6%) were infected with COVID-19 during the first wave of the pandemic. In this retrospective report, we review issues of infection control, access to interventional procedures, and communication encountered in our practice. We discuss lessons learned in patient outcomes and the importance of transitioning patients to home modalities. Further planning for a potential second wave of COVID-19 may help ensure improved quality of care for patients in the dialysis program.

Should Angiotensin-Converting Enzyme Inhibitors ever Be Used for the Management of Hypertension?

PURPOSE OF REVIEW: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are commonly used anti-hypertensive medications in a number of clinical settings. They are often used interchangeably, but we pose the provocative question as to whether they should be. We review the literature to evaluate for any differences in efficacy between the two classes in order to determine if the greater side effects associated with angiotensin-converting enzyme inhibitors are offset by any advantageous effects on outcomes to warrant their use over angiotensin receptor blockers. RECENT FINDINGS: In many clinical scenarios, the data supports similar efficacy between ACE inhibitors and ARBs, while in a minority of others, there are murky signals from previous trials that suggest ACE inhibitors may be better. However, when reviewing the literature in its entirety, and taking into account recently published pooled analysis and head to head trials, it is reasonable to conclude that ACE inhibitors and ARBs have similar efficacy. This is in contrast to data on adverse effects, which consistently favors the use of ARBs. From the available data, it is reasonable to conclude that ACE inhibitors and ARBs have equal efficacy yet unequal adverse effects. It is in this context that we take the provocative stance that ACE inhibitors should not be used to treat hypertension.

Mutational analysis implicates the amyloid fibril as the toxic entity in Huntington's disease.

In Huntington disease (HD), an expanded polyglutamine (polyQ > 37) sequence within huntingtin (htt) exon1 leads to enhanced disease risk. It has proved difficult, however, to determine whether the toxic form generated by polyQ expansion is a misfolded or avid-binding monomer, an α-helix-rich oligomer, or a ß-sheet-rich amyloid fibril. Here we describe an engineered htt exon1 analog featuring a short polyQ sequence that nonetheless quickly forms amyloid fibrils and causes HD-like toxicity in rat neurons and Drosophila. Additional modifications within the polyQ segment produce htt exon1 analogs that populate only spherical oligomers and are non-toxic in cells and flies. Furthermore, in mixture with expanded-polyQ htt exon1, the latter analogs in vitro suppress amyloid formation and promote oligomer formation, and in vivo rescue neurons and flies expressing mhtt exon1 from dysfunction and death. Thus, in our experiments, while htt exon1 toxicity tracks with aggregation propensity, it does so in spite of the toxic construct's possessing polyQ tracts well below those normally considered to be disease-associated. That is, aggregation propensity proves to be a more accurate surrogate for toxicity than is polyQ repeat length itself, strongly supporting a major toxic role for htt exon1 aggregation in HD. In addition, the results suggest that the aggregates that are most toxic in these model systems are amyloid-related. These engineered analogs are novel tools for mapping properties of polyQ self-assembly intermediates and products that should similarly be useful in the analysis of other expanded polyQ diseases. Small molecules with similar amyloid inhibitory properties might be developed into effective therapeutic agents.

An Aggregate Weight-Normalized Thioflavin-T Measurement Scale for Characterizing Polymorphic Amyloids and Assembly Intermediates.

The red shift in the fluorescence excitation spectra of thioflavin dyes upon binding to fibrils has been a boon to the amyloid field, offering simple and effective methods for the qualitative detection of amyloid in tissue samples and for quantitation of particular fibril preparations with gravimetric linearity. The quantitative aspect of the thioflavin T (ThT) response, however, comes with an important caveat that bestows both significant limitations and great untapped power. It is now well established that amyloid fibrils of different proteins, as well as polymorphic fibrils of the same protein, can exhibit vastly different ThT fluorescence intensities for the same weight concentration of aggregates. Furthermore, the aggregated intermediates commonly observed in amyloid assembly reactions can exhibit aggregate weight-normalized (AWN) ThT fluorescence intensities that vary from essentially zero through a wide range of intermediate values before reaching the intensity of homogeneous, mature amyloid. These features make it very difficult to quantitatively interpret, without additional data, the time-dependent development of ThT fluorescence intensity in an assembly reaction. In this chapter, we describe a method for coupling ex situ ThT fluorescence determinations with an analytical HPLC supported sedimentation assay (also described in detail) that can provide significant new insights into amyloid assembly reactions. The time dependent aggregation data provided by the sedimentation assay reveals a time course of aggregation that is largely independent of aggregate properties. In addition, the combination of these data with ThT measurements of the same reaction time points reveals important aspects of average aggregate structure at each time point. Examples of the use and potential value of AWN-ThT measurements during amyloid assembly Aß and polyglutamine peptides are provided.

Binding Properties of the Transforming Growth Factor-ß Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling.

Transforming growth factor (TGF) ß1, ß2, and ß3 (TGF-ß1-TGF-ß3, respectively) are small secreted signaling proteins that each signal through the TGF-ß type I and type II receptors (TßRI and TßRII, respectively). However, TGF-ß2, which is well-known to bind TßRII several hundred-fold more weakly than TGF-ß1 and TGF-ß3, has an additional requirement for betaglycan, a membrane-anchored nonsignaling receptor. Betaglycan has two domains that bind TGF-ß2 at independent sites, but how it binds TGF-ß2 to potentiate TßRII binding and how the complex with TGF-ß, TßRII, and betaglycan undergoes the transition to the signaling complex with TGF-ß, TßRII, and TßRI are not understood. To investigate the mechanism, the binding of the TGF-ßs to the betaglycan extracellular domain, as well as its two independent binding domains, either directly or in combination with the TßRI and TßRII ectodomains, was studied using surface plasmon resonance, isothermal titration calorimetry, and size-exclusion chromatography. These studies show that betaglycan binds TGF-ß homodimers with a 1:1 stoichiometry in a manner that allows one molecule of TßRII to bind. These studies further show that betaglycan modestly potentiates the binding of TßRII and must be displaced to allow TßRI to bind. These findings suggest that betaglycan functions to bind and concentrate TGF-ß2 on the cell surface and thus promote the binding of TßRII by both membrane-localization effects and allostery. These studies further suggest that the transition to the signaling complex is mediated by the recruitment of TßRI, which simultaneously displaces betaglycan and stabilizes the bound TßRII by direct receptor-receptor contact.

Calcium causes a conformational change in lamin A tail domain that promotes farnesyl-mediated membrane association.

Lamin proteins contribute to nuclear structure and function, primarily at the inner nuclear membrane. The posttranslational processing pathway of lamin A includes farnesylation of the C-terminus, likely to increase membrane association, and subsequent proteolytic cleavage of the C-terminus. Hutchinson Gilford progeria syndrome is a premature aging disorder wherein a mutant version of lamin A, Δ50 lamin A, retains its farnesylation. We report here that membrane association of farnesylated Δ50 lamin A tail domains requires calcium. Experimental evidence and molecular dynamics simulations collectively suggest that the farnesyl group is sequestered within a hydrophobic region in the tail domain in the absence of calcium. Calcium binds to the tail domain with an affinity KD ≈ 250 µM where it alters the structure of the Ig-fold and increases the solvent accessibility of the C-terminus. In 2 mM CaCl2, the affinity of the farnesylated protein to a synthetic membrane is KD ≈ 2 µM, as measured with surface plasmon resonance, but showed a combination of aggregation and binding. Membrane binding in the absence of calcium could not be detected. We suggest that a conformational change induced in Δ50 lamin A with divalent cations plays a regulatory role in the posttranslational processing of lamin A, which may be important in disease pathogenesis.