How to Determine the Role of an Additive on the Length of Supramolecular Polymers?

In polymer chemistry, modulation of sequence and control over chain length are routinely applied to alter and fine-tune the properties of covalent (co)polymers. For supramolecular polymers, the same principles underlying this control have not been fully elucidated up to this date. Particularly, rational control over molecular weight in dynamic supramolecular polymers is not trivial, especially when a cooperative mechanism is operative. We start this review by summarizing how molecular-weight control has been achieved in seminal examples in the field of supramolecular polymerizations. Following this, we propose to classify the avenues taken to control molecular weights in supramolecular polymerizations. We focus on dynamic cooperative supramolecular polymerization as this is the most challenging in terms of molecular weight control. We use a mass-balance equilibrium model to predict how the nature of the interaction of an additive B with the monomers and supramolecular polymers of component A affects the degree of aggregation and the degree of polymerization. We put forward a classification system that distinguishes between B acting as a chain capper, a sequestrator, a comonomer, or an intercalator. We also highlight the experimental methods applied to probe supramolecular polymerization processes, the type of information they provide in relation to molecular weight and degree of aggregation, and how this can be used to classify the role of B. The guidelines and classification delineated in this review to assess and control molecular weights in supramolecular polymers can serve to reevaluate exciting systems present in current literature and contribute to broaden the understanding of multicomponent systems.</p

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. Conclusions: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes

The longitudinal relationship between patient-reported outcomes and clinical characteristics among patients with focal segmental glomerulosclerosis in the nephrotic syndrome study network

Background. Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods. FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results. There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (-7.6 points, P ¼ 0.02) and mobility (-4.2, P ¼ 0.02), the number of reported symptoms was associated with worse depression (-2.7 per symptom, P ¼ 0.009) and anxiety (-2.3, P ¼ 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (-2.8 per visit, P < 0.001) and fatigue (-2.4, P ¼ 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (þ9.3, P ¼ 0.03). Conclusions. PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes

Complete remission in the nephrotic syndrome study network

Background and objectives This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). Design, setting, participants, &amp; measurements We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC)&lt;0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever. Results We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m2 (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis. Conclusions In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission

Elucidating the Supramolecular Copolymerization of N- and C-Centered Benzene-1,3,5-Tricarboxamides: The Role of Parallel and Antiparallel Packing of Amide Groups in the Copolymer Microstructure

An in-depth study of the supramolecular copolymerization behavior of N- and C-centered benzene-1,3,5-tricarboxamides (N- and C-BTAs) has been conducted in methylcyclohexane and in the solid state. The connectivity of the amide groups in the BTAs differs, and mixing N- and C-BTAs results in supramolecular copolymers with a blocky microstructure in solution. The blocky microstructure results from the formation of weaker and less organized, antiparallel hydrogen bonds between N- and C-BTAs. In methylcyclohexane, the helical threefold hydrogen-bonding network present in C- and N-BTAs is retained in the mixtures. In the solid state, in contrast, the hydrogen bonds of pure BTAs as well as their mixtures organize in a sheet-like pattern, and in the mixtures long-range order is lost. Drop-casting to kinetically trap the solution microstructures shows that C-BTAs retain the helical hydrogen bonds, but N-BTAs immediately adopt the sheet-like pattern, a direct consequence of the lower stabilization energy of the helical hydrogen bonds. In the copolymers, the stability of the helical aggregates depends on the copolymer composition, and helical aggregates are only preserved when a high amount of C-BTAs is present. The method outlined here is generally applicable to elucidate the copolymerization behavior of supramolecular monomers both in solution as well as in the solid state

Detailed approach to investigate thermodynamically controlled supramolecular copolymerizations

Elucidating the microstructure of supramolecular copolymers remains challenging, despite the progress in the field of supramolecular polymers. In this work, we present a detailed approach to investigate supramolecular copolymerizations under thermodynamic control. Our approach provides insight into the interactions of different types of monomers and hereby allows elucidating the microstructure of copolymers. We select two monomers that undergo cooperative supramolecular polymerization by way of threefold intermolecular hydrogen bonding in a helical manner, namely, benzene-1,3,5-tricarboxamide (BTA) and benzene-1,3,5-tris(carbothioamide) (thioBTA). Two enantiomeric forms and an achiral analogue of BTA and thioBTA are synthesized and their homo- and copolymerizations are studied using light scattering techniques, infrared, ultraviolet, and circular dichroism spectroscopy. After quantifying the thermodynamic parameters describing the homopolymerizations, we outline a method to follow the self-assembly of thioBTA derivatives in the copolymerization with BTA, which involves monitoring a characteristic spectroscopic signature as a function of temperature and relative concentration. Using modified types of sergeants-and-soldiers and majority-rules experiments, we obtain insights into the degree of aggregation and the net helicity. In addition, we apply a theoretical model of supramolecular copolymerization to substantiate the experimental results. We find that the model describes the two-component system well and allows deriving the hetero-interaction energies. The interactions between the same kinds of monomers (BTA-BTA and thioBTA-thioBTA) are slightly more favorable than those between different monomers (BTA-thioBTA), corresponding to a nearly random copolymerization. Finally, to study the interactions of the monomers at the molecular level, we perform density functional theory-based computations. The results corroborate that the two-component system exhibits a random distribution of the two monomer units along the copolymer chain

Supplementary Material for: Incidence and Relevance of Proteinuria in Bevacizumab-Treated Patients: Pooled Analysis from Randomized Controlled Trials

<b><i>Background:</i></b> This analysis evaluated the incidence of and risk factors for bevacizumab-related proteinuria and assessed for any associated clinical sequelae, including renal function changes. <b><i>Methods:</i></b> Patient-level adverse event and laboratory data from a pooled safety database were used to characterize alterations in urine protein excretion following interventional therapy ± bevacizumab in 17 randomized trials across multiple tumor types. Severity of renal function change was assessed using changes in serum creatinine concentration from baseline values. Potential predictors of proteinuria and the association between proteinuria and other adverse events were also investigated. <b><i>Results:</i></b> Among 14,548 patients, the incidence of any-grade proteinuria was 8.2% (733/8,917) and 4.6% (257/5,631) in the bevacizumab and control groups, respectively; rates of grade ≥3 proteinuria were 1.4 and 0.2%. Post-baseline proteinuria grade and bevacizumab were associated with increased rates of renal dysfunction. Patients developing proteinuria had an increased rate of any-grade infection but not thromboembolic events. History of diabetes was the only examined risk factor that appeared to have a significant association with proteinuria development. <b><i>Conclusions:</i></b> This analysis confirmed a significant increase in the development of proteinuria during bevacizumab treatment. We also observed an increased rate of renal dysfunction associated with bevacizumab treatment and among subjects with proteinuria, although the dysfunction was generally mild. The development of proteinuria was also associated with a modest increase in risk of infection

Temperature-dependent modulation by biaryl-based monomers of the chain length and morphology of biphenyl-based supramolecular polymers

Supramolecular copolymerizations offer attractive options to introduce structural and functional diversity in supramolecular polymer materials. Yet, general principles and structure-property relationships for rational comonomer design remain lacking. Here, we report on the supramolecular (co)aggregation of a phenylpyridine and bipyridine derivative of a recently reported biphenyl tetracarboxamide-based monomer. We show that both arylpyridines are poor monomers for supramolecular homopolymerizations. However, the two arylpyridines efficiently influence supramolecular polymers of a biphenyl-based polymer. The phenylpyridine derivatives primarily sequestrate biphenyl monomers, while the bipyridine intercalates into the polymers at high temperatures. Thereby, these two poorly homopolymerizing monomers allow for a fine control over the length of the biphenyl-based supramolecular polymers. As such, our results highlight the potential to control the structure and morphology of supramolecular polymers by tailoring the electronic properties of additives.ISSN:2041-6520ISSN:2041-653

Erratum: Endoplasmic Reticulum Stress Predicts Clinical Response to Cyclosporine Treatment in Primary Membranous Nephropathy

<b><i>Background:</i></b> Little is known about the endoplasmic reticulum stress (ERS) marker glucose regulated protein 78 (GRP78) and calcineurin in the kidney in primary membranous nephropathy (PMN) and if they could predict post-cyclosporine treatment outcome. <b><i>Methods:</i></b> This is a retrospective study using a dataset of biopsy-confirmed PMN from Peking Union Medical College Hospital from 1996 to 2014. Seventy-six adult patients treated with cyclosporine as primary immunosuppression for at least 6 months were studied. Immunohistochemistry was used to detect GRP78 and calcineurin in the kidney. Serum calcineurin was assayed by ELISA. Patients were grouped into no-remission (NR, n = 17), partial remission (PR, n = 39), or complete remission (CR, n = 20) at the end of 6 months of treatment. <b><i>Results:</i></b> There was no difference of initial dose of cyclosporine among NR, PR, and CR groups. Kidney calcineurin expression in PMN was significantly increased compared to that in controls (p < 0.0083). The glomerular GRP78 in NR PMN was higher than that in control, CR and PR patients (p < 0.0083). Kidney calcineurin expression and GRP78 expression was positively correlated. However, there were no differences in either serum calcineurin levels or kidney calcineurin expressions among NR, PR or CR groups. There was a negative correlation between serum calcineurin activity and whole kidney calcineurin expression (p = 0.034) or glomerular calcineurin expression (p = 0.007). Neither kidney calcineurin nor GRP78 expression was correlated with proteinuria. <b><i>Conclusions:</i></b> ERS marker GRP78 in the glomeruli but not serum or kidney calcineurin expression could be a useful marker in PMN to negatively predict the response to cyclosporine treatment at the sixth month

Supplementary Material for: A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR)

<b><i>Background:</i></b> Idiopathic membranous nephropathy remains the leading cause of nephrotic syndrome in Caucasian adults. Immunosuppressive therapy with cyclosporine (CSA) is often successful in reducing proteinuria, but its use is associated with a high relapse rate. Rituximab, a monoclonal antibody that specifically targets CD20 on the surface of B-cells, is effective in achieving a complete remission of proteinuria in patients with idiopathic membranous nephropathy. However, whether rituximab is as effective as CSA in inducing and maintaining complete or partial remission of proteinuria in these patients is unknown. The membranous nephropathy trial of rituximab (MENTOR) hypothesizes that B-cell targeting with rituximab is non-inferior to CSA in inducing long-term remission of proteinuria. <b><i>Methods and Design:</i></b> Patients with idiopathic membranous nephropathy, proteinuria ≥5 g/24 h, and a minimum of 3 months of Angiotensin-II blockade will be randomized into a 12-month treatment period with IV rituximab, 1,000 mg (2 infusions, 14 days apart; repeated at 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months) or oral CSA 3.5-5 mg/kg/day for 6 months (continued for another 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months). The efficacy of treatment will be assessed by the remission status (based on changes in proteinuria) at 24 months from randomization. Patient safety will be assessed via collection of adverse event data and evaluation of pre- and posttreatment laboratory data. At the 6-month post-randomization visit, patients who have been randomized to either CSA or rituximab but who do not have a reduction in proteinuria ≥25% (confirmed on repeat measurements within 2 weeks) will be considered treatment failures and exit the study. <b><i>Discussion:</i></b> This study will test for the first time whether treatment with rituximab is non-inferior to CSA in inducing long-term remission (complete or partial) of proteinuria in patients with idiopathic membranous nephropathy