HbA1c-dependent projection of long-term renal outcomes.

BACKGROUND: Diabetes mellitus is a major risk factor for the development of chronic kidney disease (CKD). There is limited data addressing the value of glycated hemoglobin (HbA1c) to predict renal outcomes independent of diabetes status. METHODS: This single-center retrospective observational study presents data of 19,285 subjects, irrespective of initial CKD or diabetes status. The primary endpoint was defined as the time to manifestation of moderate CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 ) in subjects with eGFR ≥60 mL/min/1.73 m2 at baseline. The secondary endpoint was defined as time to progression of CKD (eGFR <30 mL/min/1.73 m2 ) in subjects with eGFR 30-60 mL/min/1.73 m2 . Multivariate time-to-event and logistic regression models were applied to estimate the influences of HbA1c, sex, age, eGFR, triglycerides, and cholesterol on both endpoints. RESULTS: Lowest baseline HbA1c levels were associated with the slowest decline of kidney function (median time to manifestation of moderate CKD for HbA1c <5.7%: 15.9 years [95% confidence interval (CI): 15.2-16.7]; for HbA1c 5.7%-6.5%: 14.5 years [95% CI: 14.0-15.1]; for HbA1c 6.5%-8.5%: 11.1 years [95% CI: 10.4-11.7]; for HbA1c >8.5%: 8.3 years [95% CI: 7.8-9.2]; p < 0.001). Similar results were observed for the secondary endpoint. Covariate-adjusted time-to-event analysis demonstrated an almost linear correlation between continuous baseline HbA1c levels and the probabilities of reaching both endpoints. CONCLUSIONS: HbA1c levels are a strong predictor for eGFR decline, irrespective of diabetes status or CKD stage, demonstrating a tight concentration-dependent relationship. This association becomes apparent in the prediabetic HbA1c range and remains constant over the entire HbA1c spectrum.

Identification of Covariates Modulating B-Cell Repopulation Kinetics in Subjects Receiving Rituximab Treatment.

OBJECTIVE: B-cell depletion using the anti-CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B-cell depletion is associated with a higher risk for severe infections, and the time span of B-cell repopulation differs greatly between individuals. Data on factors influencing B-cell repopulation kinetics are limited. This study aims to identify patient-specific and therapy-associated covariates that modulate B-cell repopulation. METHODS: This single-center retrospective observational study presents data of 839 subjects receiving 2,017 courses of rituximab for autoimmune diseases. Assessed covariates are patient-specific factors (sex, age, kidney function, and underlying disease) and co-immunosuppression with common agents (azathioprine, cyclosporine A, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, tacrolimus, and corticosteroids). The primary end point is the time to B-cell repopulation (≥5/µl). The secondary end point is the time to B-cell reconstitution (≥50/µl). Multivariate time-to-event analysis and logistic regression models were applied to estimate the influence of covariates. RESULTS: Age over 60 years (hazard ratio [HR] 0.71 for repopulation, P = 0.008), impaired kidney function (HR 0.72, P = 0.001), antineutrophil cytoplasmic antibody-associated vasculitis (HR 0.61, P < 0.001), solid organ transplantation (HR 0.4, P < 0.001), and co-immunosuppression with corticosteroids (HR 0.64, P < 0.001) or azathioprine (HR 0.49, P < 0.001) were associated with impaired B-cell repopulation and reconstitution. Effects of corticosteroids (P = 0.043) and azathioprine (P = 0.025) were dose dependent. CONCLUSION: Prolonged rituximab dosing intervals may be effective to achieve B-cell depletion and reduce risk of infection in advanced age or patients with impaired kidney function. Co-medication with corticosteroids or azathioprine prolongs B-cell recovery, which may increase therapeutic effects but also the rate of adverse events.

Treating C3 glomerulopathy with eculizumab.

BACKGROUND: C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown. METHODS: Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. The key parameters to determine outcome were changes of serum creatinine and urinary protein over time. RESULTS: After treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab. CONCLUSIONS: Eculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response.

Interaction of the cotranslational Hsp70 Ssb with ribosomal proteins and rRNA depends on its lid domain.

Cotranslational chaperones assist in de novo folding of nascent polypeptides in all organisms. In yeast, the heterodimeric ribosome-associated complex (RAC) forms a unique chaperone triad with the Hsp70 homologue Ssb. We report the X-ray structure of full length Ssb in the ATP-bound open conformation at 2.6 Å resolution and identify a positively charged region in the α-helical lid domain (SBDα), which is present in all members of the Ssb-subfamily of Hsp70s. Mutational analysis demonstrates that this region is strictly required for ribosome binding. Crosslinking shows that Ssb binds close to the tunnel exit via contacts with both, ribosomal proteins and rRNA, and that specific contacts can be correlated with switching between the open (ATP-bound) and closed (ADP-bound) conformation. Taken together, our data reveal how Ssb dynamics on the ribosome allows for the efficient interaction with nascent chains upon RAC-mediated activation of ATP hydrolysis.