The reported prevalence of diabetic nephropathy (DN) among patients with diabetes varies widely. Most studies use the presence of microalbuminuria for clinical onset of DN in the absence of a histopathologic evaluation. In this autopsy study, we collected and analyzed data from a cohort of patients with type 1 or 2 diabetes and determined the prevalence of histologically proven DN in patients with or without clinical manifestations of renal disease. We also examined the distribution among histopathologic classes with respect to clinical parameters. Renal tissue specimens from autopsies and clinical data were collected retrospectively from 168 patients with diabetes. The histopathologic classification for DN was scored as were interstitial and vascular parameters. In this cohort, 106 of 168 patients had histopathologic changes in the kidney characteristic of DN. Twenty of the 106 histologically proven DN cases did not present with DN-associated clinical manifestations within their lifetime. Glomerular and interstitial lesions were associated with renal function but not with proteinuria. We also found that underdiagnosed DN may encompass all histopathologic classes except the sclerotic class. Thus, the prevalence of histologically proven DN was higher than previously appreciated, and we found a relatively high proportion of DN that was clinically underdiagnosed yet histologically proven, suggesting that DN lesions may develop before the onset of clinical findings.

LL‐37 is a cationic antimicrobial peptide and the sole human member of cathelicidins. Besides its bactericidal properties, LL‐37 is known to have direct immunomodulatory effects, among which enhancement of antiviral responses via endosomal toll‐like receptors (TLRs). Omiganan pentahydrochloride is a synthetic cationic peptide in clinical development. Previously, omiganan was primarily known for its direct bactericidal and antifungal properties. We investigated whether omiganan enhances endosomal TLR responses, similar to LL‐37. Human peripheral blood mononuclear cells were treated with endosomal TLR3, −7, −8, and −9 ligands in the presence of omiganan. Omiganan enhanced TLR‐mediated interferon‐α release. Subsequent experiments with TLR9 ligands showed that plasmacytoid dendritic cells were main contributors to omiganan‐enhanced IFN production. Based on this type I interferon‐enhancing effect, omiganan may qualify as potential treatment modality for virus‐driven diseases. The molecular mechanism by which omiganan enhances endosomal TLR responses remains to be elucidated.

Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To gain insight in this relationship, we performed in vitro experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor (TLR)3/TLR7/TLR9/RIG-I-induced cytokine production. In a placebo-controlled clinical study, these same endpoints were evaluated in healthy volunteers that were treated with a cumulative dose of 2400 mg HCQ over 5 days. In vitro, HCQ inhibited TLR responses with IC50s > 100 ng/mL and reaching 100% inhibition. In the clinical study, maximal HCQ plasma concentrations ranged from 75 to 200 ng/mL. No ex vivo HCQ effects were found on RIG-I-mediated cytokine release, but there was significant suppression of TLR7 responses and mild suppression of TLR3 and TLR9 responses. Moreover, HCQ treatment did not affect B cell and T cell proliferation. These investigations show that HCQ has clear immunosuppressive effects on human PBMCs, but the effective concentrations exceed the circulating HCQ concentrations under conventional clinical use. Of note, based on HCQ’s physicochemical properties, tissue drug concentrations may be higher, potentially resulting in significant local immunosuppression. This trial is registered in the International Clinical Trials Registry Platform (ICTRP) under study number NL8726.