The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy - A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy

Aims To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients. Methods and results We quantified fibrosis in 209 DCM patients at three levels: (i) non-invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers [amino-terminal propeptide of procollagen type III (PIIINP) and carboxy-terminal propeptide of procollagen type I (PICP)], (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life-threatening arrhythmias, after adjusting for known clinical predictors [adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90-6.60; P < 0.001 and PICP 1.02, 95% CI 1.01-1.03; P = 0.001]. The combination of LGE and PICP provided the highest prognostic benefit in prediction (likelihood ratio test P = 0.007) and reclassification (net reclassification index: 0.28, P = 0.02; and integrated discrimination improvement index: 0.139, P = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (log-rank P < 0.001). RNA-sequencing and gene enrichment analysis of EMB showed an increased expression of pro-fibrotic and pro-inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE-/PICP-). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated with distinct cardiac transcriptomic profiles. Conclusion The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro-fibrotic and pro-inflammatory transcriptomic profile in DCM patients with LGE and elevated PICP

Anti-PLA2R Antibodies as a Prognostic Factor in PLA2R-Related Membranous Nephropathy

Background: The natural course of idiopathic membranous nephropathy (MN) varies, as it is known through favorable outcomes in most patients. However, one third of patients with idiopathic MN will slowly progress to end-stage renal disease (ESRD). To prevent disease progression, patients at high risk to develop ESRD are treated with immunosuppressive agents. Therefore, a correct selection of patients who need immunosuppressive treatment is important. Methods: Here, we evaluated the prognostic value of anti-phospholipase A2 receptor 1 antibody (anti-PLA2R) levels regarding clinical outcome in a well-defined cohort of 73 PLA2R-related MN patients with long-term follow-up. At baseline, patients were subdivided into patients with either low or high antibody levels based on ELISA testing. Results: Spontaneous remission rates were highest among patients with low anti-PLA2R levels (79%; hazard ratio 2.72 (95% CI 1.22-6.08), p = 0.02) after a median follow-up of 2.9 (95% CI 0.8-5.0, p &lt;0.001) years, whereas high anti-PLA2R levels were associated with persistent proteinuria (p = 0.04) and/or the need for immunosuppressive therapy (p &lt;0.001). Renal survival rates were 97% at 5 years, 93% at 10 years, and 89% at 15 years; however, this was not different between the anti-PLA2R groups. ESRD occurred significantly faster in patients with severe proteinuria as compared to patients with either mild (p = 0.02) or moderate proteinuria (p = 0.05). Conclusions: Low anti-PLA2R levels may predict spontaneous remissions in patients with PLA2R-related MN. Therefore, we suggest that quantification of anti-PLA2R is of value to monitor these patients

Granulomatous interstitial nephritis and Crohn's disease

Granulomatous interstitial nephritis has been observed in <1% of native renal biopsies. Here, we describe two patients with granulomatous interstitial nephritis in relation to Crohn's disease. Circulating helper and cytotoxic T cells were highly activated, and both cell types predominated in the interstitial infiltrate, indicating a cellular autoimmune response. After immunosuppressive treatment, renal function either improved or stabilized in both patients. In conclusion, granulomatous interstitial nephritis is a genuine extraintestinal manifestation of Crohn's disease, the treatment of which should include immunosuppressive agents

Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities

Thrombotic microangiopathy (TMA) is a pattern of endothelial damage that can be found in association with diverse clinical conditions such as malignant hypertension. Although the pathophysiological mechanisms differ, accumulating evidence links complement dysregulation to various TMA syndromes and in particular the atypical hemolytic uremic syndrome. Here, we evaluated the role of complement in nine consecutive patients with biopsy-proven renal TMA attributed to severe hypertension. Profound hematologic symptoms of TMA were uncommon. In six Out of nine patients, we found mutations C3 in three, CFI in one, CD46 in one, and/or CFH in two patients either with or without the risk CFH-H3 haplotype in four patients. Elevated levels of the soluble C5b-9 and renal deposits of C3c and C5b-9 along the vasculature and/or glomerular capillary wall, confirmed complement activation in vivo. In contrast to patients without genetic defects, patients with complement defects invariably progressed to end-stage renal disease, and disease recurrence after kidney transplantation seems common. Thus, a subset of patients with hypertension-associated TMA falls within the spectrum of complement-mediated TMA, the prognosis of which is poor. Hence, testing for genetic complement abnormalities is warranted in patients with severe hypertension and TMA on renal biopsy to adopt suitable treatment options and prophylactic measures.</p