The Significance of Crescents on the Clinical Features and Outcomes of Primary Immunoglobin A Nephropathy.

Background: It is still controversial whether the proportion of crescents below 50% can be an independent predictive risk factor for poor prognosis in IgAN patients. We reported the significance of different proportions of crescents on the clinical features and the cut-off value of crescents in predicting the occurrence of end-stage kidney disease (ESKD) in patients with IgAN. Methods: We retrospectively analyzed biopsy-proven primary IgAN patients in Sichuan Provincial People's Hospital from 2007 to 2019. The patients were divided into 5 groups on the basis of crescent proportion as follows: 0 (n = 647), < 10% (n = 221), 10 to 24% (n = 272), 25 to 49% (n = 80), and ≥50% (n = 22). The primary endpoint was defined as ESKD, and the secondary endpoint was the combined renal endpoint (≥50% reduction in eGFR or ESKD). A validation cohort of 346 patients were enrolled from Affiliated Hospital of Southwest Medical University. Cox regression model and Kaplan-Meier survival analysis were performed. Results: A total of 1242 eligible patients with biopsy-proven IgAN were recorded in the database, compared with the non-crescent group, patients in the crescent group had lower levels of hemoglobin (Hb) and albumin (Alb), higher levels of blood urea nitrogen (BUN), 24h urinary protein and hematuria, a higher proportion of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), and tubular atrophy/interstitial fibrosis (T1/T2) (p < 0.05). A higher crescent proportion was associated with lower levels of Hb, ALB, eGFR and serum IgG (p < 0.05), higher levels of SCr, BUN, increasing amounts of 24 h urinary protein, increasing proportion of M1 and E1, and increasing severity of interstitial inflammatory infiltration. During the median follow-up of 43 months (range 6-151), 63 individuals (7.0%) reached the primary outcome of ESKD and 99 patients (11.1%) reached the combined renal endpoint. 34(7.5%), 21 (13.3%), 24(12.2%), 14(21.5%) and 6(31.6%) patients reached the combined renal endpoint in the above five groups in crescents 0, <10%, 10∼24%, 25∼49% and ≥50%, respectively. A total of 274(62.6%) cases in the crescent group and 254 (55.7%) cases in the non-crescent group received immunosuppressive therapy. Multivariate Cox regression showed that crescents ≥50% was an independent risk factor for the progression of ESKD (p = 0.003) and crescents ≥25% was an independent risk factor for the combined renal endpoint(p < 0.001). The receiver operating characteristic curve showed that IgAN patients with crescents ≥43.7% had a higher risk of ESKD, even with immunosuppressants (Sensitivity = 75.7%,specificity = 89.6%,p < 0.001). This discovery cohort and the validation cohort further confirmed that patients with crescents <43.7% had better renal prognosis than those with crescents ≥43.7% in the whole group and those with immunosuppressants (p < 0.001). Conclusion: IgAN patients with crescents had more severe clinicopathological features and poorer prognosis. Crescents ≥50% was an independent risk factor for the progression of ESKD and crescents ≥25% was an independent risk factor for ≥50% reduction in eGFR or ESKD in treated and untreated IgAN patients. Crescents ≥43.7% was an independent risk factor for ESKD in those with immunosuppressants.

The Effect of Hydroxychloroquine on Residual Proteinuria in Patients With Immunoglobulin A Nephropathy: A Retrospective Study Based on Propensity Score Matching.

Background: There is insufficient evidence to support the use of hydroxychloroquine (HCQ) in Immunoglobulin A nephropathy (IgAN) patients with high residual proteinuria in spite of 6-month supportive treatment combined with corticosteroids (P) and/or immunosuppressives (IM). This study aims to explore the effect of HCQ on residual proteinuria in IgAN. Materials and Methods: This is a retrospective study. IgAN patients who had residual proteinuria ≥0.3 g/24 h after 6-month treatment by renin-angiotensin system inhibitors (RASI) + P ± IM were included. Groups were divided based on the different regimens and then matched by the propensity score matching method. The primary outcome was defined as the cumulative frequency of residual proteinuria reduction ≥30%. Results: RASI (n = 183), HCQ + RASI (n = 59), RASI + P ± IM (n = 145), and HCQ + RASI + P ± IM (n = 38) groups were included. HCQ + RASI group had a higher level of residual proteinuria and a worse renal function than those in the RASI group. The renal function was worse in the HCQ + RASI + P ± IM group than that in the control group, but residual proteinuria levels were similar. After matching, there were 40 patients in the first two groups and 29 patients in the latter two groups, respectively. The cumulative frequency of residual proteinuria reduction ≥30% in HCQ + RASI + P ± IM group was higher than that in control group (86.2% vs. 62.1%, χ2 = 6.397, p = 0.011). HCQ combination treatment was one of independent factors. Conclusion: The addition of HCQ treatment can effectively reduce the residual proteinuria in IgAN patients previously treated with supportive treatment combined with P and IM treatment and the cumulative frequency of effective reduction of residual proteinuria can reach 86.2%.

Arginine vasopressin differentially modulates GABAergic synaptic transmission onto temperature-sensitive and temperature-insensitive neurons in the rat preoptic area.

The preoptic area (POA) of the hypothalamus, containing temperature-sensitive and temperature-insensitive neurons, plays a key role in specific thermoregulatory responses. Although arginine vasopressin (AVP) has been shown to induce hypothermia by increasing the firing activities of warm-sensitive neurons and decreasing those of cold-sensitive and temperature-insensitive neurons, the effects of AVP on POA GABAergic transmission remain unknown. Herein, inhibitory postsynaptic currents (IPSCs) of temperature-sensitive and temperature-insensitive neurons in POA slices were recorded using whole-cell patch clamp. By monitoring changes in GABAergic transmission during AVP treatment, we showed that AVP decreased the amplitudes and frequencies of spontaneous IPSCs in mostly warm-sensitive neurons and in some temperature-insensitive neurons but increased these parameters in other temperature-insensitive neurons. The IPSC amplitude was reduced for only cold-sensitive neurons. RT-PCR and Western blot analyses further confirmed the POA expression of V1a receptors and GABAA receptors, including the subunits α1, α2, α3, ß2, ß3 and γ2. The effects of AVP on IPSCs in temperature-sensitive and temperature-insensitive neurons were dependent on G proteins and intracellular Ca2+ . AVP-mediated modulation was associated with changes in the kinetic parameters (decay time, 10-90% rise time, half-width). Together, these results suggest that AVP, acting via V1a receptors but not V1b receptors, differentially modulates GABAergic synaptic transmission and fine-tunes the firing activities of temperature-sensitive and temperature-insensitive neurons in the rat POA.