Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study

Introduction: The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients. Methods: Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment. Results: A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001). Conclusion: This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies

Machine learning models to predict post-dialysis blood pressure in children and young adults on maintenance hemodialysis

Abstract Hypertension is associated with significant cardiovascular morbidity. Blood pressure (BP) control on maintenance hemodialysis (HD) is strongly impacted by volume status. The objective of this study was to assess whether machine learning (ML) is effective in predicting post-HD BP in children and young adults on HD. We collected data on BP, IDWG, pulse, and weights for patients on maintenance HD (> 3 months). Input features included DW, pre-post weight difference, IDWG and pre-HD BP. Seven models were trained and tuned using open-source libraries. Model performance was evaluated using time-series cross-validation on a rolling basis (3–12 month training, 1-day testing). Various regression scores were compared between models. Data for 35 patients (14,375 HD sessions) were analyzed. Extreme gradient boosting (XGB) and vector autoregression with exogenous regressors (VARX) achieved better accuracy in predicting post-dialysis systolic BP than K-nearest neighbor, support vector regression (SVR) with radial basis function kernel and random forest (p < 0.001 for each). The differences in accuracy between XGB, VARX, SVR with linear kernel, random forest and linear regression were not significant. Using clinical parameters, ML models may be useful in predicting post-HD BP, which may help guide DW adjustment and optimizing BP control for maintenance HD patients

Erlotinib preserves renal function and prevents salt retention in doxorubicin treated nephrotic rats.

Nephrotic syndrome is associated with up-regulation of the heparin-binding epidermal growth factor (HB-EGF). Erlotinib blocks the activation of the epidermal growth factor receptor (EGFR) in response to HB-EGF. This study investigates the effect of Erlotinib on the progression of proteinuria, renal dysfunction, and salt retention in doxorubicin treated nephrotic rats. Male rats were divided into 3 pair-fed groups (n = 13/group) as follows: Control rats (Ctrl); rats receiving intravenous doxorubicin (Dox); and rats receiving intravenous doxorubicin followed by daily oral Erlotinib (Dox + Erl). Upon establishment of high grade proteinuria, urine sodium and creatinine clearance were measured. Kidney tissue was dissected and analyzed for γ-epithelial sodium channel (γENaC), sodium-potassium -chloride co-transporter 2 (NKCC2), sodium chloride co-transporter (NCC), aquaporin 2 (AQP2), and EGFR abundances using western blot. Creatinine clearance was preserved in the Dox + Erl rats as compared to the Dox group (in ml/min: Ctrl: 5.2±.5, Dox: 1.9±0.3, Dox + Erl: 3.6±0.5). Despite a minimal effect on the degree of proteinuria, Erlotinib prevented salt retention (Urinary Na in mEq/d: Ctrl: 2.2±0.2, Dox: 1.8±0.3, Dox + Erl: 2.2±0.2). The cleaved/uncleaved γENaC ratio was increased by 41±16% in the Dox group but unchanged in the Dox + Erl group when compared to Ctrl. The phosphorylated EGFR/total EGFR ratio was reduced by 74±7% in the Dox group and by 77±4% in the Dox + Erl group. In conclusion, Erlotinib preserved renal function and prevented salt retention in nephrotic rats. The observed effects do not appear to be mediated by direct blockade of EGFR

Doxorubicin decreases AQP2 in inner medulla (IM) and Erlotinib restores levels in IM tip.

<p>Shown: AQP2 protein abundance in IM tip and base tissue of control rats (<i>Ctrl</i>; white bars), doxorubicin treated rats (<i>Dox</i>; solid black bars), and doxorubicin + Erlotinib treated rats (<i>Dox + Erl</i>; patterned bars). <b>A</b>: Representative immunoblots showing abundance of AQP2 in IM tip and base tissue lysates. Each lane containes samples from a different rat. <b>B</b>: Densitometric analysis of western blots from 3 cohorts of animals. Data were normalized for the average densitometry of untreated animals in each group. Data are expressed as means ± SE (n = 11, * p<0.05).</p

Cleaved γENaC subunit protein abundance is increased by doxorubincin relative to control or Erlotinib-treated animals.

<p>Shown is the γENaC subunit in rat cortex tissue of control rats (<i>Ctrl</i>; white bars), doxorubicin treated rats (<i>Dox</i>; solid black bars), and doxorubicin + Erlotinib treated rats (<i>Dox + Erl</i>; patterned bars). <b>A</b>: Representative immunoblots showing abundance of γENaC in rat cortex tissue lysates. Each lane was loaded with an equal amount of total protein from a different rat. <b>B</b>: Densitometric analysis of western blots from 3 cohorts of animals. Data were normalized for the average densitometry of untreated animals in each group. Separate densitometric analysis was performed for the total, cleaved, and uncleaved γENaC. <b>Left:</b> Total ENaC densitometric analysis. <b>Right:</b> The ratio of cleaved to uncleaved γENaC densitometries. Data are expressed as means ± SE (n = 11, * p<0.05).</p

Proteinuria is apparent by 10 days after doxorubicin.

<p>The lines show the progression of the proteinuria plotted over time in control rats (solid line), doxorubicin treated rats (dotted line), and doxorubicin + Erlotinib treated rats (dashed line). Data are expressed as means ± SE (n = 13, * p<0.05 for Dox or Dox+Erl vs. control at same time point).</p

The doxorubicin-induced decrease in phosphorylated EGRF/EGRF ratio is not corrected by Erlotinib.

<p>EGFR and phosphorylated EGFR protein abundances in rat cortex tissue of control rats (<i>Ctrl</i>; white bars), doxorubicin treated rats (<i>Dox</i>; solid black bars), and doxorubicin + Erlotinib treated rats (<i>Dox + Erl</i>; patterned bars). <b>A</b>: Representative immunoblots showing abundances of EGFR and phosphorylated EGFR in rat cortex tissue lysates. An equal amount of total protein from a different rat tissue sample was loaded into each lane. <b>B</b>: Densitometric analysis of western blots from 3 cohorts of animals. Data were normalized for the average densitometry of untreated animals in each group. <b>Right:</b> Total EGFR densitometric analysis. <b>Middle:</b> Phosphorylated EGFR densitometric analysis. <b>Left:</b> The ratio of phosphorylated EGFR to total EGFR densitometries. Data are expressed as means ± SE (n = 11, * p<0.05).</p

Doxorubicin-induced increases in water intake and urine output are reversed by Erlotinib treatment.

<p>Shown are the changes in weight (<b>A</b>), urine output (<b>B</b>), and water intake (<b>C</b>) plotted over time in control rats (solid line), doxorubicin (Dox) treated rats (dotted line), and doxorubicin + Erlotinib (Dox + Erl) treated rats (dashed line). Data are expressed as means ± SE (n = 13, * p<0.05 for Dox or Dox+Erl vs. control at same time point, and for Dox or Dox+Erl vs. Dox or Dox+Erl at time 0).</p

Erlotinib restores urine sodium excretion to control levels but only partially corrects creatinine clearance.

<p><b>Left:</b> Bar graph showing the average urine sodium excretion evaluated at the end of the observation period in control rats (<i>Ctrl</i>; white bar), doxorubicin treated rats (<i>Dox</i>; solid black bar), and doxorubicin + Erlotinib treated rats (<i>Dox + Erl</i>; patterned bar). <b>Right:</b> Bar graph showing the average creatinine clearance evaluated at the end of the observation period in control rats (<i>Ctrl</i>; white bar), doxorubicin treated rats (<i>Dox</i>; solid black bar), and doxorubicin + Erlotinib treated rats (<i>Dox + Erl</i>; patterned bar). <b>Bottom</b>: Bar graph showing the average fractional excretion of water (FE Water) evaluated at the end of the observation period in control rats (<i>Ctrl</i>; white bar), doxorubicin treated rats (<i>Dox</i>; solid black bar), and doxorubicin + Erlotinib treated rats (<i>Dox + Erl</i>; patterned bar). Data are expressed as means ± SE (n = 13, * p<0.05, ** p<0.001).</p