DOI: 10.1007/s00467-016-3465-7

Should we therefore employ this recommendation in future care? The first step to answering this question is to look at the quality of the reporting in the study. The pediatric nephrology community unfortunately does not have a good track record when it comes to reporting randomized controlled clinical trials using the CONsolidated Standards Of Reporting Trials (CONSORT) criteria or including the appropriate figures and checklists [8]. Trial reporting in field of pediatric renal transplantation has been criticized for its poor compliance with the CONSORT criteria. Of particular concern, the reporting of the essential components of the Methods, Results, and Discussion sections has been described as unsatisfactory [9]. The Enhancing the QUAlity and Transparency Of health Research (EQUATOR) statement (http://www.equator-network.org/) provides a one-stop source for standardized reporting guidelines for common study designs. Since the study by EM Yang et al. [4] is a retrospective cross-sectional study, the authors should have employed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement guidelines used for observational studies. This guideline can also be used for case–control and cohort studies. Many journals have embraced this stringent approach including the British Medical Journal [10], the Lancet [11], and PLOS Medicine [12]. For example, according to the STROBE guidelines, EM Yang et al. [4] should have included the study design in their title. Unfortunately, however, Pediatric Nephrology requires succinct titles that would preclude the use of “A retrospective study…” The authors did include a flow chart [checklist item 13 (c)]. Another guideline that should have been followed but was not includes consistently providing unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (e.g., 95% confidence interval)—standard 16 (a); this is one of several examples. Although Pediatric Nephrology has not yet embraced the EQUATOR statement, the publication of a very important study, such as the one by EM Yang et al., [4] should perhaps trigger a discussion about the importance of embracing such standards, especially when striving for a higher impact factor.

One other question that remains to be answered concerns the best approach for validating the proposed formula for correcting the daily protein excretion estimate based on the first morning void. EM Yang et al. [4] used the entire cohort to generate the formula. The authors could have divided their study participants into one cohort of 160 patients to generate the formula and a second cohort composed of the remaining patients to validate the formula, akin to other biomarker discovery studies [13, 14]. There are five stages for biomarker development, and the later stages focus on epidemiologic concepts within a diagnostic, prognostic, and screening framework to determine if new markers will advance clinical care [15]. Future studies should consider performing both an internal and an external prospective validation of the proposed formula to firmly establish a revised clinical practice and, in this case, to move from the current simple Prot/Cr to the modified approach proposed by the authors.

The nephrotoxic serum nephritis (NTS) model is a mouse model which is commonly used to study a type of immune complex-mediated, rapidly progressive glomerulonephritis (GN). It is induced by the injection of antibodies raised either in rabbits or sheep that are directed against the glomerular basement membrane (GBM). In the model used in our laboratory, a subcutaneous immunization against rabbit immunoglobulin G (IgG) prior to injection of the antiserum is needed to induce rapid-progressive GN within 7 to 14 days [1, 2, 3]. Other research groups using sheep anti-GBM antibody have reported that the immunization step is not required to induce a form of rapid-progressive GN [4, 5]. The so-called autologous phase of disease is characterized by nephrotic range albuminuria, a proliferative form of GN with crescent formation as well as infiltration of immune cells into the kidney [3]. The pathogenesis has been shown to be dependent on innate and adaptive immune cells as well as on the complement system. Kurts and coworkers recently published an excellent summary of the time course of kidney-infiltrating immune cells in NTS [6]. Gamma delta (γδ) T cells are the first cells to find their way into the kidney, attracting neutrophil granulocytes via the cytokine interleukin (IL)-17 [7]. Neutrophils, recruited via C-X-C motif chemokine ligand 1 (CXCL-1) [8], immediately infiltrate the kidney, mainly the glomeruli where they cause damage to glomerular cells. The absence of γδ T cells has been proven to protect mice from NTS [2]. Next, T helper (TH) 17 cells expressing CC chemokine receptor (CCR) 6 infiltrate the renal interstitium and glomeruli and in turn recruit neutrophils which infiltrate mainly the interstitium [9]. The recruitment of these neutrophils has been proven to be dependent on CXCL-5 rather than CXCL-1. CXCL-5 is induced in renal tubular epithelial cells by TH17 cells [8]. The prolonged infiltration of these adaptive immune cells seems to be dependent on dendritic cells (DCs) expressing CX3CR1 and CCR2 [10]. The latter also recruit TH1 cells, which lead to the infiltration of macrophages by the secretion of interferon-γ [11]. Depletion of either TH17 or TH1 cells significantly ameliorates the NTS phenotype in mice [5, 12]. DCs also recruit and activate effector T cells in the kidney by activation of the inflammasome and subsequent production of IL-1β and IL-18 [13]. In addition, activation of the inflammasome in macrophages by the P2X7 receptor increases disease activity [14].

Interestingly, not only pro-inflammatory cells infiltrate the kidney in NTS, but also regulatory immune cells which limit the on-going pro-inflammatory processes. In the early phase of disease, immature DCs recruit CCR6, expressing invariant natural killer T (iNKT) cells via the secretion of CXCL16 [15]. iNKT cells also have regulatory properties and suppress early infiltrating TH17 cells via the cytokines IL-4 and IL-10 [15]. TH17-specific STAT3-positive Tregs have recently been shown to infiltrate the kidney in the early phase of NTS and limit TH17 cell activation [16]. In the later phase of disease, regulatory T cells (Tregs) also infiltrate the kidney and limit TH1 activation by IL-10 secretion [6, 17, 18]. In early studies conducted in our laboratory, we did not detect early infiltration of Tregs into the kidneys [3, 19], but only infiltration in the prolonged phase of disease (Eller et al., unpublished observation). This difference might be explained by the different anti-GBM antibodies used as well as the need for immunization in our model.

Erratum to: Pediatr Nephrol