Role of urinary CD80 biomarker in pediatric nephrotic syndrome

Idiopathic nephrotic syndrome (INS) is one of the most common kidney diseases in children.INS is classically defined by severe protein excretion (≥40 mg/m2/h or 1000 mg/m2/24h) that subsequently results in hypoalbuminemia (<25 g/L), hyperlipidemia and edema.Two histological subtypes of INS in children, are minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Approximately 80–90% of children with INS achieve remission after four weeks of daily prednisone therapy at a dose of 60 mg/m2 per day and therefore, given the diagnosis of steroid sensitive nephrotic syndrome (SSNS). When biopsied, these patients are more likely to have MCD. Patients with SSNS tend to have an excellent overall prognosis, with <5% progressing to chronic kidney disease (CKD). The remaining 10–20% of patients have primary steroid resistant nephrotic syndrome (SRNS), are more likely to have FSGS on biopsy, and have up to a 50% risk of developing end stage renal disease (ESRD) within 5 years of diagnosis. Therefore response to corticosteroids correlate with the prognosis of the disease. Patients with nephrotic syndrome experience remission and relapse course. Remission is defined proteinuria <4 mg/m2/h or urinary protein/creatinine (mg/mg) ratio of <0.2 for children above age of 2 years or ratio less than 0.5 for children under the age of 2 years. Relapse is defined proteinuria ≥ 40 mg/m2/h or > 50mg/kg/day or urinary protein/creatinine (mg/mg) ratio of ≥2.0 after having been remission. In some cases of this disease specially steroid-resistant cases, to achieve a reliable diagnosis and determine the prognosis and select the most appropriate treatment, kidney biopsy is necessary. But this method is invasive and on the other hand, because the biopsy obtains only a small portion of the kidney that in some cases it may not accurately portray the disease if the affected portion of the kidney is not sampled. In other cases, the disease may be so far advanced that diagnostic features are obscured. Given that one of the major challenges that modern nephrology should face is the identification of biomarkers that are associated with the above. Advancements in the understanding of the pathogenesis of nephrotic syndrome have facilitated the identification of a growing numbers of molecules that might be useful for these objectives. Urine sample for evaluating urinary proteomes seem to be a valuable tool for biomarker discovery and can be collected easily and non-invasively. Some of urinary biomarkers that have been found after podocyte damage include: proteins (podocalyxin, nephrin, podocin, CR1, CD80, synaptopodin, GLEPP-1, mindin, alpha 3 integrin, CD59, and Wilms tumor protein1-WT1), podocyte specific messenger ribonucleic acid (mRNA) (nephrin, podocin, synaptopodin, podocalyxin, CD2-associated protein-CD2AP, ACTN4-encodes for α-actinin 4, PTPRO-encodes for GLEPP-1, WT1, and B7-1-encodes for CD80), an exosomal transcription factor (WT1), and podocalyxin positive granular structures (PPGS). These biomarkers may be used to identify specific histopathological types of nephrotic syndrome, as well as patients' response to steroids and steroid-resistant or dependent cases. One of these biomarkers is the CD80 molecule, which is a circulating molecule in nephrotic syndrome and can be found in kidney tissue or excreted in the urine. Viral Infections, Bacterial infections, Allergens and T-cell cytokines such as interleukin-13 directly stimulate the podocytes and increase CD80 expression on them which eventually cause podocyte injury. By immunofluorescence studies and CD80 staining in glomerulus of patients with INS or measuring urinary level of CD80, it is possible to diagnose a specific type of nephrotic syndrome. In this article we reviewed different studies have been conducted on the role of CD80 in nephrotic syndrome.

In this study more than 70 articles were reviewed. Papers on nephrotic syndrome of childhood, application of urinary biomarkers in determining the specific histopathological type of INS and prognosis of the patients as well as CD80:CD28 costimulatory pathway have been reviewed. Articles on congenital/infantile nephrotic syndrome, review articles and case reports as well as secondary cases of INS were excluded. The selected articles were from 2002 to 2020.This review has been done by searching in Cochrane, Scholar Google, web of science and PubMed search engines.

CD80 is normally expressed on antigen-presenting cells (APC) or natural killer cells. It functions as a ligand for CD28 and CTLA4 and depending on which ligand it binds to, can regulate immune responses, positively or negatively. CD28 and CTLA4 have opposing effects on T cell stimulation. Activating of CD80-CTLA4 pathway results in down- regulation of the responding T cells. But binding CD80-CD28 on T-cells is an important step for T-cell activation. Recent studies have indicated that podocyte cells in certain circumstances can acquire the phenotype of APC and can be induced to express the CD80 (B7.1) molecule. It has been shown that the expression of CD80 in podocytes is associated with the reorganization of actin molecules in them and can increase their permeability to protein resulting proteinuria. Indeed one of the hypotheses in pathogenesis of MCD is two-hit theory. The initial hit is the induction of CD80 on the podocyte, resulting in actin disruption and increased glomerular permeability and the second hit is sustained podocyte injury due to T cell dysfunction or impaired autoregulation in these patients.Most studies support the role of CD80 as a permeability factor in minimal change nephrotic syndrome (MCD), that was significantly elevated in the active phase of MCD but remained to be normal in the active and remission phases of other types of nephrotic syndrome and in the remission phase of MCD. A recent study has reported that high urinary CD80 excretion might be a biomarker for steroid responsiveness and a predictor for good prognosis in INS.

CD80 molecule can be used as a valuable and non-invasive biomarker to differentiate MCD-relapse from MCD-remission and other glomerulopathies and also predicts steroid responsiveness and good prognosis in patients with nephrotic syndrome and may facilitate discovering of high-risk patients at an early stage and may lead to better treatment selection. Novel therapeutic agents such as Abatacept and Belatacept which are selective T-cell costimulation blocker and directe against CD80, may assist in the stabilization and reconstruction of podocytes in MCD.