LITERATURE REVIEW: Renal disease

Urinary kidney injury molecule-1 in renal disease
Moresco RN, Bochi GV, Stein CS, De Carvalho JAM, Cembranel BM, Bollick YS. Clin Chim Acta 2018; 487: 15–21
Kidney injury molecule-1 (KIM-1), a type l transmembrane glycoprotein, is recognized as a potential biomarker for detection of tubular injury in the main renal diseases. Urinary KIM-1 increases rapidly upon the tubular injury, and its levels are associated with the degree of tubular injury, interstitial fibrosis, and inflammation in the injured kidney. Currently, the investigation of kidney diseases is usually performed through the assessment of serum creatinine and urinary albumin. However, these biomarkers are limited for the early detection of changes in renal function. Besides, the tubular injury appears to precede glomerular damage in the pathophysiology of renal diseases. For these reasons, the search for sensitive, specific and non-invasive biomarkers is of interest. Therefore, the purpose of this article is to review the physiological mechanisms of KIM-1, as well to present clinical evidence about the association between elevated urinary KIM-1 levels and the main renal diseases such as chronic kidney disease, diabetic kidney disease, acute kidney injury, and IgA nephropathy.

Prognostic impact of tumour-infiltrating CD276/Foxp3-positive lymphocytes and associated circulating cytokines in patients undergoing radical nephrectomy for localized renal cell carcinoma
Iida K, Miyake M, Onishi K, Hori S, Morizawa Y, et al. Oncol Lett 2019;17(4): 4004–4010
Renal cell carcinoma (RCC) is an immunogenic tumour and pathological specimens generally contain large quantities of tumour-infiltrating lymphocytes (TILs). Numerous cell types and cytokines could affect the immune escape mechanism of tumour cells. The aim of the present study was to investigate the prognostic impact of TILs and the associated circulating cytokines on localized clear cell RCC following radical nephrectomy. A total of 87 patients who had undergone radical nephrectomy and were pathologically diagnosed with localized clear cell RCC were included. The present study evaluated the profile of TILs with immunohistochemical analysis of tumour specimens using a panel of antibodies [cluster of differentiation (CD)-4, CD8, CD80, CD86, CD276, and Forkhead box p3 (Foxp3)]. Counts of each TIL were compared with clinicopathological variables. Based on the results of immunohistochemical analyses, putative cytokines, including interleukin (IL)-6, IL-10, IL-17, interferon-γ, tumour necrosis factor (TNF)-α, and transforming growth factor (TGF)-β, were selected, and their levels in preoperative serum were measured by ELISA. The levels were compared with TIL counts in tumour specimens. High counts of the CD276+ and Foxp3+ TILs were identified as independent factors for poor prognosis for metastasis and local recurrence following radical nephrectomy (P=0.033 and 0.006, respectively). A high CD276+ TIL count was associated with preoperative serum levels of TNF-α and IFN-γ (P=0.027 and P=0.035, respectively), whereas a high count of Foxp3+ TILs was associated with preoperative serum levels of TGF-β (P=0.021). High levels of TNF-α and TGF-β were associated with recurrence-free survival (P=0.035 and P=0.031, respectively). Topical intra-tumoral immunoreaction and systemic immune status may be associated with patients with localized RCC. The topical induction of the CD276+ and Foxp3+ TILs was suggested to be associated with high levels of serum TNF-α and IFN-γ. Preoperative serum levels of TNF-α and TGF-β could be simple and non-invasive biomarkers for risk stratification before radical surgery.

Mesangial C4d deposition may predict progression of kidney disease in pediatric patients with IgA nephropathy
Fabiano RCG, de Almeida Araújo S, Bambirra EA, Oliveira EA, Simões E Silva AC, Pinheiro SVB. Pediatr Nephrol 2017; 32(7): 1211–1220

BACKGROUND: Data on the risk factors for chronic kidney disease in children with immunoglobulin A nephropathy (IgAN) are scarce. This study was aimed at investigating whether glomerular C4d immunostaining is a prognostic marker in pediatric IgAN.

METHODS: In this retrospective cohort study, 47 patients with IgAN biopsied from 1982 to 2010 were evaluated. Immunohistochemistry for C4d was performed in all cases. For analysis, patients were grouped according to positivity or not for C4d in the mesangial area. Primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) by 50 % or more.

RESULTS: Median follow-up was 8.3 years. Median renal survival was 13.7 years and the probability of a 50 % decline in eGFR was 13 % over 10 years. Nine children exhibited the primary outcome and four developed end-stage renal disease (ESRD). Compared with C4d-negative patients (n=37), C4d-positive patients (n=10) presented higher baseline proteinuria (1.66 ± 0.68 vs 0.47 ± 0.19 g/day/1.73 m2, P<0.001), a progressive decline in eGFR (−10.04 ± 19.38 vs 1.70 ± 18.51 mL/min/1.73 m2/year; P=0.045), and more frequently achieved the primary outcome (50.0 vs 10.8 %, P=0.013), and ESRD (30.0 vs 2.7 %, P=0.026). No difference was observed in Oxford classification variables. Baseline proteinuria, endocapillary hypercellularity and mesangial C4d deposition were associated with primary outcome in univariate analysis. Proteinuria and mesangial C4d deposition at baseline independently predicted the decline in eGFR. Renal survival was significantly reduced in C4d-positive patients (8.6 vs 15.1 years in C4d-negative patients, P<0.001).

CONCLUSIONS: In this exclusively pediatric cohort, positivity for C4d in the mesangial area was an independent predictor of renal function deterioration in IgAN.

Non-invasive biomarkers of acute rejection in kidney transplantation: novel targets and strategies
Eikmans M, Gielis EM, Ledeganck KJ, Yang J, Abramowicz D, Claas FFJ. Front Med (Lausanne) 2019; 5: 358

Kidney transplantation is considered the favoured treatment for patients suffering from end-stage renal disease, since successful transplantation is associated with longer survival and improved quality of life compared to dialysis. Alloreactive immune responses against the donor kidney may lead to acute rejection of the transplant. The current diagnosis of renal allograft rejection mainly relies on clinical monitoring, including serum creatinine, proteinuria, and confirmation by histopathologic assessment in the kidney transplant biopsy. These parameters have their limitations. Identification and validation of biomarkers, which correlate with or predict the presence of acute rejection, and which could improve therapeutic decision making, are priorities for the transplantation community. There is a need for alternative, less invasive but sensitive markers to diagnose acute graft rejection. Here, we provide an overview of the current status on research of biomarkers of acute kidney transplant rejection in blood and urine. We specifically discuss relatively novel research strategies in biomarker research, including transcriptomics and proteomics, and elaborate on donor-derived cell-free DNA as a potential biomarker.