Complement Mediated Renal Inflammation Induced by Donor Brain Death: Role of Renal C5a‐C5aR Interaction

Kidneys retrieved from brain‐dead donors have impaired allograft function after transplantation compared to kidneys from living donors. Donor brain death (BD) triggers inflammatory responses, including both systemic and local complement activation. The mechanism by which systemic activated complement contributes to allograft injury remains to be elucidated. The aim of this study was to investigate systemic C5a release after BD in human donors and direct effects of C5a on human renal tissue. C5a levels were measured in plasma from living and brain‐dead donors. Renal C5aR gene and protein expression in living and brain‐dead donors was investigated in renal pretransplantation biopsies. The direct effect of C5a on human renal tissue was investigated by stimulating human kidney slices with C5a using a newly developed precision‐cut method. Elevated C5a levels were found in plasma from brain‐dead donors in concert with induced C5aR expression in donor kidney biopsies. Exposure of precision‐cut human kidney slices to C5a induced gene expression of pro‐inflammatory cytokines IL‐1 beta, IL‐6 and IL‐8. In conclusion, these findings suggest that systemic generation of C5a mediates renal inflammation in brain‐dead donor grafts via tubular C5a‐C5aR interaction. This study also introduces a novel in vitro technique to analyze renal cells in their biological environment.     

Combined C4d and CD3 immunostaining predicts immunoglobulin (Ig)A nephropathy progression

A number of molecules have been shown recently to be involved in the pathogenesis and progression of immunoglobulin (Ig)A nephropathy (IgAN). Among these, we have selected C4d (complement lectin pathway involvement), CD3 (T cell marker, traducing interstitial inflammation), transglutaminase 2 (TGase-2, involved in tissue fibrosis development) and p-extracelluar-regulated kinase (ERK)1/2 (protein kinase intracellular signaling molecule) to perform a panel of immunohistological biomarkers and assess its predictive value for disease progression. Immunohistochemical staining of these biomarkers was performed in paraffin sections from 74 renal biopsy cases with the clinical diagnosis of IgAN. Association between score analysis of these parameters and disease course was assessed through univariate and multivariate analysis, including baseline clinical and histological data. Univariate analysis showed that glomerular C4d, tubulointerstitial TGase2 and CD3 scores were associated with baseline proteinuria and disease progression. Multivariate analysis showed that only baseline estimated glomerular filtration rate (eGFR), C4d and CD3 were associated independently with progressive kidney disease (decline of at least 50% in the eGFR or progression to end-stage renal disease (ESRD) during the follow-up period). Establishing an accurate prediction model for IgAN progression is still a matter of research in clinical nephrology. The complement system, particularly lectin pathway activation, and T cell activation, have been shown previously to be potential modifiers of the disease course. Here we show that the combination of two histological biomarkers (C4d and CD3) can be a powerful predictor of IgAN progression and a potential useful tool for the clinical approach of this disease.     

The impact of robot-mediated adaptive I-TRAVLE training on impaired upper limb function in chronic stroke and multiple sclerosis

Purpose: The current study aimed to investigate proof-of-concept efficacy of an individualized, robot-mediated training regime for people with MS (pwMS) and stroke patients.

Method: Thirteen pwMS and 14 chronic stroke patients performed 36 (stroke) or 40 (pwMS) training sessions with the I-TRAVLE system. Evaluation of upper limb function was performed at baseline, after training and at 3 months follow-up. Clinical outcome measures consisted of active range of motion (ROM), Motricity Index, Jamar handgrip strength, perceived fatigue and strength, Wolf Motor Function Test (WFMT) and ABILHAND. Robot-generated outcome measures consisted of movement velocity, ROM and actual covered distance compared to straight-line distance.

Results: In pwMS, significant improvements were found after training in active shoulder ROM, handgrip strength, perceived strength and WMFT activities. No significant change in clinical outcome was found in stroke patients, except for perceived strength. Significant improvement in speed and movement duration was found after training in both groups. At follow-up, clinical outcome deteriorated in pwMS and was maintained in stroke patients.

Conclusions: Robot-mediated training resulted in improved movement coordination in both groups, as well as clinical improvement in pwMS. Absence of functional improvements in stroke patients may relate to severe upper limb dysfunction at baseline.

• Implications for Rehabilitation

• Robot-mediated training improved strength, active range of motion and upper limb capacity in pwMS.

• Robot-mediated therapy allows for adapted training difficulty.

     

Crosstalk between Complement and Toll‐like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia‐Reperfusion Injury

Two central pathways of innate immunity, complement and Toll‐like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen activated protein kinases (MAPKs) might be the key molecules linking both the complement and TLR pathways together. Complement and TLRs are important mediators of renal ischemia‐reperfusion injury (IRI). Besides IRI, complement C3 can also be upregulated and activated in the kidney before transplantation as a direct result of brain death (BD) in the donor. This local upregulation and activation of complement in the donor kidney has been proven to be detrimental for renal allograft outcome. Also TLR4 and several of its major ligands are upregulated by donor BD compared to living donors. Important and in line with the observations above, kidney transplant recipients have a benefit when receiving a kidney from a TLR4 Asp299Gly/Thr399Ile genotypic donor. The role of complement and TLRs and crosstalk between these two innate immune systems in relation to renal injury during donor BD and ischemia‐reperfusion are focus of this review. Future strategies to target complement and TLR activation in kidney transplantation are considered.     

Renal transplantation in patients with atypical haemolytic uraemic syndrome: a tailor made approach is necessary

A 33-year-old woman with a history of chronic transplant dysfunction because of repeated bouts of haemolytic uraemic syndrome (HUS) was considered for a second transplant. Extensive genetic investigation of the complement system was executed to rule out known mutations prone to development of HUS. This case illustrates the importance of genetic screening in patients with recurrent HUS.