Complement System and the Kidney: Its Role in Renal Diseases, Kidney Transplantation and Renal Cell Carcinoma
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ABSTRACT:
SUBMITTER: Lasorsa F
PROVIDER: S-EPMC10671650 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
| S-EPMC10001167 | biostudies-literature
Project description:The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss after kidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome (HUS), the membranoproliferative glomerulonephritis (MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital (genetic) or acquired (auto-antibodies) modifications of the alternative pathway of complement. These abnormalities often remain after transplantation because they are constitutional and poorly influenced by the immunosuppression. This fact justifies the high recurrence rate of these diseases. Early diagnosis of recurrence is essential for an optimal therapeutically approach, whenever possible. Patients affected by end stage renal disease due to C3 glomerulopathies or to atypical HUS, may be transplanted with extreme caution. Living donor donation from relatives is not recommended because members of the same family may be affected by the same gene mutation. Different therapeutically approaches have been attempted either for recurrence prevention and treatment. The most promising approach is represented by complement inhibitors. Eculizumab, a monoclonal antibody against C5 convertase is the most promising drug, even if to date is not known how long the therapy should be continued and which are the best dosing. These facts face the high costs of the treatment. Eculizumab resistant patients have been described. They could benefit by a C3 convertase inhibitor, but this class of drugs is by now the object of randomized controlled trials.
| S-EPMC5175220 | biostudies-other
Project description:Kidney transplant recipients (KTRs) are at increased risk of developing renal cell carcinoma (RCC). The cancer can be encountered at different steps in the transplant process. RCC found during work-up of a transplant candidate needs treatment and to limit the risk of recurrence usually a mandatory observation period before transplantation is recommended. An observation period may be omitted for candidates with incidentally discovered and excised small RCCs (<3 cm). Likewise, RCC in the donor organ may not always preclude usage if tumor is small (<2 to 4 cm) and removed with clear margins before transplantation. After transplantation, 90% of RCCs are detected in the native kidneys, particularly if acquired cystic kidney disease has developed during prolonged dialysis. Screening for RCC after transplantation has not been found cost-effective. Treatment of RCC in KTRs poses challenges with adjustments of immunosuppression and oncologic treatments. For localized RCC, excision or nephrectomy is often curative. For metastatic RCC, recent landmark trials in the nontransplanted population demonstrate that immunotherapy combinations improve survival. Dedicated trials in KTRs are lacking. Case series on immune checkpoint inhibitors in solid organ recipients with a range of cancer types indicate partial or complete tumor response in approximately one-third of the patients at the cost of rejection developing in ~40%.
| S-EPMC8667800 | biostudies-literature
Project description:Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Novel insights highlighted the role of the locally produced and intracellular complement components in the development of inflammation and the alloreactive response in the kidney allograft. In the current review, we provide the updated understanding of the complement system in kidney transplantation. We will discuss the involvement of the different complement components in kidney ischemia-reperfusion injury, delayed graft function, allograft rejection, and chronic allograft injury. We will also introduce the existing and upcoming attempts to improve allograft outcomes in animal models and in the clinical setting by targeting the complement system.
| S-EPMC8913494 | biostudies-literature
Project description: Not available
| S-EPMC9243002 | biostudies-literature
Project description:Case summaryA 10-year-old spayed female American Shorthair cat underwent renal transplantation due to worsening chronic kidney disease secondary to polycystic kidney disease. During transplantation, the right kidney grossly appeared to be more diseased than the left and was firmly adhered to the surrounding tissues. An intraoperative fine-needle aspirate of the right native kidney revealed inflammatory cells but no evidence of neoplasia. To create space for the allograft, a right nephrectomy was performed. Following nephrectomy, the right native kidney was submitted for biopsy. Biopsy results revealed a renal cell carcinoma. Although the cat initially recovered well from surgery, delayed graft function was a concern in the early postoperative period. Significant azotemia persisted and the cat began to have diarrhea. Erythematous skin lesions developed in the perineal and inguinal regions, which were suspected to be secondary to thromboembolic disease based on histopathology. The cat's clinical status continued to decline with development of signs of sepsis, followed by marked obtundation with uncontrollable seizures. Given the postoperative diagnosis of renal cell carcinoma and the cat's progressively declining clinical status, humane euthanasia was elected.Relevance and novel informationThis case is the first to document renal cell carcinoma in a cat with polycystic kidney disease. An association of the two diseases has been reported in the human literature, but such a link has yet to be described in veterinary medicine. Given the association reported in the human literature, a plausible relationship between polycystic kidney disease and renal cell carcinoma in cats merits further investigation.
| S-EPMC5954322 | biostudies-literature
Project description:The complement system is considered to be an important part of innate immune system with a significant role in inflammation processes. The activation can occur through classical, alternative, or lectin pathway, resulting in the creation of anaphylatoxins C3a and C5a, possessing a vast spectrum of immune functions, and the assembly of terminal complement cascade, capable of direct cell lysis. The activation processes are tightly regulated; inappropriate activation of the complement cascade plays a significant role in many renal diseases including organ transplantation. Moreover, complement cascade is activated during ischemia/reperfusion injury processes and influences delayed graft function of kidney allografts. Interestingly, complement system has been found to play a role in both acute cellular and antibody-mediated rejections and thrombotic microangiopathy. Therefore, complement system may represent an interesting therapeutical target in kidney transplant pathologies.
| S-EPMC5447724 | biostudies-literature
Project description:The incidence and mortality of renal cell carcinoma (RCC) after kidney transplantation (KTx) remain unclear. This study's aims were (1) to investigate the pooled incidence/incidence trends, and (2) to assess the mortality/mortality trends in KTx patients with RCC. A literature search was conducted using the MEDLINE, EMBASE and Cochrane databases from inception through October 2018. Studies that reported the incidence or mortality of RCC among kidney transplant recipients were included. The pooled incidence and 95% CI were calculated using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO; no. CRD42018108994. A total of 22 observational studies with a total of 320,190 KTx patients were enrolled. Overall, the pooled estimated incidence of RCC after KTx was 0.7% (95% CI: 0.5-0.8%, I2 = 93%). While the pooled estimated incidence of de novo RCC in the native kidney was 0.7% (95% CI: 0.6-0.9%, I2 = 88%), the pooled estimated incidence of RCC in the allograft kidney was 0.2% (95% CI: 0.1-0.4%, I2 = 64%). The pooled estimated mortality rate in KTx recipients with RCC was 15.0% (95% CI: 7.4-28.1%, I2 = 80%) at a mean follow-up time of 42 months after RCC diagnosis. While meta-regression analysis showed a significant negative correlation between year of study and incidence of de novo RCC post-KTx (slopes = -0.05, P = 0.01), there were no significant correlations between the year of study and mortality of patients with RCC (P = 0.50). Egger's regression asymmetry test was performed and showed no publication bias in all analyses. The overall estimated incidence of RCC after KTX was 0.7%. Although there has been a potential decrease in the incidence of RCC post-KTx, mortality in KTx patients with RCC has not decreased over time.
| S-EPMC6517974 | biostudies-literature
Project description:In the past 20 years, we have witnessed tremendous advances in our ability to diagnose and treat genetic diseases of the kidney caused by complement dysregulation. Staggering progress was realized toward a better understanding of the genetic underpinnings and pathophysiology of many forms of atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies that are driven by complement system abnormalities. Many of these seminal discoveries paved the way for the design and characterization of several innovative therapies, some of which have already radically improved patients' outcomes. This review offers a broad overview of the exciting developments that have occurred in the recent past, with a particular focus on single-gene (or Mendelian), complement-driven aHUS and C3-dominant glomerulopathies that should be of interest to both nephrologists and kidney researchers. The discussion is restricted to genes with robust associations with both aHUS and C3-dominant glomerulopathies (complement factor H, complement component 3, complement factor H-related proteins) or only aHUS (complement factor B, complement factor I, and membrane cofactor protein). Key questions and challenges are highlighted, along with potential avenues for future directions.
| S-EPMC8216622 | biostudies-literature
Project description:Regulatory cell therapies, including regulatory T cells and mesenchymal stromal cells, have shown promise in early clinical trials for reducing immunosuppression burden in transplantation. While regulatory cell therapies may also offer potential for treating autoimmune kidney diseases, data remains sparse, limited mainly to preclinical studies. This review synthesises current literature on the application of regulatory cell therapies in these fields, highlighting the safety and efficacy shown in existing clinical trials. We discuss the need for further clinical validation, optimisation of clinical and immune monitoring protocols, and the challenges of manufacturing and quality control under Good Manufacturing Practice conditions, particularly for investigator-led trials. Additionally, we explore the potential for expanding clinical indications and the unique challenges posed in paediatric applications. Future directions include scaling up production, refining protocols to ensure consistent quality across manufacturing sites, and extending applications to other immune-mediated diseases.
| S-EPMC11584488 | biostudies-literature