Activation of the innate immune complement system is important for normal pregnancy, but excessive activation is associated with hypertensive disorders of pregnancy such as preeclampsia. Reduced regulation of the complement system is also linked to adverse pregnancy outcomes, likely due to excessive complement activation. Preeclampsia affects both mother and child, with fetal growth restriction and increased risk for cardiometabolic and neurodevelopmental disorders developing in offspring. Previous studies of others have shown that mice deficient in the complement regulator CSMD3 (Cub and Sushi Multiple Domains 3) are growth restricted at birth and exhibit neurodevelopmental disorders similar to offspring of preeclamptic pregnancies. This suggests that the lack of CSMD3 may also increase the risk of adverse cardiovascular outcomes in the offspring. Thus, we hypothesized that CSMD3 knockout (-/+, -/-) mice would have vascular dysfunction and high blood pressure, similar to offspring of preeclamptic pregnancies. To test this hypothesis, we evaluated systolic blood pressure, as well as vasoconstriction and vasodilation of isolated mesenteric arteries from 7-14 week old female CSMD3 knockout mice compared to C57Bl/6J mice. After a 2 week acclimation period, mean systolic blood pressure measured by tail cuff plethysmography and averaged over an 8 day test period was significantly greater in female CSMD3 (-/-) mice compared to female C57Bl/6J mice (141 ± 2.6 mm Hg vs 129 ± 1.9 mm Hg, p< 0.05, n=4/group). Mesenteric arteries from C57Bl/6J and CSMD3 hetero (-/+) and homozygous (-/-) knockout mice were mounted in a wire myography system to measure vascular function in response to vasoconstrictors and vasodilators. In C57Bl/6J mice, sex differences in endothelial-dependent reactivity to acetylcholine were apparent with the maximal dilator response as well as slope of the concentration response curve being greater in female compared to male C57Bl/6J mice. Responsiveness of mesenteric arteries isolated from C57Bl/6J mice were then compared to hetero- and homozygous CSMD3 knockout mice (n=8-10/group) combined. Neither vasoconstriction in response to U46619, a thromboxane mimetic, nor vasodilation in response to the endothelial-independent dilator sodium nitroprusside were significantly different by strain. However, when hetero- and homozygous CSMD3 knockout mice combined were compared to C57Bl/6J mice, endothelial-dependent vasodilation in response to acetylcholine was impaired in female, but not male, mice. A significant decrease in the maximal dilator response as well as the slope of the concentration response curve (ANOVA sex strain effect, p< 0.05) was noted comparing female C57Bl/6J mice to female hetero- and homozygous CSMD3 knockout mice combined. Thus, these data suggest that impaired endothelial-dependent vasodilation in female CSMD3 knockout animals contributes to increased blood pressure. The similarities between offspring of hypertensive pregnancies and CSMD3 knockout mice suggests an increased risk of a preeclamptic phenotype during pregnancy in the absence of this complement regulator. Funded in part by Longer Life Foundation grant and Washington University ICTS grant (AJ) and Whiteside Institute for Clinical Research, a collaboration of St Lukes Hospital, Clinics and Foundation and the University of Minnesota Medical School Duluth Campus (JFR) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background:Plasma cell dyscrasia (PCD) is a rare but important cause of end stage kidney disease (ESKD). Kidney transplant is the treatment of choice in patients with ESKD. However, the complexity of PCD care and risk of disease recurrence poses challenges to kidney transplant candidacy and outcomes. We examined the current clinical practice patterns of clinicians who care for patients with PCD and identified barriers to kidney transplantation for patients with PCD. Methods:A web-based survey was developed and distributed from January to July 2024 to kidney transplant clinicians (American Society of Transplant (AST) members), hematologists (PCD experts), and onco-nephrologists. Results:Seventy clinicians (50 transplant nephrologists, 18 hematologists, and two surgeons) from 42 transplant centers in the US participated in the survey. Clinical practice patterns pre and post kidney transplant for patients with PCD are highly variable among institutions, and only 36% reported having a protocol for pre- and post-transplant management for patients with PCD. Particularly, the requirement for pre-transplant hematologic remission criteria, induction and maintenance immunosuppression regimens and protocols for prophylaxis and screening for opportunistic infection are areas of future study. Clinicians listed lack of data and practice guidance as well as communication challenges among multiple specialties especially hematology and kidney transplant clinicians as notable barriers. Conclusions:Our study identified the highly variable current practice patterns when evaluating and managing patients with PCD for kidney transplant. Our findings emphasize the need for collecting and sharing clinical data to support standardized practices and serve as a basis for the upcoming multi-societal management recommendation for kidney transplant for patients with PCD.

Prevention of encapsulated bacterial infection is critical for safe systemic treatment with complement inhibitors. Gaps in provider awareness and practical clinical guidance remain. In this narrative review, we highlight key aspects of how the complement inhibitors' mechanisms of action might theoretically increase the risk of infection, summarize current evidence-based recommendations, provide expert opinion to fill in the gaps in these recommendations, identify critical unanswered questions, and suggest studies to address them. Following recommendations for vaccinations and antibiotic prophylaxis are key approaches for preventing serious infections from encapsulated bacteria (especially meningococci) in patients using complement inhibitors to treat kidney or eye diseases. The duration of antibiotic prophylaxis remains a provider-dependent decision because of the lack of evidence to support more specific recommendations. Consultations with infectious disease specialists regarding local bacterial resistance/sensitivity patterns may inform the choice of agents for antibiotic prophylaxis. Patients with worrisome signs or symptoms must be promptly evaluated.

Complement-mediated thrombotic microangiopathy can be difficult to recognize when it presents in the setting of an apparent clinical trigger, such as pregnancy, severe hypertension, or kidney transplantation. These conditions can each cause endothelial injury directly, but may also unmask complement dysregulation in susceptible individuals. In these situations, the critical question is not whether a trigger exists but whether it fully explains the syndrome and whether urgent complement blockade is warranted to prevent irreversible kidney injury. In this How I Treat article, we use three real-world cases to illustrate how we approach this decision in practice. We emphasize the bedside features that most influence our threshold to treat, including the pattern and severity of kidney injury, tempo of disease progression, and lack of improvement with supportive or trigger-directed care. We also address the interpretation of complement genetic findings, pregnancy- and transplant-specific risk stratification, and individualization of treatment duration. Functional assays can support mechanistic assessment in selected cases but remain an adjunct to the diagnosis and should not drive management decisions.

Simultaneous liver-kidney transplantation (SLKT) has been the standard of care for patients with end-stage renal disease (ESRD) and primary hyperoxaluria type 1 (PH1). Lumasiran is a novel RNA interference (RNAi) therapy that targets glycolate oxidase and decreases oxalate production in the liver. Despite its availability, the use of RNAi with kidney transplant alone (KTA) for ESRD related to primary hyperoxaluria remains limited. We report a 39-year-old female with a history of KTA who presented with diarrhea and severe AKI. She rapidly progressed to anuria and allograft loss. Her kidney biopsy demonstrated calcium oxalate deposition. The patient was subsequently evaluated for a repeat kidney transplant. Given the morbidity associated with SLKT, RNAi therapy was pursued as an alternative. Initiation of Lumasiran reduced serum oxalate from 40 to 8 µmol/L, enabling successful KTA with immediate graft function. At 12 months post-transplant, renal function remained stable (creatinine 0.82 mg/dL, serum oxalate <1.5 µmol/L). This case highlights RNAi therapy as a promising strategy to facilitate KTA in patients with PH1 and ESRD, potentially reducing the need for SLKT and its associated morbidity.

Overactivation of the complement system plays a role in the pathophysiology of several serious kidney diseases, such as IgA nephropathy, complement 3 glomerulopathy, atypical hemolytic uremic syndrome, and ANCA-associated vasculitis. A key focus of recent research has been developing complement inhibitors to target the underlying disease mechanisms of these diseases and thereby improve patient outcomes. Currently, five complement inhibitors are approved by the US Food and Drug Administration as effective for the treatment of kidney diseases: eculizumab, ravulizumab, avacopan, iptacopan, and pegcetacoplan. However, some of these therapies may increase the risk of serious, potentially life-threatening infections, particularly from encapsulated organisms including Neisseria meningitidis , Streptococcus pneumoniae , and Haemophilus influenzae type b. Health care providers must recognize this risk and implement preventive measures when prescribing complement inhibitors. This review summarizes the infectious risks associated with complement inhibitors and highlights key clinical considerations for their safe and effective use in the treatment of kidney diseases. It is intended to serve as an accessible resource for providers using these agents in clinical practice.

Complement 3 glomerulopathy (C3G) is an ultra-rare glomerulonephritis caused by dysregulation of the alternative complement pathway. C3G has an estimated incidence of 1-3 cases per million people in the United States. Diagnosing C3G based solely on clinical and laboratory features is challenging because it mimics several other glomerular diseases; therefore, diagnosis requires a kidney biopsy. In the absence of disease-modifying therapies and optimal patient management strategies, C3G poses a significant physical and emotional burden on patients and caregivers. Common symptoms of glomerulonephritis include fatigue, edema, anxiety, and/or depression, which have profound effects on patients' daily lives. Approximately half of all patients progress to kidney failure within 10 years of diagnosis. Encouragingly, the treatment landscape in C3G is poised to change, with several targeted complement inhibitors in late-stage development. This perspectives article explores a patient's journey in C3G and discusses the current and future status of clinical outcomes and patient management from the viewpoints of a practicing nephrologist and a patient.

Background:Knowledge gaps exist regarding the role of coagulation pathway mutations such as those in the plasminogen (PLG) gene in the pathogenesis of thrombotic microangiopathy (TMA) and treatment outcomes. Objectives:This study aims to describe the unique phenotypic features of patients with PLG mutations and perform structural mapping of the variants to enhance variant interpretation. Methods:This was a single-center retrospective study of patients with TMA in whom genetic testing was performed between 2011 and 2023. Data were collected regarding demographics, clinical features at their first presentation, renal outcomes, genetic mutations, and recurrence for those who were found to have a PLG mutation. Structural mapping of the PLG variants was performed using X-ray structural data. Results:Over the 12-year study period, we identified 6 individuals in our TMA cohort with PLG mutations. Median age at the time of first TMA event was 45.5 years (range: 5-57 years). Nearly all were female (n = 5, 83%). Half of the cohort (n = 3, 50%) had recurrent TMA, with 1 having recurrent episodes while on long-term complement blockade therapy. Three patients are now on long-term anticoagulation with no further TMA recurrences observed. Structural mapping of the variants revealed that the mutations could be categorized into 3 groups. Among these, group 2 variants (residues K38 in the PAN-apple domain and residue R523 in kringle-5) had a more severe phenotype with severe thrombocytopenia at presentation and a recurrent TMA course. Conclusion:Patients with PLG mutation-associated TMAs appear to have a poor response to complement blockade therapy, suggesting that pathways in addition to or independent of complement dysregulation may be involved in some patients. Future studies are warranted to explore the role of anticoagulation in preventing recurrence in patients with PLG mutations.

Thrombotic microangiopathy (TMA) is a challenging and serious complication of kidney transplantation that significantly affects graft and patient survival, occurring in 0.8%-15% of transplant recipients. TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to endothelial damage and microthrombi formation in small vessels. However, clinical features can range from a renal-limited form, diagnosed only on a kidney biopsy, to full-blown systemic manifestations, which include neurologic, gastrointestinal, and cardiovascular injury. TMA can arise because of genetic or acquired defects such as in complement-mediated TMA or can occur in the context of other conditions like infections, autoimmune diseases, or immunosuppressive drugs, where complement activation may also play a role. Recurrent TMA after kidney transplant is almost always complement-mediated, although complement overactivation may also play a role in de novo post-transplant TMAs associated with ischemia-reperfusion injury, immunosuppressive drugs, antibody-mediated rejection, viral infections, and relapse of autoimmune diseases, such as antiphospholipid antibody syndrome. Differentiating between a complement-mediated process and one triggered by other factors is often challenging but critical to minimize allograft damage because the former is nonresponsive to supportive therapy, needs long-term anticomplement therapy, and has a high risk of recurrence. Given the central role of complement and effect of genetic defects on the risk of recurrence in many forms of post-transplant TMA, genetic testing for complement disorders is key for proper diagnosis and management. Given that complement activation may also play a role in a subset of TMAs associated with other conditions, prompt recognition and timely initiation of anticomplement therapy is equally important. In addition, TMA associated with noncomplement genes, often part of a broader syndromic process with distinct clinical features, has also been described. Early identification and treatment are essential to prevent graft failure and other severe complications. This review explores the pathophysiologic mechanisms underlying various post-transplant TMAs.

Atypical hemolytic uremic syndrome (aHUS) or complement-mediated thrombotic microangiopathy (CM-TMA) and C3 glomerulopathy are two prototypical diseases of complement dysregulation occurring due to genetic variants in complement proteins or acquired factors such as autoantibodies. Despite the presence of an underlying genetic etiology, an environmental trigger is often necessary to manifest disease, a phenomenon known as incomplete penetrance. These triggers could include infections, pregnancy, medication, cancers, or ischemia-reperfusion injury and antibody-mediated rejection in the setting of transplantation and highlight the complex interplay between genetic etiology and environmental factors. Other diseases in which complement activation may also be a part of the underlying pathophysiology and where the gene-environment interaction also plays out are IgA nephropathy, lupus nephritis, ANCA-associated vasculitis, and membranous nephropathy. Genetic polymorphisms and haplotypes may further skew the balance between complement over activation and control. In this article, we discuss the activation and regulation of the complement system and the role of complement in various kidney diseases. We also attempt to provide an in-depth understanding of the genetic drivers and environmental triggers associated with complement activation using aHUS as a key example. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

Introduction: Chronic Kidney Disease (CKD) affects 1 in 7 adults in the United States, yet 90% of those impacted remain unaware of their condition, and fewer than 20% of at-risk individuals are appropriately tested. Safety-net health care settings are disproportionately burdened by CKD, with a patient population enriched for CKD risk factors, social deprivation, and barriers to diagnostic testing which delay access to diagnosis and lifesaving interventions. The National Kidney Foundation partnered with a Federally Qualified Health Center (FQHC) to evaluate an approach to increase guideline-recommended testing among patients at high-risk for developing CKD. Methods: Through electronic health record (EHR) data analysis, eligible patients were identified to receive an at-home, semi-quantitative urine albumin-creatine ratio (uACR) testing kit. The kits provided immediate results via a smartphone application, as well as automatically routed to the clinic EHR for the patient’s provider to coordinate necessary follow-up care. This initiative was conducted in Missouri, USA in 2023 and evaluated using domains of the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Results: Results reflect that 1496 of 4677 (32%) eligible patients completed uACR testing with 50% receiving abnormal results indicative of albuminuria. Of those with evidence of albuminuria, 84% had follow-up visits and 32% completed appropriate follow-up testing based on clinical guidelines. Albuminuria was prevalent across all age groups, with 69% of abnormal results appearing in patients under 60 years. Consistent with national data, patients identifying as Black were significantly more likely to have albuminuria in this cohort ( P < .0001). Notably, most patients with albuminuria had an eGFR ≥60 mL/min/1.73 m 2 . Conclusions: Findings highlight the urgency of improving uACR testing for early CKD diagnosis, especially in safety-net settings. The findings also demonstrate the utility of at-home testing to improve access to care across underserved communities and represent a replicable, efficient model to identify those with high risk of CKD progression. While the program required significant time and coordination, this can be streamlined for analogous programs. Future opportunities exist to further the impacts including additional quality improvement activities to ensure follow-up testing and close gaps in CKD care.

Patients with plasma cell dyscrasia, including multiple myeloma, AL amyloidosis, and monoclonal gammopathy of renal significance, face a high burden of end-stage kidney disease, which limits survival and quality of life. Although kidney transplant offers potential benefits, it remains underused because of the high risk of recurrence and historically poor outcomes. A multidisciplinary panel of transplant nephrologists, hematologists/oncologists, and pathologists convened to evaluate contemporary evidence and evolving strategies in kidney transplant for plasma cell dyscrasias and end-stage kidney disease. Advances in plasma cell dyscrasia therapies are improving survival and expanding kidney transplant eligibility. However, key challenges remain, including optimizing hematologic response pre-kidney transplant and managing immunosuppression to mitigate recurrence and avoid infection complications. Ongoing research and multidisciplinary collaboration are essential to refine transplant selection, integrate biomarkers for risk stratification, and develop tailored post-kidney transplant surveillance. These efforts may increase access to kidney transplant and improve outcomes for patients with plasma cell dyscrasia and end-stage kidney disease.

Preeclampsia is a common pregnancy-specific vascular disorder that develops during the second half of pregnancy. Preeclampsia shares features with thrombotic microangiopathies. Here we analyzed whether sequence variants in the coagulation system genes predispose to preeclampsia. We performed targeted exomic sequencing of 58 genes in a total of 615 preeclamptic women and 2094 controls. A common missense variant rs1800385 (Val1565Leu) in the gene coding for von Willebrand Factor (VWF) (OR=1.72, p-value=3.57E-4) and a low-frequency missense variant rs41314453 (Ala732Val) in the gene coding for a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (OR=1.97, p-value=0.044) were associated with preeclampsia. rs41314453 is known to decrease ADAMTS13 expression and activity. Thus, the reduced enzyme activity could promote the formation of large vWF polymers on endothelial cells and platelets and thereby increase vascular prothrombotic activity in preeclampsia. Our results support a role for an impaired ability of ADAMTS13 to limit VWF polymerization in the pathogenesis of PE. Ultralarge multimers of VWF could mediate platelet accumulation in the turbulent intervillous spaces in preeclamptic placentae, calling upon novel therapeutics to control the VWF-ADAMTS13 axis in severe cases having low ADAMTS13 in the presence of high VWF levels and multimerization.

Introduction: Thrombotic microangiopathy (TMA), characterized by small-vessel thrombosis caused by endothelial injury, presents significant diagnostic and treatment challenges in kidney transplantation. Methods: To investigate the factors associated with posttransplant TMA, we conducted a retrospective study of 3535 kidney transplant recipients at our center from 2008 to 2023. Results: Sixty-eight patients were diagnosed with TMA, and 93% (63 of 68) underwent genetic testing. Patients were categorized into 3 groups based on the TMA etiology. Group 1 (n = 42, 62%) included patients with complement-mediated TMA associated with genetic or acquired complement abnormalities. These patients were younger and had a higher incidence of hypertension (HTN) or preeclampsia as the causes of end-stage kidney disease (ESKD). Notably, 33% of patients developed recurrent TMA, and approximately 78% of those with recurrent TMA lost their allografts. Group 2 (n = 14, 21%) had TMA associated with calcineurin inhibitors (CNIs) or ischemia-reperfusion injury (IRI), showing longer cold ischemia times (CITs) (19.9 f 8.7 hours vs. 10.7 f 8.9 hours; P = 0.0001) and a higher rate of delayed graft function (DGF) (43% vs. 13%, P = 0.0008) than the controls. Group 3 (n = 12, 17%) had TMA from diverse causes (infections or autoimmune disorders) and exhibited a poor response to anticomplement therapy. No genetic variants were identified in this group. Conclusion: Our findings underscore the need for comprehensive pre and posttransplantation genetic testing to predict and manage the risk of TMA and prevent graft loss. CNIs may exacerbate the risk of posttransplant TMA in the presence of other complement-activating factors. Our study also highlights the importance of personalized strategies and early interventions based on the functional assessment of variants of uncertain significance (VUS).

Preeclampsia affects 3-4% of pregnancies with adverse effects for both mother and child. Minimal therapeutic options are available, and biomarkers are urgently needed to identify those at greatest risk early in the pregnancy. Both the innate and adaptive immune systems are well regulated during normal pregnancy including the complement system. A functioning complement system with some degree of complement activation participates in proper placental development, ensuring a healthy pregnancy and assisting with host defense. However, aberrant complement activation can lead to adverse pregnancy outcomes such as preeclampsia. An overview of the complement system will be presented, along with review of the pre-clinical literature in animal models providing evidence for complement involvement in maintaining a normal pregnancy and contributing to symptoms of preeclampsia. In addition, clinical studies with evaluation of complement biomarkers in plasma and urine implicate complement dysregulation in the pathophysiology of subtypes of preeclampsia including HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome. Recent studies on the genetics of complement dysregulation in preeclampsia will be reviewed, along with updates on use of recently developed complement therapeutics. The potential utility of evaluating complement activation or manipulating complement during pregnancy will be discussed in view of the successful use of complement therapeutics in pregnancy in other immune diseases.