Delayed-Release Budesonide in a Patient With Progressive IgA Nephropathy and Stage 4 Chronic Kidney Disease: A Case Report.

Delayed-release (DR) budesonide received expedited approval from the US Food and Drug Administration (FDA) as a treatment for reducing proteinuria in individuals with primary IgA nephropathy (IgAN) who are at significant risk of disease progression. The approval was based on clinical trials primarily involving patients with an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m2. However, the efficacy of DR budesonide in reducing kidney function decline, especially in patients with an eGFR less than 30 mL/min/1.73 m2 and proteinuria less than 1 g/d, remains unclear. We report the case of a 43-year-old man with a long-term history of hypertension and biopsy-proven IgAN who experienced a progressive increase in proteinuria and serum creatinine, along with a decline in eGFR to 28 mL/min/1.73 m2 despite maximal supportive management. Following therapy with DR budesonide, a decreasing trend in proteinuria and a stabilization of eGFR were observed in the recent measurements. While initial data suggested the effectiveness of DR budesonide primarily in patients with an eGFR over 30 mL/min/1.73 m2, our case demonstrates the potential of DR budesonide for use in scenarios beyond its currently approved indications. This underscores the need for additional research on patients with advanced stages of chronic kidney disease.

Rituximab Resistance in Glomerular Diseases: A GlomCon Mini Review.

Resistance to rituximab B-cell depletion therapy is a clinically pertinent adverse sequela that can have significant implications for the treatment of immune-mediated glomerular diseases. The true incidence of rituximab resistance remains unknown; however, it is an increasingly recognized treatment complication. Resistance typically presents with suboptimal treatment response, rapid B-cell reconstitution, and a relapsing disease course. Although the diverse mechanisms resulting in rituximab resistance are ongoing topics of research, both primary and secondary mechanisms have been identified as key catalysts. The emergence of human antichimeric antibodies (HACAs) is a major cause of secondary resistance to rituximab therapy and typically appears following repeated drug exposure. Frequently, HACAs develop in the setting of underlying autoimmune disease and contribute to poor B-cell depletion, reduced rituximab therapeutic efficacy, and enhanced drug clearance. The clinical challenge of rituximab resistance necessitates heightened awareness among clinicians. Screening for HACAs should be considered in individuals with poor clinical response to rituximab, more rapid B-cell reconstitution, and relapsing disease. Detection of HACAs may guide treatment alterations, including addition of further immunosuppressive therapy and transitioning to a humanized B-cell depleting monoclonal antibody.

A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical models.

Long-term organ transplant survival remains suboptimal, and life-long immunosuppression predisposes transplant recipients to an increased risk of infection, malignancy, and kidney toxicity. Promoting the regulatory arm of the immune system by expanding Tregs may allow immunosuppression minimization and improve long-term graft outcomes. While low-dose IL-2 treatment can expand Tregs, it has a short half-life and off-target expansion of NK and effector T cells, limiting its clinical applicability. Here, we designed a humanized mutein IL-2 with high Treg selectivity and a prolonged half-life due to the fusion of an Fc domain, which we termed mIL-2. We showed selective and sustainable Treg expansion by mIL-2 in 2 murine models of skin transplantation. This expansion led to donor-specific tolerance through robust increases in polyclonal and antigen-specific Tregs, along with enhanced Treg-suppressive function. We also showed that Treg expansion by mIL-2 could overcome the failure of calcineurin inhibitors or costimulation blockade to prolong the survival of major-mismatched skin grafts. Validating its translational potential, mIL-2 induced a selective and sustainable in vivo Treg expansion in cynomolgus monkeys and showed selectivity for human Tregs in vitro and in a humanized mouse model. This work demonstrated that mIL-2 can enhance immune regulation and promote long-term allograft survival, potentially minimizing immunosuppression.

Recurrence of membranous nephropathy after kidney transplantation: A multicenter retrospective cohort study.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

Nephrotic-range proteinuria: a potential risk factor for failure of tixagevimab-cilgavimab prophylaxis.

BACKGROUND: Pre-exposure prophylaxis with tixagevimab-cilgavimab has been shown to reduce the incidence of SARS-CoV-2 infection in immunocompromised individuals. Individuals with nephrotic-range proteinuria can lose immunoglobulins such as tixagevimab-cilgavimab in the urine and, therefore, may derive less benefit from tixagevimab-cilgavimab. There are no published studies evaluating the association of nephrotic-range proteinuria with failure of tixagevimab-cilgavimab prophylaxis. METHODS: We conducted a retrospective observational cohort study of all individuals at our center who received tixagevimab-cilgavimab while they had nephrotic-range proteinuria. Each individual in the nephrotic group was matched 1:3 with controls who were matched for B cell depletion therapy in addition to the total dose and date of first tixagevimab-cilgavimab administration. The primary outcome was the development of breakthrough SARS-CoV-2 infection after receiving tixagevimab-cilgavimab. RESULTS: Sixteen patients received tixagevimab-cilgavimab between January 1st, 2022, and June 30th, 2022, at a time when they had nephrotic-range proteinuria. Proteinuria levels and serum creatinine levels were higher while serum albumin levels were lower in the nephrotic group compared to the control group. At a median follow-up of 251 days, 38% of individuals in the nephrotic group had developed breakthrough SARS-CoV-2 infections, compared to only 13% in the control group at a median follow-up of 238 days. Nephrotic-range proteinuria was associated with a higher incidence of breakthrough infection (log-rank P = 0.04). CONCLUSIONS: Nephrotic-range proteinuria may increase the risk of failure of tixagevimab-cilgavimab pre-exposure prophylaxis. Prospective studies to validate these findings and to evaluate the optimal dosing strategy of antibody-based prophylaxis in this group of patients are needed.

Impact of the New Glomerular Filtration Rate Formulas on Kidney Function Assessment in Living Kidney Donors and Candidates.

New estimated glomerular filtration rate (GFR) equations that do not include a race coefficient have been created to better estimate kidney function, reduce inequities in kidney disease care, and improve the historically limited access to transplantation in African Americans. The impact of these new equations on estimated GFR (eGFR) in living donors pre- and postdonation is not known. Methods: To address this, we conducted a single-center retrospective cohort study of 150 kidney donors and donor candidates. We calculated pre- and postdonation eGFR using the old and new equations and compared them with measured GFR by 2.8 mCi Tc-99m diethylene triamine penta-acetic acid clearance (mGFRDTPA) and 24-h creatinine clearance (mGFRCrCl). We evaluated the impact of the new equations on donation eligibility and postdonation eGFR. Results: We found that using the new eGFR equations resulted in higher predonation eGFR compared with the old equations but remained significantly lower than mGFRDTPA and mGFRCrCl. We also found that using the new eGFR equations would not exclude any potential donors based on our center's GFR criteria for donation. At 6 mo postdonation, the new equations resulted in higher eGFR values compared with the old equations. Conclusions: The new eGFR equations continue to underestimate GFR in healthy donor candidates but would not exclude any potential donors from donation and resulted in higher eGFR predonation and postdonation in a predominantly White population. eGFR equations designed specifically for potential kidney donors are still needed for better kidney function assessment.

Immune checkpoint inhibitors in kidney transplantation.

PURPOSE OF REVIEW: The development of immune checkpoint inhibitor (ICI) immunotherapy has revolutionized the treatment of several cancers. Malignancies are one of the leading causes of death in solid organ transplant recipients (SOTRs). Although ICI treatment may be an effective option in treating malignancies in SOTRs, concerns about triggering allograft rejection have been raised in this population. Herein, we will review currently available data regarding patients, allograft and malignancy outcomes in SOTRs who received ICI therapy. RECENT FINDINGS: Cancer incidence is three to five-fold higher among SOTRs, compared with the general population. Skin cancer is the most prevalent cancer after transplant, followed by kidney cancer, lymphoma and Kaposi sarcoma. There are no large prospective studies evaluating ICI therapy's use for treating cancers in SOTRs. However, retrospective studies have shown that ICI treatment may be associated with improved malignancy outcomes and overall survival (OS). However, the risk of allograft rejection is high (around 40%) of whom about half lose their allograft. Maintaining higher levels of immunosuppression may be associated with a lower risk of allograft rejection, but potentially worse malignancy outcomes. SUMMARY: Although ICI treatment may be associated with improved patient and malignancy outcomes, the risk of allograft rejection and loss are high. Prospective studies are needed to confirm the benefits of ICI therapy in SOTRs and to evaluate the optimal immunosuppression regimen modifications, if any, to improve patient, malignancy and allograft outcomes in transplant recipients.

The value of pre-transplant coronary angiography findings in kidney transplant candidates at high risk for cardiovascular disease.

Introduction: Cardiovascular disease is a significant cause of mortality after kidney transplantation. Whether pre-transplant screening for coronary artery disease (CAD) in asymptomatic kidney transplant candidates (KTCs) is beneficial is unclear. Methods: We conducted a retrospective cohort study evaluating post-transplant cardiovascular events in 192 high-risk KTCs who underwent pre-transplant CAD evaluation. The study aimed to identify risk factors associated with finding severe CAD on pre-transplant angiography, and to assess the relationship between screening strategies and post-transplant cardiovascular events. Results: At five years post-transplant, cardiovascular events occurred in 23.9% of subjects. Prior CAD history and left ventricular ejection fraction (LVEF) < 50% were associated with higher odds of finding severe CAD on pre-transplant angiography. Severe CAD on angiography was associated with a higher risk of early cardiovascular events within six months of transplantation. However, coronary intervention in KTCs with severe CAD was not associated with lower rates of post-transplant cardiovascular events. Conclusion: Pre-transplant coronary angiography to identify severe CAD is of highest yield in KTCs with a history of CAD or an LVEF < 50%. Our findings indicate that the identification of severe CAD in KTCs has prognostic significance for the early post-transplant period. Optimization of medical therapy in these high-risk KTCs may improve post-transplant cardiovascular outcomes.

Antibody-mediated rejection: prevention, monitoring and treatment dilemmas.

PURPOSE OF REVIEW: Antibody-mediated rejection (AMR) has emerged as the leading cause of late graft loss in kidney transplant recipients. Donor-specific antibodies are an independent risk factor for AMR and graft loss. However, not all donor-specific antibodies are pathogenic. AMR treatment is heterogeneous due to the lack of robust trials to support clinical decisions. This review provides an overview and comments on practical but relevant dilemmas physicians experience in managing kidney transplant recipients with AMR. RECENT FINDINGS: Active AMR with donor-specific antibodies may be treated with plasmapheresis, intravenous immunoglobulin and corticosteroids with additional therapies considered on a case-by-case basis. On the contrary, no treatment has been shown to be effective against chronic active AMR. Various biomarkers and prediction models to assess the individual risk of graft failure and response to rejection treatment show promise. SUMMARY: The ability to personalize management for a given kidney transplant recipient and identify treatments that will improve their long-term outcome remains a critical unmet need. Earlier identification of AMR with noninvasive biomarkers and prediction models to assess the individual risk of graft failure should be considered. Enrolling patients with AMR in clinical trials to assess novel therapeutic agents is highly encouraged.

Tixagevimab/cilgavimab pre-exposure prophylaxis is associated with lower breakthrough infection risk in vaccinated solid organ transplant recipients during the omicron wave.

The neutralizing monoclonal antibody combination of tixagevimab/cilgavimab has been shown to reduce the risk of SARS-CoV-2 infection in unvaccinated individuals during the Alpha (B.1.1.7) and Delta (B.1.617.2) waves. However, data on the efficacy and safety of tixagevimab/cilgavimab in vaccinated solid organ transplant recipients during the Omicron wave is limited. To address this, we conducted a retrospective cohort study comparing 222 solid organ transplant recipients (SOTRs) who received tixagevimab/cilgavimab for pre-exposure prophylaxis and 222 vaccine-matched solid organ transplant recipients who did not receive tixagevimab/cilgavimab. Breakthrough SARS-CoV-2 infections occurred in 11 (5%) of SOTRs who received tixagevimab/cilgavimab and in 32 (14%) of SOTRs in the control group (p < .001). In the tixagevimab/cilgavimab group, SOTRs who received the 150-150 mg dose had a higher incidence of breakthrough infections compared to those who received the 300-300 mg dose (p = .025). Adverse events were uncommon, occurring in 4% of our cohort and most were mild. There was no significant change in serum creatinine or liver chemistries in kidney and liver transplant recipients, respectively. In conclusion, we found that tixagevimab/cilgavimab use is safe and associated with a lower risk of breakthrough SARS-CoV-2 infection in vaccinated solid organ transplant recipients during the Omicron wave.

T cell depletion increases humoral response by favoring T follicular helper cells expansion.

Antibody-mediated rejection is a major cause of long-term graft loss in kidney transplant patients. T follicular helper (Tfh) cells are crucial for assisting B cell differentiation and are required for an efficient antibody response. Anti-thymocyte globulin (ATG) is a widely used lymphocyte-depleting induction therapy. However, less is known about how ATG affects Tfh cell development and donor-specific antibody (DSA) formation. We observed an increase in circulating Tfh cells at 6 months after kidney transplant in patients who received ATG. Using an NP-OVA immunization model, we found that ATG-treated mice had a higher percentage of Tfh cells, germinal center B cells, and higher titers of antigen-specific antibodies compared to controls. ATG-treated animals had lower levels of IL-2, a known Bcl-6 repressor, but higher levels of IL-21, pSTAT3 and Bcl-6, favoring Tfh differentiation. In a mouse kidney transplant model, ATG-treated recipients showed an increase in Tfh cells, DSA and C4d staining in the allograft. Although ATG was effective in depleting T cells, it favored the expansion of Tfh cells following depletion. Concomitant use of IL-2, tacrolimus, or rapamycin with ATG was essential to control Tfh cell expansion. In summary, ATG depletion favors Tfh expansion, enhancing antibody-mediated response.

Non-Invasive Monitoring for Rejection in Kidney Transplant Recipients After SARS-CoV-2 mRNA Vaccination.

Introduction: Studies have shown reduced antiviral responses in kidney transplant recipients (KTRs) following SARS-CoV-2 mRNA vaccination, but data on post-vaccination alloimmune responses and antiviral responses against the Delta (B.1.617.2) variant are limited. Materials and methods: To address this issue, we conducted a prospective, multi-center study of 58 adult KTRs receiving mRNA-BNT162b2 or mRNA-1273 vaccines. We used multiple complementary non-invasive biomarkers for rejection monitoring including serum creatinine, proteinuria, donor-derived cell-free DNA, peripheral blood gene expression profile (PBGEP), urinary CXCL9 mRNA and de novo donor-specific antibodies (DSA). Secondary outcomes included development of anti-viral immune responses against the wild-type and Delta variant of SARS-CoV-2. Results: At a median of 85 days, no KTRs developed de novo DSAs and only one patient developed acute rejection following recent conversion to belatacept, which was associated with increased creatinine and urinary CXCL9 levels. During follow-up, there were no significant changes in proteinuria, donor-derived cell-free DNA levels or PBGEP. 36% of KTRs in our cohort developed anti-wild-type spike antibodies, 75% and 55% of whom had neutralizing responses against wild-type and Delta variants respectively. A cellular response against wild-type S1, measured by interferon-γ-ELISpot assay, developed in 38% of KTRs. Cellular responses did not differ in KTRs with or without antibody responses. Conclusions: SARS-CoV-2 mRNA vaccination in KTRs did not elicit a significant alloimmune response. About half of KTRs who develop anti-wild-type spike antibodies after two mRNA vaccine doses have neutralizing responses against the Delta variant. There was no association between anti-viral humoral and cellular responses.