PLA2R Antibody Does Not Outperform Conventional Clinical Markers in Predicting Outcomes in Membranous Nephropathy.

Introduction: The prognostic value of PLA2R antibody (Ab) test in clinical practice remains unclear. We aimed to evaluate its ability in predicting hard outcomes in primary membranous nephropathy (PMN) after adjustments to conventional markers of disease activity. Methods: A total of 222 patients diagnosed with PMN from January 2003 to July 2019 having had a serum PLA2R Ab test, were included from 3 centers in the north of England. Baseline conventional markers, PLA2R-Ab-status (positive vs. negative), Ab-titer (high vs. low), and time of testing (pre-PLA2R era vs. PLA2R era) were evaluated for association with outcomes. Primary outcome was time to progression (composite of doubling of creatinine, stage 5 chronic kidney disease, or death). Secondary outcomes were time to partial remission (PR) and time to immunosuppression. Cox proportional hazard testing was used. Results: During a median follow-up of 5.26 years, progression was seen in 65 (29.3%) and PR in 179 of 222 patients (80.6%). There was a clear association of estimated glomerular filtration rate (eGFR) (standardized hazard ratio [HRZ] = 0.767, P < 0.05) and urine protein-to-creatinine ratio (uPCR) (HRZ = 1.44, P < 0.005) with time to progression among all patients, and eGFR (HRZ = 0.606, P < 0.005) in Ab-positive patients. Baseline Ab-positivity was not associated with time to progression (adjusted hazard ratio [aHR] = 0.93, P = 0.71) or time to PR (aHR = 0.84, P = 0.13). Similarly, baseline high Ab-titer was not associated with time to progression (aHR = 1.07, P = 0.77) or time to PR (aHR = 0.794, P = 0.08). Conclusion: Once adjusted to conventional markers of disease activity, baseline PLA2R Ab-positivity or Ab-titer do not predict disease progression or time to PR. Further studies are needed to harness the utility of PLA2R Ab test in prognostication in PMN.

Anti-thymocyte globulin for treatment of T-cell-mediated allograft rejection.

Anti-thymocyte globulin (ATG) is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients. Commercially available as Thymoglobulin (rabbit-derived, Sanofi, United States), ATG-Fresenius S (rabbit-derived), and ATGAM (equine-derived, Pfizer, United States), these formulations share a common mechanism of action centered on their interaction with cell surface markers of immune cells, imparting immunosuppressive effects. Although the prevailing mechanism predominantly involves T-cell depletion via the com plement-mediated pathway, alternate mechanisms have been elucidated. Optimal dosing and treatment duration of ATG have exhibited variance across ran domised trials and clinical reports, rendering the establishment of standardized guidelines a challenge. The spectrum of risks associated with ATG administration spans from transient adverse effects such as fever, chills, and skin rash in the acute phase to long-term concerns related to immunosuppression, including susceptibility to infections and malignancies. This comprehensive review aims to provide a thorough exploration of the current understanding of ATG, encom passing its mechanism of action, clinical utility in the treatment of acute renal graft rejections, specifically steroid-resistant cases, efficacy in rejection episode reversal, and a synthesis of findings from different eras of maintenance immunosuppression. Additionally, it delves into the adverse effects associated with ATG therapy and its impact on long-term graft function. Furthermore, the review underscores the existing gaps in evidence, particularly in the context of the Banff classification of rejections, and highlights the challenges faced by clinicians when navigating the available literature to strike the optimal balance between the risks and benefits of ATG utilization in renal transplantation.

Non-invasive cardiac stress studies may not offer significant benefit in pre-kidney transplant evaluation: A retrospective cohort study.

BACKGROUND: Screening with cardiac non-invasive stress studies (NISS) prior to listing for kidney transplantation can help in identifying treatable coronary disease and is considered an integral part of pre-kidney transplant evaluation. However, few studies assessed their effectiveness in all patients evaluated for transplantation in clinical practice. To evaluate the role of NISS in pre-kidney transplant evaluation we analyzed their impact prior to waitlisting in 1053 adult CKD-5 patients consecutively evaluated in Greater Manchester, UK during a 6-year period. METHODS: 918 waitlisted patients were grouped based on presence or absence of Diabetes or Cardio-Vascular Disease (CVD): Group-1 (255 DM-/CVD-/NISS-), Group-2 (368 DM-/CVD-/NISS+) and Group-3 (295 with DM or CVD). RESULTS: Group-2 patients had longer 'time-to-listing' (5.5months in Group-1 vs 6.9months in 'Normal-NISS' vs 9.9months in 'Abnormal-NISS', p<0.01) but none with 'Abnormal-NISS' needed coronary revascularization before listing. NISS was followed by revascularization in 8 Group-3 patients (3%). In multi-variate analyses, there was no association of NISS on death or MACE in listed patients. During follow up, Transplantation was the most significant factor associated with improved outcomes in all subgroups (HR:0.97, p<0.001). 135 patients were considered unsuitable for waitlisting, with NISS influencing management in 11 of these patients (8%). CONCLUSIONS: Pre-kidney transplant evaluation with NISS influenced clinical management in 19 of 1053 (2%) patients. Screening with NISS added limited benefit but contributes to significant delays in listing and adding resource implications. Further studies are needed to assess clinical and cost effectiveness of NISS in pretransplant evaluation to optimize outcomes and resources.

Intravenous pulse cyclophosphamide and steroids induce immunological and clinical remission in New-incident and relapsing primary membranous nephropathy.

AIM: Primary membranous nephropathy is associated with progression to end stage renal diseasein some patients. Standard therapy with cyclical cyclophosphamide and corticosteroids can be associated with significant adverse effects. We aimed to assess immunological and clinical response with intravenous pulse cyclophosphamide and oral steroids in patients with severe nephrotic syndrome - in a prospective observational cohort study. METHODS: A total of 17 consecutive patients (nine new-incident and eight relapses) with severe nephrotic syndrome received monthly intravenous pulse cyclophosphamide and oral steroids after failure to achieve remission with supportive therapy. Immunosuppressive therapy was discontinued at 6 months or earlier if proteinuria regressed to <100 mg/mmol and patients were followed for 12 months. Achievement of partial remission was primary outcome; changes in clinical parameters and anti-PLA2 R were secondary outcomes. RESULTS: Dose of cyclophosphamide received was 5.4 g in New-incident patients and 4.2 g in patients with relapses. All 17 patients achieved partial remission within 6 months: proteinuria improved from 656 to 102 mg/mmol at 6 months and 55 mg/mmol at 12 months (P < 0.001); eGFR improved from 31 to 48 mL/min per 1.73 m2 at 6 months and 45 mL/min per 1.73 m2 at 12 months (P < 0.05). Anti-PLA2 R levels reduced from 244 to 10 U/L at 6 months and 10 U/L at 12 months (P < 0.001). Two out of nine patients in the New-incident group developed subsequent relapse. Cumulative doses of cyclophosphamide and steroids that patients received was about half of the standard regime. CONCLUSION: Pulse cyclophosphamide with oral steroids induced immunological and clinical partial remission at significantly reduced doses in primary membranous nephropathy.