Longitudinal Analysis of Prophylactic Anticoagulation in Primary Nephrotic Syndrome: Low Incidence of Thromboembolic Complications.

Introduction: Thromboembolic events (TEEs) are a serious and potentially fatal complication of nephrotic syndrome (NS). Despite this, there is a lack of evidence examining the benefits of prophylactic anticoagulation (PAC) in NS. It was our objective to review the risk factors, rates of TEEs, and patterns of PAC in patients with primary NS, with the aim to provide a pragmatic approach to PAC in primary NS. Methods: This is a retrospective longitudinal cohort study of adult patients with primary NS. Included were as follows: biopsy-proven minimal change disease and focal segmental glomerulosclerosis (described as a combined podocytopathy cohort) plus membranous nephropathy (MN) over an 8-year period from a single centre. Anticoagulation practice, TEEs, and longer term outcomes were recorded. Results: Fifty-four patients with MN and 48 patients with podocytopathies were included. Baseline demographics and severity of NS were comparable. Those with MN were more likely to develop TEE 12 (22%) versus 4 (8%) (p = 0.027) though this difference was predominantly seen at index diagnosis. Only 2 patients developed TEEs during active incident NS. Rates of PAC were similar when comparing MN (53%) and podocytopathies (58%). Those with a serum albumin <20 g/L and HAS-BLED score <3 were most likely to receive PAC (22/30, 73% in MN vs. 21/30, 70% in podocytopathy). Warfarin was the most common agent used in MN cohort 18/26 (69%) versus prophylactic dose low-molecular-weight heparin in the podocytopathy cohort 12/28 (43%). Discussion/Conclusion: PAC practices applied in this cohort of patients were pragmatic and effective, with low TEE rates during active NS.

Thromboembolism in nephrotic syndrome: controversies and uncertainties.

Thromboembolism is one of the most serious complications of nephrotic syndrome, including both arterial and venous thromboembolic events. Rates of thromboembolism depend on a multitude of factors, including the severity and cause of nephrotic syndrome, with primary membranous nephropathy having the highest reported rates. In relation to arterial thromboembolism, the risk can be as high as 8 times that of an age- and sex-matched population. However, extrapolating risks is challenging, with published studies not being homogeneous, several being single center and retrospective, and including different causes of primary nephrotic syndrome. Determining thromboembolic risk in nephrotic syndrome is essential to enable decision making on preventive strategies. However, lack of proven strategies to help estimate risk-benefit aspects underpins variations in clinical practice. Although the use of anticoagulation following a thrombotic event is clear, this still leaves us with a clinical dilemma as to if, and who, should receive prophylactic anticoagulation, with what agent, and for how long. In the absence of clear evidence to answer these questions, prophylactic anticoagulation strategies for nephrotic syndrome currently rely on expert consensus opinion, such as in the recently published 2021 Kidney Disease Improving Global Outcomes glomerular disease guidelines. In the mainstay, these recommendations relate to patients with membranous nephropathy. Here, we detail the current controversies still faced by clinicians around the risk of thromboembolism in nephrotic syndrome, use of prophylactic anticoagulation in nephrotic syndrome and propose ways of advancing existing knowledge and practice in this field to unravel the conundrum.

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.

Long-Term Safety, Clinical and Immunological Outcomes in Primary Membranous Nephropathy with Severe Renal Impairment Treated with Cyclophosphamide and Steroid-Based Regimen.

Introduction and Aims: Therapy of primary membranous nephropathy (PMN) with progressive advanced kidney dysfunction is challenging with limited literature and no clear therapeutic strategies. This is due to the scant evidence of effectiveness and uncertainty around the risk-benefit profile of immunosuppression (ImS) when eGFR is less than 30 mL/min. We aimed to determine long-term clinical outcomes in patients with PMN and severe renal impairment treated with combined cyclophosphamide and steroids. Methods: The study is a single-center retrospective longitudinal cohort study. All patients (between 2004 and 2019) with biopsy confirmed PMN who initiated combination therapy with steroids and cyclophosphamide and had an eGFR of ≤30 mL/min/1.73 m2 at the time of initiation of therapy were included for analysis. Clinical and laboratory parameters including anti-PLA2R-Ab were monitored as per standard clinical guidance. Primary outcome was achievement of partial remission. Secondary outcomes included immunological remission, need for renal replacement therapy, and adverse effects. Results: Eighteen patients with median age of 68 (IQR 58-73) years and 5:1 M:F ratio received the combination therapy when eGFR was ≤30 mL/min/1.73 m2 (CKD-EPI). At time of ImS, median eGFR and uPCR were 23 (IQR 18-27) mL/min/1.73 m2 and 8.4 (IQR 6.9-10.7) g/g, respectively. Median follow-up was for 67 (IQR 27-80) months. 16 patients (89%) achieved partial remission and 7 (39%) achieved complete remission. eGFR increased by 7 mL/min/1.73 m2 (27%) after 1 year of starting ImS treatment and 12 mL/min/1.73 m2 at end of follow-up. Two patients (11%) developed end-stage renal disease needing renal replacement therapy. 67% achieved both immunological and clinical remission. At the end of the follow-up period, 2 (11%) patients required hospitalization secondary to infections, 4 (22%) patients developed cancer and 4 patients died (22%). Conclusion: Combination therapy with cyclophosphamide and steroids is effective in achieving partial remission and improving renal function in PMN with advanced renal dysfunction. Prospective controlled studies are required to provide further evidence to rationalize treatment and improve outcomes in such patients.

Can use of the serum anti-PLA2R antibody negate the need for a renal biopsy in primary membranous nephropathy?

BACKGROUND: Since the emergence of the anti-PLA2R antibody (PLA2R-Ab) test, nephrology practice has not changed dramatically, with most nephrologists still relying on a kidney biopsy to diagnose membranous nephropathy. In this study, we examined the clinical accuracy of the anti-PLA2R antibody test using ELISA in routine clinical care. METHODS: We conducted a retrospective analysis of PLA2R-Ab testing in 187 consecutive patients seen at a single UK centre between 2003 and 2020. We compared the kidney biopsy findings with the PLA2R-ab antibody test. Patients' demography, urine protein creatinine ratios, serum albumin, and treatment characteristics including supportive and immunosuppressive treatment were recorded. The clinical accuracy of the test (e.g. sensitivity and specificity, positive [PPV] and negative [NPV] predictive values) was calculated using the kidney biopsy findings as the diagnostic reference. RESULTS: Mean levels of PLA2R-Ab titre in primary membranous nephropathy were 217RU/ml in comparison to 3RU/ml for both secondary membranous nephropathy and other diagnoses. Most patients with a positive PLA2R-Ab test had a confirmed renal biopsy diagnosis of primary membranous nephropathy with: PPV of 97.3%, sensitivity 75.5%, NPV was 79.8% and specificity was 97.8% at a cut-off threshold of >20 RU/ml. CONCLUSION: The anti-PLA2R antibody test is a highly specific test for diagnosing membranous nephropathy, and the test has the potential to allow for the diagnosis and treatment in up to 75% of PMN cases without the need for a renal biopsy. Nevertheless, patients with negative PLA2R-Ab tests will still require a biopsy to confirm their diagnosis.