Omar Ragy

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.

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.

IntroductionThe 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.MethodsA 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.ResultsDuring 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).ConclusionOnce 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.

The phospholipase A2 receptor antibody (PLA2R-Ab) test is a valuable first-line diagnostic tool for primary membranous nephropathy (MN), helping to identify PLA2R-related MN and potentially eliminating the need for a kidney biopsy in some individuals. By reducing the reliance on biopsies, the test streamlines diagnosis and improves patient care. However, determining the optimal PLA2R measurement method and cut-off is critical to maximizing the benefits of the test and minimizing any harms. A systematic review and meta-analysis were performed to evaluate serum- and urine-based biomarkers for distinguishing between PLA2R-related MN and non-PLA2R MN. Searches were conducted in databases including Medline, Embase, Cochrane Library, Scopus, Web of Science, International HTA Database and ClinicalTrials.gov. The methodology followed Cochrane-recommended guidelines for systematic reviews and meta-analyses, and the QUADAS-2 tool was utilized to assess the overall risk of bias. Ninety-one studies met the eligibility criteria for inclusion in the review. Of these, 38 studies reporting the accuracy of the PLA2R-Ab test using the EUROIMMUN enzyme-linked immunosorbent assay (ELISA) method and 27 using the EUROIMMUN immunofluorescence (IF) method were suitable for meta-analysis. The pooled sensitivity and specificity of EUROIMMUN ELISA at a cut-off value of 20 RU/mL were 0.64 [95% confidence interval (CI) 0.56-0.72] and 94.7% (95% CI 90.5-97.1%), respectively. The pooled sensitivity and specificity of EUROIMMUN IF at a threshold of 1:10 was 0.69 (95% CI 0.637-0.739) and 0.98 (95% CI 0.931-0.994), respectively. Risk of bias was higher for studies evaluating the IF compared with ELISA test. We also explored whether the timing of the index test had an impact on the pooled diagnostic accuracy results; no significant differences were found. By evaluating the specificity and sensitivity of EUROIMMUN ELISA PLA2R-Ab and IF, we demonstrate that at ELISA levels ≥20 RU/mL, alongside thorough secondary screening, a kidney biopsy may be unnecessary. However, lower or negative levels still warrant a biopsy.

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; 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. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; 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. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; 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%) (&lt;i&gt;p&lt;/i&gt; = 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 &amp;lt;20 g/L and HAS-BLED score &amp;lt;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%). &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; PAC practices applied in this cohort of patients were pragmatic and effective, with low TEE rates during active NS.