To the best of our knowledge, this is the first study that describes the timing of the TEs relative to the diagnosis and (ii) the risk factors (including disease activity) for TEs in patients with idiopathic membranous nephropathy. We found that the majority of TE events occurred before or at diagnosis of IMN and 7.4% suffered a TE over the next 6
months after the IMN diagnosis was established. No events occurred after 6
months of IMN diagnosis in our study population. Moreover, in patients with TE events compared to those without TE events, proteinuria and serum albumin are found to be independent risk factors for thromboembolic events in adult IMN patients.
In our study, 19% of IMN patients (when analysed cross-sectionally) had at one time in their disease course a TE (either prior to or directly after IMN diagnosis). Our finding suggests that the incidence rate of first thromboembolic event in IMN patients is high when compared to the available rates in general population (0.3 per 100 person-years) and in patients with lupus (1 per 100 person-years)
]. It is comparable to patients with Wegener’s granulomatosis (7 per 100 person-years) and people who had a previous deep vein thrombosis (7 per 100 person-years)
]. The incidence of TE in our cohort (7.6% over 6
months) is less than the incidence reported by Bellomo and colleagues in their MN cohort (16.9%). This could be partly explained by the difference in the proportion of immunosuppressed patients to treat the nephrotic range proteinuria (25% of their patients with TE were immunosuppressed versus 100% of our patients with TE). However, how the incidence was measured was not mentioned in the latter study. A recent retrospective cohort study confirmed high absolute risk (approximately eight times) of venous TEs in patients with nephrotic range proteinuria and in addition, found a high annual incidence of 1.40 among the MN patients with nephrotic syndrome
]. However, the study was not specifically aimed at studying MN patient and included patients with as diverse as patients with diabetic nephropathy (28%) and nephrotic syndrome not otherwise specified (46%). In both these studies, no information was available on the underlying etiology of MN (i.e. primary vs secondary), the relation of TEs to the timing of diagnosis and disease activity and the predictors specific to IMN patients.
Another question is why IMN patients are at an exaggerated risk of TEs when compared to patients with other causes of similar profound non-selective nephrotic range proteinuria such as FSGS or amyloid nephropathy. It is tempting to hypothesize that perhaps the underling trigger unique to IMN pathology render IMN patients at higher risk of TEs. We found that all the TEs occurred when the IMN was active. This suggests that the exaggerated risk of TEs in IMN patients is due to the underlying nephrotic syndrome.
In our study, pulmonary embolism was the most common thromboembolic event followed by deep vein thrombosis. Our findings are in line with those reported by Bellomo et al. A recent review of the coding data from the discharged patients in the United States with nephrotic syndrome found deep vein thrombosis in 1.5% and PE in 0.5% and less than 0.5% had renal vein thrombosis
]. In contrast, the studies conducted in late 1970s and early 1980s reported renal vein thrombosis as the commonly encountered TE in MN patients
]. This discrepancy may be explained by the fact that the latter studies evaluated patients with nephrotic syndrome with renal venography to specifically determine renal vein thrombosis.
Bellomo et al. found that the baseline serum albumin and 24-h proteinuria, between the patients who suffered a TE and those with no TE, were similar, though significantly greater proportion of patients in the TE group had nephrotic syndrome with albumin
g/l. Based on this observation, it was concluded that the presence of the nephrotic syndrome and of a low serum albumin (< 2.5
g/l) at presentation was associated with a significantly greater risk of TE. Our study, for the first time, has formally quantified the increased odds of TE associated with lower serum albumin in adult IMN patients. In addition, we also find that the magnitude of proteinuria should be taken into account while assessing the risk of TE in patients with IMN. The 24-h proteinuria greater than 10
g/day could be regarded as an independent risk factor for thromboembolic events in patients with IMN, irrespective of the serum albumin. This is not surprising as one of the major mechanisms of thrombophilia in IMN patients is urinary loss of critical proteins involved in coagulation including plasminogen, factors IX, X and XII, and antithrombin III
]. None of our patients after 6
months of diagnosis had thromboembolic events. One may therefore consider primary thromboprophylaxis in the first six months following the diagnosis of IMN especially in patients with significant proteinuria (>10
g/day) and/or serum albumin (<20
g/dl). Similar to our finding, the Midwest Pediatric Nephrology Consortium Study (MWPNC study), found proteinuria (p
0.0001) as a significant independent risk factor of TE in children with nephrotic syndrome
]. The possible link between microalbuminuria or proteinuria and the risk of thromboembolic events have also been demonstrated in the general population, in patients with atrial fibrillation and in a cohort of hospitalized patients with nephrotic syndrome who underwent imaging study for TE
Our study has all limitations that are inherent to observational studies. These include confounding by other factors, which we have not measured. We had clear diagnostic criteria so exposure or outcome misclassification is unlikely. Our study lacks the detailed thrombophilia profile of the study population. In spite of the above limitations, these results may have important implications for clinical care of patients with IMN. Our study provides vital information that may help in, firstly, regarding the timing and the possible duration of prophylactic anti-coagulation; secondly, about the patient number that could benefit from prophylactic anti-coagulation; and thirdly, identification of proteinuria, as an independent risk factor that may aid in better risk assessment of such patients. In addition, the demographic characteristics of our patient population, including patients from various ethnicities, support the generalizability of our findings to IMN patients elsewhere. The results of our study may help in appropriate power calculation of future prospective randomized controlled trials in IMN patients with regards to thromboprophylaxis. Furthermore, the findings highlight the importance of urine dipstick testing in patients with TE, as TE could be a presenting clinical feature of nephrotic syndrome, in particular membranous nephropathy. Further prospective large studies are required to confirm the findings of our study.