Acute lesions
Chronic lesions
Thrombotic microangiopathy (TMA)
Arterial fibrous intimal hyperplasia (FIH) or arterial occlusion by organized thrombi with or without recanalization
Focal cortical atrophy (FCA)
Tubular thyroidization
APS nephropathy was also observed in SLE-related APS patients, independently of lupus nephritis, and in catastrophic APS (especially thrombotic microangiopathy) [17].
Thrombotic microangiopathy (TMA) in APS patients is the best-known feature of APS nephropathy as it was observed previously also by other authors [18, 19], and it is histopathologically characterized by the absence of inflammatory cells and of vascular immune deposits and by the presence of fibrin thrombi in glomeruli and in the entire intrarenal vascular circulation. Immunofluorescence studies reveal that fibrin is the main constituent of thrombi in the absence of immunoglobulins. These lesions resemble the histological picture of the other thrombotic microangiopathies such as thrombocytopenic purpura and hemolytic uremic syndrome. TMA represents the most important vascular lesion threatening the renal prognosis in SLE-related APS [20], and it is the predominant renal lesion seen in catastrophic APS [17].
Fibrous intimal hyperplasia (FIH) is characterized by an intense myofibroblastic intimal cellular proliferation which reduces the arteriolar lumen. The intima tends to be much more cellular than that seen in typical arteriosclerosis of aging, assuming an onion-skin arrangement in biopsy cross sections. Sometimes the lumina could be obstructed by fibrous tissue and permeated with endothelialized channels indicative of recanalizing thromboses (organizing thrombi).
Focal cortical atrophy (FCA) involves the superficial cortex under the renal capsule, forming foci or triangles that led to retraction of the tissue, with a sharp border with the rest of the normal cortex, and it is accompanied by a depression of the contour of the remaining renal capsule.
In these atrophic areas all elements of the renal parenchyma are altered as a part of the ensemble of lesions comprising FCA: the glomeruli appear either small and sclerotic or large but virtually lacking the glomerular tuft, the tubules are atrophic and packed with eosinophilic casts, resembling thyroid tissue (tubular thyroidization), and the arterioles are occluded by fibrin microthrombi or by fibrous tissue.
The presence of identical lesions of FIH and tubular thyroidization in surgical nephrectomies performed for renal artery stenosis (in order to reduce hypertension secondary to unilateral stenosis) led to speculate that tissue ischemia and the activation of the renin-angiotensin system are possible causes of those lesions in APS [5].
9.4.1 Clinical Manifestations and Diagnosis
Clinical presentation of APS nephropathy can vary widely ranging from arterial hypertension, which is the prominent and sometimes the only clinical sign suggestive of nephropathy, to sudden acute renal failure or to mild and progressive chronic renal insufficiency with different levels of proteinuria. Lupus anticoagulant (LA) positivity seems to be more frequently present among APS patients with an intrarenal involvement (2).
In all APS patients with clinical and laboratory findings that suggest renal involvement (new onset of hypertension, proteinuria, hematuria, or renal insufficiency), renal biopsy should be performed [21].
On the other hand, every time it is found in a biopsy section, a combination of any two of three elements which represents a constellation more or less characteristic of APS (TMA, FIH, or FCA), the pathologist should be alerted to the possibility of PAPS diagnosis which has to be clinically confirmed [5].
Moreover, in patients with biopsy-proven APS nephropathy lesions and persistently positive aPL, the diagnosis of APS should be considered even without thrombotic events or pregnancy morbidity [21].
9.4.2 Treatment
Since no evidence-based recommendations are available, the optimum management of patients with only intrarenal vascular lesions (APS nephropathy), alone or in combination with SLE nephropathy, is unknown.
Several empirical therapeutic approaches have been used, ranging from the pharmacological management of hypertension, associated with aspirin and/or oral anticoagulants, with steroids, and in some cases with additional immunosuppressive treatment.
Pons-Estel et al. [7] on the basis of their personal experience recommend starting anticoagulation with an INR target of 2.0–3.0 (as for any other patient with thrombotic APS) and adding antiplatelet agents or increasing target INR levels to 3.0–4.0 if no improvement is achieved.
In other recent studies, a stabilization of renal function and proteinuria by use of rituximab is reported. These studies proposed that rituximab might have a function in the treatment of persistently aPL-positive patients with non-criteria manifestations of APS, by reducing the production of autoantibodies [22, 23].
9.5 Glomerular Disease
Besides the vaso-occlusive abnormalities of the intrarenal arteries and glomerular capillaries, other types of histological lesions have been also described in primary APS patients with renal involvement. These lesions include membranous glomerulonephritis (the most frequent), IgA nephropathy, pauci-immune crescentic glomerulonephritis, mesangial C3 nephropathies, vasculitis, and minimal change disease/focal segmental glomerulosclerosis [6, 2, 24].
Glomerulonephritis in PAPS can’t be ascribed to thrombosis; instead other mechanisms such as immune complex deposition seem to be implicated. PAPS is considered a systemic autoimmune disease, and it has been described a number of different circulating autoantibodies and a different degree of complement reduction especially among patients who had PAPS with nephropathy.
The autoantibodies positivity, such as antinucleosome (anti-NSC) ab, and complement reduction found in renal PAPS support the idea of heterogeneity of renal involvement and suggest the presence of a continuum between SLE and PAPS.
As expected, anti-NCS antibodies are more frequently detected in PAPS with lupus-like disease, and patients with MN or proliferative glomerulonephritis, especially when C1q deposits and hypocomplementemia are present, should be considered at high risk for developing SLE. So a careful monitoring is mandatory in these patients [2].
9.5.1 Clinical Manifestations and Diagnosis
The clinical presentation is not different from APS nephropathy, with only a more frequent presence of nephrotic range proteinuria. As it was stated before, renal biopsy should be performed every time a renal APS involvement is suspected.
Moreover, a complete nephrologic workup should be performed especially in these kinds of patients, in which a differential diagnosis is very important to classify and treat them correctly.
9.5.2 Treatment
Since no evidence-based recommendations are available, several different therapeutic approaches have been used in these cases. The treatments usually consist in steroids, also IV pulses, associated with different immunosuppressive drugs, on the basis of the scheduled treatments for the same but not APS-related glomerulonephritis.
9.6 ESRD and Renal Transplantation
ESRD is a rare complication of primary APS. This was clearly revealed in different prospective and retrospective studies in which only few PAPS patients developed ESRD [2, 25]. Instead, several studies have revealed that there is a higher incidence of aPL positivity among patients with ESRD and on dialysis, than that found in the general population [26, 27]. This association of ESRD and aPL is irrespective of age, sex, type of dialysis membrane, drug treatment, and chronic B and C hepatitis. Possible causes include bioincompatibility problems as dialysis membranes, trauma to blood passing through the hemodialysis circuit, and induction by microbial agents or their products, for example, endotoxins present in the dialysate. However, it is still uncertain if these antibodies are truly pathogenic in ESRD patients or are just an epiphenomenon.
Moreover, evidence suggests that aPL-positive patients undergoing renal transplantation are at increased risk of renal and systemic vascular thrombosis and graft failure. For this reason, recently the somministration of perioperative immunosuppressives, given in addition to anticoagulation, has been proposed for aPL-positive patients undergoing renal transplantation [28].
In Table 9.2 the main reports from the literature concerning renal involvement in primary antiphospholipid syndrome are summarized.
Table 9.2
Main reports on renal involvement in primary antiphospholipid syndrome (PAPS)
Author, year | Type of study | n° of patients | Result |
|---|---|---|---|
D’Agati et al. (1990) [18] | Biopsy-documented report | 3 patients: | In all pts:
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