Antiphospholipid syndrome nephropathy and
lupus nephritis have similar clinical and laboratory manifestations and achieving the accuracy of diagnosis required for correct treatment frequently necessitates a kidney biopsy.
We report the case of a 29-year-old woman referred to the nephrology service for de novo hypertension, decline of renal function and proteinuria. She had had systemic lupus erythematosus and antiphospholipid
syndrome since the age of 21 and was taking oral anticoagulation. Two weeks later, after treatment of hypertension and achievement of adequate coagulation parameters, a percutaneous renal biopsy was performed. The biopsy revealed chronic lesions of focal cortical atrophy, arterial fibrous intimal hyperplasia and arterial thromboses, which are typical features of antiphospholipid syndrome nephropathy.
We describe the clinical manifestations and histopathology of antiphospholipid syndrome nephropathy and review the literature on renal biopsy in patients receiving anticoagulation

Bordalo, J

Carvalho, F

Ferreira, A

Ribeiro Santos, J

Viana, H

Repositório do Centro Hospitalar de Lisboa Central, EPE

CMYKP    357 ABSTRACTAntiphospholipid syndrome nephropathy and lupus nephritis have similar clinical and laboratory manifestations and achieving the accuracy of diag-nosis required for correct treatment frequently neces-sitates a kidney biopsy.We report the case of a 29-year-old woman referred to the nephrology service for de novo hypertension, decline of renal function and proteinuria. She had had systemic lupus erythematosus and antiphospholipid syndrome since the age of 21 and was taking oral anticoagulation. Two weeks later, after treatment of hypertension and achievement of adequate coagula-tion parameters, a percutaneous renal biopsy was performed. The biopsy revealed chronic lesions of focal cortical atrophy, arterial fibrous intimal hyper-plasia and arterial thromboses, which are typical features of antiphospholipid syndrome nephropathy.We describe the clinical manifestations and his-topathology of antiphospholipid syndrome neph-ropathy and review the literature on renal biopsy in patients receiving anticoagulation. Key-Words: Antiphospholipid syndrome; hypertension; kidney biopsy; systemic lupus erythematosus. INTRODUCTIONAlthough the renal manifestations of antiphos-pholipid syndrome (APS) have received scant atten-tion until recently, the kidney is probably a major target organ in this syndrome. Antiphospholipid antibodies are detected in 30-40% of patients with systemic lupus erythematosus (SLE) and APS will develop in nearly one third of these patients1. More-over, the kidney is commonly involved in SLE, with 60–80% of patients developing urine or renal func-tion abnormalities at some time during their clinical course2.APS nephropathy and lupus nephritis have similar clinical and laboratory manifestations and a kidney biopsy is frequently required for accurate diagnosis and correct treatment. CASE REPORTA 29-year-old woman was referred to the nephrol-ogy department for evaluation of declining renal function and proteinuria. Systemic lupus erythema-tosus (SLE) and antiphospholipid syndrome (APS) had been diagnosed at the age of 21 years old. The diagnosis of APS had been established after she had De novo hypertension and decline of renal function in a young woman with systemic lupus erythematosus and antiphospholipid syndromeHelena Viana, Aníbal Ferreira, Fernanda Carvalho, Joaquim Bordalo, João Ribeiro SantosServiço de Nefrologia, Hospital de Curry Cabral. Lisbon, Portugal.Received for publication: 02/05/2009Accepted in revised form: 17/08/2009CASE REPORTPort J Nephrol Hypert 2009; 23(4): 357-361Advance Access publication 06 September 2009Nefro - 23-4 MIOLO.indd   357 08-10-2009   17:41:33CMYKP358    Port J Nephrol Hypert 2009; 23(4): 357-361Helena Viana, Aníbal Ferreira, Fernanda Carvalho, Joaquim Bordalo, João Ribeiro Santosdeveloped a left lower leg deep venous thrombosis. The lupus disease had cutaneous, articular and psychiatric involvement, without known renal mani-festations. Over the next 8 years she had been treated with warfarin (INR target: 2-3), prednisolone (10 mg/day) and hydroxychloroquine (200 mg/day). She had some cutaneous and articular lupus relaps-es needing temporary increases of prednisolone dose. There had been no further clinically evident thrombosis episodes. She had never been pregnant. Her records showed proteinuria (0.5 mg/24 hours) over the previous 2 years and an increase in serum creatinine from 0.9 to 1.3 mg/dl in the previous 3 months.She presented to the nephrologist with de novo hypertension (150/110 mmHg), cutaneous lesions (butterfly malar rash, alopecia, livedo reticularis and purpuric vasculitis of fingers, toes and nail folds) and musculoskeletal manifestations (arthralgia and arthritis of finger and toe joints).Investigations showed: 1) positive antinuclear, double stranded DNA, anti Ro/SSA antibodies; 2) slightly low complement fractions: C3 (67.4 mg/dl; N: 75-140) and C4 (9.50 mg/dl; N: 10-34); 3) positive antiphospholipid antibody: Anticardiolipin antibody (>120 units GPL; N<12), Anti-B2 glycoprotein-I (>100 units SGU; N<12) and Lupus anticoagulant (1.65 R; N: 0.8-1.2); 4) slight reduction in size of the right kidney (10.1 cm vs 11.3 cm), with bilateral normal echogenicity, and regular contours.The patient’s anticoagulation status did not allow immediate kidney biopsy and she began mycophenolate mofetil (500 mg/day) and lisinopril (20 mg/day).Two weeks later, warfarin was stopped and low molecular weight heparin (LMWH) introduced (interrupted 24 hours before biopsy). With normo-tension and adequate coagulation parameters (PT, PTT, platelet count, anti-Xa activity), a percutane-ous renal biopsy was performed using a semi-automated device with real time ultrasonic guid-ance. In the absence of biopsy complication, LMWH was restarted after 48 hours, and warfarin one week later.The kidney histology revealed a cortical specimen with 50 glomeruli: 25 glomeruli showed ischaemic retraction of the tuft – some with a pseudocystic appearance (Fig. 1); 10 were globally sclerosed by ischaemia and 15 were normal. Focal zones of atro-phy were present in the subcapsular area, where 5 of the 10 sclerosed glomeruli were seen, and in the deep cortex (Fig. 2). The ischaemic and sclerotic alterations described were mainly in these zones, where some infiltration by mononuclear inflamma-tory cells could be observed. Many vessels (arterioles and medium interlobular arteries) were patent but organised thrombi filled the lumens of 2 medium-Figure 1Retracted ischaemic glomerular tuft forming pseudocystic lesions. Magni-fication 250X, Silver stain.Figure 2Focal cortical atrophy in subcapsular and deep cortical areas. Magnification 60X, Silver stain.FIGURE 1: .FIGURE 2:Nefro - 23-4 MIOLO.indd   358 08-10-2009   17:41:35CMYKPPort J Nephrol Hypert 2009; 23(4): 357-361    359De novo hypertension and decline of renal function in a young woman with systemic lupus erythematosus and antiphospholipid syndromesized vessels (Figures 3 and 4). Some intimal hyper-plasia could be seen in 2 further vessels. Vascular lesions were located exclusively in atrophic and fibrotic areas. Immunofluorescence revealed 8 glom-eruli with IgM segmental deposits (++/+++). There was no deposition of IgG, IgA, C3, C4, C1q and fibrin in the glomeruli or in other parenchymal structures. The histological diagnosis was APS nephropathy so the warfarin dose was increased to obtain an INR around 3.5 and immunosuppressive therapy was not changed.At present, 6 months later, the patient is in clinical remission from lupus and has stable renal function. DISCUSSIONThe renal manifestations of APS result from thrombosis occurring at any location within the renal vasculature, that is, in the renal arterial trunk or branches, intraparenchymal arteries and arterioles, glomerular capillaries, and renal veins. APS neph-ropathy (APSN) describes the parenchymal renal lesions following intrarenal thrombosis. Proven intrarenal thromboses, once other conditions result-ing in similar renal lesions are excluded, have recently been included in the Classification Criteria for APS3. Daugas and colleagues4 studied the fre-quency and clinical relevance of APSN in lupus patients. This retrospective study showed that APSN was present in 32% of the patients with SLE, in addition to, or independent of, lupus nephritis.The more frequent clinical renal manifestations of APSN and lupus nephritis are proteinuria (ranging from mild to nephrotic), haematuria, hypertension (often severe) and acute or chronic renal insuffi-ciency.The literature reveals that patients with APSN have a high frequency of hypertension and elevated serum creatinine levels at the time of kidney biopsy5. Hypertension was one of the first major features described in association with livedo reticularis and APS6. Patients with APS complicated by hyperten-sion should be vigorously investigated for an under-lying renal lesion, especially in the presence of livedo reticularis7. Thus, renal involvement should be considered in any patient suffering from APS and hypertension, regardless of whether it is accompa-nied by renal insufficiency, proteinuria, or haematu-ria8. The pathophysiology of hypertension in the context of APS includes thrombosis/occlusion of the trunk of a renal artery leading to renovascular hyperten-sion as well as stimulation of the renin-angiotensin-aldosterone system secondary to intrarenal vascular lesions9.APSN is a vaso-occlusive process associated with acute intrarenal thromboses and chronic vascular Figure 3Fibrous organised thrombi and fibrous intimal hyperplasia in medium-calibre artery. Magnification 250X, Periodic acid-shiff stain.Figure 4Fibrous thrombi filling lumen of medium-sized artery and ischaemic glom-eruli. Magnification 160X, Silver stain.Nefro - 23-4 MIOLO.indd   359 08-10-2009   17:41:36CMYKP360    Port J Nephrol Hypert 2009; 23(4): 357-361lesions. The acute manifestations are the result of thrombotic microangiopathy (TMA). However, chronic vascular changes of APSN are more frequent than acute events, but have received little attention until recently. They are characterised by arterial fibrous intimal hyperplasia (FIH), arteriosclerosis and organised thrombosis with or without recanalisation. The throm-bosis progresses to fibrous occlusion of vessels and lead to focal cortical atrophy (FCA) in the region served by the involved vessels, often including subcapsular areas8. Progression of acute thrombotic lesions to chronic proliferative, obstructive and fibrotic forms may occur, as observed by Tektonidou and colleagues 10.Thrombosis of parenchymatous vessels results in focal ischaemia and/or necrosis with corresponding reduction in kidney size or areas of cortical infarction on ultrasound or DMSA scanning11.Our case demonstrates that accurate assessment of the relative contributions of APSN and lupus nephritis may only be possible with a renal biopsy. Histological examination is fundamental for diagnosis and therapeutic decision that is immunosuppression and/or anticoagulation, and the amount of each. Ultrasound-guidance and the use of semi-automated devices have made renal biopsy safe and reliable12. However, in patients on chronic anticoagulation two main problems must be considered: the risk of thrombosis if treatment is stopped versus the risk of bleeding after biopsy if anticoagulation is main-tained. APS patients are classified as high risk for thromboembolism, and are usually considered to require “bridging” anticoagulation13 if oral antico-agulation is stopped. Presently, there is no good evidence, nor clear consensus, for the management of patients receiving long-term oral anticoagulant therapy who need renal biopsy. The available data refers to experience with patients submitted to surgery. In the general population and in perioperative experience, the use of LMWH seems to be safer, more effective, simpler and less costly for short-term bridg-ing therapy than unfractionated heparin14. However, if LMWH is used in patients with creatinine clearance < 40 ml/min, the anticoagulant effect of LMWH should be measured with an anti-factor Xa level 4 hours after LMWH administration, with a targeted therapeu-tic anti-factor Xa level of 0.5-1.5 U/ml10. Jaffer et al.13 counsel about general patients and in perioperative cases: 1) to stop warfarin 5 days before; 2) to start LMWH 36 hours after the last war-farin dose; 3) to give the last dose of LMWH approx-imately 24 hours before; 4) to restart LMWH 24 hours after the procedure if there is no contraindication; 5) to restart warfarin 24 hours later; 6) to discontinue LMWH when INR is 2-3 for 2 consecutive days.In nephrology, the data are lacking and some nephrologists preferred unfractionated heparin for all patients or in cases of reduced renal function. The timing of warfarin restarting is also debatable. In our experience, we use the following scheme with satisfactory results: 1) stop warfarin 5-7 days before renal biopsy; 2) introduced low molecular weight heparin (LMWH) when INR<2; 3) interrupt LMWH 24 hours before biopsy; 4) evaluate/correct coagulation parameters (PT, PTT, platelet count, anti-Xa activity) and haemoglobin level in biopsy day; 5) evaluate/optimise arterial pressure; 6) perform per-cutaneous renal biopsy using a semi-automated device with real time ultrasonic guidance; 7) restart LMWH after 48 hours in the absence of biopsy com-plication; 8) restart warfarin 5-7 days later.The intensity of long-term oral anticoagulation required for APS patients has been debated15. Ran-domised controlled trials have suggested that INR levels of 2.0-3.0 may be sufficient in uncomplicated APS patients with only venous thrombotic events. In patients with arterial events or with recurrent thrombotic events despite INR in this range, the anticoagulation intensity should probably be increased, with a target INR between 3.0 and 4.0. CONCLUSIONThe clinical patterns of lupus nephritis and APSN are often similar. Biopsy is essential for an accurate diag-nosis and institution of appropriate therapy. Even in anticoagulated patients, renal biopsy may be performed safely if appropriate peribiopsy measures are taken.Conflict of interest statement. None declared.Helena Viana, Aníbal Ferreira, Fernanda Carvalho, Joaquim Bordalo, João Ribeiro SantosNefro - 23-4 MIOLO.indd   360 08-10-2009   17:41:38CMYKPPort J Nephrol Hypert 2009; 23(4): 357-361    361References 1. Love PE, Santoro SA. Antiphospholipid Antibodies: Anticardiolipin and the Lupus Anticoagulant in Systemic Lupus Erythematosus (SLE) and in Non-SLE Disorders. Prevalence and Clinical Significance. Ann Intern Med 1990;112:682-698 2. Cameron JS. Lupus Nephritis. J Am Soc Nephrol 1999;10:413-424. 3. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306 4. Daugas E, Nochy D, Huong DT, et al. Antiphospholipid Syndrome Nephropathy in Systemic Lupus Erythematosus. J Am Soc Nephrol 2002;13:42-52 5. Tektonidou MG, Sotsiou F, Nakopoulou L, Vlachoyiannopoulos PG, Moutsopoulos HM. Antiphospholipid Syndrome Nephropathy in Patients With Systemic Lupus Erythema-tosus and Antiphospholipid Antibodies. Prevalence, Clinical Associations, and Long-Term Outcome. Arthritis Rheum 2004;50:2569-2579 6. Hughes, G.R. The Prosser-White oration 1983. Connective tissue disease and the skin. Clin Exp Dermatol 1984;9:535-544 7. Sangle, S, D’Cruz, D., Khamashta, M., Hughes, G.R.V. Prevalence of hypertension in 600 patients with antiphospholipid syndrome. Rheumatology (Oxford) 2004;43:105-110 8. Nochy D, Daugas E, Droz D, et al. The Intrarenal Vascular Lesions associated with Primary Antiphospholipid Syndrome. J Am Soc Nephrol 1999;10:507-518 9. Amigo MC. Kidney disease in Antiphospholipid Syndrome. Rheum Dis Clin North Am 2006;32:509-522 10. Tektonidou MG, Sotsiou f, Nakpoulou L, Vlachoyannopoulos PG, Moutsopoulos HM. Antiphospholipid Syndrome Nephropathy in Patients with Systemic Lupus Erythema-tosus and Antiphospholipid antibodies. Arthritis and Rheumatism 2004;8:2569-2579 11. Calhoun WB, Hartshorne MF, Servilla KS, Tzamaloukas AH. Renal cortical perfusion defects caused by antiphospholipid syndrome seen on fusion imaging. Clin Nucl Med 2003;28:853-854 12. Hergesell O, Felten H, Andrassy K, Kühn K, Ritz E. Safety of ultrasound-guided percu-taneous renal biopsy-retrospective analysis of 1090 consecutive cases. Nephrol Dial Transplant 1998;13:975-977 13. Jaffer AK, Brotman DJ, Chukwumerije N. When patients on warfarin need surgery. Cleveland Clin J Med 2003;11:973-984 14. Douketis JD, Johnson JA, Turpie AG. Low-Molecular-Weight Heparin as Bridging Anti-coagulation During Interruption of Warfarin. Assessment of a Standardized Periproc-edural Anticoagulation Regimen. Arch Intern Med 2004;164:1319-1326 15. Lim W, Crowther MA, Eikelboom JW. Management of Antiphospholipid Antibody Syndrome: A Systematic Review. JAMA 2006;295:1050-1057Correspondence to: Dr Helena VianaServiço de Nefrologia, Hospital de Curry CabralRua da Beneficência, 81069-166 Lisboa. Portugalviana.helena@gmail.comDe novo hypertension and decline of renal function in a young woman with systemic lupus erythematosus and antiphospholipid syndromeNefro - 23-4 MIOLO.indd   361 08-10-2009   17:41:39

De Novo Hypertension and Decline of Renal Function in a Young Woman with Systemic Lupus Erythematosus and Antiphospholipid Syndrome

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