Catastrophic antiphospholipid syndrome: report of 4 cases.

Catastrophic antiphospholipid syndrome (CAPS), described by Asherson in 1992, is a rare form of antiphospholipid syndrome resulting in multiorgan failure with a mortality rate of about 50%. The syndrome occurs in patients with either systemic lupus erythematosus and other rheumatic diseases (systemic sclerosis, rheumatoid arthritis, primary Sjogren syndrome) or alone. Whereas in "classic" antiphospholipid syndrome (APS), medium-large vessels are involved, a diffuse small vessel ischemia and thrombosis (microangiopathic disease) leading to a severe multiorgan dysfunction is predominant in CAPS. "Trigger" factors have been demonstrated in 45% of patients, but in the majority, they remain unknown. Not infrequently, CAPS arises in patients without any previous thrombotic history. The kidney is the organ most commonly affected, followed by the lung, the central nervous system, the heart and the skin. Disseminated intravascular coagulation occurs in approximately 13% of patients. The present study reports the clinical and serological features of 4 patients affected by this rare form of antiphospholipid syndrome. Nephrologists should be aware of the possibility of this syndrome as a cause of multiorgan failure since prompt recognition is essential for effective treatment.

[New insights in the treatment of ANCA-associated systemic vasculitis]. / Nuove acquisizioni in tema di terapia delle vasculiti ANCA-associate.

The prognosis of untreated ANCA-associated systemic vasculitis (AASV) is poor with up to 90% of patients dying within 2 years. The combination of prednisone and cyclophosphamide is now established as the treatment of choice and leads to control of the disease in 80-90% of the patients. Such treatment has turned these acutely fatal diseases into chronic relapsing disorders with accumulating drug-related morbidity in over 50% of the patients, including diabetes, bladder and lympho-proliferative malignancy and infertility. Treatment of AASV can be divided into three phases: therapy for induction of remission, for maintenance of remission and therapy for refractory and relapsing disease. In addition, the treatment must be tailored to the stage and severity of the disease and a new classification of AASV was introduced: localized vasculitis, early systemic vasculitis, generalized vasculitis, severe renal vasculitis and refractory vasculitis. Different randomized clinical trials have been performed with the aim of optimizing the existing therapeutic regimens: some of these have been concluded, others are still ongoing. Newer therapeutic approaches are currently being tested and have involved the use of mycophenolate mofetil, anti tumour necrosis factor (TNF) drugs (anti TNF antibody infliximab and humanized soluble TNF receptor etanercept), monoclonal anti- lymphocyte antibody (anti-CD20). These new alternative therapies could be used in patients with frequent relapses, in patients who fail to achieve remission with standard induction therapy and in those with severe side effects due to cumulative doses of cyclophosphamide.

[Non SLE connective tissue diseases: general aspects and kidney]. / Connettiviti non LES: aspetti generali e rene.

Connective tissue diseases represent a group of heterogeneous disorders that share certain common features, including inflammation of the skin, joints and other structures rich in connective tissue, as well as altered immunoregulation patterns, including autoantibody production and cell-mediated immunity abnormalities. While certain distinct clinical entities can be defined, manifestations can vary considerably from patient to patient, and the overlap of clinical features between and among specific diseases is common. Genetic, environmental and sex hormonal factors are likely to be of pathogenic importance. Among these diseases, systemic lupus erythematosus is the most frequent, followed by systemic sclerosis or scleroderma (SSc), Sjogren's disease, polymyositis and dermatomyositis and mixed connective tissue disease. Systemic sclerosis involves multiple organs in a process consisting of disseminated sclerosis affecting all compartments. Prominent vascular lesions typify the renal lesions. Scleroderma crisis is a major complication of SSc, characterized by severe hypertension, rapidly progressive renal failure, thrombotic microangiopathy with hemolitic anemia and low platelet count: the prompt use of angiotensin-converting enzyme (ACE) inhibitors significantly increased the 1-yr survival rate from 15 to 76%. Sjogren's syndrome is an immunologic disorder characterized by progressive lymphocytic destruction of the exocrine gland, frequently resulting in symptomatic eye and mouth dryness. The interstitial lesions constitute the principal renal manifestations: interstitial infiltrates and small lymphocytes, which can be homogenous and massive. In polymyositis and dermatomyositis renal involvement is rare.

[ANCA-associated vasculitis]. / Vasculiti anca-associate.

ANCA-associated vasculitis. The term "antineutrophil cytoplasm antibody (ANCA)- associated vasculitis" (AASV) ihighers generally used to include primary vasculitis syndromes in which circulating ANCA against proteinase 3 (PR3) and myeloperoxidase (MPO) are commonly found. AASV syndromes include Wegener's granulomatosis, microscopic polyangiitis, idiopathic pauci- immune necrotizing crescentic glomerulonephritis and Churg-Strauss syndrome (CSS). AASV syndromes share some general clinical-histological manifestations, such as rapidly progressive renal failure and focal necrotizing glomerulonephritis with extracapillary proliferation in the absence (or in the presence of modest) immunoglobulins deposits (pauci- immune). Untreated AASV follow a progressive course with a fatal outcome due to vital organ failure. The combination of cyclophosphamide and prednisone is now established as the treatment of choice for patients with AASV, but there is considerable debate over the duration of therapy and the best way to administer cyclophosphamide. Treatment of AASV can be divided into two phases: an induction of remission and a maintenance of remission phase. Patients with AASV and renal involvement (serum creatinine less than 500 ml/L or 5.6 mg/dl) should be treated with a combination of oral prednisone with gradual tapering and cyclophosphamide. Once remission is achieved, usually after 3-6 months, azathioprine should replace cyclophosphamide. It is not known for how long treatment should be continued but at least one year of treatment after remission is warranted. When serum creatinine is than 500 ml/L (5.6 mg/dl) and/or oliguria is present, the addition of methylprednisolone pulses and/or plasma exchange should be considered.

SDS-PAGE patterns and polymeric albumin in proteinuria of lupus glomerulonephritis.

Proteinuria was characterized by SDS-PAGE and by immunoblotting with anti-human albumin sera for the detection of urinary polymers of albumin (PA) in 40 patients with biopsy proven lupus glomerulonephritis (LN) (6 pts class III WHO, 24 pts class IV, 10 pts class V) with various clinical presentations (nephrotic syndrome with normal or impaired renal function, 14 pts; urinary abnormalities with normal or impaired renal function, 21 pts; clinical remission, 5 pts); in 25 pts, for whom the characterization of proteinuria and the renal biopsy were performed at the same time, the activity and chronicity index scores were calculated. The mixed SDS-PAGE patterns, characterized by the presence of low molecular weight proteins, were the more frequently found; the mixed patterns were significantly associated with interstitial leukocyte infiltration (p = 0.05) and glomerular sclerosis (p = 0.046) and nonsignificantly associated with higher values of serum creatinine; no SDS-PAGE pattern had predictive value on functional outcome at 36 months. Albumin polymers were present in 67% of pts; in active disease they were present in 33% of class III, in 100% of class IV and in 45% of class V WHO (p = 0.026); PA were not present in 5 pts with clinical remission (4 class IV and 1 class V WHO). The presence of PA was significantly associated with high values (> 10) of activity index (p = 0.009) and with extracapillary proliferation (p = 0.041). Serum creatinine was lower in patients without PA (Scr 1.0 +/- 0.4 mg/dl) than in those with PA (Scr 1.5 +/- 1.0 mg/dl), but the difference was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

The impact of prolonged immunosuppression on the outcome of idiopathic focal-segmental glomerulosclerosis with nephrotic syndrome in adults. A collaborative retrospective study.

In this retrospective study we report the outcome of 59 adults with idiopathic focal-segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS) treated with corticosteroids and/or immunosuppressive drugs. Twenty-seven patients were initially treated with corticosteroids alone for 9.3 +/- 8 months; nineteen patients received corticosteroids and immunosuppressive agents associated or every other month for 5.5 +/- 4 months; thirteen patients received either azathioprine or cyclophosphamide alone for 25 +/- 27 months. At the end of a mean follow-up of 75 +/- 51 months, 35 patients (60%) were in complete (CR) or partial (PR) remission, 6 (10%) were stable and 18 (30%) had either chronic renal failure (CRF) or end-stage renal failure (ESRF). Out of 36 patients (61%) initially responsive to therapy, 30 (83%) obtained CR, 4 (11%) PR, one (2.7%) developed CRF and one (2.7%) ESRF. Only 10 of the responders (28%) attained remission within 8 weeks of treatment. Out of the 23 (39%) patients originally resistant to therapy, only one (4%) had CR, 6 (26%) remained unchanged, 6 (26%) developed CRF and 10 (43%) ESRF. The presence at initial renal biopsy of interstitial fibrosis was the only feature which could predict a poor renal outcome. These data show that prolonged treatment of FSGS can obtain sustained remission of the disease and improved renal survival in a consistent proportion of adult patients which would be considered refractory to a two-month course with corticosteroids.

Characterization of interstitial infiltrating cells in Berger's disease.

The role of infiltrating blood-borne cells in the pathogenesis of renal damage in human glomerulonephritis is under active investigation. We have evaluated leukocyte infiltrates (number of cells/mm2) in the renal interstitium of 21 patients with Berger's disease and eight normal kidneys with monoclonal antibodies and a four-layer immunoperoxidase technique. In our population of patients, the number of infiltrating T-lymphocytes (OKT11+ cells) was significantly higher (median, 132) than in the normal kidneys (median, 60). This increase was mainly due to T-suppressor/cytotoxic lymphocytes (OKT8+ cells; median, 68), while T-helper/inducer lymphocytes (Leu 3A+ cells) and monocytes were in the normal range. T-lymphocyte infiltration was more marked in ten patients with impaired glomerular filtration rate (GFR) at the time of biopsy (median, 167) than in patients with normal GFR (median, 88). In addition, ten patients who showed deterioration of renal function during the subsequent follow-up, whatever their serum creatinine levels at the time of biopsy, had significantly more total T cells (median, 269), OKT8+ cells (median, 143), and Leu 3A+ cells (median, 105) than 11 patients with persistently stable GFR and normal controls. More data are necessary to establish whether this T-lymphocyte infiltration is the consequence of a cell-mediated mechanism acting in the interstitium, concomitant with the immune-complex-mediated mechanism acting in the glomerulus, or is a nonspecific consequence of the tubulointerstitial damage induced by the immunologically mediated glomerular disease.

Identification of glomerular immune deposits in cryoglobulinemia glomerulonephritis.

To provide further evidence of the nature of intraglomerular immune deposits in essential mixed cryoglobulinemia (EMC), we used two mouse monoclonal antibodies against cross-reactive idiotypes present on monoclonal rheumatoid factors (MoRFs) from patients with type II-EMC. MoAb Cc1 reacted with 9 of 16 circulating IgMk MoRFs tested, and MOAb Lc1 with four of the remaining. Using indirect immunofluorescence and immunoperoxidase techniques, we could identify the same cross-reactive idiotype of the serum MoRF in the renal biopsy specimens from 11 of 13 patients with EMC glomerulonephritis. Kidney specimens from the three patients, whose MoRF was not recognized by MoAbs Cc1 and Lc1, were negative. Two out of 30 control renal biopsies from patients with other forms of glomerulonephritis were shown to contain idiotype (Cc1 and Lc1) positive material. Both patients had serum polyclonal RF which could account for this finding. In conclusion, our results provide direct evidence that serum cryo-MoRF participate in the formation of glomerular immune deposits and, presumably, in the pathogenesis of renal damage in EMC glomerulonephritis.

Cardiopulmonary receptor modulation of plasma renin activity in normotensive and hypertensive subjects.

Cardiopulmonary receptors modulate renin release in several animals species. However, their involvement in reflex control of this humoral substance in humans is controversial. Furthermore, no information is available on the alteration of this control in hypertension. We studied the modulation of plasma renin activity (radioimmunoassay) in 12 normotensive subjects and in 12 age-matched subjects with untreated hypertension of mild or moderate degree. Cardiopulmonary receptors were stimulated by increasing central venous pressure (right atrial catheter) and cardiac volume (echocardiographic measurement) through passive leg raising and deactivated by reducing central venous pressure and cardiac volume through lower body negative pressure. The stimuli were maintained for 20 to 30 minutes, and their degree was set to avoid changes in blood pressure (indirect or direct measurements) and heart rate, thus avoiding involvement of arterial baroreceptors. In normotensive subjects, deactivation of cardiopulmonary receptors induced a progressive rise in plasma renin activity and stimulation of cardiopulmonary receptors induced a progressive fall. The reflex gain (ratio between plasma renin activity and central venous pressure or cardiac volume changes) was similar for deactivation and stimulation. During cardiopulmonary receptor deactivation, the gain corresponded to that obtained by dividing the increase in plasma renin by the reduction in central venous pressure induced by tilting. Cardiopulmonary receptor deactivation and stimulation also induced clear-cut changes in plasma renin activity in hypertensive subjects, but the percent magnitude of the reflex plasma renin activity excursion was less than that in normotensive subjects. These observations indicate that cardiopulmonary receptors modulate plasma renin activity in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of celiprolol on reflex control of the cardiovascular system in essential hypertension.

We have previously shown that baroreceptor control of the cardiovascular system and the cardiopulmonary receptor control of peripheral circulation are preserved or only moderately reduced during antihypertensive treatment with acebutolol or nadolol, which indicates that treatment with beta blockers with or without intrinsic sympathomimetic activity does not impair fundamental neural mechanisms involved in circulatory homeostasis. In the present study we have investigated the reflex control of circulation before and during antihypertensive treatment with celiprolol, which, in addition to its beta-blocking action, has vasodilator properties that may stem from interference with neural cardiovascular control. In six essential hypertensive subjects we measured blood pressure (intraarterial catheter), heart rate (ECG recording), central venous pressure (right atrial catheter), and forearm blood flow and resistance (plethysmography) before and during alterations in the activity of the arterial baroreceptors obtained by means of lower body suction and passive leg raising. The study was performed before and after 5-7 days of oral administration of celiprolol at 200-400 mg once a day. Compared to the values obtained in the control, condition celiprolol caused a reduction in blood pressure, a slight change in heart rate, and an increase in forearm blood flow, which indicated the occurrence of a clear-cut forearm vasodilatation. The heart rate responses to arterial baroreceptor manipulation were unchanged by celiprolol which reset the carotid baroreflex so that its tonic restraint on blood pressure increased despite the hypotension induced by the drug. The inhibitory restraint tonically exerted by the cardiopulmonary receptors on peripheral circulation was also increased by celiprolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic converting enzyme inhibition reduces the vasomotor response to reflex sympathetic activation in man.

Several lines of evidence indicate that angiotensin II (ANG II) may potentiate the vascular response to sympathetic stimulation. However, there are no clear signs that this action of ANG II is physiologically relevant in man. To investigate this problem, we used the lower body negative pressure technique (LBNP, -15 mmHg) to deactivate cardiopulmonary receptors and reflexly stimulate the sympathetic nervous system. The haemodynamic (changes in blood pressure, heart rate, central venous pressure, forearm blood flow) and humoral effects [changes in plasma noradrenaline (PNA) and plasma renin activity (PRA)] of this manoeuvre were examined before and after blockade of angiotensin formation achieved by the administration of the converting enzyme inhibitor, captopril. Studies were performed in patients with essential hypertension in control conditions and after acute and chronic captopril treatment. We found that the reduction in forearm blood flow induced by LBNP was significantly diminished after acute and chronic captopril in spite of the fact that the fall in central venous pressure and the increases in PNA were similar to those observed in control conditions. In contrast, the response of renin to LBNP was enhanced, at least after acute captopril administration. These findings suggest that efficiency of the reflexes originating from the cardiopulmonary receptors is impaired after captopril. Angiotensin II contributes to the vasoconstrictive ability of the sympathetic nervous system, either through a direct vascular action or by enhancing the vascular responsiveness to noradrenaline stimulation. However, this sympathetic facilitatory action of ANG II does not appear to be extended on the adrenergic mechanisms which regulate renin release.

Role of cardiopulmonary receptors in reflex control of renin release in man.

Animal studies have shown that renin release is reflexly modulated by cardiopulmonary and arterial baroreceptors, and that during changes in posture the former receptors play a major role. This role has been challenged in man, however, by reflex modulation of renin secretion which has been claimed to take place only if arterial and cardiopulmonary receptor areas are engaged together. We studied 19 normotensive and essential hypertensive subjects in which plasma renin activity was assessed by radioimmunoassay during a mild 20 min increase and a mild 20 min reduction in central venous pressure (+1.1 +/- 0.2 mmHg and -2.6 +/- 0.4 mmHg). The increase and reduction in central venous pressure were accompanied by no change in systolic blood pressure, diastolic blood pressure and heart rate which indicated that the increased and reduced stimulus had involved only cardiopulmonary receptors and not arterial baroreceptors as well. During the increase in central venous pressure plasma renin activity showed a significant (P less than 0.01) reduction (-18 +/- 3%) whereas during the reduction in central venous pressure it showed a significant (P less than 0.01) and more marked increased (+64 +/- 17%). The plasma renin activity increase observed during lower body suction was not significantly different from that observed during a 20 min tilting, a manoeuvre that reduced central venous pressure to an extent similar to that observed during lower body suction, but that also deactivated carotid baroreceptors by positioning the carotid sinuses above the heart and reducing their transmural pressure. Thus in normotensive and hypertensive humans renin release can be reflexly modulated by selective engagement of cardiopulmonary receptors.(ABSTRACT TRUNCATED AT 250 WORDS)