How to recognise and treat peripheral nervous system vasculitis.

Peripheral neuropathy can be the first and only manifestation of necrotising primary immune-mediated vasculitis which, carries a high mortality. A clear idea of how to both recognise and treat peripheral nervous system vasculitis is important. We provide a practical approach to immediate and longer term treatment protocols.

Alemtuzumab in the treatment of IVIG-dependent chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an idiopathic immune mediated neuropathy causing demyelination and conduction block thought to occur as the result of an aberrant autoimmune response resulting in peripheral nerve inflammation mediated by T cells and humoral factors. Diagnosis commonly prompts initial treatment with steroids or intravenous immunoglobulin (IVIG) on which 5-35% subsequently become dependent to maintain function. Despite a number of small scale trials, the role for alternative long-term immunosuppression remains unclear. Alemtuzumab is a humanised monoclonal antibody targeting the CD52 antigen present on the surface of lymphocytes and monocytes. A single intravenous infusion results in rapid and profound lymphopoenia lasting >12 months. We report its use and clinical outcome in a small series of patients with severe IVIG-dependent CIDP. Seven patients (4 Males; 3 Females) who had failed to respond to conventional immunosuppression were treated in 5 centres receiving 9 courses of alemtuzumab (dose range 60-150 mg). Following treatment, mean monthly IVIG use fell 26% from 202 to 149 g and IVIG administration frequency from 22 to 136 days. Two patients had prolonged remission, two patients had a partial response and no clear benefit was observed in the remaining three patients (2 Males, 1 Females). Responding patients had a younger age at onset (19.5 years) and shorter disease duration than non-responders. Three patients developed autoimmune disease following treatment. Alemtuzumab may offer an alternative treatment for a subset of early onset IVIG dependent CIDP patients failing conventional immunosuppressive agents, but concerns about toxicity may limit its use.

The character of the atrial natriuretic response: pressure and volume effects.

Synthetic atrial natriuretic factor (ANF) was compared to the well-characterized diuretics hydrochlorothiazide and furosemide in rats. While ANF was markedly more potent than either agent, its natriuretic potency more closely resembled hydrochlorothiazide. Probenecid, a drug that competes with diuretics such as furosemide for secretion into the renal tubular lumen and thereby decreases diuretic effectiveness, did not interfere with the natriuretic actions of ANF. In rats, continuous infusion of ANF resulted in a bell-shaped dose-response relationship. Above a dose of approximately 100 pmol/kg per min, the response waned and at the highest doses studies, 1-2 nmol/kg per min, urinary sodium excretion fell below control levels. A similar bell-shaped dose-response curve was observed in anaesthetized volume-expanded monkeys. During euvolaemia, conscious monkeys showed a marked fall in blood pressure without concomitant natriuresis. The blood pressure was sustained for the 3-h duration of the ANF infusion. One percent body weight volume expansion blunted the fall in blood pressure in these monkeys and the restored natriuretic response did not wane during 3-h infusion. When the fall in blood pressure was prevented by angiotensin II infusion in conscious euvolaemic monkeys, the natriuretic response to ANF was expressed.

Effects of atrial natriuretic factor on renal function and cyclic GMP production.

Anesthetized beagle dogs received increasing doses of continuous infusions of a 26-amino-acid synthetic atrial natriuretic factor (ANF). Urinary sodium excretion rose in a dose-dependent manner to a maximum level similar to that seen after hydrochlorothiazide administration. Mean arterial blood pressure decreased, but only modestly, and not in a dose-dependent fashion. Dogs chronically retaining NaCl secondary to constriction of the thoracic inferior vena cava showed only modestly enhanced natriuresis when infused with similar levels of ANF. When ANF was infused directly into the renal artery of anesthetized beagles, a dose-dependent natriuresis and calciuresis were observed with maximal fractional sodium excretion averaging approximately 8%. Although glomerular filtration tended to increase, the average dose-related changes were not significant. Cyclic GMP excretion was increased during intra-renal-arterial infusion of ANF. Excretion of cyclic GMP by both the infused and noninfused kidneys was equal, which suggests that urinary cyclic GMP was not nephrogenous but derived from the elevated circulating levels. These and other data from rats dissociate changes in urinary cyclic GMP excretion and sodium excretion.

Renal and blood pressure responses to synthetic atrial natriuretic factor in spontaneously hypertensive rats.

Atrial natriuretic factor (ANF) is a potent natriuretic and vasorelaxant agent that also stimulates guanosine 3',5'-cyclic monophosphate (cGMP) excretion in normotensive animals. These properties suggest that ANF may be involved in the regulation of blood pressure. To test a pure preparation of ANF in both normotensive and hypertensive animals, a synthetic 26 amino acid peptide (sANF) contained within endogenous rat ANF was infused intravenously into conscious Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at doses from 12 to 190 pmol/minute. Mean arterial pressure fell progressively as doses of sANF were increased until maximum responses of -41 +/- 5 mm Hg and -29 +/- 5 mm Hg were obtained during infusion of 95 pmol/minute sANF in SHR and WKY, respectively. Heart rate was not significantly affected in either group. At sANF doses of 12 to 50 pmol/minute, urinary electrolyte excretion rose in a dose-related fashion and was similar in WKY and SHR. At infusions of 95 to 190 pmol/minute, the diuretic and saluretic responses were diminished in the hypertensive animals. Only the 190 pmol/minute sANF dose significantly enhanced cGMP excretion in SHR (p less than 0.05); however, in WKY urinary cGMP excretion was elevated in a dose-related fashion. At the highest sANF dose, cGMP excretion was approximately 15 times that observed in the pretreatment urine. The differences in the renal and blood pressure responses to sANF in SHR and WKY suggest that the actions of endogenous ANF may be altered in hypertension.

Synthetic atrial natriuretic factor in conscious normotensive and hypertensive rats.

Synthetic atrial natriuretic factor (Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly -Leu- Gly-Cys-Asn-Ser-Phe-Arg-Tyr-COOH [disulfide bond between cysteines]) was infused intravenously into conscious normotensive and deoxycorticosterone, one-kidney, one-clip, and two-kidney, one-clip hypertensive rats. Mean arterial pressure, urine volume, and electrolyte excretion rates were measured during a 20-minute infusion of a single dose (ranging from 0-1520 pmol/min) into each animal; 95 to 380 pmol/minute of synthetic atrial natriuretic factor maximally reduced mean arterial pressure by -20 +/- 4, -29 +/- 2, and -39 +/- 7 mm Hg in normotensive, one-kidney, one-clip, and two-kidney, one-clip hypertensive rats, respectively. In deoxycorticosterone rats, a dose of 760 pmol/minute was required to produce the largest depressor response (-58 +/- 12 mm Hg). Sodium excretion increased to 8.8 +/- 2.5 muEq/minute at 760 pmol/minute in normotensive rats, to 6.5 +/- 1.1 muEq/minute at 50 pmol/minute in deoxycorticosterone rats, and to 5.8 +/- 1.5 muEq/minute at 95 pmol/minute in one-kidney, one-clip animals. The natriuretic effect was consistently greater at all doses of synthetic atrial natriuretic factor in the two-kidney, one-clip hypertensive model, in which the maximum response was 15.3 +/- 4.7 muEq/minute at 190 pmol/minute. The changes in urine volume and excretion rates of potassium and chloride tended to parallel the increases in sodium excretion in each model. Interestingly, the maximally effective hypotensive dose of synthetic atrial natriuretic factor was different from the maximally effective natriuretic dose in all four groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolation and sequence determination of peptide components of atrial natriuretic factor.

The independent isolation and sequence determination in our laboratories of three closely related Atrial Natriuretic Factor peptides from rat atria confirm the sequences of ANF peptides reported by Seidah et al and synthesized by Nutt et al [Proc. Natl. Acad. Sci., (1984) in press] and contain the sequences reported by Flynn et al [Biochem. Biophys. Res. Commun. (1983) 117: 859-865] and by Currie et al [Science (1984) 223: 67-69]. In addition, we provide proof for a C-terminal tyrosine rather than tyrosine amide in our isolated peptides.