Cinacalcet for secondary hyperparathyroidism: from improved mineral levels to improved mortality?

Secondary hyperparathyroidism is an almost inevitable complication of advanced kidney failure. The introduction of the calcimimetic cinacalcet for the treatment of secondary hyperparathyroidism in patients on dialysis was based on its ability to reduce elevated levels of parathyroid hormone (PTH). Subsequent clinical studies confirmed the beneficial effects of cinacalcet on biochemical parameters reflecting mineral disturbances and bone disease. In this review we summarise the impact of cinacalcet on biochemical, intermediate and clinical outcomes. We also present previously unpublished mineral metabolism data from 144 Dutch dialysis patients treated with cinacalcet who participated in the pan-European ECHO observational study. Although secondary hyperparathyroidism tended to be more severe in our Dutch cohort, compared with the entire ECHO cohort, cinacalcet was nevertheless effective in reducing PTH in these patients. Two recent clinical studies evaluated, respectively, the efficacy of cinacalcet in improving the intermediate endpoint of cardiovascular calcifications (ADVANCE trial), and its impact on clinical outcomes, including all-cause mortality and cardiovascular events (EVOLVE trial). The ADVANCE trial provided evidence that cinacalcet may indeed improve calcification in both large arteries and cardiac valves. The EVOLVE trial, however, did not meet its clinical primary endpoint (time to all-cause mortality, myocardial infarction, hospitalisation for unstable angina, heart failure or a peripheral vascular event), although secondary and sensitivity analysis suggested a beneficial effect. The clinical implications of these important studies are also addressed in this review.

Restrictive use of immunosuppressive treatment in patients with idiopathic membranous nephropathy: high renal survival in a large patient cohort.

BACKGROUND: Immunosuppressive treatment initiated at an early stage in patients with idiopathic membranous nephropathy (iMN) improves renal survival. Treatment should ideally be restricted to high-risk patients. AIM: To evaluate the efficacy of a restrictive immunosuppressive treatment strategy for patients with iMN. DESIGN: Prospective cohort study evaluating a predefined treatment protocol. METHODS: From 1988, we adopted a restrictive treatment strategy: immunosuppressive treatment, mainly consisting of cyclophosphamide and steroids, was advised only in patients with renal insufficiency or severe intolerable nephrotic syndrome. We evaluated this strategy in a large patient cohort. To exclude any bias, we included all adult patients with iMN biopsied in the study period with a serum creatinine (Scr) < 135 micromol/l, a proteinuria > or = 3.0 g/day and/or a serum albumin (Salb) < or = 30 g/l at the time of biopsy. Analysis was according to the intention-to-treat principle. RESULTS: We studied 69 patients. At the time of biopsy, mean age was 51 years, Scr 90 micromol/l, Salb 23 g/l and proteinuria 6.7 g/day. Average follow-up was 5.5 years. Thus far 33 (48%) patients have received immunosuppressive therapy, mainly because of renal insufficiency (n = 24). Status at the end of follow-up was: complete remission n = 22 (32%), partial remission n = 24 (35%), nephrotic syndrome n = 15 (22%), persistent proteinuria n = 1 (1.4%), ESRD n = 6 (8.7%), death n = 1 (1.4%; due to bladder carcinoma after cyclophosphamide therapy). Patient survival was 100% at 5 and 7 years. Renal survival was 94% at 5 years and 88% at 7 years. DISCUSSION: In patients with iMN, a restrictive treatment policy assures a favourable prognosis, while preventing exposure to immunosuppressive therapy in >50% of the patients.

Swelling of hand and forearm caused by Mycobacterium bovis.

A 75-year-old native Dutch farmer presented with a painless swelling of his right hand extending into his forearm, accompanied by general malaise and low grade fever. His medical history revealed coxitis tuberculosa in 1954 and injury of the same hand in 1978. His present swelling appeared to be caused by Mycobacterium bovis, probably due to endogenous reactivation. Whether the mycobacteria reached the hand hematogenously or were directly inoculated at the time of injury of his hand in 1978 remains unclear.

Skin vasomotor reflexes during inspiratory gasp: standardization by spirometric control does not improve reproducibility.

Arteriovenous anastomoses (AVA) in skin microcirculation are mediated by the sympathetic stimuli. The inspiratory gasp test (IG test) triggers the sympathetic nervous system, resulting in a decrease in AVA skin blood flow, as measured by laser Doppler fluxmetry (LDF). We studied the reproducibility of the IG test under carefully standardized respiratory conditions. In each of 19 healthy (young) volunteers with a mean skin temperature during the experiment above 28 degrees C 13 IG tests were performed, either under spirometric control or uncontrolled and by using a negative pressure transducer. Starting the IG test end-inspiratory results in the most pronounced absolute LDF decrease [140 PU (70-490)], median (minimum-maximum) as compared to starting end-expiratory [100 PU (40-260)] and during inspiration [110 PU (50-350)], respectively, p < 0.001 and p < 0.001. Inspiration as fast as possible results in a larger absolute LDF decrease [150 PU (40-450)], compared to inspiration in 5 s [120 PU (60-340); p < 0.02] and in 10 s [130 PU (40-350); p < 0.05]. Continuously sucking negative mouth pressure results in a larger LDF decrease [140 PU (30-420)] in comparison with taking one deep breath and holding it for 10 s [110 PU (30-270); p < 0.01]. However, standardization of the IG test did not improve its reproducibility.

Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil.

The occurrence of rhabdomyolysis is one of the rare side-effects of the cholesterol-lowering agent simvastatin. During the use of lovastatin, an agent related to simvastatin, the risk of this side-effect might be increased when cyclosporin or gemfibrozil are used concomitantly. It is possible that this also applies for simvastatin. We present two patients who developed rhabdomyolysis during the concomitant use of simvastatin and gemfibrozil.