Targets for adapting intravenous iron dose in hemodialysis: a proof of concept study.

BACKGROUND: Intravenous iron is widely used to control anemia in dialysis patients and limits costs related to erythropoiesis-stimulating agents (ESA). Current guidelines do not clearly set upper limits for serum ferritin (SF) and transferrin saturation (TSAT). International surveys such as the Dialysis Outcomes and Practice Patterns Study (DOPPS) showed that this lack of upper limits potentially led nephrologists to prescribe iron infusions even for patients with a high SF. Recent publications have suggested a risk of short- and long-term adverse effects related to iron overload. We conducted a proof of concept study to assess the impact of reducing intravenous iron administration. METHODS: In a prospective 8-month study conducted in a hospital dialysis unit, we assessed the impact of a strategy designed to reduce iron infusions. Instead of the usual strategy targeting 30-50% TSAT irrespective of SF, intravenous iron was administered if and only if TSAT was below 20% and SF below 200 µg/L. Routine practices for ESA remained unchanged: hemoglobin target 10-12 g/dL; ESA delivered monthly and dose corrected by 25% as necessary; ESA discontinued temporarily if hemoglobin >13 g/dL; methoxy polyethylene glycol-epoetin beta generally used. Tests were ordered monthly to monitor hemoglobin. Intravenous iron was administered weekly and ESA monthly. Baseline and 6-month TSAT, SF and hemoglobin levels were compared. RESULTS: Six-month data were available for 45 patients (31 M/14 F; 67.6 ± 14.0 y; 53.9 ± 85.7 months on dialysis). Patients experienced the following comorbidities: ischemic heart disease (n = 29, 44%), diabetes mellitus (n = 14; 31%), malignant disease (n = 11; 24%), transplantation (n = 11; 24%) and severe heart failure (n = 6; 13%). The mean weekly dose of iron declined from 77.8 ± 87.6 to 24.4 ± 52.9 mg per patient (p = 0.0003). SF decreased from 947.7 ± 1056.4 to 570.7 ± 424.4 µg/L (p = 0.0001), and TSAT from 41.5 ± 22.4 to 32.6 ± 13.7% (p = 0.01). Hemoglobin levels remained stable (11.13 ± 1.05 vs. 11.00 ± 1.16 g/dL, p = 0.54) as did ESA dose (126.4 ± 91.9 vs. 108.2 ± 112.7 µg/28 days, p = 0.07). CONCLUSIONS: Our study suggests that a regular hemoglobin level can be maintained using regular ESA doses combined with intravenous iron doses adapted to TSAT and SF thresholds lower than those used in routine practice. This strategy reduces the risk of iron overload.

Smoking cessation guidelines: evidence-based recommendations of the French Health Products Safety Agency.

Tobacco use is the leading preventable cause of death in developed countries. Millions of smokers are willing to stop, but few of them are able to do so. Clinicians should only use approaches that have demonstrated their efficacy in helping patients to stop smoking. This article summarizes the evidence-based major findings and clinical recommendations for the treatment of tobacco dependence of the French Health Products Safety Agency (AFSSAPS). Clinicians should enquire about the smoking status of each patient and provide information about health consequence of smoking and effective treatments available. These treatments include counseling (mainly individual or social support and behavioral and cognitive therapy) and pharmacological treatment with either nicotine replacement therapy (NRT) or bupropion LP. Pharmacological treatments should be used only for proven nicotine dependence, as assessed by the Fagerstrom test for Nicotine Dependence. The choice of pharmacologic treatment depends of the patient's preference and history and of the presence of contra-indications. The clinician should start with a single agent, but these treatments may be used in combination. Smoking behavior is a chronic problem that requires long-term management and follow-up. Access to intensive treatment combining pharmacological treatment and extensive behavioral and cognitive therapy should be available for highly dependent patients.

Schönlein-henoch purpura in children and adults: diagnosis, pathophysiology and management.

Schönlein-Henoch syndrome is a form of systemic small-vessel vasculitis, characterised by vascular and/or mesangial immunoglobulin A1 deposits. The main clinical manifestations are vascular purpura, predominating on the lower limbs, and articular, gastrointestinal and renal symptoms. Pulmonary, cardiac, genital and neurological symptoms have also be observed. The syndrome usually affects children, whereas it is rare in adults. The frequency of renal involvement varies between individual studies (from 20 to 100%). Renal manifestations are usually mild and transient, although chronic nephropathies may occur. Overall, an estimated 2% of children with Schönlein-Henoch purpura progress to renal failure and up to 20% of children with nephritis treated in specialised centres require haemodialysis. The renal prognosis appears to be worse in adults. Aetiological investigations are required, as a triggering factor is found in approximately half the patients (e.g. viral, bacterial and parasitic infections, drugs, toxins, systemic diseases and cancer). Dapsone has beneficial effects on cutaneous, gastrointestinal and articular manifestations in adults, especially those with chronic forms. Corticosteroids may be useful for refractory abdominal pain. Methylprednisolone pulse therapy, immunosuppressive drugs (e.g. cyclophosphamide and azathioprine), plasma exchange and polyclonal immunoglobulin therapy are beneficial in very rare life-threatening forms of the disease and in rare instances where renal function is compromised.

Increased intestinal intra-epithelial T lymphocytes in primary glomerulonephritis: a role of oral tolerance breakdown in the pathophysiology of human primary glomerulonephritides?

BACKGROUND: There is increasing evidence that some organ-specific and generalized autoimmune diseases in humans might be related to a breakdown of oral tolerance. We explored this hypothesis in human primary glomerulonephritides. We prospectively counted intraepithelial T lymphocytes in the duodenal mucosa (as a marker of rupture of oral tolerance), together with IgA1 and IgA2 mucosal plasma cells, in patients with primary glomerulonephritides. METHODS: We investigated eight adults with immune-complex glomerulopathy (membranous nephropathy+membranoproliferative glomerulonephritis), 16 adults with an idiopathic nephrotic syndrome, and 25 adults with IgA nephropathy. Patients with glomerulonephritides were compared to two control groups: group 1 consisted of nine healthy adults; group 2 comprised five adults with coeliac disease before dietary gluten withdrawal or during a clinical relapse related to gluten ingestion. (The latter disease is associated with increased numbers of intraepithelial T lymphocytes, and a breakdown of oral tolerance to gliadins is involved in the pathogenesis of coeliac disease). Duodenal fibroscopy was performed under neuroleptanalgesia. Four to six endoscopic biopsy specimens were taken from the second duodenum. Intraepithelial T lymphocytes were blindly counted on paraffin sections stained with haematein-eosin-saffron (HES), within the epithelium of a villus in a zone with at least 100 cells. Mucosal IgA1 and IgA2 plasma cells were blindly counted in a mucosal tissue unit by using specific mouse monoclonal antibodies directed against IgA1 and IgA2, with alkaline phosphatase anti-alkaline phosphatase (APAAP) revelation. As values were not normally distributed, we used non-parametric analysis of variance with the Kruskal-Wallis test, and compared median values by using the non-parametric Mann-Whitney test. RESULTS: Intraepithelial T lymphocytes were significantly more abundant in patients with primary glomerulonephritides and coeliac disease than in healthy controls (P < 0.0001 in the Kruskal-Wallis test): healthy controls, median 11 (range 4.65-16); immune complex glomerulopathy, 27.45*** (15-93); idiopathic nephrotic syndrome, 16.5** (9-26.5); IgA nephropathy, 26.10*** (11.3-47.5); coeliac disease, 55*** (20-80) (*P <0.05; **P <0.01; ***P < 0.005, Mann-Whitney test). No difference was found in the number of duodenal IgA1 and IgA2 plasma cells between controls and patients with primary glomerulonephritides. IgA1 and IgA2 plasma cells were increased in patients with coeliac disease. CONCLUSION: The significant increase in intestinal intraepithelial T lymphocytes in primary glomerulonephritides suggests a pathophysiological role of oral tolerance breakdown.

Vascular hyperpermeability in nephrotic edema.

BACKGROUND/AIM: There is increasing evidence that hypoalbuminemia and the inability of the renal distal tubule to excrete salt are not the only factors responsible for nephrotic edema. We tested the possibility that vascular hyperpermeability also plays a role in the pathophysiology of nephrotic edema in human primary glomerulonephritis. METHODS: We investigated the capillary permeability by means of a standardized test using albumin labelled with technetium (99mTc-albumin) in 20 healthy adults and in 101 nephrotic adult patients comprising 60 patients with idiopathic nephrotic syndrome (INS; minimal-change nephropathy and segmental glomerulosclerosis), 32 with idiopathic membranous nephropathy (IMN) and 9 patients with idiopathic type I membranoproliferative glomerulonephritis (MPGN). The patients and healthy controls were also compared with a group of women (n = 25) with idiopathic cyclic edema, a disease in which an increase in capillary permeability plays a pivotal role. The capillary permeability measured by the Landis isotope test is normal in edematous patients with cardiac and renal impairment unrelated to glomerular disease, cirrhosis, hypothyroidism, lymphatic obstruction and diuretic abuse. As values were not normally distributed, nonparametric analysis of variance was used (Kruskal-Wallis test), and patient groups were compared with healthy controls and with women with idiopathic cyclic edema by means of the two-tailed nonparametric Mann-Whitney test. The effects of high-dose steroids and Ginkgo biloba extract (Tanakan); an agent able to improve capillary permeability) were analyzed by means of the two-tailed nonparametric Wilcoxon test. RESULTS: The capillary permeability was significantly increased (Mann-Whitney test) in each glomerular disease group compared with the healthy controls. 99mTc-albumin extravasation values (%; median and range in parentheses were the following: healthy controls 0 (0-8.4); idiopathic cyclic edema patients 11.5 (8-24), p < 0.001; INS 20 (0-50), p < 0.0001; IMN 12.5 (0-40), p < 0.001, and MPGN 10 (0-40), p < 0.05. An increase in capillary permeability exceeding the upper limit of control values (>8% of 99mTc-albumin extravasation) was observed in 88% of INS, in 53% of IMN and in 44% of MPGN patients. The increase in capillary permeability (%) was greater in idiopathic nephrotic patients than in idiopathic cyclic edema patients (p < 0. 005, Mann-Whitney test) and was markedly reduced in nephrotic patients receiving high-dose steroids (n = 8) [before 25 (8-40); after 0 (0-25), p < 0.005 (Wilcoxon's test)] and high doses of G. biloba extract (n = 16) [before 30 (8-50); after 2.5 (0-20, p < 0. 0005 (Wilcoxon's test)]. CONCLUSIONS: We conclude that capillary permeability is severely altered in most of the nephrotic patients with primary glomerulonephritis. These results strongly suggest that the capillary hyperpermeability plays a role in the pathophysiology of nephrotic edema in primary glomerular disease, especially in INS. We postulate that this widespread abnormality in capillary permeability is related to the release of vascular permeability factor and other cytokines by immune cells.

Imbalances in serum proinflammatory cytokines and their soluble receptors: a putative role in the progression of idiopathic IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis, and a potential target of immunoglobulin therapy?

Following recent experimental data suggesting an aggravating effect of circulating proinflammatory cytokines on the histological lesions of IgAN, we studied changes in serum proinflammatory cytokines and their soluble receptors and antagonists in patients treated with polyvalent immunoglobulins (15 with severe nephropathy who had indicators of poor prognosis: heavy proteinuria, hypertension, altered renal function and Lee's histological grade III or IV; and 14 with moderate forms of IgAN who had permanent albuminuria > 300 mg/day and < 2000 mg/day, Lee's histological grade II and a glomerular filtration rate > 70 ml/min) in comparison with healthy controls (n = 20) and patients with non-IgA nephritides (n = 50). These were measured by means of specific immunometric assays before and after 9 months of immunoglobulin therapy. Total tumour necrosis factor (TNF) serum and IL-6 levels were elevated in IgAN patients before therapy, relative to controls, and normalized after immunoglobulin therapy. Levels of soluble TNF receptor of type I (sR55) and type II (sR75) increased on immunoglobulin therapy. TNF index alpha-55,75 used to assess biologically available TNF-alpha (ratio of total TNF-alpha divided by levels of soluble TNF receptors sR55 and sR75) was elevated before therapy and was below healthy control values after 9 months of immunoglobulin administration. Levels of serum IL-1 receptor antagonist were low prior to immunoglobulin administration in patients with severe forms of IgAN, and normalized on therapy. Serum interferon-gamma was unmodified. The histological activity index correlated with serum total TNF-alpha, TNF index alpha-55,75 and serum IL-6 levels, whereas proteinuria correlated with serum total TNF-alpha and TNF index alpha-55,75 but not with serum IL-6. These data suggest that the overproduction of proinflammatory cytokine is unbalanced by their natural antagonists in IgAN and Henoch-Schönlein syndrome. This process may play a role in the progression of the disease and be one of the targets of immunoglobulin therapy.

Therapy of IgA nephropathy.

IgA nephropathy is the commonest form of glomerulonephritis worldwide, and is one of the major causes of terminal renal failure in most industrialised countries. It is defined by the dominance of IgA mesangial deposits in immunofluorescence studies. Corticosteroid-sensitive nephrosis lipoides (minimal change disease) with IgA deposits and superimposed crescentic glomerulonephritis are to be differentiated from primary IgA nephropathy (Berger's disease). In the latter, clinical manifestations are dominated by synpharyngitic macroscopic haematuria and permanent proteinuria. Terminal renal failure occurs in about 25% of patients after 10 years or more. Heavy proteinuria, hypertension, altered renal function and severe histological lesions at diagnosis are markers of poor prognosis. Primary IgA nephropathy is thought to be related to mesangial deposition of polymeric IgA1-containing immune complexes, owing to altered B cell responses to exogenous and endogenous antigens, together with hyperactivity of T helper type 1 and type 2 cells, both favoured by a genetic background. The 2 compartments of the IgA system (medullary and mucosal) may participate in the pathogenesis of the disease. Modulation of gut-associated lymphoid tissue and immune tonsillectomy are current lines of research. Although impressive results were obtained with an oligoantigenic diet, it is somewhat impractical. Pharmacological modulation of the mucosal immune response seems more promising. There is no proof that phenytoin, a drug which reduces bone marrow IgA synthesis, is beneficial. Emerging data suggest the potential of immune intervention in severely proteinuric patients before sclerotic lesions have occurred, using azathioprine and intravenous immunoglobulins. The benefit of early corticosteroid therapy is still unknown in both adults and children, and the efficiency of alkylating agents is unproven. The search for bacterial foci in primary IgA nephropathy is mandatory, as appropriate treatment may have a protective effect on renal function and help to improve or stabilise some patients. Slowing the progression of renal failure by a combination of ACE inhibitors, fish oil and, possibly, antiplatelet drugs is a promising therapeutic approach.

Role of lipoprotein-bound NEFAs in enhancing the specific activity of plasma CETP in the nephrotic syndrome.

Plasma cholesteryl ester transfer protein (CETP) activity, evaluated by the transfer of radiolabeled cholesteryl esters from a tracer dose of tritiated HDL to the plasma apolipoprotein B-containing lipoproteins, was significantly higher in patients with untreated idiopathic nephrotic syndrome (n = 15) than in normolipidemic control subjects (n = 22) (81.5 +/- 8.4 versus 43.1 +/- 3.1 micrograms CE.mL-1.h-1, respectively; P < .001). The increased CETP activity in nephrotic plasma was explained by a significant rise in both the CETP mass concentration (3.2 +/- 0.2 versus 2.1 +/- 0.1 mg/L; P < .001), and the specific CETP activity, calculated as the ratio of CETP activity to CETP mass (25.3 +/- 1.7 versus 20.4 +/- 1.6 micrograms CE.mg-1.h-1; P < .05). Elevated CETP activity in nephrotic patients was shown to be associated with a significant decrease in the mean size of LDL (24.4 +/- 0.5 versus 26.3 +/- 0.5 nm; P < .0001) as well as in the relative abundance of HDL2a (29.6 +/- 1.6% versus 34.8 +/- 1.1%; P < .05). The nephrotic syndrome was characterized by a significant increase in the relative proportion of lipoprotein-bound nonesterified fatty acids (NEFAs) (35.4 +/- 7.7% versus 7.6 +/- 3.0% of total; P < .01), leading to a significant increase in the electronegative charge of LDL (-4.3 +/- 0.1 versus -3.9 +/- 0.1 mV; P < .05) and HDL (-11.5 +/- 0.1 versus -11.1 +/- 0.2 mV; P < .05). Compared with native, non-supplemented plasma, removal of lipoprotein-bound NEFAs by addition of fatty acid-poor albumin to total plasma from nephrotic patients or control subjects significantly decreased CETP activity and specific CETP activity. Specific CETP activity no longer differed between nephrotic and control groups after albumin supplementation (19.7 +/- 1.5 versus 17.7 +/- 1.5 micrograms CE.mg-1.h-1; NS). It is concluded that, in addition to elevated CETP mass concentration, lipoprotein-bound NEFAs, by increasing the negative electrostatic charge of nephrotic lipoproteins, can facilitate the CETP-mediated neutral-lipid transfer reaction in total plasma from nephrotic patients.

Drug-induced linear IgA disease: target antigens are heterogeneous.

No information is available concerning the target antigen(s) in drug-induced linear IgA disease. The purpose of this study was to define better drug-induced linear IgA disease by studying its immunopathological, immunoultrastructural and immunochemical characteristics in three patients. In the first patient, IgA deposits were seen in the lamina lucida. In the second and the third patients, IgA deposits were seen on each side of the lamina densa. Immunoblotting of the first patient's serum showed that IgA reacted with a protein of 230 kDa similar to the bullous pemphigoid-associated antigen 1 (BPAG 1). The second patient's serum did not react with specific bands. In the third patient IgA antibodies reacted with a protein of 97 kDa on epidermal extracts. Our findings suggest that, as in idiopathic forms, the target antigen is not unique in drug-induced linear IgA disease. In some patients, drug-induced linear IgA disease may represent an IgA class response to the BPAG 1.

A cost analysis of the prevention of end-stage renal disease: immunoglobulin therapy for IgA nephropathy.

A cost analysis was used to evaluate three possible immunoglobulin (IgG) treatment protocols for end-stage renal disease due to IgA nephropathy. The perspective chosen for the cost analysis was that of the health-care delivery system. The baseline strategy was the absence of IgG treatment, and alternative strategies corresponded to three protocols presently on trial: all three included a high initial dose of intravenous IgG. Protocol 1 followed with intramuscular IgG injections only, protocol 2 with intramuscular plus intravenous injections, and protocol 3 with intravenous injections only. The costs of treatment included the costs of immunoglobulins, outpatient hospital costs, and the costs of tests; the saving (costs averted) resulted from kidney dialysis averted. The bottom line for the health-care system is a net savings of $233,000, $213,000, or $83,000, depending on the protocol chosen. The computation of costs did not value physical and psychological health benefits. Thus, any subjective benefit, such as improved comfort, or objective benefit, such as longer life expectancy, would be an improvement over the results presented here.

Type I membranoproliferative glomerulonephritis and HCV infection.

Type I membrano-proliferative glomerulonephritis (MPGN) is secondary to chronic bacterial, parasitic, viral (HB) infections, to autoimmune disorders or primary or malignant haemopathies. MPGN are thought to be linked to the deposition of immune complexes preformed in the circulation or formed in situ in the glomeruli. A link between HCV and type I MPGN was reported for the first time in 1993. In some patients, the renal clinical pattern is the most obvious (nephrotic syndrome) whereas in others liver disease or cryoglobulinaemia prevail. A risk factor of HCV infection exists in 80% of cases. Renal biopsy and scanning electron microscopy usually substantiate cryoglobulinaemia. Circulating cryoglobulins are most often detected, usually of type II. CH50 is decreased in 90% of patients and rheumatoid factors have been found in two-thirds of patients. The cryoprecipitate contains viral RNA and anti-HCV antibodies. The viral RNA is nearly always found in the cryoprecipitate. Analysing the viral genotype does not elicit predominance of any particular type. Viral genome detection in renal biopsy specimens appears to be technically difficult. Type I MPGN secondary to HCV infection appear to be improved by interferon-alpha therapy but treatment suspension is immediately followed by the recurrence of viraemia and nephrotic syndrome. Serological tests to detect anti-HCV antibodies and viral RNA by PCR in type I MPGN, so far considered as 'primary', are scarce and produce conflicting results: there might be a link between those glomerulopathies and HCV infection in the USA and in Japan only, not in Europe.

Further identification of human plasma glycoproteins interacting with the galactose-specific lectin Jacalin.

In this report we show that Jacalin binds the heme-binding protein hemopexin and the C4b-binding protein sgp120 in human plasma. The interaction of Jacalin with hemopexin confirms that a single O-linked oligosaccharide is sufficient to mediate binding of a protein to this lectin. Retention of sgp120 by immobilized Jacalin demonstrated that this protein was O-glycosylated and, therefore, clearly different from another C4b-binding protein, the complement protein C2 which is physicochemically similar but exclusively N-glycosylated. In addition, Jacalin was also shown to bind several proteolytic enzymes which remain to be identified.