Marc Bauwens

Glycaemic control in type 2 diabetic patients on chronic haemodialysis: use of a continuous glucose monitoring system

BACKGROUND The proportion of diabetic patients undergoing haemodialysis is rapidly increasing. Glucose control among such patients is difficult to assess. We aimed to evaluate the clinical performance of a continuous glucose monitoring system (CGMS) in type 2 diabetic patients on chronic haemodialysis. METHODS We used a 4-day CGMS to monitor glucose levels in 19 haemodialysed type 2 diabetic patients (HD T2) including 2 days with and 2 days without dialysis session, and 39 non-HD T2 in a double-centre study. RESULTS The glucose concentration according to the glucose meter and CGMS were correlated in HD T2 patients (r = 0.90, P < 0.0001) and in non-HD T2 patients (r = 0.81, P < 0.0001). The relative absolute difference (RAD) between glucose determined by a glucose meter and glucose determined by the CGMS did not differ between HD T2 and non-HD T2 patients (9.2 +/- 10.5 vs. 8.2 +/- 7.6%; P = 0.165). Glycated haemoglobin (A1c) and mean glucose concentration were strongly correlated in non-HD T2 patients (r = 0.71; P < 0.0001) but weakly correlated in HD T2 patients (r = 0.47; P = 0.042). Fructosamine was correlated with the mean glucose concentration in non-HD T2 (r = 0.67; P < 0.0001) but not in HD T2 patients (r = 0.04; P = 0.88). CONCLUSION CGM is a validated marker of glycaemic control in HD diabetic patients. This tool showed that A1c and fructosamine, despite being good markers of glycaemic control in non-HD diabetic patients, are of poor value in HD diabetic patients.

Acute immuno-allergic interstitial nephritis caused by fluindione.

Fluindione is a vitamin K antagonist that is commonly prescribed for the treatment of cardiovascular disease and venous thromboembolism in France. Bleeding is the most common side effect of fluindione, whereas hypersensitivity reactions are rare. We describe here a patient with acute immuno-allergic interstitial nephritis caused by fluindione. Initial symptoms included fever, eosinophilia, low albuminuria, microscopic hematuria, eosinophiluria and acute renal failure. Kidney biopsy showed severe interstitial nephritis with interstitial edema, inflammatory infiltrates and tubulorrhexis. Fluindione withdrawal and corticosteroid treatment resulted in rapid recovery of renal function. A review of the literature revealed a very low incidence of fluindione-induced interstitial nephritis, with variable renal and extra-renal signs. Early recognition of this rare complication may prevent the development of severe chronic renal injury.

Cyclosporin Maintenance Monotherapy After Renal Transplantation

The use of cyclosporin monotherapy as maintenance immunosuppression in primary cadaveric renal transplant recipients is not popular except in a few European centres. Corticosteroid withdrawal is becoming more popular, and is usually attempted with the newer immunosuppressants which have a more corticosteroid-sparing effect than cyclosporin. The adverse effects and morbidity associated with maintenance regimens consisting of 2 or 3 immunosuppressive drugs are well known, but the potential benefits of cyclosporin monotherapy must be balanced against an increased risk of graft loss by rejection.We selected patients for a trial of corticosteroid withdrawal and subsequent cyclosporin monotherapy. These patients received an individually designed immunosuppressive regimen with careful control of cyclosporin trough concentrations. The cyclosporin formulations used were its original oil-based solution or gelatin capsule (Sandimmun®, Sandimmune®) until mid-1996 and then the microemulsion formulation (Neoral®).Corticosteroid withdrawal was attempted in 89% of patients with a graft functioning at 3 months after transplantation and was effective in 88% of them. At a mean follow-up time of 98 ± 23 months, 69% of grafts were functioning and 92% of patients were alive. 50% of patients with a functioning graft were receiving long term cyclosporin monotherapy. Mild rejection episodes occurred in 6% of patients receiving cyclosporin monotherapy per year of treatment, and chronic rejection caused graft loss in 1.4% of patients per year of treatment.Comparison of successful and unsuccessful outcomes allows us to define favourable predictive factors. For corticosteroid withdrawal these are: older recipient age, lower creatininaemia at months 6 and 8 and higher trough cyclosporin concentrations at month 6. For cyclosporin monotherapy these are: later timing of azathioprine withdrawal, recipient age >25 years, donor age ≤40 years, creatininaemia ≤125 μmol/L at initiation of monotherapy and no rejection episode before initiation of monotherapy.We have observed a low incidence of nonmelanoma skin cancers and of squamous-cell carcinoma in our series. This is perhaps the result of the azathioprinesparing effects of the regimen (7 azathioprine-free years per patient with successful cyclosporin monotherapy, and 4 azathioprine-free years per patient with unsuccessful monotherapy). This important point will need further studies but is encouraging.Maintenance cyclosporin monotherapy is feasible and probably useful in selected primary graft recipients without deleterious effects on overall results in terms of graft and patient survival. Careful patient selection using the predictive factors we have defined should make cyclosporin monotherapy more effective, allowing the present 57% success rate at 5 years post-transplantation to be increased by 15 or 20%.

Comparison of hemodialysis with medium cut-off dialyzer and on-line hemodiafiltration on the removal of small and middle-sized molecules

BACKGROUND Recent data suggest that the use of medium cut-off (MCO) dialyzers in hemodialysis (HD) promotes greater clearance and reduction ratio (RR) for myoglobin and other large-sized molecules than on-line hemodiafiltration (ol-HDF), but its effects on β2-microglobulin are not clear. We compared RR and clearances of small and middle-sized molecules between high-flux ol-HDF and MCO (Theranova) dialyzer in HD (MCO-HD) as well as nutritional parameters. MATERIALS AND METHODS We retrospectively analyzed 10 patients treated first with ol-HDF who were thereafter switched to MCO-HD over a 1-year period. Three dialysis sessions in each 6-month period were examined. We calculated RR and clearance of small and middle-sized molecules. RESULTS There was no significant difference between ol-HDF and MCO-HD for median serum albumin and prealbumin level, mean KT/V, mean urea and creatinine RR, mean β2-microglobulin (81 ± 5 vs. 81 ± 6%, p = 0.72) and myoglobin (60 ± 9% vs. 61 ± 7%, p = 0.59), RR or clearances. CONCLUSION The use of MCO (Theranova) dialyzer in HD produces similar removal of urea, creatinine, β2-microglobulin and myoglobin as does ol-HDF, with good tolerance profile and without modification of nutritional status.
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Cinacalcet in HIV haemodialysis patients

Sir, Cinacalcet HCL (MIMPARA®), a positive allosteric modulator of the calcium-sensing receptor (CaR) on the surface of the parathyroid glands, reduces serum parathyroid hormone (PTH) levels in more than 80% of haemodialysis (HD) patients [1]. The efficacy and safety of cinacalcet has been demonstrated in several studies [1,2], but its use in HIV patients on chronic dialysis is not described. We report two HD patients with HIV infection treated simultaneously with anti-retroviral therapy and cinacalcet. A 24-year-old black woman was admitted in July 2002 for end-stage renal disease (ESRD) of unknown origin that required chronic HD. Simultaneously, HIV-1 infection was diagnosed. A tritherapy with efavirenz 600 mg, lamivudine 25 mg and didanosine 100 mg per day was initiated in January 2004, resulting in sustained undetectable HIV plasma viral load and stable T4 levels (>550/mm3). Cinacalcet was started in May 2007 at 30 mg/day and progressively increased to 90 mg without any efficacy (intact parathyroid hormone (iPTH) > 1000 pg/ml). In December 2007, cinacalcet was stopped and a parathyroidectomy was performed. Histological examination revealed a bilateral parathyroid adenoma. Efavirenz residual serum concentration after surgery and cinacalcet withdrawal was 1.5 μg/ml (normal range: 1.1–4 μg/ml). A 45-year-old Caucasian man was treated by chronic HD for ESRD of unknown aetiology since July 2003. HIV-1 and hepatitis B virus (HBV) co-infection was discovered at the time of dialysis initiation. A combination of efavirenz 600 mg, lamivudine 50 mg, didanosine 125 mg per day and tenofovir 245 mg per week resulted in undetectable HBV and HIV plasma viral load with sustained stable T4 levels (>600/mm3). Because of high serum iPTH (>1000 pg/ml), cinacalcet was initiated in May 2007 at 30 mg per day and further increased to 120 mg in November 2007 without efficacy. Efavirenz mean residual serum concentration on three consecutive measurements under cinacalcet therapy (120 mg) was 1.3 ± 0.5 (SD) μg/ml. The two patients received concomitant treatment with sevelamer, calcium carbonate and vitamin D3 during cinacalcet therapy. In both the cases, tolerance of cinacalcet and anti-retroviral treatment was good. Monthly monitoring of pancreatic and liver enzymes and serum calcium levels was not modified. Analysis of the literature shows that more than 80% of HD patients on cinacalcet therapy achieve an ≥30% reduction in iPTH level from the baseline over 6 months [1]. In our cases, whereas cinacalcet was administered for more than 6 months, no effect on iPTH was observed despite increased cinacalcet dosage. Little is known about the pathophysiology of resistance to cinacalcet. A role for non-compliance to the drug was excluded in both the cases. Defective sensitivity of the parathyroid cell to the calcimimetic drug has been proposed. Additionally, a relative resistance to cinacalcet was demonstrated in the case of severe decreased expression of CaR in parathyroid glands [3]. In our cases, resistance to cinacalcet was likely the result of drug interaction. Cinacalcet is metabolized through cytochrome P450 (CYP) isoenzymes 3A4, 2D6 and 1A2. In vitro studies have demonstrated that cinacalcet is a potent inhibitor of CYP2D6. Additionally, data suggest that during concomitant treatment with cinacalcet, dose adjustment may be necessary for CYP3A4 and CYP1A2 inductors or inhibitors [4]. As the metabolism of lamivudine, didanosine and tenofovir do not involve CYP450, the culprit drug seems to be efavirenz. Efavirenz is metabolized via CYP450, particularly by 3A4 and 2B6 isoenzymes. Although efavirenz is an in vitro inhibitor for 2C9, 2C19, 3A4, 2D6 and 1A2 isoenzymes, it has been demonstrated in humans that efavirenz can be inductor for CYP450 enzymes and can also induce its own metabolism by this mechanism [5,6]. This enzymatic induction, especially for CYP3A4 isoenzyme, is probably responsible for most drug interactions with efavirenz. Despite the absence of a known pharmakokinetics interaction between cinacalcet and efavirenz, enzymatic induction of CYP3A4 metabolism by efavirenz is probably responsible for therapeutic failure of cinacalcet in the present cases. Unfortunately, this hypothesis could not be verified, as the measurement of the serum cinacalcet level is not currently available. However, a role for decreased numbers of CaR or defective sensitivity of parathyroid cells cannot be excluded. In summary, cinacalcet in HD patients with chronic HIV infection treated by efavirenz seems inappropriate. Nephrologists need to be aware of this rare potential interaction. Surgical parathyroidectomy should be recommended. Conflict of interest statement. None declared. The results presented in this paper have not been published previously in whole or part, except in abstract format.

Glomerulonephritis with organized immunoglobulin deposits: fibrillar and microtubular deposits are associated with distinct immunological features

Non-amyloid glomerulopathies characterized by Congo-red negative organized immunoglobulin (Ig) deposits display two characteristic patterns by electron microscopy (EM); either randomly arranged (pseudo-amyloid) fiibrils or microtubules usually larger and ordered in parallel arrays 1–23. It is currently unclear whether this morphological distinction is relevant. Certain investigators consider that such a distinction is of no clinical or pathophysiological basis, and propose that fiibrillar and microtubular Ig deposits are merely variants of the same glomerulopathy, referred to as fiibrillary-immunotactoid GN3,1 5,1 g,2o They also advocate that this diagnosis should be limited to patients with primary renal disorders, thus excluding patients with monoclonal gammopathy, systemic diseases or lymphoproliferative disorders3,7. Others suggest that distinguishing immunotactoid (IT) GN and FGN is critical 10,12–14,19 In immunotactoid GN, defiined by the presence of orderly arranged microtubules usually more than 30 nm in width, glomerular Ig are often monotypic. Immunotactoid GN may be associated with monoclonal gammopathy and/or hematological malignancy with improved renal prognosis after chemotherapy6,10,13,14 On the contrary, in FGN the diameter of fiibrils is less than 30 nm and these patients present without underlying hematological disease5,8,12,13,22,23 Moreover, a predominance of polyclonal IgG4 in glomerular deposits has been reported in FGN 12,16,23, but not in immunotactoid GN3,6,14.

Serum monoclonal immunoglobulins in renal transplant recipients: A study using high resolution electrophoresis and western blotting

Transplant patients are prone to develop B cell lymphomas with a frequency increased by “high-dose” immunosuppressive regimens. Some studies suggest that transplant patients should be carefully screened to detect the occurrence of serum monoclonal immunoglobulins (moIg) which could be the first step of a patent immunoproliferative disorder.