Thiol-inducing and immunoregulatory effects of flavonoids in peripheral blood mononuclear cells from patients with end-stage diabetic nephropathy.

The cellular thiol status and its relationship to T-cell activation and cytokine synthesis of mononuclear cells was investigated in patients with end-stage diabetic nephropathy (ESDN) undergoing dialysis treatment. The functional effects of thiol repair by in vitro and in vivo treatment with flavonoids were elucidated. The thiol status of peripheral blood lymphocytes from 30 ESDN patients on hemodialysis and healthy controls was determined by flow cytometry. T-cell activation in response to pokeweed mitogen was analyzed by CD69 expression; cytokines were determined in cell culture supernatants. In result, compared to age-matched healthy subjects, a significant thiol deficiency in ESDN patients was obvious. The lowered total intracellular thiol levels correlated directly to a significant diminished T-cell activation and an elevated synthesis of TNF-alpha in the patient group. The treatment with flavonoids led to a restoration of the thiol status within 72 h in vitro and in vivo. This effect showed a biphasic kinetic that first utilized cell surface thiols and secondly intracellular thiols. In parallel, the T-cell activation was improved substantially along with a significant decrease in TNF-alpha release. These data provide the rational for clinical trials using flavonoids in ESDN to normalize immunoregulatory defects via restoration of the cellular thiol status.

Ambulatory treatment with intravenous norepinephrine in a patient with end stage renal disease and generalized AA amyloidosis.

A 35-year-old man with juvenile rheumatoid arthritis and generalized AA amyloidosis of 10 years duration developed end stage renal failure. Following appendectomy, the patient experienced progressive circulatory failure which required IV treatment with norepinephrine. All attempts to discontinue IV norepinephrine failed, each leading to recurrent life-threatening hypotension. Finally, a central venous port with a portable mechanical infusion pump system was implanted supplying a continuous norepinephrine infusion. The patient then became independently mobile and could be discharged. For three months, the patient was monitored as an outpatient and treated by ambulatory intermittent hemofiltration. Finally, the patient suffered from a hemorrhagic infarction of the small bowel due to postoperative adhesions and died shortly after surgery. At autopsy, advanced generalized AA amyloidosis was found. Amyloid deposits had almost entirely replaced the cortex and the medulla of the adrenal glands. It can be speculated that the requirement of exogenous norepinephrine may be in part due to an adrenal insufficiency whereas it was initially considered as being only related to cardiac involvement. A continuous ambulatory treatment with catecholamines could be a possible treatment - at least temporarily - in amyloid cases in which all other attempts have failed to prevent chronic life-threatening hypotension.

Monthly administration of a continuous erythropoietin receptor activator provides efficient haemoglobin control in non-dialysis patients during routine clinical practice: results from the non-interventional, single-cohort, multicentre, SUPRA study.

BACKGROUND: The continuous erythropoietin receptor activator (C.E.R.A.) has a long half-life, a relatively low binding affinity for the erythropoiesis receptor and low systemic clearance. These characteristics permit once-monthly dosing, which could reduce staffing requirements and be advantageous for patients. However, outcomes observed during controlled trials of C.E.R.A. have not been assessed under everyday clinical conditions in which physicians make all therapeutic decisions based on their own experience, rather than according to a pre-defined protocol. OBJECTIVE: This study aimed to assess whether the efficacy and safety of C.E.R.A. reported during controlled trials are reproducible under routine clinical conditions. METHODS: This was a non-interventional, single-cohort, multicentre study carried out in 92 specialist nephrology clinics and private practices in Germany. The study included patients with non-dialysis chronic kidney disease and anaemia, with or without current erythropoiesis stimulating agent (ESA) therapy. C.E.R.A. initiation and dosing was at the discretion of the physician. The primary efficacy variable was the proportion of patients for whom all measured haemoglobin (Hb) values during months 7-9 were within the range 11-12 g/dL ('responders'). RESULTS: 335 patients received ≥1 dose of C.E.R.A.; 150 had previously received ESA therapy. The mean number of doses was 7.6 per patient over a mean follow-up of 7.9 months. Mean ± SD Hb was 10.7 ± 1.1 g/dL at baseline and 11.3 ± 1.1 g/dL at the final visit (efficacy population, n = 205). The primary endpoint, all measured Hb values during months 7-9 within the range 11-12 g/dL, was achieved by 19.0% (39/205) of patients, increasing to 41.5% for Hb 11-13 g/dL, 42.0% for 10-12 g/dL and 76.6% for Hb ≥10 g/dL. Hb fluctuation during months 7-9 was ≤1 g/dL in 185/205 patients (90.2%). C.E.R.A. was well tolerated without novel safety concerns. CONCLUSION: Hb levels remained stable during routine use of C.E.R.A. in an unselected population of non-dialysis chronic kidney disease patients with anaemia. C.E.R.A. was administered approximately monthly compared with 3-7 doses per month on previous ESA therapy.