IgA nephropathy (IgAN) is characterised by the mesangial deposition of polymeric IgA1 (pIgA1). pIgA1 production is reduced in the mucosal immune system in IgAN and increased in the marrow; this ...switch may be secondary to a defect in gammadeltaT cell control of IgA production. However this does not explain the mechanism by which pIgA1 deposits in the mesangium. There is no direct evidence that classical immune complex deposition occurs in IgAN and alternative mechanisms resulting from physicochemical abnormalities of the IgA1 molecule, particular altered glycosylation, have been proposed. IgA1 has a distinctive hinge region which is a site for O-glycosylation. There is reduced terminal galactose on the hinge region O-glycans of circulating IgA1 in IgAN, perhaps due to a defect in B cell beta1,3 galactosyltransferase. A concomitant O-glycan defect in mesangial IgA1 has not yet been proven. Altered hinge O-glycosylation may have substantial impact on the quaternary structure of the IgA1 molecule influencing its capacity to interact with matrix proteins, IgA receptors on mesangial cells and leucocytes, and complement; it may therefore play a key role in the pathogenesis of mesangial deposition of IgA1 and subsequent glomerular injury in IgAN.
Sexual dysfunction remains a common and often distressing problem in the male dialysis population. Traditionally its management has consisted of correction of anemia, optimization of dialysis, ...removal of implicated medication, and finally depot injections of a testosterone ester. At a dedicated renal impotence clinic, we studied the effectiveness of testosterone replacement in men with biochemically proven hypogonadism and then vacuum tumescence therapy in those with continued erectile dysfunction. Depot testosterone was given to 27 patients (aged 52.4+/-2.5 years; duration of dialysis, 2.00+/-0.40 years; and duration of sexual dysfunction, 2.92+/-0.49 years): sexual function was fully restored in only three (11.1%), and two gradually lost the response over 18 months. Nineteen patients (70.3%) had partial responses, varying from an increased sense of well-being alone to restored sexual function apart from an impairment of the duration of penile erection. Five patients (18.5%) had no response, and testosterone was contraindicated in another four. Four of the treated patients (14.8%) reported fluid retention. Vacuum tumescence devices were then offered to 32 patients who remained impotent but declined by six. Twenty-six patients (aged 49.6+/-2.2 years; duration of dialysis, 2.50+/-0.58 years; and duration of sexual dysfunction, 3.26+/-0.56 years) used the devices, with 19 (73.1%) having full correction of their erectile dysfunction; six also continued with depot testosterone to maintain their libido. Penile discomfort was described by five patients (19.2%) whose potency was not restored. A further five predialysis patients have used the devices, and all had correction of their erectile dysfunction. The correction of biochemical hypogonadism in the male dialysis population with testosterone rarely restores sexual function to normal, whereas vacuum tumescence therapy corrects penile erection dysfunction in most patients. (Am J Kidney Dis 1998 Feb;31(2):313-9)
A physician with endocarditis Feehally, J.
The Lancet (British edition),
07/1995, Letnik:
346, Številka:
8968
Journal Article
Recenzirano
Feehally, a physician, discovered what it was like to be a patient when he was diagnosed with endocarditis. He discovered that there are many aspects of his life that he will never again take for ...granted.
IgA nephropathy (IgAN) is characterized by the mesangial deposition of polymeric IgA1 (pIgA1). The original view that this pIgA1 is derived from the mucosal immune system can no longer be sustained. ...Studies of duodenal mucosa and marrow indicate increased production of pIgA1 in the marrow and decreased production in the mucosa. These changes are consistent with immunization studies showing exaggerated and prolonged pIgA responses to systemic immunization, and reduced mucosal responses to mucosal neoantigens. However, the IgA1 and IgG systemic responses to mucosal antigen are increased in IgAN, a finding consistent with impairment in oral tolerance, the process by which systemic immune responses to mucosal antigen challenge are normally suppressed. Both IgA1 production and the induction of oral tolerance are under T‐cell control. T‐cell populations involved in these processes include γδ T cells, Tr cells and T‐helper (Th)3 cells; cytokines with a key role in the control of IgA production include interleukin (IL)‐10 and transforming growth factor (TGF)‐β. There is evidence of abnormal γδ T‐cell V region usage in both mucosa and marrow in IgAN. Increased expression of relevant cytokines has also been reported in circulating T cells in IgAN. The increased O‐glycosylation of circulating IgA1 in IgAN may also be further evidence of a shift in the production of mucosal‐type pIgA1 from the mucosa to marrow. These findings suggest that the specific lymphocyte homing mechanisms that normally maintain oral tolerance and control the site of IgA production require further study in IgAN.
Turnover of human tubular cells exposed to proteins in vivo and in vitro.
The cause of tubulointerstitial pathology in glomerular disease is uncertain. Proteinuria may be a causative factor and has ...been shown to increase the turnover of tubular cells in a rat model of proteinuria. We investigated whether increased tubular cell proliferation occurs in human proteinuric renal disease. A human cell culture model was used to investigate the effects of proteins on tubular cell turnover further.
Tubular proliferation in renal biopsies from patients with membranous nephropathy (MN) and minimal change nephropathy (MCN) was assessed by in situ hybridization for histone mRNA. Proliferation was measured in polarized human tubular cell cultures using tritiated thymidine, following addition of proteins to the apical medium. Toxicity was assessed by lactate dehydrogenase (LDH) release and monolayer permeability to inulin.
Increased tubular cell histone mRNA expression occurred in biopsies in MN (3.0-fold increase, P < 0.002) and MCN (3.6-fold increase, P < 0.02). Serum proteins added to the medium on human tubular cell cultures increased thymidine uptake (1.3-fold, P < 0.005), LDH release (1.5-fold, P < 0.001), and monolayer permeability (1.7-fold, P < 0.005). The effects were reproduced by a fraction of molecular weight 40 to 100 kD, but not by pure albumin or transferrin.
Proliferation of tubular cells is associated with proteinuria in vivo and is caused by proteins in cell culture. Toxicity of proteins to tubular cells and increased cell turnover may contribute to tubulointerstitial pathology in glomerular disease.
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