Antibody mediated rejection associated with complement factor h-related protein 3/1 deficiency successfully treated with eculizumab.

Antibody mediated rejection (AMR) activates the classical complement pathway and can be detrimental to graft survival. AMR can be accompanied by thrombotic microangiopathy (TMA). Eculizumab, a monoclonal C5 antibody prevents induction of the terminal complement cascade (TCC) and has recently emerged as a therapeutic option for AMR. We present a highly sensitized 13-year-old female with end-stage kidney disease secondary to spina bifida-associated reflux nephropathy, who developed severe steroid-, ATG- and plasmapheresis-resistant AMR with TMA 1 week post second kidney transplant despite previous desensitization therapy with immunoglobulin infusions. Eculizumab rescue therapy resulted in a dramatic improvement in biochemical (C3; creatinine) and hematological (platelets) parameters within 6 days. The patient was proven to be deficient in complement Factor H-related protein 3/1 (CFHR3/1), a plasma protein that regulates the complement cascade at the level of C5 conversion and has been involved in the pathogenesis of atypical hemolytic uremic syndrome caused by CFH autoantibodies (DEAP-HUS). CFHR1 deficiency may have worsened the severe clinical progression of AMR and possibly contributed to the development of donor-specific antibodies. Thus, screening for CFHR3/1 deficiency should be considered in patients with severe AMR associated with TMA.

Deletion of p47phox attenuates the progression of diabetic nephropathy and reduces the severity of diabetes in the Akita mouse.

AIMS/HYPOTHESIS: Reactive oxygen species (ROS) contribute to diabetes-induced glomerular injury and endoplasmic reticulum (ER) stress-induced beta cell dysfunction, but the source of ROS has not been fully elucidated. Our aim was to determine whether p47(phox)-dependent activation of NADPH oxidase is responsible for hyperglycaemia-induced glomerular injury in the Akita mouse, a model of type 1 diabetes mellitus resulting from ER stress-induced beta cell dysfunction. METHODS: We examined the effect of deleting p47 (phox) (also known as Ncf1), the gene for the NADPH oxidase subunit, on diabetic nephropathy in the Akita mouse (Ins2 (WT/C96Y)) by studying four groups of mice: (1) non-diabetic mice (Ins2 (WT/WT)/p47 (phox+/+)); (2) non-diabetic p47 (phox)-null mice (Ins2 (WT/WT)/p47 (phox-/-)); (3) diabetic mice: (Ins2 (WT/C96Y)/p47 (phox+/+)); and (4) diabetic p47 (phox)-null mice (Ins2 (WT/C96Y)/p47 (phox-/-)). We measured the urinary albumin excretion rate, oxidative stress, mesangial matrix expansion, and plasma and pancreatic insulin concentrations in 16-week-old mice; we also measured glucose tolerance and insulin sensitivity, islet and glomerular NADPH oxidase activity and subunit expression, and pro-fibrotic gene expression in 8-week-old mice. In addition, we measured NADPH oxidase activity, subunit expression and pro-fibrotic gene expression in high glucose-treated murine mesangial cells. RESULTS: Deletion of p47 (phox) reduced kidney hypertrophy, oxidative stress and mesangial matrix expansion, and also reduced hyperglycaemia by increasing pancreatic and circulating insulin concentrations. p47 (phox-/-) mice exhibited improved glucose tolerance, but modestly decreased insulin sensitivity. Deletion of p47 (phox) attenuated high glucose-induced activation of NADPH oxidase and pro-fibrotic gene expression in glomeruli and mesangial cells. CONCLUSIONS/INTERPRETATION: Deletion of p47 (phox) attenuates diabetes-induced glomerular injury and beta cell dysfunction in the Akita mouse.

Our approach to a renal transplant biopsy.

Kidney transplantation has become increasingly common in major health centres, making renal allograft evaluation through biopsy a common procedure. Early allograft dysfunction occurs in 30-50% of all transplants, while chronic graft failure is almost uniform at a rate of 2-4% a year. Allograft biopsy remains the gold standard for the diagnosis of graft dysfunction. Rejection, albeit the most important, is only one of many causes of allograft dysfunction. The widely accepted Banff classification has set criteria for the diagnosis of acute and chronic rejection. The major differential diagnoses are acute ischaemic injury, calcineurin inhibitor toxicity (acute and chronic), infections, including pyelonephritis and polyomavirus nephropathy, chronic obstruction/reflux, hypertension, and recurrent and de novo disease. In this review, there is an outline of the Banff criteria and their implications, the various causes of graft dysfunction, and a discussion on morphological guidelines towards the various diagnoses.

Renal toxicity of therapeutic drugs.

A number of therapeutic agents can adversely affect the kidney, resulting in tubulointerstitial, glomerular or vascular disease. Drug-induced tubulointerstitial nephritis and acute tubular necrosis are common, and are often cause by antibiotics or non-steroidal anti-inflammatory drugs. Drug-induced glomerular and vascular disease is relatively rare. This review describes the morphological patterns of drug-induced disease in the kidney. The histopathological changes are often similar to disease that is idiopathic or due to other causes, so that awareness and clinical correlation are most helpful to arrive at the aetiology.

Rituximab treatment of idiopathic membranous nephropathy.

Idiopathic membranous nephropathy is a common cause of nephrotic syndrome whose pathogenesis may involve B-cell functions. Rituximab is a monoclonal antibody that binds to the CD20 antigen on B cells thereby deleting them. We conducted an open-label pilot trial of rituximab treatment in 15 severely nephrotic patients with proteinuria refractory to angiotensin-converting enzyme inhibition and/or receptor blockade but with adequately controlled blood pressure. Rituximab was given 2 weeks apart and, at 6 months, patients who remained proteinuric but had recovered B-cell counts were given a second course of treatment. Proteinuria was significantly decreased by about half at 12 months. Of the 14 patients who completed follow-up, full remission was achieved in two and partial remission in six patients based upon the degree of proteinuria. Side effects were minor; however, we found no relationship between the response and number of B cells in the blood, CD20 cells in the kidney biopsy, degree of tubulointerstitial fibrosis, starting proteinuria or creatinine values. Rituximab appears effective in reducing proteinuria in some patients with idiopathic membranous nephropathy but prospective identification of responsive patients was not possible.

Distinguishing diabetic nephropathy from other causes of glomerulosclerosis: an update.

Diabetic nephropathy is a common cause of end-stage renal disease worldwide. It is characterised by diffuse or nodular glomerulosclerosis, afferent and efferent hyaline arteriolosclerosis, and tubulointerstitial fibrosis and atrophy. Diffuse and nodular diabetic glomerulosclerosis share similar histological features with other clinical conditions. Immunofluorescence and electron microscopy studies, and clinicopathological correlation are essential to differentiate diabetic nephropathy from other conditions that result in diffuse and nodular glomerulosclerosis.

Renal pathology in idiopathic membranous nephropathy: a new perspective.

Histology findings in idiopathic membranous nephropathy (MGN) have been associated with the risk of renal failure, but whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy is uncertain. Renal biopsies of 389 adult MGN patients were evaluated semiquantitatively for interstitial fibrosis, tubular atrophy, vascular sclerosis, focal and segmental glomerulosclerosis lesions (FSGS), complement deposition, and stage and synchrony of deposits by electron microscopy (EM). Associations were tested between these findings and the rate of renal function decline (slope), renal survival, remission in proteinuria, and response to immunosuppression. Patients with a greater degree of tubulo-interstitial disease, vascular sclerosis, and secondary FSGS were older, had a higher mean arterial pressure, and a lower creatinine clearance at presentation. Although these histologic features were associated with a reduced renal survival, they did not predict this outcome independently of the baseline clinical variables nor did they correlate with the rate of decline in function or with baseline proteinuria. Furthermore, the severity of tubulo-interstitial and vascular lesions did not preclude a remission in proteinuria in those who received immunosuppressive therapy. Neither stage nor synchronicity of EM deposits nor the amount of complement deposition predicted renal survival but the latter did correlate with progression rate. In MGN, certain histologic changes are associated with renal survival outcome. However, the indicators of chronic injury are associated with age, blood pressure, and creatinine clearance at presentation and not with rate of disease progression or initial proteinuria.

Heavy chain deposition disease: recurrence in a renal transplant and report of IgG(2) subtype.

Heavy chain deposition disease (HCDD) is a rare entity characterized by tissue deposition of monoclonal heavy chains without light chains. Previous reports of HCDD include gamma(1)-, gamma(3)-, gamma(4)-, and alpha-heavy chain subtypes. Renal transplantation for HCDD has not been previously reported. We report a case of gamma(2)-HCDD in a 67-year-old patient who presented with proteinuria, hematuria, and renal insufficiency and progressed to end-stage renal failure after 6 months. The second case involves a 26-year-old woman who had a renal transplant for HCDD and recurrent gamma(1)-HCDD in the transplant. Neither patient had myeloma. The complete spectrum of gamma-HCDD subtypes has now been reported. Further data are required to make conclusive statements about the true recurrence rate of HCDD in renal transplants.

Idiopathic nodular glomerulosclerosis.

Idiopathic nodular glomerulosclerosis is an unusual entity with light microscopic and ultrastructural features similar to those of nodular diabetic glomerulosclerosis but without evidence of abnormal glucose metabolism. We report 2 patients whose renal biopsies showed nodular glomerulosclerosis with afferent and efferent arteriolosclerosis, glomerular basement membrane thickening, focal mesangiolysis and capillary microaneurysm formation, and who had no evidence of abnormal glucose metabolism or other features of diabetes mellitus. Review of the literature shows that, of the 27 reported cases of idiopathic nodular glomerulosclerosis (not including the 2 cases reported herein), 11 showed evidence of abnormal glucose metabolism or were frankly diabetic. Of the remaining 16 cases with normal serum blood glucose measurements, 3 had diabetic retinopathy and 1 had a delayed insulin response curve. The cause and pathogenesis of the glomerular nodules are discussed, and it is suggested that arteriolar stenosis and glomerular ischemia may be involved in the development these lesions.

Thrombotic microangiopathy associated with cryoglobulinemic membranoproliferative glomerulonephritis and hepatitis C.

Cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) and increased incidence of vascular thromboses are complications of hepatitis C virus (HCV) infection. This report describes the clinical, laboratory, and renal biopsy findings in two HCV-positive patients with cryoglobulinemic MPGN and thrombotic microangiopathy (TMA). Testing for circulating antiphospholipid antibodies, which are detected in a significant proportion of patients with HCV, was negative in the one case in which it was done. This article discusses the possible cause of the TMA in these two cases.

Monoclonal heavy chain (immunoglobulin G3) deposition disease: report of a case.

Seven cases of nonamyloid heavy chain (gamma chain) deposition disease have been previously reported. We describe one case of a 79-year-old woman presenting with proteinuria and microscopic hematuria whose renal biopsy showed nodular glomerulosclerosis with deposition of gamma3 heavy chains and complement in the glomeruli and tubular basement membranes with no associated light chain deposition. The patient did not have multiple myeloma. This case is unique in that in all previously reported cases of heavy chain deposition disease the gamma chain subtype has been either gamma1 or gamma4.

Monoclonal antibodies raised against coccidia and malarial parasites recognize antigenic epitopes found in lankesterellid and adeleorin parasites.

Three murine monoclonal antibodies (MAbs) raised against poultry coccidia or murine malarial parasites were tested for cross-reactivity with 2 sporozoan parasites with different life histories and hosts: Lankesterella minima (Eimeriorina), an intraerythrocytic parasite of frogs that is transmitted by leeches; and Heptazoon catesbianae (Adeleinorina) that infects the red blood cells of frogs and is transmitted by mosquitoes. MAb 1209 recognized both refractile bodies of sporozoites of L. minima, using the indirect fluorescent antibody (IFA) technique and immunoelectron microscopy, and recognized antigens with relative rates of migration (M(r)) of 17, 23, 26, 43, and 48 kDa on a chemiluminescent western blot of L. minima sporozoite antigens. MAbs C(3)4F1 and E12 demonstrated spotty cytoplasmic staining and labeling of the anterior pellicle of L. minima sporozoites, respectively. Gamonts of H. catesbianae labeled with only MAb E12, using IFA. These gamonts exhibited staining similar to that observed with the L. minima sporozoites. The presence of the cross-reactive epitopes recognized by these MAbs in the same conserved locations suggests that these antigens are homologous.