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Background Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults, but is less frequent in children. Antibodies against four antigens leading to MN have been described in children: phospholipase A.sub.2 receptor 1 (PLA.sub.2R1), thrombospondin type-1 domain-containing 7A (THSD7A), neutral endopeptidase (NEP), and cationic bovine serum albumin (BSA). Methods Twelve children with MN were included in this study. Sera of all patients were analyzed for antibodies against PLA.sub.2R1, THSD7A, NEP, and BSA. All sera were also analyzed using Western blot with human glomerular extracts (HGE) under non reducing conditions. In 5 cases renal biopsies were analyzed for PLA.sub.2R1, THSD7A, NEP, BSA, and all IgG subclasses. Results Six patients were PLA.sub.2R1-antibody-positive, whereas THSD7A, NEP, and BSA antibodies were not found in any of our 12 patients. All sera were analyzed by Western blot using human glomerular extracts; however, no further potential antigens were found. Five kidney biopsies from 2 PLA.sub.2R1-antibody-positive and 3 PLA.sub.2R1-antibody-negative patients were available for additional analyses, confirming the diagnosis of PLA.sub.2R1-associated MN in 2 cases, whereas none of the biopsies revealed enhanced staining for THSD7A, NEP or BSA. IgG2 and IgG4 stainings were positive in both patients with PLA.sub.2R1-associated MN and negative in the other biopsies. During follow-up (median 24 months), 4 children with PLA.sub.2R1-associated MN went into remission, preceded by decline of PLA.sub.2R1 antibodies. Five of the 6 PLA.sub.2R1-antibody-negative children went into remission. Conclusions In children with MN, PLA.sub.2R1-associated MN appears to be common, whereas MN associated with THSD7A, NEP or BSA was not encountered. PLA.sub.2R1 antibody levels are closely associated with disease activity, whereas PLA.sub.2R1-antibody-negative patients often have a good prognosis. However, the pathophysiology of MN in a considerable number of children remains unclear., Author(s): Anne K. Dettmar [sup.1] , Thorsten Wiech [sup.2] , Markus J. Kemper [sup.3] , Armin Soave [sup.4] , Michael Rink [sup.4] , Jun Oh [sup.1] , Rolf A. K. [...]

Background: Membranous nephropathy (MN) is an autoimmune disease induced by circulating antibodies against the podocyte protein phospholipase A2 receptor 1 (PLA2R1-ab) in 80% of patients and represents the leading cause of nephrotic syndrome in adults. PLA2R1-ab levels correlate with disease activity and treatment response. However, their predictive role for long-term renal outcome is not clear. Methods: The aim of this prospective observational multicenter study was to investigate the predictive role of PLA2R1-ab levels at the time of diagnosis for long-term outcome in a cohort of 243 patients with newly diagnosed biopsy-proven PLA2R1-associated MN. Statistical analyses included Cox proportional hazard models. The primary study endpoint was defined prior to data collection as doubling of serum creatinine or development of end-stage renal disease. Results: During the median follow-up time of 48 months, 36 (15%) patients reached the study endpoint. Independent predictors for reaching the study endpoint were baseline PLA2R1-ab levels (HR = 1.36, 95%CI 1.11–1.66, p = 0.01), percentage of tubular atrophy and interstitial fibrosis (HR = 1.32, 95%CI 1.03–1.68, p = 0.03), PLA2R1-ab relapse during follow-up (HR = 3.22, 95%CI 1.36–7.60, p = 0.01), and relapse of proteinuria (HR = 2.60, 95%CI 1.17–5.79, p = 0.02). Fifty-four (22%) patients received no immunosuppressive treatment during the study, in 41 (76%) of them PLA2R1-ab spontaneously disappeared during follow-up, 29 (54%) patients had a complete remission of proteinuria, and 19 (35%) had a partial remission. Patients not treated with immunosuppression were more often females and had lower PLA2R1-ab levels, proteinuria, and serum creatinine at baseline compared to patients receiving immunosuppression. However, no conclusion on the efficacy of immunosuppressive therapies can be made, since this was not a randomized controlled study and treatment decisions were not made per-protocol. Conclusions: PLA2R1-ab levels are, in addition to pre-existing renal damage, predictive factors for long-term outcome and should therefore be considered when deciding the treatment of patients with MN. [ABSTRACT FROM AUTHOR]

The role of CX3CR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CX3CR1 in hypertensive renal and cardiac injury. Expression of CX3CR1 was determined using CX3CR1GFP/+ mice that express a green fluorescent protein (GFP) reporter in CX3CR1+ cells. FACS analysis of leukocytes isolated from the kidney showed that 34% of CD45+ cells expressed CX3CR1. Dendritic cells were the majority of positive cells (67%) followed by macrophages (10%), NK cells (6%), and T cells (10%). With the use of confocal microscopy, the receptor was detected in the kidney only on infiltrating cells but not on resident renal cells. To evaluate the role of CX3CR1 in hypertensive end-organ injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of angiotensin II (ANG II, 1.5 ng·g−1·min−1) and a high-salt diet in wild-type (n = 15) and CX3CR1-deficient mice (n = 18). CX3CR1 deficiency reduced the number of renal dendritic cells and increased the numbers of renal CD11b/F4/80+ macrophages and CD11b/Ly6G+ neutrophils in ANG II-infused mice. Surprisingly, CX3CR1-deficient mice exhibited increased albuminuria, glomerular injury, and reduced podocyte density in spite of similar levels of arterial hypertension. In contrast, cardiac damage as assessed by increased heart weight, cardiac fibrosis, and expression of fetal genes, and matrix components were not different between both genotypes. Our findings suggest that CX3CR1 exerts protective properties by modulating the invasion of inflammatory cells in hypertensive renal injury. CX3CR1 inhibition should be avoided in hypertension because it may promote hypertensive renal injury. [ABSTRACT FROM AUTHOR]

Atrial natriuretic peptide attenuates ANG II-induced hypertrophy of renal tubular cells. Am J Physiol Renal Physiol 281: F81-F90, 2001.--ANG II arrests LLC-[PK.sub.1] cells in the [G.sub.1] phase of the cell cycle and induces hypertrophy, an effect mediated by induction of [p27.sup.Kip1]. We studied whether atrial natriuretic peptide (ANP) may modulate ANG II-induced hypertrophy and [p27.sup.Kip1] expression in tubular LLC-[PK.sub.1] cells. ANP, through its fragments 3--28 and 4--27, prevented ANG II-induced cell cycle arrest. ANP inhibited [is greater than] 80% of ANG II-induced [p27.sup.Kip1] protein expression (Western blots). ANP stimulated expression of MKP-1, a phosphatase involved in dephosphorylation of p44/42 mitogen-activated protein (MAP) kinase, up to 12 h. ANP prevented the ANG II-mediated phosphorylation peak of MAP kinase after 12 h of stimulation. 8-Bromo-cGMP mimicked all the effects of ANP. Transfection with MKP-1 antisense, but not sense, oligonucleotides abolished the modifying role of ANP on ANG II-mediated cell cycle arrest. The effect of ANP on ANG II-mediated hypertrophy of LLC-[PK.sub.1] cells is regulated on the level of MAP kinase phosphorylation, a key step in the induction of [p27.sup.Kip1]. Although ANP and ANG II both stimulate generation of reactive oxygen species, ANP additionally induces expression of MKP-1, leading to interference with ANG II-mediated MAP kinase phosphorylation. tubular hypertrophy; cell cycle arrest; signal transduction; LLC-[PK.sub.1] cells; mitogen-activated protein kinases