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Background Macrophages play an important role in the pathogenesis of lupus nephritis (LN), but less is known about macrophage subtypes in pediatric LN. Here we compared renal inflammation in LN with other inflammatory pediatric kidney diseases and assessed whether inflammation correlates with clinical parameters. Methods Using immunofluorescence microscopy, we analyzed renal biopsies from 20 pediatric patients with lupus nephritis (ISN/RPS classes II–V) and pediatric controls with other inflammatory kidney diseases for infiltration with M1-like (CD68 + /CD206 − , CD68 + /CD163 −), M2a-like (CD206 + /CD68 +), and M2c-like macrophages (CD163 + /CD68 +) as well as CD3 + T-cells, CD20 + B-cells, and MPO + neutrophilic granulocytes. In addition, the correlation of macrophage infiltration with clinical parameters at the time of renal biopsy, e.g., eGFR and serum urea, was investigated. Macrophage subpopulations were compared with data from a former study of adult LN patients. Results The frequency of different macrophage subtypes in biopsies of pediatric LN was dependent on ISN/RPS class and showed the most pronounced M1-like macrophage infiltration in patients with LN class IV, whereas M2c-like macrophages were most abundant in class III and IV. Interestingly, on average, only half as many macrophages were found in renal biopsies of pediatric LN compared to adult patients with LN. The distribution of frequencies of macrophage subpopulations, however, was different for CD68 + CD206 + (M2a-like) but comparable for CD68 + CD163 − (M1-like) CD68 + CD163 + (M2c-like) cells in pediatric and adult patients. Compared to other inflammatory kidney diseases in children, fewer macrophages and other inflammatory cells were found in kidney biopsies of LN. Depending on the disease, the frequency of individual immune cell types varied, but we were unable to confirm disease-specific inflammatory signatures in our study due to the small number of pediatric cases. Worsened renal function, measured as elevated serum urea and decreased eGFR, correlated particularly strongly with the number of CD68 + /CD163 − M1-like macrophages and CD20 + B cells in pediatric inflammatory kidney disease. Conclusion Although M1-like macrophages play a greater role in pediatric LN patients than in adult LN patients, M2-like macrophages appear to be key players and are more abundant in other pediatric inflammatory kidney diseases compared to LN.

Cardiovascular complications are extremely frequent in patients with chronic kidney disease (CKD) and death from cardiac causes is the most common cause of death in this particular population. Cardiovascular disease is approximately 3 times more frequent in patients with CKD than in other known cardiovascular risk groups and cardiovascular mortality is approximately 10-fold more frequent in patients on dialysis compared to the age- and sex-matched segments of the nonrenal population. Among other structural and functional factors advanced calcification of atherosclerotic plaques as well as of the arterial and venous media has been described as potentially relevant for this high cardiovascular morbidity and mortality. One potential explanation for this exceedingly high vascular calcification in animal models as well as in patients with CKD increased systemic and most importantly local (micro)inflammation that has been shown to favor the development of calcifying particles by multiple ways. Of note, local vascular upregulation of proinflammatory and proosteogenic molecules is already present at early stages of CKD and may thus be operative for vascular calcification. In addition, increased expression of costimulatory molecules and mast cells has also been documented in patients with CKD pointing to a more inflammatory and potentially less stable phenotype of coronary atherosclerotic plaques in CKD.

The glomerular filtration barrier (GFB) produces primary urine and is composed of a fenestrated endothelium, a glomerular basement membrane (GBM), podocytes, and a slit diaphragm. Impairment of the GFB leads to albuminuria and microhematuria. The GBM is generated via secreted proteins from both endothelial cells and podocytes and is supposed to majorly contribute to filtration selectivity. While genetic mutations or variations of GBM components have been recently proposed to be a common cause of glomerular diseases, pathways modifying and stabilizing the GBM remain incompletely understood. Here, we identified prolyl 3-hydroxylase 2 (P3H2) as a regulator of the GBM in an a cohort of patients with albuminuria. P3H2 hydroxylates the 3' of prolines in collagen IV subchains in the endoplasmic reticulum. Characterization of a P3h2ΔPod mouse line revealed that the absence of P3H2 protein in podocytes induced a thin basement membrane nephropathy (TBMN) phenotype with a thinner GBM than that in WT mice and the development of microhematuria and microalbuminuria over time. Mechanistically, differential quantitative proteomics of the GBM identified a significant decrease in the abundance of collagen IV subchains and their interaction partners in P3h2ΔPod mice. To our knowledge, P3H2 protein is the first identified GBM modifier, and loss or mutation of P3H2 causes TBMN and focal segmental glomerulosclerosis in mice and humans.

Objective: Complement deposition is prevalent in kidney biopsies of patients with arterial hypertension and hypertensive nephropathy, but an association of hypertension and complement deposition or involvement of complement in the pathogenesis of hypertensive nephropathy has not been shown to date. Methods: In this study, we analyzed complement C1q and C3c deposition in a rat model of overload and hypertension by subtotal nephrectomy (SNX) and in archival human renal biopsies from 217 patients with known hypertension and 91 control patients with no history of hypertension using semiquantitative scoring of C1q and C3c immunohistochemistry and correlation with parameters of renal function. To address whether complement was only passively deposited or actively expressed by renal cells, C1q and C3 mRNA expression were additionally analyzed. Results: Glomerular C1q and C3c complement deposition were significantly higher in kidneys of hypertensive SNX rats and hypertensive compared to nonhypertensive patients. Mean arterial blood pressure (BP) in SNX rats correlated well with the amount of glomerular C1q and C3c deposition and with left ventricular weight, as an indirect parameter of high BP. Quantitative mRNA analysis showed that C3 was not only deposited but also actively produced by glomerular cells of hypertensive SNX rats and in human renal biopsies. Of note, in patients CKD-stage correlated significantly with the intensity of glomerular C3c staining, but not with that of C1q. Conclusion: Renal complement deposition correlated with experimental hypertension as well as the presence of hypertension in a variety of renal diseases. To answer the question, if and how exactly renal complement is causative for the pathogenesis of arterial hypertension in men, further studies are needed.

Background/Aims: Crucial steps in the initiation of lupus nephritis are the deposition of (auto-)antibodies and consequent complement activation. In spite of aggressive treatment patients may develop terminal renal failure. Therefore, new treatment strategies are needed. In extension to our previously published data we here analyzed the potential renoprotective mechanisms of bortezomib (BZ) in experimental lupus nephritis by focusing on morphological changes. Methods: Female NZB×NZW F1 mice develop lupus-like disease with extensive nephritis that finally leads to lethal renal failure. Treatment with 0.75 mg/kg BZ i.v. or placebo (PBS) twice per week started at 18 or 24 weeks of age. Antibody production was measured with ELISA and kidney damage was determined by quantitative morphological and immunohistochemical methods. Results: BZ treatment completely inhibited antibody production in both BZ-treated groups and prevented the development of nephritis in comparison to PBS-treated animals. Glomerular and tubulointerstitial damage scores, collagen IV expression, mean glomerular volume as well as tubulointerstitial proliferation and apoptosis were significantly lower after BZ treatment. Glomerular ultrastructure and in particular podocyte damage and loss were prevented by BZ treatment. Conclusions: BZ effectively prevents the development of nephritis in the NZB/W F1 mouse model. Specific protection of podocyte ultrastructure may critically contribute to renoprotection by BZ, which may also represent a potential new treatment option in human lupus nephritis. Copyright © 2012 S. Karger AG, Basel [PUBLICATION ABSTRACT]

Background/Aims: One potential pathomechanism how low nephron number leads to hypertension in later life is altered salt handling. We therefore evaluated changes in electrolyte and water content in wildtype (wt) and GDNF+/- mice with a 30% reduction of nephron number. Methods: 32 GDNF+/- and 36 wt mice were fed with low salt (LSD, 0.03%, normal drinking water) or high salt (HSD, 4%, 0.9% drinking water) diet for 4 weeks. Blood pressure was continuously measured by telemetry in a subgroup. At the end of the experiment and after standardized ashing processes electrolyte- and water contents of the skin and the total body were determined. Results: We found higher blood pressure in high salt treated GDNF+/-compared to wt mice. Of interest, we could not confirm an increase in total-body sodium as predicted by prevailing explanations, but found increased total body and skin chloride that interestingly correlated with relative kidney weight. Conclusion: We hereby firstly report significant total body and skin chloride retention in salt sensitive hypertension of GDNF+/-mice with genetically determined lower nephron number. Thus, in contrast to the prevailing opinion our data argue for the involvement of non-volume related mechanisms.

A 16-year-old patient with steroid-dependent nephrotic syndrome with more than 35 relapses developed severe relapsing idiopathic thrombocytopenic purpura (ITP). At the age of 2 years, nephrotic syndrome was diagnosed and successfully treated with a standard prednisone regimen. Frequent relapses occurred. Treatment with oral cyclophosphamide followed by cyclosporine was successful, but several attempts to withdraw steroids failed and the patient suffered from multiple relapses. At the age of 12 years, renal biopsy revealed focal segmental glomerulosclerosis and cyclosporine toxicity. A second course of oral cyclophosphamide was unsuccessful and tacrolimus resulted in the development of diabetes mellitus, which was reversed after discontinuation of the drug. At the age of 15 years the patient, still being steroid dependent, developed ITP. Neither steroids nor intravenous immunoglobulins induced permanent remission. Only weekly immunoglobulin infusions could temporarily restore the platelet count. To treat ITP in this desperate situation we decided to deplete B-cells with the monoclonal anti-CD20 antibody rituximab. Intravenous infusions of rituximab (375 mg/m(2)) were given once weekly for 4 consecutive weeks without adverse events. Four weeks after the first rituximab dosage, the thrombocyte count increased to normal values. There has been no subsequent relapse of either thrombocytopenia or nephrotic syndrome (on cyclosporine, without steroids) to date. We conclude that B-cell depletion with rituximab might have altered the course of steroid-dependent nephrotic syndrome in our patient.

Patients with renal failure develop cardiovascular alterations which contribute to the higher rate of cardiac death. Blockade of the renin angiotensin system ameliorates the development of such changes. It is unclear, however, to what extent ACE-inhibitors can also reverse existing cardiovascular alterations. Therefore, we investigated the effect of high dose enalapril treatment on these alterations. Male Sprague Dawley rats underwent subtotal nephrectomy (SNX, n = 34) or sham operation (sham, n = 39). Eight weeks after surgery, rats were sacrificed or allocated to treatment with either high-dose enalapril, combination of furosemide/dihydralazine or solvent for 4 weeks. Heart and aorta were evaluated using morphometry, stereological techniques and TaqMan PCR. After 8 and 12 weeks systolic blood pressure, albumin excretion, and left ventricular weight were significantly higher in untreated SNX compared to sham. Twelve weeks after SNX a significantly higher volume density of cardiac interstitial tissue (2.57±0.43% in SNX vs 1.50±0.43% in sham, p<0.05) and a significantly lower capillary length density (4532±355 mm/mm(3) in SNX vs 5023±624 mm/mm(3) in sham, p<0.05) were found. Treatment of SNX with enalapril from week 8-12 significantly improved myocardial fibrosis (1.63±0.25%, p<0.05), but not capillary reduction (3908±486 mm/mm(3)) or increased intercapillary distance. In contrast, alternative antihypertensive treatment showed no such effect. Significantly increased media thickness together with decreased vascular smooth muscles cell number and a disarray of elastic fibres were found in the aorta of SNX animals compared to sham. Both antihypertensive treatments failed to cause complete regression of these alterations. The study indicates that high dose ACE-I treatment causes partial, but not complete, reversal of cardiovascular changes in SNX.

Background Severe renal manifestation of systemic lupus erythematosus (SLE) is not uncommon and is associated with an indeterminate prognosis. Complete remission can be obtained, however, at least in the young when chronic lesions are absent and adequate anti-inflammatory therapy is immediately initiated. Case presentation We report the unusual case of a 12-year-old girl who presented with severe oliguric renal failure, macrohematuria and skin rash. Renal biopsy revealed the diagnosis of severe diffuse proliferative glomerulonephritis (GN) with cellular crescents in 15 out of 18 glomeruli and full-house pattern in immunofluorescence indicating lupus nephritis IVB according to WHO, IV-G(A) according to ISN/RPS classification. The serological parameters confirmed the diagnosis of SLE and the patient was immediately treated with methylprednisolone, cyclophosphamide and immunoadsorption. Initially, despite rapid amelioration of her general condition, no substantial improvement of renal function could be achieved and the patient needed hemodialysis treatment for 12 weeks. Unexpectedly, in the further follow-up at first diuresis increased and thereafter also creatinine levels substantially declined so that hemodialysis could be discontinued. Today, 6 years after the initial presentation, the patient has normal renal function and a SLEDAI score of 0 under a continuous immunosuppressive therapy with Mycophenolate mofetil (MMF) and low dose steroid. Conclusion Despite the severity of the initial renal injury and the unfavourable renal prognosis the kidney apparently has a tremendous capacity to recover in young patients when the damage is acute and adequate anti-inflammatory therapy is initiated without delay.

Aims: To test the suggested association of low nephron number and later development of renal and cardiovascular disease we investigated the effects of high sodium diet in heterozygous GDNF+/- mice. Methods: Aged wild type and GDNF+/- mice were grouped together according to high sodium (HS, 4%) or low sodium (LS, 0.03%) diet for 4 weeks. The heart, the aorta and the kidneys were processed for morphometric and stereological evaluations and TaqMan PCR. Results: On HS GDNF+/- mice showed significantly higher drinking volume and urine production than wt and mean arterial blood pressure tended to be higher. Heart weight was higher in GDNF+/- than in wt, but the difference was only significant for LS. HS significantly increased cardiac interstitial tissue in GDNF+/-, but not in wt. On LS GDNF+/- mice had significantly larger glomeruli than wt and HS led to an additional two fold increase of glomerular area compared to LS. On electron microscopy glomerular damage after HS was seen in GDNF+/-, but not in wt. Dietary salt intake modulated renal IL-10 gene expression in GDNF+/-. Conclusion: In the setting of 30% lower nephron number HS diet favoured maladaptive changes of the kidney as well as of the cardiovascular system.