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Background: Delayed graft function (DGF) is a frequent complication after kidney transplantation affecting long-term outcome., Patients and Methods: A total of 525 consecutive recipients (age 54.2 ± 13.4 years, 33% female) of kidneys from deceased donors transplanted between 2005 and 2012 were retrospectively examined. DGF was defined as the need of dialysis within the first week after transplantation., Results: DGF developed in 21.1% (n = 111). Factors associated with DGF (P ≤ .035, respectively) were recipient body mass index, C-reactive protein of the recipient, residual diuresis, cold ischemia time, donor age, and diuresis in the first hour after transplantation. Median duration of DGF was 16 (2-66) days. Patients after DGF had a significantly lower GFR compared with recipients without DGF either after 3 (32.9 ± 16.5 vs 46.3 ± 18.4 mL/min/1.73 m 2 ) or after 12 months (38.9 ± 19.3 vs 48.6 ± 20.4 mL/min/1.73 m 2 , P < .001, resp.). During DGF, 12.4% developed BANFF II and 18.0% BANFF I rejection, 20.2% had signs of transplant glomerulitis (first biopsy), and 16.2% (n = 18) remained on dialysis., Conclusion: DGF affects 1 out of 5 kidney transplants from deceased donors. Minimizing modifiable risk factors, in particular immunologic risk, may ameliorate the incidence and outcome of DGF. The outcome of DGF depends mainly on the diagnosis of any rejection and worsens upon detection of transplant glomerulitis and pronounced interstitial fibrosis and tubular atrophy (IFTA)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background/aims: We have previously shown that advanced glycation-endproducts (AGEs) induced NFκB activation in differentiated mouse podocytes. This NFκB activation may contribute to the progression of renal disease and mediation of fibrosis by various mechanisms. This study was undertaken to test whether this detrimental response may be reversed by vitamin D3 or its analogue paricalcitol., Methods: Differentiated mouse podocytes were challenged with glycated bovine serum albumin (AGE-BSA), or non-glycated control BSA (in the presence or absence of various concentrations of vitamin D3 (decostriol, 1α,25-dihydroxyvitamin D3)) or its active analog paricalcitol. Quantitative mRNA expressions were measured by real-time PCR, whereas protein expressions were determined by Western blotting followed by densitometry. Cytoplasmic and nuclear protein expression of the NFκB subunit p65 (Rel A) were determined by Western blotting. Furthermore, the ratio of phosphorylated to non-phosphorylated IκB-α was measured using specific antibodies. Electrophoretic mobility shift assays and a capture ELISA assay were used to assess NFκB transactivation in vitro. In addition, NFκB transactivation was also monitored in HEK-NFκBIA reporter cells using live cell luminometry., Results: Podocytes expressed the receptor for vitamin D. The vitamins did not suppress receptor for AGEs (RAGE) expression; instead, they rather upregulated RAGE. Although vitamin D3 and paricalcitol partly and differentially modified some of the studied parameters, both hormones inhibited AGE-BSA-induced NFκB transactivation, presumably by various mechanisms including the upregulation of IκB-α protein, keeping NFκB sequestered in an inactive state in the cytoplasm., Conclusion: Vitamin D3 or its analog paricalcitol partly prevented AGE-mediated NFκB activation, an important feature of diabetic nephropathy (DN). Whether this in vitro finding is of clinical relevance to prevent/treat DN requires further studies., (© 2016 S. Karger AG, Basel.)

Only described in the last 10 years, IgG4-related disease is a fibroinflammatory disorder characterized by tumorous lesions with dense lymphoplasmacytic infiltration by IgG4-positive plasma cells and often elevated concentration of serum IgG4. In this paper, we present a male patient with this disease involving the lymph nodes and possibly the joints and kidneys. Infiltration of lymph node tissue with IgG4-positive plasma cells was demonstrated. The general condition of the patient improved considerably by immunosuppressive therapy.

The rapid growth in obesity worldwide contributes to an increase in metabolic syndrome and obesity-related kidney disease with an enhanced increased risk for chronic kidney disease, finally progressing to end-stage renal disease. Adipose tissue is a highly active endocrine organ secreting numerous factors that contribute to renal and cardiovascular complications. In renal damage, various adipokines are involved through mediating endothelial dysfunction, inducing oxidative stress and inflammation as well as stimulating renal sympathetic nervous activity, and it reduces cancellous bone but conversely increases cortical bone. Adipokines may also be involved in the development of renal anaemia. A balance exists between more protective adipokines (adiponectin) and factors mediating pathophysiological effects (angiotensin II, TNFα). Obesity may cause a disruption of this delicate balance, thereby inducing renal disease. Consequently, weight reduction and lifestyle changes affecting all components of the metabolic syndrome are essential to disrupt this vicious cycle.

Severe systemic infections are one of the leading causes of death in patients with end-stage renal disease and are often associated with hospitalization. Since bacteria can be identified in used hemofilters in an ICU setting, it was investigated whether this method might be useful in patients undergoing regular intermittent hemodialysis. By analyzing used hemodialyzers in (n = 13) patients, we identified systemic bacteremia in two patients (15.4%) while corresponding blood cultures were negative. In two further patients, positive microbiological findings from hemodialyzers appeared to be of unclear clinical relevance. Cultures from hemodialyzers might be an add-on approach for the identification of bacteria in the blood stream of patients undergoing regular intermittent hemodialysis.

Podocyte damage and accumulation of advanced glycation end products (AGEs) are characteristics of diabetic nephropathy (DN). The pathophysiology of AGE-challenged podocytes, such as hypertrophy, apoptosis, and reduced cell migration, is closely related to the induction of the cell cycle inhibitor p27(Kip1) and to the inhibition of neuropilin 1 (NRP1). We have previously demonstrated that treatment with erythropoietin is associated with protective effects for podocytes in vitro. db/db mice with overt DN aged 15-16 wk were treated with either placebo, epoetin-β, or continuous erythropoietin receptor activator (CERA) for 2 wk. db/db mice compared with nondiabetic db/m control mice revealed the expected increases in body weight, blood glucose, albumin-to-creatinine ratio, and AGE accumulation. Whereas there were no differences in body weight, hyperglycemia and AGEs were observed among diabetic mice that received epoetin-β compared with CERA and placebo treatment, indicating that epoetin-β/CERA treatment does not interfere with the development of diabetes in this model. However, the albumin-to-creatinine ratio was significantly lower in db/db mice treated with epoetin-β or CERA. Furthermore, kidney weights in db/db mice were increased compared with db/m control mice, indicating renal hypertrophy, whereas the increase in renal weight in epoetin-β- or CERA-treated db/db mice was significantly lower than in placebo-treated control mice. Induction of p27(Kip1) and suppression of NRP1 were significantly reduced in the epoetin-β treatment group versus the CERA treatment group. Furthermore, erythropoietin treatment diminished the diabetes-induced podocyte loss. Together, independently from hematopoetic effects, epoetin-β or CERA treatment was associated with protective changes in DN, especially that NRP1 and p27(Kip1) expressions as well as numbers of podocytes returned to normal levels. Our data show, for the first time, that medication of overt DN with erythropoietin for a short time can ameliorate albuminuria and podocyte loss.

Background: Idiopathic membranous nephropathy (MN) is a major cause of nephrotic syndrome. Conventional treatment strategies induce remission but the relapse rates are high. Different doses of rituximab (RTX) appeared effective in reducing proteinuria in MN but long-term follow-up data are rare., Methods: Since 2006, a total of 14 patients (median age 51 (26 - 69) years, 4 women, 10 men) with biopsy-proven MN (1 - 4 relapses, MN since 4 (1 - 13) years) were treated with RTX (4 doses of RTX 375 mg/m2 on Days 0, 30, 60, 90). All patients had prior immunosuppressive therapy with Cyclosporin A, 7 with alkylating agents. In 11 patients, an additional renal biopsy was performed 2 (1 - 10) months before RTX., Results: Three months after the last RTX infusion, proteinuria decreased from a baseline of 5.5 (2.9 - 11.9) g/24 h to 1.8 (0.03 - 8.7) g/24 h (p = 0.012). Creatinine clearance remained stable (53 (29 - 160) ml/min at 3 months vs. 44 (29 - 159) at baseline). Until now, patients could be followed for a median of 3 (1 - 6) years. After 1 year, 21.4% (n = 3) had a complete response, 50.0% (n = 7) partial response. Two relapses occurred after 1 and 3.5 years. The presence of glomerulosclerosis before RTX was associated with a poorer outcome., Conclusions: The 4 × 4-weekly infusion of RTX is a reasonable option for the second- and third line therapy of MN providing a better safety profile compared to other immunosuppressive treatments of MN.

Obesity is an independent risk factor for the development and progression of chronic kidney disease and one of the emerging reasons for end-stage renal disease owing to its dramatic increase worldwide. Among the potential underlying pathophysiologic mechanisms, activation of the renin-angiotensin-aldosterone-system (RAAS) plays a central role. Increased angiotensin II (AngII) levels also are central in hypertension, dyslipidemia, and insulin resistance, which, taken together with obesity, represent the metabolic syndrome. Increased AngII levels contribute to hyperfiltration, glomerulomegaly, and subsequent focal glomerulosclerosis by altering renal hemodynamics via afferent arteriolar dilation, together with efferent renal arteriolar vasoconstriction as well as by its endocrine and paracrine properties linking the intrarenal and the systemic RAAS, adipose tissue dysfunction, as well as insulin resistance and hypertension. The imbalance between increased AngII levels and the angiotensin converting enzyme 2/Ang (1-7)/Mas receptor axis additionally contributes to renal injury in obesity and its concomitant metabolic disturbances. As shown in several large trials and experimental studies, treatment of obesity by weight loss is associated with an improvement of kidney disease because it also is beneficial in dyslipidemia, hypertension, and diabetes. The most promising data have been seen by RAAS blockade, pointing to the central position of RAAS within obesity, kidney disease, and the metabolic syndrome., (Copyright © 2013 Elsevier Inc. All rights reserved.)

To investigate possible mechanisms of pain pathophysiology in patients with peritoneal endometriosis, a clinical study on sensory and sympathetic nerve fibre sprouting in endometriosis was performed. Peritoneal lesions (n=40) and healthy peritoneum (n=12) were immunostained and analysed with anti-protein gene product 9.5 (PGP 9.5), anti-substance P (SP) and anti-tyrosine hydroxylase (TH), specific markers for intact nerve fibres, sensory nerve fibres and sympathetic nerve fibres, respectively, to identify the ratio of sympathetic and sensory nerve fibres. In addition, immune cell infiltrates in peritoneal endometriotic lesions were analysed and the nerve growth factor (NGF) and interleukin (IL)-1β expression was correlate with the nerve fibre density. Peritoneal fluids from patients with endometriosis (n=40) and without endometriosis (n=20) were used for the in vitro neuronal growth assay. Cultured chicken dorsal root ganglia (DRG) and sympathetic ganglia were stained with anti-growth associated protein 43 (anti-GAP 43), anti-SP and anti-TH. We could detect an increased sensory and decreased sympathetic nerve fibres density in peritoneal lesions compared to healthy peritoneum. Peritoneal fluids of patients with endometriosis compared to patients without endometriosis induced an increased sprouting of sensory neurites from DRG and decreased neurite outgrowth from sympathetic ganglia. In conclusion, this study demonstrates an imbalance between sympathetic and sensory nerve fibres in peritoneal endometriosis, as well as an altered modulation of peritoneal fluids from patients with endometriosis on sympathetic and sensory innervation which might directly be involved in the maintenance of inflammation and pain., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Inhibitors of the renin-angiotensin-aldosterone system attenuate glomerulosclerosis and interstitial fibrosis. Although the mechanisms underlying their antifibrotic effects are complex, angiotensin II (Ang II) emerges as a major profibrogenic cytokine. Ang II modulates renal cell growth, extracellular matrix synthesis, and degradation by multiple fibrotic pathways. One of the main targets of Ang II in renal fibrosis is TGFβ. Many, but not all, of the stimulatory effects of Ang II on fibrogenesis depend on the induction of TGFβ and its downstream mediators of matrix accumulation, inflammation, and apoptosis. However because of the difficulty in targeting TGFβ, connective tissue growth factor β (CTGF), a downstream mediator of TGFβ, has become a more promising antifibrotic target. Ang II can directly induce expression of renal CTGF and mediate epithelial-mesenchymal transition. Other profibrotic factors stimulated by Ang II include endothelin-1, plasminogen activator inhibitor-1, matrix metalloproteinase (MMP)-2, and a tissue inhibitor of metalloproteinase-2. Finally, connections among Ang II, hypoxia, and the induction of hypoxia-inducible factor-1α contribute to fibrogenesis. A better understanding of the multiple morphogenic effects of Ang II may be necessary to develop better strategies to halt the progression of renal disease., (Copyright © 2011 by the American Society of Nephrology)

Objectives: Advanced glycation end products (AGEs) have been implicated in the pathogenesis of bone-destructive disorders. Yet reports on the influence of AGEs on human osteoblasts remain lacking. The aim of the study is to investigate the influence of AGE-modified bovine serum albumin (AGE-BSA) on cell growth and expression of osteoblastic markers associated with osteogenesis and osteoclastogenesis., Methods: Human osteoblasts established from bone tissue specimens were stimulated with AGE-BSA and investigated in vitro. Expression of mRNA for the receptor for AGEs (RAGE), nuclear factor kappa B subunit p65 (NFκB p65), tumour necrosis factor alpha (TNF-α), matrix metallo proteinase-1 (MMP-1), receptor activator of NFκB ligand (RANKL), osteoprotegerin, collagen type I (Col1), osteocalcin (OC) and alkaline phosphatase (ALP) were measured using real-time polymerase chain reaction (PCR). Respective protein expressions were evaluated by western blot analysis or ELISA. NFκB activation was investigated by luciferase assay and electrophoretic mobility shift assay (EMSA). Cell cycle analysis, cell proliferation and markers of necrosis and early apoptosis were assessed., Results: AGE-BSA was actively taken up into osteoblasts and induced cell cycle arrest and an increase in necrotic, but not apoptotic cells. The increased expression of RAGE and TNF-α together with NFκB activation indicates an AGE-mediated inflammatory response. The decreased expression of Col1, OC and ALP presumably reflects a diminished osteogenic potential, whereas upregulation of RANKL and TNF-α enhances osteoclastogenesis., Conclusions: The present study demonstrates that AGE-BSA affects the growth and function of osteoblasts. Modulation of the expression of various target genes involved in bone metabolism provides evidence that AGEs accumulated in the bone matrix have the potential to suppress osteogenic and to promote osteoclastogenic properties of osteoblasts in vivo, thereby leading to functional and structural impairment of bone.

Background/aims: The interaction of 'advanced glycation end products' (AGEs) and their receptor 'RAGE' plays an important role in diabetic nephropathy. We have previously found that in cultured differentiated podocytes, angiotensin II (ANG II) induces RAGE expression via an AT2 receptor-mediated pathway., Methods: To further confirm our results in an in vivo study, AT2 receptor knockout mice (AT2(-/-)) and wild-type mice were infused with ANG II by osmotic minipumps for 14 days., Results: As shown by immunohistochemistry, ANG II treatment of wild-type animals (C57BL6) allowed a significantly increased RAGE expression in renal podocytes in comparison to sham-operated C57BL6 mice. In contrast, RAGE expression in podocytes of ANG II-treated knockout mice (AT2(-/-)) was only moderately higher than in control animals, but significantly lower than in ANG II-treated wild-type mice. For the AGE species Nε-carboxymethyllysine, a similar immunohistochemical staining pattern was found. There was no significant change in glomerular AT1a receptor expression. However, no difference in RAGE mRNA expression could be found between ANG II-infused wild-type and AT2(-/-) animals by real-time PCR using whole kidney mRNA, presumably due to the low abundance of podocyte mRNA in these preparations. No effects were seen on glomerular apoptosis., Conclusion: These data support the fact that ANG II-mediated RAGE induction in podocytes occurs via AT2 receptors. The present findings may suggest that not all ANG II-mediated changes in diabetic nephropathy can be treated with AT1 receptor blockers., (Copyright © 2011 S. Karger AG, Basel.)

Background: Advanced glycation end-products (AGEs) are increased in situations with hyperglycemia and oxidative stress such as diabetes mellitus. They are products of nonenzymatic glycation and oxidation of proteins and lipids. The kidney plays an important role in clearance and metabolism of AGEs., Methods: Medline and other relevant databases were searched. In addition, key review articles were scanned for relevant original publication. Finally, original data from our research group were also included., Results: Kidney podocytes and endothelial cells express specific receptors for AGEs. Their activation leads to multiple pathophysiological effects including hypertrophy with cell cycle arrest and apoptosis, altered migration, and generation of proinflammatory cytokines. AGEs have been primarily implicated in the pathophysiology of diabetic nephropathy and diabetic microvascular complications. AGEs are also involved in other primary renal diseases as well as in the development and progression of atherosclerosis. However, serum or plasma concentrations of AGEs do not correlate well with cardiovascular events in patients with chronic kidney disease (CKD). This is likely due to the fact that serum concentrations failed to correlate with AGEs deposited in target tissues. Several inhibitors of the AGE-RAGE axis are currently tested for various indications., Conclusion: AGEs and their receptors are involved in the pathogenesis of vascular and kidney disease. The role of circulating AGEs as biomarkers for cardiovascular risk estimation is questionable. Whether putative inhibitors of AGEs will get the maturity for its therapeutic use in the future remains open.