Christian Morath

Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR–β3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.

Renal Insulin Resistance Syndrome, Adiponectin and Cardiovascular Events in Patients with Kidney Disease: The Mild and Moderate Kidney Disease Study

The relationship among insulin resistance, adiponectin, and cardiovascular (CV) morbidity in patients with mild and moderate kidney disease was investigated. Insulin sensitivity (Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]) and adiponectin plasma levels were assessed in 227 nondiabetic renal patients at different degrees of renal dysfunction and in 76 healthy subjects of similar age and gender distribution and body mass index. In renal patients, association with prevalent CV events was evaluated, and incident CV events were evaluated in a prospective study. HOMA-IR was markedly higher in patients than in healthy subjects (3.59 +/- 3.55 versus 1.39 +/- 0.51; P < 0.01). In renal patients, HOMA-IR was significantly correlated with body mass index (r = 0.477; P < 0.01), triglycerides (r = 0.384; P < 0.01), adiponectin plasma levels (r = -0.253; P < 0.01), and age (r = 0.164; P < 0.05), but not with renal function (GFR by iod-thalamate clearance). Patients with previous CV events were significantly older, had higher HOMA-IR and serum triglycerides, and had lower adiponectin plasma levels (all P < 0.05). Logistic regression analysis revealed age (P < 0.001) and adiponectin (P < 0.002) as independent variables related to prevalent CV events. In the prospective study, median follow-up was 54 mo. Patients who experienced CV events had significantly higher serum glucose and lower adiponectin plasma levels (both P < 0.05). In patients with chronic kidney diseases, a syndrome of insulin resistance is present even in the earliest stage of renal dysfunction, and several components of this syndrome are associated with CV events. Moreover, hypoadiponectinemia is a novel putative CV risk factor in patients with mild and moderate renal failure.

Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease Study

Reduced bioavailability of nitric oxide (NO) is thought to play an important role in progression of renal damage. The hypothesis that the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is involved in progression of kidney disease was tested. Plasma ADMA concentrations and other putative progression factors were assessed in 227 relatively young patients (45.7 +/- 12.6 yr) with nondiabetic kidney diseases and mild to moderate renal failure. Progression assessed as doubling of serum creatinine and/or renal replacement therapy was evaluated prospectively. Baseline plasma ADMA concentrations in renal patients correlated significantly with serum creatinine (r = 0.595), GFR (r = -0.591), age (r = 0.281), and proteinuria (r = 0.184; all P < 0.01). Patients who reached an end point during follow-up were significantly older (P < 0.05) and had significantly higher creatinine, ADMA, and parathyroid hormone blood concentrations and protein excretion rates at baseline, whereas GFR and hemoglobin were significantly lower (all P < 0.01). Cox regression analysis revealed baseline serum creatinine (odds ratio 2.00; 95% confidence interval [CI] 1.61 to 2.49; P < 0.001) and ADMA (odds ratio 1.47; 95% CI 1.12 to 1.93 for an increment of 0.1 mumol/L; P < 0.006) as independent predictors of disease progression. In patients with ADMA levels above median, progression was significantly faster (P < 0.0001), and their mean follow-up time to a progression end point was 52.8 mo (95% CI 46.9 to 58.8) as compared with 71.6 mo (95% CI 66.2 to 76.9) in patients with ADMA levels below the median. The endogenous NO synthase inhibitor ADMA is significantly associated with progression of nondiabetic kidney diseases. Lowering plasma ADMA concentrations may be a novel therapeutic target to prevent progressive renal impairment.

Malignancy in Renal Transplantation

Eberhard Ritz : Feature Editor An increased incidence of malignant tumors in transplant recipients was recognized as early as in the 1970s, and this effect was ascribed to the administration of immunosuppressive medication ([1,2][1][⇓][2]). In the early days of transplantation medicine, however

No Improvement of Patient or Graft Survival in Transplant Recipients Treated with Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Type 1 Receptor Blockers: A Collaborative Transplant Study Report

It was reported recently that treatment of kidney transplant recipients with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) is associated with strikingly improved long-term graft and patient survival. This finding has important implications for future posttransplantation therapy recommendations. In an analysis of 17,209 kidney and 1744 heart transplant recipients, an association of treatment with ACEI/ARB with improved transplant outcome could not be confirmed. It is concluded that recommendations for a widespread use of ACEI/ARB treatment in transplant recipients are unwarranted.

Metabolic Control Improves Long-Term Renal Allograft and Patient Survival in Type 1 Diabetes

It is a matter of debate whether pancreas allografts independently contribute to renal allograft and patient survival in individuals who have type 1 diabetes and receive a simultaneous pancreas and kidney transplant (SPK). Using data from the Collaborative Transplant Study, we studied patients who had type 1 diabetes and were recipients of deceased-donor kidneys (DDK), living-donor kidneys (LDK), or SPK. We analyzed graft and patient survival rates with a maximum of 18 yr of follow-up. DDK recipients had inferior graft and patient survival compared with LDK and SPK recipients. LDK recipients had superior graft and patient survival rates initially, but SPK recipients demonstrated equal survival rates toward the end of follow-up. Multivariate analysis, adjusting for pretransplantation cardiovascular risk, showed that patient survival of SPK recipients was superior to that of LDK recipients beyond the 10th year after transplantation (hazard ratio 0.55; P = 0.005). In summary, the early survival advantage of LDK over SPK is lost during long-term follow-up, probably as a result of improved glycemic control in SPK recipients.

Damage to the Peritoneal Membrane by Glucose Degradation Products Is Mediated by the Receptor for Advanced Glycation End-Products

Peritoneal dialysis is limited by morphologic changes of the peritoneal membrane. Use of peritoneal dialysis fluids (PDF) that contain glucose degradation products (GDP) generates advanced glycation end-products (AGE) within the peritoneal cavity. It is unknown whether peritoneal damage is causally related to AGE-receptor for AGE (RAGE) interaction. The effects of PDF were compared with different amounts of GDP on morphologic changes of the peritoneal membrane in 48 wild-type (WT) and 48 RAGE-deficient mice. PDF (1 ml) were instilled twice daily over a period of 12 wk. Groups with eight animals each received no manipulation (sham); sham instillation (sham i.p.); or filter-sterilized, glucose-free, conventional low GDP- or high GDP PDF. In vitro (generation of AGE fluorescence in PDF) and in vivo (immunohistochemistry for carboxymethyllysine), a GDP-dependent increase of AGE formation occurred. Inflammation and neoangiogenesis were augmented in WT mice that were treated with high GDP accompanied by upregulation of CD3+ T cells, increased NF-kappaB binding activity, increased lectin, and vascular endothelial growth factor expression. Furthermore, pronounced submesothelial fibrosis was found with increased expression of TGF-beta1. Exposure to low GDP resulted in only mild inflammation and neoangiogenesis (compared with sham i.p.) and no fibrosis in WT mice. The findings in WT contrasted with those in RAGE-deficient mice, which showed no increased inflammation (CD3+ T cells and NF-kappaB binding activity), neoangiogenesis (by lectin and vascular endothelial growth factor expression), or fibrosis (expression of TGF-beta1) after long-term exposure to GDP-containing PDF. Peritoneal damage by GDP in PDF is dependent at least in part on AGE-RAGE interaction.

Sustained low efficiency dialysis using a single-pass batch system in acute kidney injury - a randomized interventional trial: the REnal Replacement Therapy Study in Intensive Care Unit PatiEnts

Th e authors noticed after the publication of their article [1] an error in their methods. Under “Randomization and treatment assignments”, the Asahi APS 650 membrane was used together with the Octo Nova device (Octo Nova, Diamed, Köln, Germany) and not the Prisma device as indicated in the manuscript. Th is section should therefore read as follows; “Patients randomly assigned to the CVVH-group (Prisma, Gambro Hospal, Lyon, France and Octo Nova, Diamed, Köln, Germany) were treated with 35 ml/kg per hour replacement fl uid in predilution. Treatment was scheduled for 24-h and blood fl ow was maintained between 100 and 120 ml/min. For all CVVH treatments, high-fl ux fi lters (AN69-M100, Gambro Hospal, Lyon, France and Asahi Kasei APS-650, Asahi Kasei Medical Co, Ltd., Japan) were used.” In addition, the funding of this study was erroneously deleted in-house and should read as follows; “Grant of the European Nephrology and Dialysis Institute, Bad Homburg, Germany”.

Real-Time Contrast-Enhanced Sonography of Renal Transplant Recipients Predicts Chronic Allograft Nephropathy

Real‐time contrast‐enhanced sonography (RT‐CES) can assess microvascular tissue perfusion using gas‐filled microbubbles. The study was performed to evaluate the feasibility of RT‐CES in detecting chronic allograft nephropathy (CAN) in comparison to color Doppler ultrasonography (CDUS). A total of 26 consecutive renal transplant recipients were prospectively studied using RT‐CES and conventional CDUS. Transplant tissue perfusion imaging was performed by low‐power imaging during i.v. administration of the sonocontrast Optison™. Renal tissue perfusion was assessed quantitatively using flash replenishment kinetics of microbubbles to estimate renal blood flow A *β (A = peak signal intensity, β= slope of signal intensity rise). In contrast to conventional CDUS resistance and pulsatility indices, renal blood flow estimated by CES was highly significant related to S‐creatinine (r =–0.62, p = 0.0004). Determination of renal blood flow by CES reached a higher sensitivity (91% vs. 82%, p < 0.05), specificity (82% vs. 64%, p < 0.05) and accuracy (85% vs. 73%, p < 0.05) for the diagnosis of CAN as compared to conventional CDUS resistance indices. Perfusion parameters derived from RT‐CES significantly improve the early detection of CAN compared to conventional CDUS. RT‐CES using low‐power real‐time perfusion imaging is a feasible method to evaluate microvascular perfusion in renal allograft recipients.

Antifibrotic actions of mycophenolic acid

Abstract:  Mycophenolic acid (MPA) is a highly selective, non‐competitive and reversible inhibitor of the inosine monophosphate dehydrogenase (IMPDH), the rate‐limiting enzyme in the de novo biosynthesis of guanosine nucleotides. Mycophenolate mofetil (MMF, the ester prodrug of MPA) strongly inhibits both T‐ and B‐lymphocyte proliferation and has now been widely used in the prevention of acute and chronic allograft rejection. Recent evidence, however, suggests that MMF is also capable of inhibiting the proliferation of non‐immune cells. In various cell lines, e.g. smooth muscle cells, renal tubular cells, mesangial cells, and fibroblasts, MPA reduced or even abrogated proliferation in response to proliferative stimuli. In animal studies, MMF ameliorated renal lesions in immune‐mediated disease, e.g. in the Anti‐Thy 1.1 model and experimental lupus nephritis, but was also effective in non‐immune‐mediated renal damage, e.g. in the rat remnant kidney model or in a model of chronic cyclosporine nephrotoxicity in the rat. In humans, MMF reduced proteinuria in steroid‐resistant nephrotic syndrome and had beneficial effects in the prevention and treatment of chronic allograft nephropathy and calcineurin inhibitor toxicity through the reduction of immune‐ and non‐immune‐mediated renal damage. MMF is well tolerated and has proven to be a relatively safe drug. Taken together, there is a growing body of evidence pointing to therapeutic applications of MMF other than immunosuppression, in particular the prevention of fibrosis.