Magnetic Resonance Imaging in Clinical Trials of Diabetic Kidney Disease

Chronic kidney disease (CKD) associated with diabetes mellitus (DM) (known as diabetic kidney disease, DKD) is a serious and growing healthcare problem worldwide. In DM patients, DKD is generally diagnosed based on the presence of albuminuria and a reduced glomerular filtration rate. Diagnosis rarely includes an invasive kidney biopsy, although DKD has some characteristic histological features, and kidney fibrosis and nephron loss cause disease progression that eventually ends in kidney failure. Alternative sensitive and reliable non-invasive biomarkers are needed for DKD (and CKD in general) to improve timely diagnosis and aid disease monitoring without the need for a kidney biopsy. Such biomarkers may also serve as endpoints in clinical trials of new treatments. Non-invasive magnetic resonance imaging (MRI), particularly multiparametric MRI, may achieve these goals. In this article, we review emerging data on MRI techniques and their scientific, clinical, and economic value in DKD/CKD for diagnosis, assessment of disease pathogenesis and progression, and as potential biomarkers for clinical trial use that may also increase our understanding of the efficacy and mode(s) of action of potential DKD therapeutic interventions. We also consider how multi-site MRI studies are conducted and the challenges that should be addressed to increase wider application of MRI in DKD

Risk-Stratified Cardiovascular Screening Including Angiographic and Procedural Outcomes of Percutaneous Coronary Interventions in Renal Transplant Candidates

Background. Benefits of cardiac screening in kidney transplant candidates (KTC) will be dependent on the availability of effective interventions. We retrospectively evaluated characteristics and outcome of percutaneous coronary interventions (PCI) in KTC selected for revascularization by a cardiac screening approach. Methods. In 267 patients evaluated 2003 to 2006, screening tests performed were reviewed and PCI characteristics correlated with major adverse cardiovascular events (MACE) during a follow-up of 55 months. Results. Stress tests in 154 patients showed ischemia in 28 patients (89% high risk). Of 58 patients with coronary angiography, 38 had significant stenoses and 18 cardiac interventions (6.7% of all). 29 coronary lesions in 17/18 patients were treated by PCI. Angiographic success rate was 93.1%, but procedural success rate was only 86.2%. Long lesions (P=0.029) and diffuse disease (P=0.043) were associated with MACE. In high risk patients, cardiac screening did not improve outcome as 21.7% of patients with versus 15.5% of patients without properly performed cardiac screening had MACE (P=0.319). Conclusion. The moderate procedural success of PCI and poor outcome in long and diffuse coronary lesions underscore the need to define appropriate revascularization strategies in KTC, which will be a prerequisite for cardiac screening to improve outcome in these high-risk patients

Multiparametric Magnetic Resonance Imaging Allows Non-Invasive Functional and Structural Evaluation of Diabetic Kidney Disease

BackgroundWe sought to develop a novel non-contrast multi-parametric MRI (mpMRI) protocol employing several complementary techniques in a single scan session for a comprehensive functional and structural evaluation of diabetic kidney disease (DKD).MethodsIn the cross-sectional part of this prospective observational study, 38 subjects aged 18‒79 years with type 2 diabetes and DKD (estimated glomerular filtration rate [eGFR] 15‒60 ml/min/1.73 m2), and 20 age- and gender-matched healthy volunteers (HV) underwent mpMRI. Repeat mpMRI was performed in 23 DKD subjects and 10 HV. By measured GFR (mGFR), 2 DKD subjects had GFR stage G2, 16 stage G3, and 20 stage G4/5. A wide range of MRI-biomarkers associated with kidney hemodynamics, oxygenation, and macro/micro-structure were evaluated. Their optimal sensitivity, specificity and repeatability to differentiate diabetic versus healthy kidneys, and categorize various stages of disease as well as their correlation with mGFR/albuminuria was assessed.ResultsSeveral MRI-biomarkers differentiated diabetic from healthy kidneys and distinct GFR stages (G3 versus G4/5); mean arterial flow (MAF) was the strongest predictor (sensitivity = 0.94 and 1.0, specificity = 1.00 and 0.69, p = 0.04 and 0.004, respectively). Parameters significantly correlating with mGFR were specific measures of kidney hemodynamics, oxygenation, microstructure and macrostructure, with MAF being the strongest univariate predictor (r = 0.92, p<0.0001).ConclusionsA comprehensive and repeatable non-contrast mpMRI protocol was developed that as a single, non-invasive tool allows functional and structural assessment of DKD, which has the potential to provide valuable insights into underlying pathophysiology, disease progression and analysis of efficacy/mode of action of therapeutic interventions in DKD

Glycaemic control and antidiabetic therapy in patients with diabetes mellitus and chronic kidney disease - cross-sectional data from the German Chronic Kidney Disease (GCKD) cohort

Background: Diabetes mellitus (DM) is the leading cause of end-stage renal disease. Little is known about practice patterns of anti-diabetic therapy in the presence of chronic kidney disease (CKD) and correlates with glycaemic control. We therefore aimed to analyze current antidiabetic treatment and correlates of metabolic control in a large contemporary prospective cohort of patients with diabetes and CKD. Methods: The German Chronic Kidney Disease (GCKD) study enrolled 5217 patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) between 30-60 mL/min/1.73 m(2) or proteinuria >0.5 g/d. The use of diet prescription, oral anti-diabetic medication, and insulin was assessed at baseline. HbA1c, measured centrally, was the main outcome measure. Results: At baseline, DM was present in 1842 patients (35 %) and the median HbA1C was 7.0 % (25th-75th percentile: 6.8-7.9 %), equalling 53 mmol/mol (51, 63);24.2 % of patients received dietary treatment only, 25.5 % oral antidiabetic drugs but not insulin, 8.4 % oral antidiabetic drugs with insulin, and 41.8 % insulin alone. Metformin was used by 18.8 %. Factors associated with an HbA1C level >7.0 % (53 mmol/mol) were higher BMI (OR = 1.04 per increase of 1 kg/m(2), 95 % CI 1.02-1.06), hemoglobin (OR = 1.11 per increase of 1 g/dL, 95 % CI 1.04-1.18), treatment with insulin alone (OR = 5.63, 95 % CI 4.26-7.45) or in combination with oral antidiabetic agents (OR = 4.23, 95 % CI 2.77-6.46) but not monotherapy with metformin, DPP-4 inhibitors, or glinides. Conclusions: Within the GCKD cohort of patients with CKD stage 3 or overt proteinuria, antidiabetic treatment patterns were highly variable with a remarkably high proportion of more than 50 % receiving insulin-based therapies. Metabolic control was overall satisfactory, but insulin use was associated with higher HbA1C levels

Blood pressure control in chronic kidney disease: A cross-sectional analysis from the German Chronic Kidney Disease (GCKD) study

We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30 +/- 60 mL/min/1.73 m 2 or overt proteinuria in the presence of an eGFR> 60 mL/min/1.73 m 2. Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use

Differential prognostic utility of adiposity measures in chronic kidney disease

Objective Adipose tissue contributes to adverse outcomes in chronic kidney disease (CKD), but there is uncertainty regarding the prognostic relevance of different adiposity measures. We analyzed the associations of neck circumference (NC), waist circumference (WC), and body mass index (BMI) with clinical outcomes in patients with mild to severe CKD. Methods The German Chronic Kidney Disease (GCKD) study is a prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate (eGFR): 30–60 mL/min/1.73 m2, or >60 mL/min/1.73 m2 in the presence of overt proteinuria. Associations of NC, WC and BMI with all-cause death, major cardiovascular events (MACE: a composite of non-fatal stroke, non-fatal myocardial infarction, peripheral artery disease intervention, and cardiovascular death), kidney failure (a composite of dialysis or transplantation) were analyzed using multivariable Cox proportional hazards regression models adjusted for confounders and the Akaike information criteria (AIC) were calculated. Models included sex interactions with adiposity measures. Results A total of 4537 participants (59% male) were included in the analysis. During a 6.5-year follow-up, 339 participants died, 510 experienced MACE, and 341 developed kidney failure. In fully adjusted models, NC was associated with all-cause death in women (HR 1.080 per cm; 95% CI 1.009–1.155), but not in men. Irrespective of sex, WC was associated with all-cause death (HR 1.014 per cm; 95% CI 1.005–1.038). NC and WC showed no association with MACE or kidney failure. BMI was not associated with any of the analyzed outcomes. Models of all-cause death including WC offered the best (lowest) AIC. Conclusion In Caucasian patients with mild to severe CKD, higher NC (in women) and WC were significantly associated with increased risk of death from any cause, but BMI was not

Neue extrahepatische Manifestationen von Hepatitis C Infektion nach Nieren- und Lebertransplantation

Chronic HCV infection is an important health problem in kidney and liver transplant recipients with a deleterious impact on both patient and graft survival. Apart from hepatic manifestations, HCV infection is also associated with a variety of extrahepatic manifestations both in native kidneys as well as after organ transplantation. Of these, essential mixed cryoglobulinemia with or without membranoproliferative glomerulonephritis is the most extensively documented one. In some of our pioneering work presented in this cumulative Habilitation, we identified a few other novel extrahepatic manifestations associated with HCV infection in kidney and/or liver transplant recipients, such as de novo renal thrombotic microangiopathy, chronic transplant glomerulopathy and new onset posttransplant diabetes mellitus. We also showed that the graft and/or patient survival may be affected by these extrahepatic manifestations associated with HCV infection or by virtue of the complications of antiviral therapy. Further, we identified increased insulin resistance i.e. impaired insulin sensitivity as the underlying mechanism for HCV-associated posttransplant diabetes mellitus in both liver and kidney transplant populations. More work is needed to further elucidate the implicated mechanisms and identify the potential strategies to prevent some of these specific extrahepatic syndromes after kidney and liver transplantation.Chronische HCV-Infektion ist ein bedeutendes Gesundheitsproblem bei Nieren-und Lebertransplantationspatienten mit erheblichen negativen Auswirkungen auf das Patienten- und Transplantatüberleben. Abgesehen von hepatischen Manifestationen, wird HCV-Infektion auch mit einer Vielzahl von extrahepatischen Manifestationen sowohl in gesunden Nieren wie auch nach Organtransplantation in Verbindung gebracht. Die essentielle gemischte Kryoglobulinämie mit oder ohne membranoproliferative Glomerulonephritis ist von allen die am besten dokumentierte extrahepatische Manifestationsform. In einigen unserer in dieser Habilitationsschrift zusammengefassten Originalarbeiten haben wir mehrere extrahepatischen Manifestationen von HCV Infektionen bei Nieren- oder Lebentransplantationsempfängern wie die de novo Nieren-thrombotische Mikroangiopathie, die chronische Transplantat- Glomerulopathie und neu auftretender Diabetes mellitus nach Transplantation entdeckt. Wir zeigten auch, dass das Transplantat- und / oder Patientenüberleben von den extrahepatischen Manifestationen mit einer HCV- Infektion oder aufgrund der Komplikationen einer antiviralen Therapie abhängig sein kann. Darüber hinaus identifizierten wir erhöhte Insulinresistenz, d.h. eingeschränkte Insulinsensitivität als den zugrunde liegenden Mechanismus für den HCV-assoziierten posttransplantations Diabetes mellitus bei sowohl Leber- wie auch Nierentransplantationspopulationen. Weitere Arbeiten sind erforderlich, um den zugrundeliegenden Mechanismen zu analysieren und mögliche Behandlungsstrategien zu identifizieren, um einige dieser spezifischen extrahepatischen Syndrome nach Nieren-und Lebertransplantation zu vermeiden