Dienstag, 18.08.2020

14:00 - 15:30

Poster DGfN 2020

Diabetes (P045 - P047; LA12)

Consistent Effects of Empagliflozin on Cardiovascular and Kidney Outcomes Irrespective of Diabetic Kidney Disease Categories – Insights from the EMPA-REG OUTCOME trial

C. Wanner, S. E. Inzucchi, B. Zinman, A. Koitka-Weber, M. Mattheus, J. George, M. von Eynatten, B. J. Kraus, S. Hauske; Würzburg, New Haven/USA, Toronto/CDN, Ingelheim

Objective: Diabetes is the leading cause of end-stage kidney disease. Furthermore, elevated albuminuria predicts increased cardio-renal risk. Diabetic Kidney Disease (DKD) is generally characterised by high levels of albuminuria, usually referred to as overt albuminuria (urinary albumin-to-creatinine ratio [UACR] >300 mg/g). However, recent evidence indicates a shift towards phenotypes without overt albuminuria, (UACR ≤300 mg/g). Currently there is no approved treatment for non-albuminuric forms of DKD. There is a need for interventions that could lower cardio-renal risk in patients with DKD across the spectrum of albuminuria. Although the phenotype without overt albuminuria is now representing the most common form of DKD, this subgroup is rarely studied in clinical trials. We investigated the effect of empagliflozin on cardio-renal outcomes in both clinical phenotypes of DKD, with and without overt albuminuria at baseline from EMPA-REG OUTCOME.
Method: This was a post hoc analysis of the EMPA-REG OUTCOME placebo-controlled randomised clinical trial. Participants with type 2 diabetes, glycated haemoglobin ≥7% to ≤10%, and established cardiovascular (CV) disease were randomised (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo, in addition to standard of care. Patients with different clinical phenotypes of DKD at baseline were categorised in three subgroups: 1) albuminuric DKD (overt albuminuria [UACR >300 mg/g] with any eGFR; n=769); 2) non-albuminuric DKD (renal impairment [eGFR <60 ml/min/1.73m²] without overt albuminuria [UACR ≤300mg/g]; n=1290); 3) ‘all others’ (eGFR ≥60 ml/min/1.73m² without overt albuminuria; n=4893). Analyses included CV outcomes (CV death, hospitalisation for heart failure, all-cause hospitalisation) and selected kidney outcomes, change in eGFR, and renal safety. Cox proportional hazards models were used to assess consistency of treatment effect across subgroups.
Results: Empagliflozin significantly reduced the risk of CV and kidney outcomes across all subgroups (p-values for interaction >0.05), consistent with findings in the overall trial population. Empagliflozin also significantly lowered the annual loss of eGFR, assessed by chronic slopes, in all subgroups. The adverse event profile of empagliflozin was similar across all subgroups.
Conclusion: Empagliflozin may improve CV and kidney outcomes and slow the progression of kidney disease in type 2 diabetes patients with DKD, irrespective of its clinical phenotype, both with or without the presence of overt albuminuria.

Peritoneal dialysis in patients with diabetes mellitus – practical insights and center experience with an interdisciplinary approach

M. Guthoff, M. Sayer, F. Artunc, A. L. Birkenfeld, N. Heyne; Tübingen, Dresden

Objective: Peritoneal dialysis (PD) is challenging in patients with diabetes mellitus with respect to glucose control, especially in patients with low residual beta-cell function and PD regimens containing high glucose solutions. In individual patients, this may limit both access to and time on peritoneal dialysis. As a large university PD center, we describe our experience with a comprehensive interdisciplinary approach to PD patients with diabetes.
Method: In parallel to the implementation of an urgent start program, an interdisciplinary approach to patients with diabetes was established. In a case-based manner, specific key aspects of this approach are presented, focusing on glucose monitoring, treatment of diabetes and PD regimen.
Results: For monitoring glucose control, HbA1c is not a reliable marker in patients on PD, nor is glycated albumin. Glucose self-monitoring is useful but will leave gaps with unrecognized hypo- and hyperglycemia. Even though not officially labelled in dialysis patients, continuous glucose monitoring (CGM) reflects glucose best and can also be used in PD patients to detect highs and lows, especially during night.
External insulin administration is associated with severe risk of hypoglycemia in patients on dialysis, due to markedly reduced clearance, a fact to be kept in mind when titrating insulin doses. In patients on APD, NPH-insulin, which might additionally be combined with a bolus of regular insulin, is best to control nighttime hyperglycemia. In patients on CAPD, additional rapid acting insulin analogue can help to attenuate post-infusion hyperglycemia. Glucose sparing solutions and timing of dwell and meals may further contribute to minimizing glucose peaks.
Conclusion: Diabetes mellitus is not a contraindication for PD, however, practical management of glucose control may be challenging. A diabetologist´s view significantly adds to the nephrologists’ expertise in initiating and maintaining PD, assuring dialysis adequacy and avoiding complications. An interdisciplinary approach enables for adequate care of these patients.

Intravital Single Nephron GFR Assessment reveals glomerular protective mechanism by ACE inhibition in STZ diabetic mice

H. Kröger, F. Kessel, J. Sradnick, F. Gembardt, N. Bunk, M. Gerlach, V. Todorov, C. Hugo; Dresden

Objective: Diabetes mellitus is one of the main reasons for the development of end stage renal disease in patients. Diabetic nephropathy is pathophysiological marked by glomerular hyperfiltration. ACE inhibition leads to a general decrease in GFR, thus having protective effects in the progression of diabetic nephropathy. Here, we describe a detailed analysis of functional (Single Nephron GFR) factors for single glomeruli during disease and treatment. Therefore, we use longitudinal intravital microscopy as an advanced technique to visualize dynamic processes and disease parameters on a single glomerular level.
Method: C57BL/6J mice were treated with low dose STZ for five days (7,5 mg/kg). Controls received the same volume of buffer. 35 days after onset of diabetes (blood glucose > 25 mmol/L) and 24 hours before initial microscopy abdominal body windows were implanted for repeated kidney imaging without further surgery. Single superficial glomeruli were longitudinally examined (d0, d3) by 2-photon microscopy. After initial microscopy (d0) enalapril administration (7,5 mg/kg/day) via drinking water started. Fluorescent dyes visualized the glomeruli. SN GFR was measured in superficial glomeruli by injection of freely filtered Lucifer Yellow. SN GFR was then semi automatically calculated in 10 glomeruli by measuring the fluorescence intensity change over the length of the early proximal tubular segment. We analyzed the data with ImageJ, 3D analysis was performed with Bitplane Imaris.
Results: On the first day of microscopy, STZ diabetic mice showed up to four fold elevated SN GFR compared to healthy controls. Administration of enalapril for three days reduced SN GFR by 50% in diabetic mice but did not influence SN GFR in normal control mice.
Conclusion: By utilizing advanced microscopy techniques in live animals we show the influence of diabetes and direct regulatory effects of intervention with enalapril on single glomerular filtration function. With this new approach, we are able to characterize longitudinal the effects of disease progression and medical intervention on functional and morphological parameters in single glomeruli.

Poor performance of estimated glomerular filtration rate in detecting glomerular hyperfiltration in patients with type 2 diabetes

J. Kolwelter, K. Striepe, A. Bosch, D. Kannenkeril, C. Ott, M. Schiffer, R. E. Schmieder; Erlangen

Objective: Diabetic nephropathy is a serious complication in patients with diabetes and is associated with higher cardiovascular mortality and total death. In the early stage of renal involvement, glomerular hyperfiltration is often found in patients with type 2 diabetes (T2DM, 6-73%), preceding the onset on albuminuria, leading to a slow decline of renal function and finally to end-stage kidney disease. The disease course shows how important it is to detect early glomerular hyperfiltration. Currently, clinicians rely on estimating equations on daily basis. Our study aim was to assess the identification of patients with glomerular hyperfiltration by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
Method: In a cross-sectional study, we analysed 190 patients with T2DM in the early stage of their disease, having no overt renal impairment by the CKD-EPI equation. In each patient, we measured glomerular filtration rate (mGFR) and renal plasma flow (RPF) by applying constant infusion input clearance technique with inulin. Simultaneously, a standardized analysis of serum creatinine was performed and eGFR was estimated by the CKD-EPI equation (eGFR). In our study cohort, glomerular hyperfiltration was defined as mGFR by inulin clearance above 138±10 ml/min/1.73m² and eGFR by estimating equations above 128±15 ml/min/1.73m² (see review CJASN 2015;10:382-9). Alternatively, we used the 90th percentile of eGFR as glomerular hyperfiltration threshold, corresponding in our cohort to 110 ml/min/1.73m².
Results: A total of 190 patients were enrolled, aged 59±9 years and including 135 (71%) males. Median value for known diabetes duration was 5.4 years (interquartile range 2.6-8.6) and mean value for HbA1c was 7.1±0.9%. Average mGFR was 111±20 ml/min/1.73m², whereas eGFR was lower with 93±13 ml/min/1.73m². 12 (6.3%) out of 190 patients showed glomerular hyperfiltration according to mGFR, whereas only one patient (0.5%) showed glomerular hyperfiltration according to eGFR. If we use the 90th percentile of eGFR as threshold of glomerular hyperfiltration, 19 (10%) patients were detected. Only one (0.5%) of this 19 patients was identified correctly by eGFR and the remaining patients were misclassified as they all had an mGFR < 138 ml/min/1.73m².
Conclusion: In our analysis, the CKD-EPI equation was not accurately enough to detect patients in the early stage of T2DM with glomerular hyperfiltration and thereby at risk for diabetic kidney disease.


Fragen und Antworten der Posterbewerter und Autoren

Kommentar von Thomas Ebert |

1) Would results change if cystatin C-CKD-EPI equations had been used, i.e. combined creatinine-cystatinC equation or cystatin c-equation?
2) What about other equations. At the virtual EASD meeting 2020, the revised Lund-Malmö equations performed best in patients with diabetes.

Kommentar von Thomas Ebert |

1) As albuminuria is associated with mortality already in the normoalbuminuric category (Prevend study), woudl the results change if the groups were separated by an UACR cutoff at 30 mg/g, i.e. KDIGO A1 vs. KDIGO A2+A3?
2) How did the authors calculate the eGFR slope, as linear regression analyses for each individual patient and then averaging the standardized B?

Kommentar von Julie Kolwelter |

1) In our study population, the analysis with CKD-EPI cystatin C equation and with CKD-EPI creatinine-cystatin C equation lead to similar results as the CKD-EPI equation. The detection of patients with glomerular hyperfiltration was not accurate with these alternative estimating equations.
2) We have not done the analysis with the revised Lund-Malmö equation. We will consider adding it to our further analysis.

Thank you for your insightful comments and constructive criticism.

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