Renal Hemodynamics in Patients With HFpEF
Condition: Heart Failure With Normal Ejection Fraction
MeSH terms: Heart Failure
Study type: Observational

Summary: 
      Impaired renal function and heart failure with preserved ejection fraction (HFpEF) are two
      often co-existing medical conditions and are known to be associated with adverse
      cardiovascular outcome and increased mortality. The relationship between HFpEF and renal
      impairment is bidirectional. On the one hand, renal dysfunction has been shown to be an
      independent risk factor for the development of HFpEF. On the other hand, an increase in
      central venous pressure leading to renal dysfunction by a reduction of renal blood flow (RBF)
      and perfusion pressure (RPP) as well as activation of the renin-angiotensin-aldosterone
      system (RAAS) in patients with HFpEF has been previously described.

      In the literature, several studies aimed to investigate the association between renal (dys-)
      function and HFpEF. In all these studies, renal function was assessed by determination of
      standard kidney function parameters such as serum creatinine, eGFR and urinary albumin to
      creatinine ratio (UACR). Constant infusion input clearance technique however offers a more
      detailed evaluation of renal function and hemodynamics. To the best of knowledge, renal
      hemodynamics in patients with HFpEF have not yet been investigated by clearance technique.
      Therefore, the aim of the present study is to evaluate renal function and hemodynamics by
      means of constant infusion input clearance technique with sodium p-aminohippuric acid (PAH)
      and Iohexol in 40 patients with HFpEF. The constant infusion input clearance technique offers
      an exact evaluation of renal function by measuring (not estimating) glomerular filtration
      rate and renal hemodynamic parameters such as renal plasma flow (RPF), filtration fraction
      (FF) and intraglomerular pressure (IGP). These results will be compared to 140 subjects
      without HFpEF that have participated in various studies and have been analyzed with the same
      constant infusion input clearance technique performed in the Clinical Research Center of the
      University Hospital Erlangen-Nuremberg. Additionally, flow mediated vasodilation (FMD), pulse
      wave velocity and parameters of retinal vascular remodeling by means of scanning laser
      Doppler flowmetry (SLDF) will be assessed in patients with HFpEF thereby allowing to examine
      the relationship between vascular remodeling in the systemic and renal circulation.
    

Detailed description: 
      Several studies evaluating the outcome among patients with HFpEF revealed that this entity of
      heart failure (HF) is associated with high mortality rates and some studies even indicate
      that mortality is similar to patients with heart failure and reduced ejection fraction
      (HFrEF). Hospitalization for HFpEF is increasing relative to HFrEF, highlighting the need for
      a better understanding of the pathogenetic processes in order to develop new treatment
      strategies for this type of HF. Recently, the PARAMOUNT study revealed that in patients with
      HFpEF, treatment with the dual-acting angiotensin receptor neprilysin inhibitor (ARNI) LCZ696
      was associated with lower levels of creatinine and higher estimated glomerular filtration
      rates (eGFR) indicating a better preservation of renal function in comparison to treatment
      with valsartan only. Another observation of this study was an increase in urinary albumin to
      creatinine ratio (UACR) in the group of LCZ696-treatment, which was not visible in patients
      randomized to the valsartan group. Additionally, analysis of the relation between albuminuria
      and/or decreased eGFR and cardiovascular function and structure revealed that renal
      dysfunction was common in this group of patients and associated with cardiac remodeling and
      dysfunction.

      Up to two thirds of patients with HFpEF are suffering from chronic kidney disease (CKD). A
      bidirectional cardiorenal relation has been recently described and is known to be associated
      with adverse cardiovascular outcome and increased mortality. On the one hand, renal
      dysfunction has been shown to be an independent risk factor for the development of HFpEF due
      to inflammatory processes and endothelial dysfunction. On the other hand, an increase in
      central venous pressure leading to renal dysfunction by a reduction of renal blood flow (RBF)
      and perfusion pressure (RPP) as well as activation of the renin-angiotensin-aldosterone
      system (RAAS) in patients with HFpEF has been previously described.

      This association has also been demonstrated for patients with HFrEF. However, several studies
      comparing patients with the two subtypes of HF in the context of CKD indicate that this
      association is more pronounced in patients with HFpEF. For example, a community-based cohort
      study by Brouwers et al. including 8592 subjects of the PREVEND trial showed that renal
      function parameters such as urinary albumin excretion (UAE) and cystatin C were associated
      with a high risk for the development of HFpEF but not HFrEF. Ahmed et al. even reported a
      higher CKD-related mortality in HFpEF than in HFrEF patients with an underlying
      graded-response relation as CKD-associated mortality increased with higher left ventricular
      ejection fraction (LVEF). These findings suggest different pathogenetic processes for these
      two subtypes of HF. Therefore, detailed exploration of the pathophysiological mechanisms
      behind the relationship of HFpEF and renal function represents a matter of major research
      interest.

      Recently, several studies aimed to investigate the association between renal (dys-) function
      and HFpEF. Unger et al. retrospectively examined the relationship between renal function and
      echocardiographic parameters in 299 patients with HFpEF. The analysis revealed that CKD was
      independently associated with worse cardiac mechanics and outcomes in this population.9
      Studying 217 participants from the PARAMOUNT trial with HFpEF, Gori et al. demonstrated that
      renal dysfunction was associated with abnormal left ventricular geometry, lower midwall
      fractional shortening and higher NT-proBNP. In both studies, renal function was assessed with
      commonly used tests such as determination of serum creatinine, eGFR and urinary albumin to
      creatinine ratio (UACR). However, these parameters only allow an approximate estimation of
      renal function. Constant infusion input clearance technique offers a more complete approach
      towards evaluation of renal function and perfusion, allowing an exact quantification of
      glomerular filtration rate (GFR) and renal hemodynamic parameters such as renal plasma flow
      (RPF), filtration fraction (FF) and intraglomerular hemodynamics.

      The definition of HFpEF in literature is rather inconsistent. In some studies, HFpEF was
      defined by an ejection fraction of ≥ 45%, whereas other authors used a cut-off value of 50%.
      In the present study, the categorization of heart failure as HFpEF will follow the 2016
      European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and
      chronic heart failure applying a cut-off value of 50%.

      The purpose of the present study is to evaluate renal function and hemodynamics by means of
      constant infusion input clearance technique with PAH and Iohexol in 40 patients with HFpEF
      with the aim to better characterize the relationship between renal dysfunction and HFpEF.
      These results will be compared to 140 subjects without HFpEF who participated in different
      studies during which renal clearance examination has been performed with the constant
      infusion input clearance technique in the Clinical Research Center of the University Hospital
      Erlangen-Nuremberg. In parallel, pulse wave velocity, flow mediated vasodilation and other
      vascular parameters, reflecting the vascular wall properties of small and large arteries,
      will be assessed. Additionally, there will be a non-invasive retinal examination to assess
      vascular remodeling of retinal arterioles (wall to lumen ratio, WLR), retinal capillary flow
      (RCF) and capillary rarefaction.
    

Intervention name(s): Renal clearance examination
Intervention type(s): Other
Intervention description(s): Evaluation of renal hemodynamic parameters by constant-infusion input clearance technique with p-aminohippuric acid and Iohexol
Other intervention name(s): Scanning laser Doppler flowmetry, SphygmoCor, UnexEF
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        HFpEF patients: recruitment from the investigator's outpatient clinics and referring
        physicians.

        Control subjects without HFpEF: individuals who already participated in different studies
        during which renal clearance examination has been performed with the constant infusion
        input clearance technique in our Clinical Research Center (clin. gov. numbers: NCT00627952,
        NCT01835678, NCT00136188, NCT00905528, NCT00160745)
      
Biospecimen description: 
      -  Biochemistry (urea, serum creatinine, eGFR, cystatin C, uric acid, sodium, potassium,
           calcium, phosphate, lipid levels, total protein, SGOT, SGPT, AP, ɣ-GT)

        -  Hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood
           cell count)

        -  Fasting blood glucose, HbA1c

        -  NT-proBNP

        -  TSH

        -  Spot-urine (urinary creatinine and albumin, urinary sodium and potassium)

        -  Urinary dip stick analysis
    
Keywords: Heart failure; Renal clearance technique; Preserved ejection fraction