Nephron Sparing Renal Surgery and Total Nephrectomy
Condition: Kidney Diseases
MeSH terms: Kidney Diseases
Study type: Observational [Patient Registry]

Summary: 
      The incidence of the diagnosis of renal cell carcinoma has increased during the past two
      decades because of the detection of small renal tumours that occur incidentally because of
      increased use of CT-scanning (1,2). Postoperative renal insufficiency was a significant
      independent predictor of overall and cardiovascular specific survival (3). "Nephron-sparing"
      surgical techniques are now preferred for small tumor masses and laparoscopic intervention is
      replacing open surgery at centers that master this technique. This is an area of priority
      within the Regions of Zaeland and Southern Denmark.

      The primary endpoint is:

      The early plasma (5 days) [NT-proBNP] response predicts long-term total renal function and
      function of the remaining kidney.

      The second endpoint:

      Plasma [NT-proBNP] increases acutely after partial nephrectomy and the change reflects the
      renal mass reduction.

      Chronic blood pressure change is inversely related to plasma [BNP].
    

Detailed description: 
      Irreversible kidney damage is described beyond thirty minutes of warm ischemia time (WIT),
      even in completely normal systems (4). Gill et al. (5) reported 18% kidney function loss
      after thirty-two minutes of WIT. Preliminary data from our center shows a reduction in WIT to
      eleven minutes (6) associated with a reduction in renal function loss to 11%. There is
      however, an increasing need to understand the pathophysiology associated with partial
      nephrectomy procedure beyond the ischemia time and a need for biomarkers with predictive
      value in order to create an evidence-based, mechanistic frame for protective intervention.
      The current proposal seeks to address these issues in this highly specialized area.

      Specific background for the study After unilateral total nephrectomy, the contralateral
      kidney within hours undergoes a functional adaptation with an increase in renal blood flow
      (RBF) and glomerular filtration rate(GFR) and thereby maintains whole body fluid and
      electrolyte homeostasis. In a collaborative project (Schweda et al. submitted), we show that
      the cardiac hormone "Brain Natriuretic Peptide", BNP (measured as the prohormone NT-pro-BNP),
      but not Atrial Natriuretic Peptide (ANP), could play an important role in this adaptation.
      Plasma [NT-proBNP] rapidly increases 6-fold in human kidney donors. The figure shows single
      kidney GFR (left) and plasma NT-proBNP (right) before total unilateral nephrectomy (UNx) and
      4 days after in family kidney donors. In animal experiments, BNP infusion to mice increases
      GFR and RBF and targeted deletion of the receptor for BNP (GC-A) abolished these effects. BNP
      relaxed microdissected intrarenal human arteries isolated in our center. For termination of
      action, BNP depends to a large degree on renal excretion and thus our data could suggest an
      "automatic", built-in protective mechanism when renal function displays an acute decline. In
      fact, its clinical utility as a biomarker in cardiology for ventricular function/load is
      discussed in relation to its dependence on renal function for excretion. Thus renal
      dysfunction is a cause for elevated BNP in the absence of left ventricular dysfunction (7) It
      is clear that 1) NT-proBNP changes parallel to BNP, and 2) and they are equally dependent on
      renal function for their clearance (8). Degradation of peptides occur enzymatically and, of
      note, there is a beneficial effect of Dipeptidyl peptidase 4 (DPP4) inhibitors on kidney
      function during ischemic injury of kidney (9). Since BNP signals through a series of
      catalytic receptors with guanylyl cyclase activity and cyclic guanidine monophosphate (cGMP)
      formation, it is highly interesting that administration of phosphodiesterase-5 (PDE-5)
      inhibitor sildenafil improved immediate renal function in an kidney autotransplant pig model
      and in a warm ischemia-reperfusion pig model (10,11). Moreover, mice deficient in the
      receptor for ANP and BNP (GC-A) display hypertension. It is therefore likely that BNP
      increases acutely in the immediate post-nephrectomy phase which promotes glomerular
      filtration in remaining nephrons and contributes to maintain low blood pressure (12). There
      is a paucity of direct examinations of the mechanistic relationship between renal function
      and plasma BNP. This is now possible in a setting with acute surgical removal of defined
      renal mass. We aim to characterize acute and longitudinal changes in BNP (NT-proBNP) in
      patients with e.g partial nephrectomy and other "nephron-sparing" interventions and compare
      them to total nephrectomy patients with respect to correlation to GFR and prediction of
      long-term renal function.

      Aim of the Study The overall aims are to preserve and protect remaining kidney function and
      improve the long-term renal outcome of renal surgical intervention with renal mass reduction.

      Objective The project aim is to investigate the functional response and predictive
      significance of Brain Natriuretic Peptide (NT-proBNP) for renal function and blood pressure
      level after renal surgical intervention and in particular, to focus on the changes after
      partial nephrectomy compared to total nephrectomy.

      Specific Hypotheses

        1. The early plasma (5 days) [NT-proBNP] response predicts long-term total renal function
           and function of the remaining kidney (primary effect)

        2. Plasma [NT-proBNP] increases acutely after partial nephrectomy and the change reflects
           the renal mass reduction

        3. Chronic blood pressure change is inversely related to plasma [BNP] Design: The study is
           designed as an observational, longitudinal study where plasma [NT-proBNP], renal
           function and blood pressure is followed in patients undergoing partial or total
           nephrectomy ("nephron sparing surgery") and relate this to plasma BNP.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        The study is designed as an observational, longitudinal study where plasma [NT-proBNP],
        renal function and blood pressure is followed in patients undergoing partial or total
        nephrectomy ("nephron sparing surgery") and relate this to plasma BNP.