Patient case: 72-year-old male with melanoma; genetic feature: TP53 loss of function

Clinical trial: Nephron Sparing Renal Surgery and Total Nephrectomy

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.

Eligibility: Inclusion Criteria:
  1. Patients suspected to have renal tumors by CT/Ultrasonic-scanning and eligible for intervention.
  2. Healthy kidney donors scheduled for donation
  3. Patients aged between 25 and 80 years
  4. Patients can read and understand Danish
  Exclusion Criteria:
  1. Severe hypertension or congestive heart failure in New York Heart Association (NyHA) classes III-IV.
  2. Renal insufficiency with glomerular filtration rate (eGFR) <50%
  3. Failure to comply

Relevance to patient case: not relevant