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. 2018 Feb 6;8(1):20160134.
doi: 10.1098/rsfs.2016.0134. Epub 2017 Dec 15.

Simulating a Virtual Population's Sensitivity to Salt and Uninephrectomy

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Free PMC article

Simulating a Virtual Population's Sensitivity to Salt and Uninephrectomy

John S Clemmer et al. Interface Focus. .
Free PMC article

Abstract

Salt sensitivity, with or without concomitant hypertension, is associated with increased mortality. Reduced functional renal mass plays an important role in causing salt-sensitive hypertension for many individuals. Factors that are important in the condition of decreased renal mass and how they affect blood pressure (BP) or salt sensitivity are unclear. We used HumMod, an integrative mathematical model of human physiology, to create a heterogeneous population of 1000 virtual patients by randomly varying physiological parameters. We examined potential physiological mechanisms responsible for the change in BP in response to high-salt diet (8× change in salt intake for three weeks) with full kidney mass and again after the removal of one kidney in the same group of virtual patients. We used topological data analysis (TDA), a clustering algorithm tool, to analyse the large dataset and separate patient subpopulations. TDA distinguished five unique clusters of salt-sensitive individuals (more than 15 mmHg change in BP with increased salt). While these clusters had similar BP responses to salt, different collections of variables were responsible for their salt sensitivity, e.g. greater reductions in glomerular filtration rate (GFR) or impairments in the renin-angiotensin system. After simulating uninephrectomy in these virtual patients, the three most salt-sensitive clusters were associated with a blunted increase in renal blood flow (RBF) and higher increase in loop and distal sodium reabsorption when compared with the salt-resistant population. These data suggest that the suppression of sodium reabsorption and renin-angiotensin system is key for salt resistance, and RBF in addition to GFR may be an important factor when considering criteria for kidney donors. Here, we show that in our model of human physiology, different derangements result in the same phenotype. While these concepts are known in the experimental community, they were derived here by considering only the data obtained from our virtual experiments. These methodologies could potentially be used to discover patterns in patient sensitivity to dietary change or interventions and could be a revolutionary tool in personalizing medicine.

Keywords: hypertension; kidney; mathematical modelling; salt; salt sensitivity; topological data analysis.

Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Figure 1.
Figure 1.
Mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR) during chronic changes in salt intake (90–720 mmol d−1). (a) MAP, (b) CO and (c) TPR for normal (100% kidney mass) are denoted by solid lines and by dotted lines for the nephrectomy simulation (50% kidney mass).
Figure 2.
Figure 2.
Renal haemodynamics and renal resistance during changes in salt intake. (a) Glomerular filtration rate, (b) renal blood flow, (c) afferent arteriolar resistance and (d) efferent arteriolar resistance during changes in salt intake from 90 to 720 mmol d−1 in the virtual population before and after kidney removal.
Figure 3.
Figure 3.
Plasma angiotensin II (Ang II), aldosterone and atrial natriuretic peptide (ANP) in response to chronic changes in salt intake. Changes in (a) Ang II, (b) plasma aldosterone and (c) ANP from low to high salt intake.
Figure 4.
Figure 4.
Reabsorption of sodium (Na+) at different nephron segments at different salt intakes. (a) Proximal tubular (PT), (b) loop, (c) distal tubular (DT) and (d) collecting duct (CD) Na+ reabsorption in mmol min−1 for the entire population at two kidney masses.
Figure 5.
Figure 5.
Clustering of the 1000 virtual patients with full kidney mass using TDA. Salt-sensitive clusters are designated with darker blue/purple colouring and labelled 1–5. The colour legend indicates the change in blood pressure (BP) from 90 to 720 mmol d−1.
Figure 6.
Figure 6.
Absolute changes from low to high salt in (a) mean arterial pressure (MAP) and (b) total peripheral resistance (TPR) of the salt resistant (SR) and salt-sensitive clusters (1–5) in the full kidney mass population.
Figure 7.
Figure 7.
Absolute changes from low to high salt in (a) glomerular filtration rate (GFR), (b) renal blood flow (RBF) and renal (c) afferent and (d) efferent arteriolar resistances for the salt resistant (SR) and salt-sensitive clusters (1–5) in the full kidney mass population.
Figure 8.
Figure 8.
Absolute changes from low to high salt in (a) plasma angiotensin II (Ang II) concentration, (b) proximal tubular (PT) sodium (Na+) reabsorption, (c) loop Na+ reabsorption and (d) distal tubular (DT) Na+ reabsorption for the salt resistant (SR) and salt-sensitive clusters (1–5) in the full kidney mass population.
Figure 9.
Figure 9.
Absolute changes in (a) mean arterial pressure (MAP), (b) plasma angiotensin II (Ang II) concentration, (c) renal blood flow (RBF), (d) glomerular filtration rate (GFR), (e) afferent arteriolar resistance and (f) loop sodium (Na+) reabsorption from low to high salt for the original salt resistant (SR) and salt-sensitive clusters (1–5) at 50% kidney mass.

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