Merge code into master branch

README.md

@@ -1,2 +1,14 @@
 # RenalModel
 A quantitative systems physiology model of renal function and blood pressure regulation
+
+#####Author: K. Melissa Hallow
+University of Georgia
+Athens, GA
+10-15-2016
+
+***
+
+####Introduction
+The model describes the key physiological processes involved in renal function and its role in maintaining sodium and water homeostasis,  at the systems level based on the governing  physiological and feedback mechanisms (Figure 1). The model is not meant to be an exhaustive molecular to organ level model, but rather, to provide a backbone for further investigation. 
+
+![Alt text](/Schematic.png?raw=true "Optional Title")

calcNomParams_human.R

@@ -0,0 +1,333 @@
+calcNomParams <- function(){
+
+
+########################################################################################
+#Parameters of normal human physiology based on literature and commmon medical knowledge
+########################################################################################
+
+####Systemic parameters
+nominal_map_setpoint=93  		#mmHg
+CO_nom= 5					#L/min
+ECF_nom = 15				#L
+blood_volume_nom = 5			#L
+Na_intake_rate=100/24/60		#mEq/min  - 100mmol/day or 2300 mg/day
+nom_water_intake = 2.1			#L/day
+ref_Na_concentration=140 	   	#mEq/L
+plasma_protein_concentration = 7   	#g/dl
+equilibrium_serum_creatinine=0.92	#mg/dl
+P_venous=4					#mmHg
+R_venous=3.4				#mmHg
+nom_right_atrial_pressure=0.87 	#mmHg
+nom_mean_filling_pressure=7 		#mmHg
+venous_compliance = 0.13
+
+
+####Renal parameters
+nom_renal_blood_flow_L_min = 1	#L/min
+baseline_nephrons=2e6
+nom_Kf=3.9					#nl/min*mmHg
+nom_oncotic_pressure_difference= 28 #mmHg
+P_renal_vein=4  				#mmHg
+
+#Renal Vasculature
+nom_preafferent_arteriole_resistance= 19 	#mmHg
+nom_afferent_diameter=1.5e-5		 	#mmHg
+nom_efferent_diameter=1.1e-05 		#mmHg
+
+#Renal Tubules
+Dc_pt_nom  = 27e-6			#m
+Dc_lh = 17e-6				#m
+Dc_dt = 17e-6				#m
+Dc_cd = 22e-6				#m
+
+L_pt_s1_nom = 0.005			#m
+L_pt_s2_nom = 0.005			#m
+L_pt_s3_nom =0.004			#m
+L_lh_des = 0.01 				#m
+L_lh_asc = 0.01 				#m
+L_dct = 0.005				#m	
+L_cd = L_lh_des	
+
+tubular_compliance = 0.2	
+Pc_pt_mmHg = 14				#mmHg
+Pc_lh_des_mmHg = 10.5			#mmHg
+Pc_lh_asc_mmHg = 7			#mmHg
+Pc_dt_mmHg = 3				#mmHg
+Pc_cd_mmHg = 2				#mmHg
+P_interstitial_mmHg = 5
+nominal_pt_na_reabsorption=0.7	#fraction
+nominal_loh_na_reabsorption = 0.8	#fraction
+nominal_dt_na_reabsorption=0.5	#fraction
+LoH_flow_dependence = 1
+
+
+####RAAS Pathway parameters
+concentration_to_renin_activity_conversion_plasma = 61 
+nominal_equilibrium_PRA = 1000 	 	#fmol/ml/hr
+nominal_equilibrium_AngI = 7.5 		#fmol/ml
+nominal_equilibrium_AngII = 4.75 		#fmol/ml
+nominal_renin_half_life = 0.1733		# (hr)
+nominal_AngI_half_life = 0.5/60 		#(hr)
+nominal_AngII_half_life = 0.66/60 		#(hr)
+nominal_AT1_bound_AngII_half_life = 12/60 #hr
+nominal_AT2_bound_AngII_half_life = 12/60 #hr
+ACE_chymase_fraction = 0.95     		#% of AngI converted by ACE. The rest is converted by chymase
+fraction_AT1_bound_AngII = 0.75    		#assume AngII preferentially binds to AT1 vs AT2
+
+
+########################################################################################
+#The following parameters are calculated at equilibrium using the parameters above
+########################################################################################
+
+#This pressure is the setpoint that determines the myogenic response of the preafferent vasculature
+nom_preafferent_pressure = nominal_map_setpoint - nom_renal_blood_flow_L_min*nom_preafferent_arteriole_resistance;
+
+#This pressure is the setpoint that determines the myogenic response of the afferent vasculature
+nom_glomerular_pressure = nom_preafferent_pressure - nom_renal_blood_flow_L_min*(L_m3*viscosity_length_constant/(nom_afferent_diameter^4)/baseline_nephrons);
+
+#This pressure is the setpoint that determines the tubular pressure-natriuresis response 
+nom_postglomerular_pressure = nom_preafferent_pressure - nom_renal_blood_flow_L_min*(L_m3*viscosity_length_constant*(1/(nom_afferent_diameter^4)+1/(nom_efferent_diameter^4))/baseline_nephrons);
+
+RIHP0 = nom_postglomerular_pressure 	
+
+# The rate of sodium excretion must equal the rate of sodium intake. Sodium reabsorption rates vary along the tubule, but based on literature
+# measurements we have a good, and literature data provides estimates for these rates. However, there is a precise
+# rate of sodium reabsorption required to achieve the equilibrium defined by the parameters above.
+# Assuming that reabsorption rates are known in all but one segment of the tubule, the exact rate
+# of reabsorption of the remaining segment can be calculated. We chose to calculate the CD rate of reabsorpion based on estimates for
+# PT, LoH, and DT reabsorption.  
+nom_GFR = nom_Kf*(nom_glomerular_pressure - nom_oncotic_pressure_difference - (Pc_pt_mmHg+P_interstitial_mmHg))/nL_mL*baseline_nephrons;
+nom_filtered_sodium_load = nom_GFR/L_mL*ref_Na_concentration;
+nom_PT_Na_outflow = nom_filtered_sodium_load*(1-nominal_pt_na_reabsorption);
+
+nom_Na_in_AscLoH = nom_PT_Na_outflow/baseline_nephrons;
+AscLoH_Reab_Rate =(2*nominal_loh_na_reabsorption*nom_Na_in_AscLoH)/L_lh_des; #osmoles reabsorbed per unit length per minute. factor of 2 because osmoles = 2
+
+nom_LoH_Na_outflow = nom_PT_Na_outflow*(1-nominal_loh_na_reabsorption);
+nom_DT_Na_outflow = nom_LoH_Na_outflow*(1-nominal_dt_na_reabsorption);
+nominal_cd_na_reabsorption = 1-Na_intake_rate/nom_DT_Na_outflow;
+
+
+
+#RBF = (MAP - P_venous)/RVR. Given MAP, P_venous, RBF, and preafferent, afferent, and efferent resistances, the remaining peritubular resistance at steady state can be determined
+nom_RVR = (nominal_map_setpoint - P_venous)/nom_renal_blood_flow_L_min
+nom_peritubular_resistance = nom_RVR - (nom_preafferent_arteriole_resistance + L_m3*viscosity_length_constant*(1/nom_afferent_diameter^4+1/nom_efferent_diameter^4)/baseline_nephrons);
+
+
+#Given the values for baseline MAP and CO above, the baseline TPR required to maintain this MAP and CO can be calculated. Since TPR includes renal vascular resistance, the baseline systemic (non-renal) resistance
+#can be calculated from this TPR and the values for baseline renal resistances defined above. 
+nom_TPR = nominal_map_setpoint/CO_nom
+nom_systemic_arterial_resistance= nom_TPR-R_venous
+
+#Creatinine synthesisrate at equilibrium
+creatinine_synthesis_rate  = equilibrium_serum_creatinine * dl_ml * nom_GFR #Units: mg/min
+
+
+####RAAS Pathway parameters
+#Values for half lives and equilibrium concentrations of RAAS peptides available in the literature and 
+# defined above to calculate nominal values for other RAAS parameters not available in the literature:
+#ACE activity
+#Chymase activity
+#AT1 receptor binding rate
+#AT2 receptor binding rate
+#equilibrium AT1_bound_AngII
+#These values are then assumed to be fixed unless specified otherwise.
+#Calculating these nominal parameter values initially in a separate file is required so that these parameters can then be varied independently in the main model
+nominal_equilibrium_PRC = nominal_equilibrium_PRA/concentration_to_renin_activity_conversion_plasma
+nominal_AngI_degradation_rate = log(2)/nominal_AngI_half_life #/hr
+nominal_AngII_degradation_rate = log(2)/nominal_AngII_half_life #/hr
+nominal_AT1_bound_AngII_degradation_rate = log(2)/nominal_AT1_bound_AngII_half_life
+nominal_AT2_bound_AngII_degradation_rate = log(2)/nominal_AT2_bound_AngII_half_life
+#ACE converts 95% of AngI, chymase converts the rest
+nominal_ACE_activity = (ACE_chymase_fraction*(nominal_equilibrium_PRA - nominal_AngI_degradation_rate*nominal_equilibrium_AngI)/nominal_equilibrium_AngI)#Therapy_effect_on_ACE
+nominal_chymase_activity = (1-ACE_chymase_fraction)*(nominal_equilibrium_PRA - nominal_AngI_degradation_rate*nominal_equilibrium_AngI)/nominal_equilibrium_AngI
+#75% of bound AngII is AT1, the rest is AT2
+nominal_AT1_receptor_binding_rate = fraction_AT1_bound_AngII*(nominal_equilibrium_AngI*(nominal_ACE_activity+nominal_chymase_activity)-nominal_AngII_degradation_rate*nominal_equilibrium_AngII)/nominal_equilibrium_AngII
+nominal_AT2_receptor_binding_rate = (1-fraction_AT1_bound_AngII)*(nominal_equilibrium_AngI*(nominal_ACE_activity+nominal_chymase_activity)-nominal_AngII_degradation_rate*nominal_equilibrium_AngII)/nominal_equilibrium_AngII
+nominal_equilibrium_AT1_bound_AngII = nominal_equilibrium_AngII*nominal_AT1_receptor_binding_rate/nominal_AT1_bound_AngII_degradation_rate
+nominal_equilibrium_AT2_bound_AngII = nominal_equilibrium_AngII*nominal_AT2_receptor_binding_rate/nominal_AT2_bound_AngII_degradation_rate
+
+########################################################################################
+#The following parameters were determined indirectly from many different literature studies on the response
+#various changes in the system (e.g. drug treatments, infusions of peptide, fluid, sodium, etc.....)
+########################################################################################
+
+#Effects of AT1-bound AngII on preafferent, afferent, and efferent resistance, and aldosterone secretion
+AT1_svr_slope = 0
+AT1_preaff_scale = 0.5
+AT1_preaff_slope = 7 
+AT1_aff_scale=0.5
+AT1_aff_slope=7
+AT1_eff_scale=0.3
+AT1_eff_slope=7
+AT1_PT_scale = 0.1
+AT1_PT_slope = 7
+AT1_aldo_slope = 0.05
+
+
+#Effects of Aldosterone on distal and collecting duct sodium reabsorption
+nominal_aldosterone_concentration=85
+aldo_DCT_scale=0
+aldo_DCT_slope = 0.5
+aldo_CD_scale=0.3
+aldo_CD_slope = 0.5
+aldo_renin_slope =-0.05
+
+#Na and water transfer between blood, ECF
+Q_water = 1
+Q_Na = 1
+
+#Osmolarity control of vasopressin secretion
+Na_controller_gain=2  
+Kp_VP = 0.05
+Ki_VP = 0.00002
+
+nom_ADH_urea_permeability = .98
+nom_ADH_water_permeability = .98
+
+#Effects of Vasopressin on water intake and reabsorption
+nominal_vasopressin_conc=4
+water_intake_vasopressin_scale = 0#1.5
+water_intake_vasopressin_slope = -0.5
+
+
+#Magnitude and Steepness of tubuloglomerular feedback
+S_tubulo_glomerular_feedback=0.7
+F_md_scale_tubulo_glomerular_feedback=6
+MD_Na_concentration_setpoint = 62.4
+
+#Effect of macula densa sodium flow on renin secretion 
+md_renin_A = 1
+md_renin_tau = 2
+
+#Responsiveness of renal vasculature to regulatory signals
+preaff_diameter_range=0.25
+afferent_diameter_range=1.2e-05 
+efferent_diameter_range=3e-06 
+preaff_signal_nonlin_scale=3
+afferent_signal_nonlin_scale=3
+efferent_signal_nonlin_scale=3
+
+#RAAS pathway (these parameters can be set to different values than used to calculate the equilibrium state above)
+AngI_half_life=0.008333 
+AngII_half_life=0.011 
+AT1_bound_AngII_half_life=0.2 
+AT1_PRC_slope=-1.2 
+AT1_PRC_yint=0
+AT2_bound_AngII_half_life=0.2
+concentration_to_renin_activity_conversion_plasma=61
+fraction_AT1_bound_AngII=0.75
+nominal_ACE_activity=48.9
+ nominal_AT1_receptor_binding_rate=12.1
+nominal_AT2_receptor_binding_rate=4.0 
+nominal_chymase_activity=1.25  
+nominal_equilibrium_AT1_bound_AngII=16.63
+nominal_equilibrium_PRC=16.4 
+renin_half_life=0.1733 
+
+#Transfer constants for ODEs - determine speed of processes
+C_aldo_secretion=1000
+C_P_bowmans = 1000
+C_P_oncotic = 1000
+
+C_tgf_reset=0
+C_cardiac_output_delayed=.001
+C_co_error=0.00001
+C_vasopressin_delay = 1
+
+C_md_flow = 0.001 #Time delay between MD sodium flow and renin secretion
+C_tgf=1
+C_na_excretion_na_amount=-1
+C_na_intake_na_amount=1
+C_urine_flow_ecf_volume=-1
+C_water_intake_ecf_volume=1
+C_Na_error=1/6
+C_serum_creatinine = 1
+
+
+
+#Therapy effects
+HCTZ_effect_on_DT_Na_reabs = 1 
+HCTZ_effect_on_renin_secretion = 1
+DRI_effect_on_PRA = 1
+CCB_effect_on_preafferent_resistance = 1
+CCB_effect_on_afferent_resistance = 1
+CCB_effect_on_efferent_resistance = 1
+MR_antagonist_effect_on_aldo_MR = 1
+pct_target_inhibition_ARB = 0 
+pct_target_inhibition_ACEi = 0 
+
+
+#Metabololic tissue autoregulation of cardiac output
+tissue_autoreg_scale=1
+Kp_CO=1.5
+Ki_CO=30
+
+
+#Normalized_aldo_secretion
+K_Na_ratio_effect_on_aldo = 1; 
+
+#Renal autoregulation of glomerular pressure
+gp_autoreg_scale=0
+preaff_autoreg_scale = 0.5
+myogenic_steepness=2
+
+
+#Pressure natiuresis effect 
+
+max_pt_reabs_rate = 0.995
+pressure_natriuresis_PT_scale = 3
+pressure_natriuresis_PT_slope = 1
+
+pressure_natriuresis_LoH_scale = 3
+pressure_natriuresis_LoH_slope = 1
+
+pressure_natriuresis_DCT_scale = 3
+pressure_natriuresis_DCT_slope = 1
+
+max_cd_reabs_rate = 0.995
+pressure_natriuresis_CD_scale = 3
+pressure_natriuresis_CD_slope=1
+
+
+
+#Constants and Unit conversions
+nL_mL=1e+06
+dl_ml=0.01
+L_dL=10
+L_mL=1000
+L_m3=0.001
+g_mg=0.001
+ng_mg=1e-06
+secs_mins=60
+min_hr=60
+hr_day=24
+min_day=1440
+MW_creatinine=113.12
+Pi=3.1416
+pi=3.14
+viscosity_length_constant=1.5e-09 
+gamma =  1.16667e-5;  #  viscosity of tubular fluid
+mmHg_Nperm2_conv = 133.32
+
+
+#Scaling parameters - can be used to parameterize model for other species
+ECF_scale_species = 1
+BV_scale_species=1
+water_intake_species_scale = 1
+CO_scale_species = 1
+
+
+t=sort(ls())
+param=sapply(t,names)
+for (i in 1:length(t)){
+  param[i]=get(t[i])
+}
+param$param=NULL
+
+return(param)
+}
+
+
+
+