General renal pathophysiology

• 1. Relationship between plasma solute concentration and its excretion by kidneys

• 2. Renal perfusion and filtration

1. Relationship between plasma solute concentration and its excretion by kidneys

General scheme of a feedback regulation (Fig. 1)

1

The activity of kidneys could be represented as an activity of a controlling organ, maintaining (together with lungs and gastrointestinal tract) the composition of plasma at a constant level. Homeostased levels of plasma components are deviated by disturbing influences, from the point of view of renal excretory functions, predominantly by sc. extrarenal load (EL) of various metabolites.

Plasma concentration of solutes (PX) is disturbed by extrarenal load. On the other hand, it itself interferes with individual components of EL (with production, supply, metabolism, and storage of a substance).PX is corrected by renal excretion. However, it must have a possibility to modify the excretion in a feebdback manner; this is realized by a direct, trivial manner during filtration, or indirectly by neural and hormonal feedbacks (Fig. 2)

K+

Ca2+

HPO42-

H+

.

.

.

Feedback homeostasing of plasma components by kidneys

EL

Controlling organ (kidney)

Controlling systems

Filtration

Resorption Control- ler

Controlled system (plasma)

GFR * Px = (V * Ux)With simple filtration (creatinine, inulin)More complicated instan-ces of direct effects of Px

(Fig. 8 and 9)Concentration of substan-ces in tubular cells

Control viaN.S., ADH, ALDO, PTH

Signals to the controlling systems

Indirect effects of Px2

Direct effects of Px

.

on zero value (creatinine, uric acid)

Substances are on a “precise” value (Na+, K+, H+,...)homeostased

above a threshold – on its value (HPO4

--, glucose in hyperglycaemia)

In detail:

1. If PX rises due to enhanced ELX with an undisturbed renal function (normal glomerular filtration rate, GFR), a new steady state is established after some time, where EL = PX * GFR (Fig. 3)

2

RELATIONSHIP BETWEEN PLASMA CONCENTRATIONOF A METABOLITE AND ITS DISCARDING BY KIDNEYS

EL

AFTER SOME TIME

95% ARE NOT FILTE- RED

STEADY STATE

IN WHICH EL = Px * GFR

Qf

.

ABSORPTION,PRODUCTION,MOBILIZATION MINUSEXTRARENALDISCARDING,DECOMPOSITION,STORING

Px* GFR

Px INDICATES HEREONLY RELATIONSHIP EL GFR

EL

Px

3

Px* GFR

GFRTIME STEADY

STATEIN WHICH EL = Px * GFR

EXCRETION INDICATES HERE PRODUCTION, NOT GFR

Px

4

2. If the renal function (GFR) declines with an unchanged ELX, a new steady state is established after some time, where EL = PX * GFR (Fig. 4)

5

These examples refer to creatinine, inulin, glucose (above the resorption threshold) etc., where reabsorption or secretion of the substance in renal tubuli is absentThe relationship between PCREATININE and GFR is a hyperbolic one according to the equation ELCREATININE = PCREATININE * GFR ; therefore, PCREATININE is a relatively insensitive indicator from a diagnostic point of view (Fig. 5)

Even a direct (ie., not mediated by hormones and neural system) influence of PX on the excretion of the substance X is complicated in case when the tubuli interfere with the excretion by reabsorption

1. An example without reabsorption (inulin), Fig. 6 and 7 left

2. An example with a proportional resorption (urea), Fig. 6 and 7 right

Feedback by means of Px varies according to the different behaviour of the substance in tubuli

Substance filtered only Substance with proportionalresorption (UREA)

Excretedquantity

Px*GFR

Qf

Reabsorption

EL

Px Px

Resorption 50% Qf

.

Excreted quantity

6

The movement along the lineis not instantaneous and stopslater at: EL = Px* GFR

Ation Ation

.

INULIN

IS VALID FOR ALL SUBSTANCES IN STEADY STATE

V * Ux

GFR

Px

Cx

.

7

EL = V * Ux

.

UREA

RELATIONSHIP

For all substances in a steady state the following eq. is valid:

EL = UX * V

In case of a resorption with a saturation point (threshold), renal excretion is dependent on the maximal resorption rate and on the affinity of the transporters to the substance3. Resorption with a threshold and a high affinity: everything under the resorption maximum is resorbed (glucose, some aminoacids); excretion is an effective regulator of plasma concentration in the region of bending of the resorption curve, Fig. 8

.

PTH

EXCRETION

RES.

GLAA

SUBTHRESHOLD PGL

RESORPTION WITH SATURATION

HIGH AFFINITY:

FLOWX

REGULATESEFFECTIVELY GLUCOSE

TM

8

F

Px DOES NOT REGULA-TE ANYTHING,ALL FLUCTUATIONSEL Px WILL BEUNCORRECTED

-3PO4-2

SO4

LOW AFFINITY:

TM

EXCR.

RES.

AA URIC ACID

EVERYTHING RESOR-BED, PAA DOES NOTREGULATE ANYTHING

PUA REGULATES,NOT TOO EFFECTIVELY,HOWEVER

4. Resorption with a low affinity; excretion serves again as a regu- lator of plasma concentration, but less effectively, Fig. 9

9

F

PX

K+

Ca2+

HPO42-

H+

.

.

.

EL

Controlling organ (kidney)

Controlling systems

Filtration

Resorption Control- ler

Controlled system (plasma)

GFR * Px = (V * Ux)With simple filtration (creatinine, inulin)More complicated instan-ces of direct effects of Px

(Fig. 8 and 9)Concentration of substan-ces in tubular cells

Control viaN.S., ADH, ALDO, PTH

Signals to the controlling systems

Indirect effects of Px2

Direct effects of Px

.

Now, we could better understand how the plasma components are homeostased by a kidney (again Fig. 2)

The concept of renal clearance: The effectivity of renal activity could be assesed by means of the amount of a substance which a hypothetical volume of plasma is completely got off per time interval.It is evident that a completely cleared volume of plasma Cx had to bear the same “load” as the same volume of plasma before did, therefore the amount of the substance which had to be cleared per minute is CX * PX. This amount must be discarded by the kidneys:

CX * PX = UX * V.

This is valid regardless the ways of excretion or reabsorption.Substances behave differently in the tubulus (Fig. 10) and accordingly, their clearance has a different relationship to GFR (Fig. 11 – 13)

.

10

CLEARANCE

GLUKOSE

CGL = ————— = * V PGL

.

11

Cx = ————— < GFRUx * V PxUx

Px

Px * Cx = Ux * V

GFRCx

V.

.

.

GENERAL CASE:

12

CALCULATION OF GFR:

GFR = Ukr * V PCREAT

PCREAT * GFR = UCREAT * V.

GFR .

UCREAT * V.

CCREAT

13

PAH

RPF

RPF * PPAH

RPF * PPAH = V * UPAH

V * UPAH

.

.

14

Clearance of substances which are secreted nearly exclusively by the tubular wall (and are not filtered in the glomeruli) may directly serve as indicators of the renal perfusion, eg., PAH (Fig. 14 )

Osmolal and free water clearance:Osmolal clearance is quite analogical to the clearance concept of common metabolites a and is calculated in an analogical manner. Free water clearance represents a difference between the quantity of urine and the osmolal clearance. A close relationship must be between both of them (Fig. 15).

OSMOLEL AND WATER CLEARANCE

COSM * POSM = V * UOSM

COSM = V * UOSM

POSM

IF

POSM = UOSM

THEN

COSM = V

.

.

.

15

OSMOLEL CLEARANCE :

IF

THEN

.

POSM > UOSM

COSM < V

(urine hypoosmolal, the body loses water)

1 > UOSM

POSM

0 < 1 -UOSM

POSM

IF

THEN

.

POSM < UOSM

COSM > V

(urine hyperosmolal, the body retains water)

.

.

.

0 < V - COSM

.

V > COSM

.

0 > V - COSM

.

V < COSM

.

0 < V ( 1 - ) UOSM

POSM

0 < V V * UOSM

POSM COSM

.

..

.

.

.

free water clearance free water clearance,loss of water is less than

loss of solutes

16

The decline of osmotic clearance is – in contradistinction to diuresis – a sensitive sign of renal failure (Fig. 16)