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 (P X ) 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). P X 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 + Ca 2+ HPO 4 2- H +. Feedback homeostasing of plasma components by kidneys EL Controlling organ (kidney) Controlling systems Filtration Resorption Control- ler Controlled system (plasma) GFR *  P x = (V * U x )  With simple filtration (creatinine, inulin) More complicated instan- ces of direct effects of P x (Fig. 8 and 9) Concentration of substan- ces in tubular cells Control via N.S., ADH, ALDO, PTH Signals to the controlling systems Indirect effects of P x 2 Direct effects of P x.

on zero value (creatinine, uric acid) Substances are on a “precise” value (Na +, K +, H +,...) homeostased above a threshold – on its value (HPO 4 --, glucose in hyperglycaemia) In detail: 1. If P X rises due to enhanced EL X with an undisturbed renal function (normal glomerular filtration rate, GFR), a new steady state is established after some time, where  EL =  P X * GFR (Fig. 3) 2

RELATIONSHIP BETWEEN PLASMA CONCENTRATION OF A METABOLITE AND ITS DISCARDING BY KIDNEYS  EL AFTER SOME TIME 95% ARE NOT FILTE- RED STEADY STATE IN WHICH  EL =  P x * GFR QfQf. ABSORPTION, PRODUCTION, MOBILIZATION MINUS EXTRARENAL DISCARDING, DECOMPOSITION, STORING P x * GFR P x INDICATES HERE ONLY RELATIONSHIP EL GFR EL PxPx 3

P x * GFR  GFR TIMESTEADY STATE IN WHICH EL =  P x *  GFR EXCRETION INDICATES HERE PRODUCTION, NOT GFR PxPx 4 2. If the renal function (GFR) declines with an unchanged EL X, a new steady state is established after some time, where EL =  P X *  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 absent The relationship between P CREATININE and GFR is a hyperbolic one according to the equation EL CREATININE = P CREATININE * GFR ; therefore, P CREATININE 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 P X 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 P x varies according to the different behaviour of the substance in tubuli Substance filtered onlySubstance with proportional resorption (UREA) Excreted quantity P x *GFR QfQf Reabsorption  EL PxPx PxPx Resorption 50% Q f. Excreted quantity 6 The movement along the line is not instantaneous and stops later at: EL = P x * GFR Ation.

INULIN IS VALID FOR ALL SUBSTANCES IN STEADY STATE V * U x GFR PxPx CxCx. 7 EL = V * U x. UREA RELATIONSHIP

For all substances in a steady state the following eq. is valid: EL = U X * 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 substance 3. 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. GL AA SUBTHRESHOLD P GL RESORPTION WITH SATURATION HIGH AFFINITY: FLOWXFLOWX REGULATES EFFECTIVELY  GLUCOSE TMTM 8 F P x DOES NOT REGULA- TE ANYTHING, ALL FLUCTUATIONS EL  P x WILL BE UNCORRECTED -3 PO 4-2 SO 4

LOW AFFINITY: TMTM EXCR. RES. AA URIC ACID EVERYTHING RESOR- BED, P AA DOES NOT REGULATE ANYTHING P UA 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 PXPX

K + Ca 2+ HPO 4 2- H +. EL Controlling organ (kidney) Controlling systems Filtration Resorption Control- ler Controlled system (plasma) GFR *  P x = (V * U x )  With simple filtration (creatinine, inulin) More complicated instan- ces of direct effects of P x (Fig. 8 and 9) Concentration of substan- ces in tubular cells Control via N.S., ADH, ALDO, PTH Signals to the controlling systems Indirect effects of P x 2 Direct effects of P x. 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 C x 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 C X * P X. This amount must be discarded by the kidneys: C X * P X = U X * 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).

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CLEARANCE GLUKOSE C GL = ————— =   * V P GL. 11

C x = ————— < GFR U x * V P x UxUx PxPx P x * C x = U x * V GFR CxCx V... GENERAL CASE: 12

CALCULATION OF GFR: GFR = U kr * V P CREAT P CREAT * GFR = U CREAT * V. GFR. U CREAT * V. C CREAT 13

PAH RPF RPF * P PAH RPF * P PAH = V * U PAH V * U PAH.. 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 C OSM * P OSM = V * U OSM C OSM = V * U OSM P OSM IF P OSM = U OSM THEN C OSM = V OSMOLEL CLEARANCE :

IF THEN. P OSM > U OSM C OSM < V (urine hypoosmolal, the body loses water) 1 > U OSM P OSM 0 < 1 - U OSM P OSM IF THEN. P OSM < U OSM C OSM > V (urine hyperosmolal, the body retains water)......

0 < V - C OSM. V > C OSM. 0 > V - C OSM. V < C OSM. 0 < V ( 1 - ) U OSM P OSM 0 < V V * U OSM P OSM C OSM free water clearancefree 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)