4.3. Peculiarities of renal blood flow 263 and endoplasmic reticulum and secretory granules. physiologic capacity is variable, it varies about Some of these granules are considered to be specific 300 ml. The urinary bladder wall consists of three secretory granules containing renin the other gran- muscle coats, the lining of a superfiacial layer of flat ules do not contain renin, but it is suggested, that cells, and a deep layer of cuboid cells. In the region renin could be deposited in these cells in a non gran- of trigonum vesicae urinariae is an inner sfincter. ular form. The man urethra is divisible into three portions: In the juxtaglomerular triangle cells called lacis prostatic, membranous and cavernous. The female cells occur designated also as extraglomerular mesan- urethra is short. It’s lining consists of pavement ep- gial, or Goormaghtig’s cells. They have numerous ithelium. microvilli forming a fine network. The interstitium consists of cells and cell-free sub- stance. Interstitial cells resemble in their struc- ture to fibroblasts. They contain lipoid drops of prostaglandin precursors and a system of fibrils, 4.3 Peculiarities of renal probably identical with elastic fibrils. The thicker fibres cross the juxtaglomerular cells entering the blood flow Bowman’s capsule and the podocytes.

4.2.2 The urinary outflow tract Concerning the blood flow the kidneys are exep- Urine from collecting ducts is excreted into the renal tional organs. The peculiarity of renal haemody- pelvis, passing calyces renales minores et maiores. namics is a consequence of the fact, that the kid- From the renal pelvis is the urine transported into neys have 100 times greater blood flow than other the urinary bladder by the contractive activity of organs and tissues in human organism. The arteri- ureters. The wall of the urinary excretory system ovenous difference in blood oxygen content is low in has in all its segments almost the same structure. It renal blood vessels. In healthy adult man at rest the cosits of three coats: mucous, muscularis nad fibrous. renal blood flow is about 1200 ml per minute repre- The mucosa is lined by transitional epithelium. In senting 25 per cent of cardiac output. In fact, almost the proximal parts of urinary outflow tract 2-3 cellu- the whole blood flows through the glomeruli, only 5- lar layers in the more distal portion 5-7 layers can be 10 per cent of it courses trhough the paraglomerular found. Lamina propria mucosae lying beneath the anastomoses. epithelium consists of collagenous connective tissue. It was found that the blood pressure whitin the The middle coat of urinary tract excretory system glomerular capillaries is about 50-60 per cent of the consists of an inner longitudinal and an outer cir- blood pressure in systemic arteries – 10 kPa (80 torr). cular layer of smooth muscle. Calyces renales have The blood pressure in peritubular capillaries is about two muscle layers enabling contraction waves wich 1,9 kPa (15 torr) and in vena renalis about 0,8 kPa aid the urine transport into the renal pelvis. The re- (6 torr). The glomerular capillary network can be so nal pelvis has the same structure, consisting of two considered to be a high – pressure capillary network muscle layers. The distal third of ureters consists of in contrast to the low – pressure peritubular capillary three muscle coats – the thirth, outer coat is formed network. The striking difference in pressure between of longitudinally oriented smooth muscle layer. The the glomerular and peritubular capillaries is caused peristaltic waves of ureter occur 1-5/min. shifting by the high resistance within the vas efferens. the urine towards the urinary bladder. The stim- The high-pressure region of cortical glomerular ulus initiating these movements is not understood network resembles the arterial end of capillaries. In till now. It could be a certain filling pressure in re- the low-pressure peritubular capillary network pre- nal pelvis. The oblique ”entrance” of ureters into vails the retrograde diffusion of fluids according to the urinary bladder inhibits the urine reflux, though Starling’s law, thus the peritubular capillary bed ureters are not provided with sfincters at their ter- functions as the venous end of capillaries. Blood minal portion. flowing through the peritubular capillary network is Urinary bladder is the reservoir for urine. Its deprived of the water volume which has been filtered 264 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hul´ın) in glomeruli, thus its osmotic pressure is high, and wall of vas afferens, stimulated by tension changes thereby it has the ability to reabsorb the water. affecting the vessel wall. If this tension is dimin- The rate of blood flow within the perilobular ar- ished e.g. during reduction of blood flow through teries is relatively high, hence the erythrocytes move kidneys the renin secretion by these cells rises and mainly in the centre of this flow. Vasa afferentia are vice versa. The second type of receptors (chemore- derived from the aa. interlobulares in a nearly rectan- ceptors) is found in the wall of distal tubules in their gular direction, therefore more plasma than erythro- portion lying near to glomeruli: - the granular cells of cytes flow in them. Owing to this fact the cortical macula densa. They respond to changes in sodium glomeruli are supplied with blood containing more concentration of tubular fluid. The stimulation of erythrocytes than plasma. renin secretion occurs if the NaCl concentration in The arrangement of two successive capillary net- the vicinity of macula densa cells decreases. On the works is very important concerning urine production contrary, an augmented NaCl content in this area and its concentration. For understanding the disor- supresses renin release. Renin is releases from cells ders arising in kidneys during glomerular blood flow into the intersticium and from there it gets into the alterations is very important to know these facts. capillaries. Renin is a specific endopeptidase con- The blood distribution in kidneys is uneven. Al- verting angiotensinogen. A glycoprotein present in blood plasma - to angiotensin I which is converted by most 80 per cent of renal blood perfuses the outer converting enzyme to a substance with very strong cortical regions. This is why all changes in blood vasoconstrictive activity - the angiotensin II. flow will be reflected in alterations of this region. The blood flow in renal medulla does not depend of Renin-angiotensin system is one of the key sys- systemic arterial blood pressure. tems regulating the blood pressure. Despite of ex- Blood flow through the juxtamedullar glomeruli tensive research projects, all facts concerning the re- enables to maintain the blood flow in renal medulla lease and regulation of this very important factor are to the detriment of cortical glomeruli, especially not known in detail till now. The baroreceptor and when the blood supply of kidneys is diminished, or chemoreceptor mechanism explaining the triggering the systemic arterial pressure falls considerably. off this system is in principle accepted. The high blood flow through the renal cortex The mechanism of angiotensin action is not well responds sensitively to blood volume and pressure understood. Angiotensin II stimulates the calcium changes. An important fall of blood pressure or vol- uptake and the calcium release from celullar or- ume can elicit development of ischaemia, even of ganelles in target cells. Angiotensin II induces vaso- necrosis in outer cortical layers. Inflammatory al- constriction of renal vessels, above all in vas efferens. terations in the renal cortex can vice versa affect the In vas afferens is its vasoconstrictive action probably blood flow through the medulla renalis. masked by vasodilatation due to prostaglandins, syn- Oxygen consumption in cortical region is 9 ml per thesis of which is stimulated by angiotensin. During minute, it is about 20 times higher than in medullar decreased blood flow the constriction of vas efferens region (0,4 ml per minute). Thus, the renal blood ensures the glomerular filtration. This vas efferens flow supplies the organ with oxygen and nutriments constriction causes blood pressure fall in peritubular for its own metabolic processes and it ensures simul- capillary network leading further to improvement of taneously the processes of ultrafiltration of plasma fluid resorption in proximal tubule. The angiotensin and thereby of urine formation. Kidneys are there- receptors are situated also on mesangial cells within fore provided with several mechanisms enabling the the glomeruli. These cells may influence the per- adaptation of blood flow according the given require- meability of glomerular capillaries. Enhanced an- ments of organism. giotensin level suppresses by feedback mechanism the The autoregulation of renal blood flow is accom- renin release from juxtaglomerular apparatus. But plished by nerves and humoral factors. The most the suppression of renin production can be induced important regulation is accomplished by the renin- by an other pathway – by aldosterone release, sodium angiotensin system. There are two types of in- reabsorption and by its increased concentration in re- trarenal receptors recording stimuli for renin release: gion of macula densa. the first type are the baroreceptors localized on the The renin-angiotensin system is involved not only 4.3. Peculiarities of renal blood flow 265 in regulation of renal functions but it plays a very tion of vasoconstrictive substances is the result of en- important role in control of systemic arterial blood hanced sympathetic activity. In this situation have pressure. Angiotensin II by its strong vasoconstric- the prostaglandins a protective influence upon the tive effect increases the peripheral resistance of ves- renal circulation. sels and maintains so the blood pressure on appro- The natriuretic hormone is very probably sub- priate desired level. Apart from this, angiotensin II stance with low molecular weight, produced in brain, stimulates the sympathetic activity and facilitates mainly in hypothalamus. In experiments it inhibits the noradrenaline release from peripheral endings. the sodium transport through the frog skin. The Angiotensin II indirectly promotes the sodium and mechanism of this effect is the inhibition of the trans- water retention in organism. By its action is aldos- porting enzyme Na+–K+–ATP–ase activity. Natri- terone released from suprarenal glands ensuring the uretic hormone enhances the contractility of smooth tubular reabsorption of sodium. It also stimulates musle cells in the vessel wall. Increased sodium ex- the vasopressin release and induces the dipsogen ef- cretion induced by natriuretic hormone is explained fect in central nervous system (CNS). This complex by inhibition of the sodium pump in proximal tubule action results in correction of disproportion between and in other parts of tubular system. Elevated natri- the capacity and filling of the vessel system during uretic hormone activity was found in patients with arterial hypotension and hypovolaemia. The correc- chronic renal failure, with essential hypertension and tion is performed by renin-angiotensin-aldosterone with low renin hypertension. Nevertheless, in pa- system that induces vasoconstriction, increase of wa- tients with heart failure and in patients with oedemas ter intake with reduction of its elimination, and en- of various origin a zero activity of natriuretic hor- hancement of sodium retention. mone was observed. These facts indicate that natri- In the regulation of renal blood flow participates uretic hormone regulates the volume of extracelullar the nervous system. The adrenergic fibres of sym- fluid under physiological circumstances and in patho- pathetic system come from Th 10 to Th 12 segments logic conditions. The chemical structure of natri- and a part of them in Th 12 to L2 segments. These uretic hormone was not identified till now. fibres enter the kidneys with renal arteries and pass On the other hand, the atrial natriuretic peptide along them. They innervate afferent and efferent ar- (factor) was identified in heart atrial tissue. It is terioles, intrarenal veins and tubules. Parasympa- a peptide with a molecular weight of 2 500 to 3 000 thetic fibres were found in the same areas. Applica- daltons. Applied to experimental animals it induces tion of alfa-adrenergic agonists (e.g. noradrenaline) acceleration of renal sodium excretion without in- elicits vasoconstriction of a. afferens and a. effer- hibition of Na+–K+–ATP–ase, thus it is not an in- ens resulting in blood flow decrease through kidneys. hibitor of this enzyme and it does not exhibit vaso- Only minor changes of glomerular filtration arise constrictive activity, but has vasodilating effects. Its thereby. Also hypoxia can be the stimulus triggering release into the blood is initiated by expansion of cir- the renal vasoconstriction mediated by chemorecep- culating blood volume, by enlargement of heart atria tors. and enhanced plasmic sodium concentration. The Activity of the sympathetic system is low under mechanism how the natriuretic factor increases the basal circumstances. Renal flow is therefore not con- renal sodium excretion is not fully understood. It siderably increased by adrenergic receptor blocking is known at present that it enhances the glomeru- agents or by renal denervation, but it can be raised lar fitration and causes vasodilatation in kidneys. under the influence of vasodilating agents which can Glomerular filtration is increased by influencing vas reduce the myogenic tonus of vessels. This is ac- efferens and vas afferens, resulting in elevation of fil- cepted at present, although the myogenic theory does tration pressure and thereby of sodium and water not explain the renal blood floow changes. load in tubules. Sodium is not completely absorbed Adrenergic stimuli induce in kidney the vasodilat- in tubules, but the water reabsorption influenced by vasopressin is unchanged leading to natriuresis. ing prostaglandin PGE2 and PGA2 release. They an- tagonize the vasoconstrictive adrenergic stimuli. In- Thanks to regulating mechanisms remains the re- creased level of noradrenaline or angiotensin II trig- nal blood flow relatively constant even during mean gers the prostaglandin release. Increased concentra- arterial pressure fluctuations in extent of 10 to 24 kPa 266 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hul´ın)

(80 to 180 torr). The ability of autoregulation is per- urine) contains few proteins (maximally 150 mg/l), sisting even following denervation (renal transplan- non-electrolyte substances with low molecular weight tation), indicating that neural mechanism does not (glucose, aminoacids, urea etc.), monovalent ions play an important role in renal blood flow regulation. (sodium, potassium, chlorides etc.) approximately Mechanisms of autoregulation fail only in conditions in the same concentration as in plasma. As the pro- where the blood pressure is extremely low occuring teins of plasma are not diffusible, the rules of Gibbs- in massive bleeding when the renal blood flow is con- Donnans distribution governs the process of monova- siderabily restricted. Global blood flow falls also in lent diffusible ions distribution. Small differences in anatomic restriction of vessel bed, e.g. in chronical concentration are due to Gibbs-Donnans effect, ow- renal disease and in all renal diseases connected with ing to which is the cation concentration in ultrafil- shrinkage of renal parenchyma. trate lower by about 5 per cent and the concentration of anions by about 5 per cent higher than in plasma. In severe paraproteinaemia and hyperlipidaemia is the concentration of these lowmolecular substances higher in ultrafiltrate than in plasma. The diva- 4.4 The urine formation lent ions concentration (calcium, magnesium) and the concentration of organic acids and bases, con- cerning their binding to the plasmic proteins, is sub- stantionally lower in ultrafiltrate than in plasma. Urine formation is a very complex process includ- Should a substance pass from blood into the pri- ing glomerular ultrafiltration, tubular resorption and mordial urine it has to cross three barriers: excretion (see figure 4.5, page 267). 1. the endothelial layer with pores-fenestrations on 4.4.1 Glomerular filtration the inner surface of glomerular capillaries 180 l of plasma is daily filtered through glomeru- 2. the basement membrane composed of three lay- lar capillaries and 120 ml of ultrafiltrate is produced ers. The central layer is the proper filtering each minute. The glomerular filter is permeable for membrane. It consits of thin collagenous fi- substances in a manner as if it would be provided by bres arranged in a three-dimensional network pores with diameter measuring 10 nm. Substances inserted in a homogenous matrix provided by with molecular weight under 70 000 daltons appear in pores of 30 to 60 nm in diameter glomerular filtrate depending on the molecular con- figuration. The plasmic globulines with molecular 3. the layer of epithelial cells (podocytes) with nu- weight of about 90 000 daltons are not at all filtered, merous foot processes spanning the outer wall but few amounts of albumines (m. w. 69 000 dal- of glomerular capillaries. At the surface of tons) is filtered and reabsorbed in proximal tubules. podocytes is a layer of acid mucopolysaccha- Glomerular filtration does not differ substantially rides (glycocalyx) filling the gaps between the from filtration process occuring at arterial end of podocytes. The permeability of capillaries is af- capillaries anywhere in the body. The driving force fected also by electric charge and the configu- of ultrafiltration is the hydrostatic pressure of blood ration of particles permeating into the ultrafil- ensured by heart action. Ultrafiltration of blood trate. plasma does not require local energy supply. In com- parison with capillaries in striated muscles is the per- Concerning the electrolyte and fluid metabolism meability of glomerular capillaries 400 times greater is the glomerular filtration extremely important. It and the pressure considerably higher. The resulting follows from the fact that kidney filter daily a four- effective filtering pressure is given by the difference fold volume of the entire body fluid, the fifteenfold between hydrostatic blood pressure, the oncotic pres- volume of extracelullar fluid, and sixtyfold volume of sure of plasmic proteins and the pressure inside the blood plasma. Bowmans capsule. The effective filtrations pressure Glomerular filtration is affected by following fac- is about 3,3 kPa (25 torr). The ultrafiltrate (primary tors: