Factor VII deficiency
pH 7.4 PCO2
C. Effects of Renal Failure on Mineral Balance
Renal Hypertension
Most renal diseases can cause hypertension;
about 7 % of all forms of hypertension can be traced back to renal disease. In addition, the kidneys play a significant role in the genesis and course of hypertensive disease, even when there is no primary renal disease (→p. 222 ff.).
Renal ischemia is an important cause of hy-pertension brought about by renal disease. This happens regardless of the site where renal blood flow is decreased, whether intrarenally in the course of renal disease (e.g., glomerulo-nephritis [→p. 112], pyelonephritis [→p. 116], polycystic kidney disease [→p. 110]), in the re-nal artery (rere-nal artery stenosis), or in the aor-ta above the origin of the renal arteries (aortic coarctation) (→A 1).
Reduced perfusion of the kidney results, among others, in hypertension via stimulation of the renin–angiotensin mechanism (→A 2), in which renin is released in the juxtaglomeru-lar apparatus, for example, by renal ischemia, and splits off angiotensin I from angiotensino-gen, a plasma protein originating in the liver.
Angiotensin I is then changed into angiotensin II through the mediation of a converting en-zyme (ACE) that is present in many tissues. An-giotensin II has a strong vasoconstrictor action which causes a rise in blood pressure. At the same time angiotensin II stimulates the release of aldosterone and ADH, which bring about the retention of NaCl and of water through the ac-tivation of Na+channels and water channels, respectively (→A 3).
A renin-producing renal tumor may similar-ly result in hypertension. The plasma concen-tration of the angiotensinogen formed in the liver does not saturate renin, i.e., an increase in angiotensinogen concentration can raise the blood pressure further. Thus, overexpression of angiotensinogen favors the development of hypertension as does overexpression of renin.
Hypertension is caused by the retention of sodium and water even without the renin–an-giotensin mechanism as in primary increase of aldosterone release (hyperaldosteronism;
→p. 106). Several rare genetic defects affecting renal tubular Na+transport lead to hyperten-sion, including Liddleʼs syndrome (overactive Na+channel), Gordon syndrome (lacking inhi-bition of the NaCl cotransporter by defective
WNK kinase),“hypertension exacerbated by pregnancy” (mutation of the mineralocorticoid receptor, which allows stimulation of the re-ceptor by progesterone) and“apparent miner-alocorticoid excess” (AME, defective 11-β-hy-droxysteroid dehydrogenase and thus lacking inactivation of cortisol, which then stimulates the mineralocorticoid receptor,→p. 288).
A variety of more common gene variants in-crease blood pressure only moderately, but predispose a large proportion of the common population to the development of hyperten-sion. The genes associated with hypertension include those encoding renin, angiotensinogen, angiotensin converting enzyme, 11 β-hydroxy-lase (aldosterone synthesis), prostacyclin syn-thase, growth hormone, IGF1, CRH (corticotro-phin releasing hormone), several receptors (angiotensin, ANP, insulin, glucocorticoids, dopamine, epinephrine, leptin), or signaling molecules (G proteins, guanylate cyclase A, se-rum and glucocorticoid inducible kinase, addu-cin). The gene variants are, at least partially, ef-fective through influence on renal salt excre-tion.
The effects of hypertension are, primarily, damage to heart and vessels (→A, bottom). Ev-ery form of hypertension leads to damage to the kidney. Longer lasting hypertension dam-ages the renal arterioles (→p. 222 ff.) and the glomeruli (nephrosclerosis) and in due course leads to renal ischemia. Thus, primary extrare-nal hypertension can develop into reextrare-nal hyper-tension through the development of nephro-sclerosis. All this results in a vicious circle in which the renal ischemia and hypertension mutually reinforce one another. A kidney with renal arterial stenosis or both kidneys in aortic coarctation are unaffected by this vicious circle, because there is a normal or even reduced blood pressure distal to the stenosis, prevent-ing arteriolar damage. A special case arises when the development of hypertension due to renal artery stenosis damages the contralater-al, originally healthy, kidney. After removal of the stenosis, the hypertension due to enhanced renin production of the contralateral kidney may persist.
124
5Kidney,SaltandWaterBalance
Plate5.13RenalHypertension
125 Na+
K+
Na+ K+ 1
2
3
Na+ Cl K+ Kidney disease,
e.g. glomerulonephritis
Renal artery stenosis Coarctation of the aorta Ischemia
Angiotensinogen
Angiotensin l
Hypervolemia Aldosterone
ADH
Angiotensin ll
Hypertension Vasoconstriction
Damage to arterioles
Nephrosclerosis Increased
after-load on heart Vascular damage Vessel hypertrophy Cardiac
output Renin
Converting enzymes
Blood Lumen
Genetic defects, gene variants
IGF1, Insulin etc.
NaCl retention A. Renal Hypertension
Kidney Disease in Pregnancy
Normal pregnancy (→A) is paralleled by re-lease of gestagens and relaxin, which stimulate the endothelial formation of NO and thereby cause vasodilatation. As a result, the peripheral vascular resistance (R) is decreased and blood pressure falls. In the kidney, too, the vascular resistance, the RPF, and the GFR rise markedly.
The hyperfiltration predisposes to albumin-uria. Na+reabsorption in the proximal tubules does not keep in step with a high GFR. In addi-tion, estrogens inhibit K+channels in the proxi-mal tubules. The resulting depolarization re-tains HCO3–in the cell, and the intracellular acidosis inhibits the Na+/H+ exchanger (→p. 105 A). The depolarization also inhibits the electrogenic transport processes for glu-cose, amino acids, etc. Due to the reduced reab-sorption of Na+and fluid, uric acid is less con-centrated within the lumen and thus also less of it is reabsorbed. Among the consequences of reduced proximal tubular reabsorption are a fall in the renal threshold for glucose (ten-dency toward glycosuria).
Enhanced delivery of Na+to the distal neph-ron stimulates distal tubular reabsorption, which increases the formation of prostaglandin E2(PGE2) (→p. 318). Estrogens and PGE2both stimulate the release of renin, which raises the plasma concentrations of angiotension II and aldosterone. Angiotensin II elicits thirst and in-creases ADH release. ADH stimulates the renal H2O reabsorption, aldosterone the renal Na+ reabsorption and the salt appetite. All in all, NaCl and water are retained in pregnancy, de-spite a rise in GFR, and extracellular and plas-ma volumes increase. However, because of the low reactivity of peripheral vessels to vasocon-strictor stimuli, no hypertension develops, de-spite the high angiotensin level and hypervole-mia.
Edema, proteinuria, and hypertension (EPH) occur in ca. 5 % of all pregnant women (pre-eclampsia, toxemia of pregnancy, or EPH-ges-tosis). The symptoms point to renal damage, hence the term nephropathy of pregnancy (→B).
In patients who are suffering from EPH ges-tosis, the (ischemic) placenta produces en-hanced levels of sFlt-1 (soluble fms-like tyro-sine kinase-1), a truncated soluble VEGF
tor (vascular endothelial growth factor recep-tor). The soluble receptor binds VEGF and PIGF (placental growth factor) and thereby lowers the concentration of free VEGF and PIGF. The placenta further produces endoglin. Both sFlt-1 and endoglin counteract the angiogenesis and endothelial function. In patients suffering from EPH gestosis the formation of NO and prostacyclin are decreased, the release of vaso-constricting endothelin enhanced, and the rea-gibility of vascular smooth muscle cells to vaso-constrictive agents (e.g., angiotensin II) in-creased. By virtue of their effect on the vascular smooth muscle cells, sFlt-1 and endoglin lead to hypertension, glomerular injury, and pro-teinuria. The patients experience hypoalbu-minemia. The resulting decrease of the oncotic pressure and the damage to the peripheral ves-sels leads to peripheral edema at the expense of the plasma volume. Occasionally the disor-der leads to lung edema.
In EPH gestosis the formation of thrombosis-inhibiting proteins (antithrombin III, protein C, protein S;→p. 68) is decreased. Deficiency of those proteins and absent formation of prosta-cyclin (see above) foster the coagulation. The sensitivity of thrombocytes to activators is en-hanced and their number decreased. Massive activation of thrombocytes may damage eryth-rocytes and the liver (HELLP syndrome, Hemol-ysis, Elevated Liver enzymes, Low Platelets).
The impairment of the hepatic albumin synthe-sis contributes to the hypoalbuminuria.
The increase of the renal vascular resistance (→B 3) lowers the renal plasma flow (RPF) and, even more so, the GFR. As a consequence of the volume depletion, the Na+reabsorption in the proximal renal tubule is enhanced and the lu-minal flow rate is decreased. As a result, the contact time of luminal fluid with the reab-sorbing epithelium is enhanced, which increas-es the renal tubular reabsorption of uric acid.
The plasma concentration of uric acid increas-es, a valuable diagnostic parameter.
The deranged coagulation may lead to fibrin deposits in the cerebral circulation on the one hand and to bleeding on the other. Patients may develop brain edema with subsequent se-vere headache, sensory loss, convulsions, and coma (eclampsia).
126
5Kidney,SaltandWaterBalance
Plate5.14KidneyDiseaseinPregnancy
127 RPF
R
R RPF
GFR GFR
Na+ Na+ Na+ Na+
Na+ Na+ Na+
H2O
Na+ and H2O retention
Vasoconstriction
Renin Angiotensin
Aldosterone Blood pressure
Uric acid, glucose
Blood volume
Vasodilation
Hypertension
Blood volume
Blood clotting Fibrin
Abnormal permselectivity Edema
Proteins
Proteinuria
Renin Angiotensin
Aldosterone Vasoconstriction
Placenta
Uric acid
Na+ and H2O retention
CNS:ischemia Gestagens, relaxin
Estrogens
Erythropoiesis
Endoglin VEGF , PIGF
NO , prostacyclin
Hypoproteinemia HELLP
sFlt-1
Angiogenesis ,
Antithrombin III, protein C and S
endothelial function
Activation of thrombozytes A. Normal Pregnancy