Factor VII deficiency
pH 7.4 PCO2
B. Nephropathy of Pregnancy
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
Hepatorenal Syndrome
Renal ischemia and ultimately oliguric renal fail-ure, a disease combination called hepatorenal syndrome, occurs relatively frequently in pa-tients with cirrhosis of the liver. Several factors contribute to the development of this syndrome.
In liver cirrhosis, the narrowing of the vas-cular bed within the liver (→p. 184) leads to congestion in the portal venous system. The hydrostatic pressure in the capillaries rises and excessive amounts of fluid are filtered into the abdominal cavity (ascites,→p. 184). Be-cause of the high protein permeability of the liver sinusoid, plasma proteins are also lost into the extravascular space. In addition, fewer plasma proteins are produced in the liver pa-renchyma. The resulting hypoproteinemia re-sults in the increased filtration of plasma water and thus in the development of peripheral ede-mas (→p. 250). The formation of ascites and peripheral edemas occurs at the expense of the circulating plasma volume with decrease of central venous pressure, of right ventricular filling, and of cardiac stroke volume.
The disease further leads to peripheral vaso-dilation. Vasodilating mediators (e.g., sub-stance P) produced in the gut and endotoxins released by bacteria are normally detoxified in the liver. In liver cirrhosis the loss of liver pa-renchyma and the increased amount of blood passing from the portal circulation directly into the systemic circulation, short-circuiting the liver (→p. 184), brings those substances into the systemic circulation unhindered. The mediators have a direct vasodilator effect, while the endotoxins exert a vasodilator effect by stimulating the expression of nitric oxide synthase (iNOS). This may lead to a fall in blood pressure, causing massive sympathetic stimu-lation. The stimulation of the renal sympathet-ic nerves results in diminished renal perfusion and thus a fall in GFR. The reduced renal blood flow promotes the release of renin and thus the formation of angiotensin II, ADH, and aldoste-rone (→p. 288). ADH and aldosterone increase the tubular reabsorption of water and sodium chloride (leading to loss of potassium!
→p. 134), and the kidney excretes small vol-umes of highly concentrated urine (oliguria).
Administration of vasoconstrictive drugs (e.g., vasopressin or related substances and
α-adrenergic agonists) in combination with albu-min are effective in two-thirds of the patients with hepatorenal syndrome. In those patients the decrease of the effective plasma volume is the major cause for the hepatorenal syndrome.
Nevertheless, further mechanisms may con-tribute to this life-threatening complication of liver insufficiency.
Renal vasoconstriction may be fostered by he-patic encephalopathy (→p. 188). The compro-mised hepatic metabolism alters plasma amino acid concentrations and increases the NH4+ centration in blood and cerebral fluid. The con-sequences include glial cell swelling and pro-found derangement of transmitter metabolism, which may, through activation of the sympa-thetic nerve tone, lead to renal vasoconstriction.
Incomplete hepatic inactivation of media-tors that exert a direct vasoconstrictor effect on the kidney (e.g., leukotrienes) also contrib-utes to renal vasoconstriction. Due to impaired hepatic metabolism, the kininogen production is decreased leading to reduced formation of vasodilating kinins, such as bradykinin. More-over, hepatorenal syndrome may be paralleled by a decreased ability to form vasodilating prostaglandins.
Renal ischemia normally stimulates the re-lease of vasodilating prostaglandins that pre-vent further reduction in renal perfusion (→p. 318). If there is insufficient formation of prostaglandins (e.g., due to administration of prostaglandin synthesis inhibitors), this protec-tive mechanism is abolished and the develop-ment of renal failure accelerated. A decreased ability to synthesize prostaglandins (lack of precursors?) has in fact been found in patients with the hepatorenal syndrome.
A decrease in GFR may further result from a hepatorenal reflex, triggered by hepatocyte swelling.
Lastly, an abnormal fat metabolism may con-tribute to kidney damage in liver failure. Among other consequences, the liver forms less leci-thin-cholesterol acyltransferase (LCAT), an en-zyme that esterifies cholesterol with fatty acids (→p. 264) and plays an important part in break-ing down or transformbreak-ing lipoproteins. Com-plete familial LCAT deficiency leads to glomeru-lar injury and thus to renal failure.
128
5Kidney,SaltandWaterBalance
Plate5.15HepatorenalSyndrome
129 Portal vein
congestion
Capillary pressure
Ascites
Hypoproteinemia
Peripheral edemas
CO
Liver cirrhosis Gut
Substance P Endotoxins
Abnormal inactivation
NO synthase
Vasodilation
Drop in blood pressure
Activation of sympathetic nerves
Ammonia Blood Leukotrienes
Abnormal amino acid balance
Abnormal transmitter metabolism
Encephalopathy
Renal perfusion GFR
Renin Angiotensin
ADHAldosterone Reabsorption of H2O and NaCl
Oliguria
Prostaglandin Vasoconstriction
Prostaglandin synthesis inhibitor Disorders of metabolism
Decreased protein synthesis
Oncotic pressure
Central venous pressure
LCAT deficiency Hepatorenal reflex
Glomerular damage Decreased kininogen
Bradykinin A. Hepatorenal Syndrome
130
Urolithiasis
Concrement-forming urinary components (→A 1) can reach concentrations in the urine that lie above their solubility threshold. In the so-called metastable range the formation of crystals may not occur at all, or only slowly, de-spite supersaturation of the solution. However, when the concentrations rise beyond the meta-stable range, crystallization occurs. Dissolving already formed crystals is possible only by re-ducing the concentration to below the meta-stable range.
The most frequently found components in kidney stones are calcium oxalate (ca. 70 %), calcium phosphate or magnesium-ammonium phosphate (ca. 30 %), uric acid or urate (ca.
30 %) as well as xanthine or cystine (< 5%). Sev-eral substances may be contained in one stone, because crystals that have already formed act as nuclei for crystallization and facilitate the deposition of other metastably dissolved sub-stances (hence the total is > 100 %).
Certain substances that form complexes, such as citrate, pyrophosphate, and (acid) phos-phate, can bind Ca2+and, by reducing the Ca2+ concentration, are able to prevent calcium phos-phate and calcium oxalate from precipitating.
Causes of stone formation. The raised con-centration of stone-forming substances can be the result of prerenal, renal‚ and postrenal fac-tors:
Prerenal causes produce the increased filtra-tion and excrefiltra-tion of stone-producing sub-stances via a raised plasma concentration (→p. 102). Thus, prerenal hypercalciuria and phosphaturia are the result of raised intestinal absorption or mobilization from bone, for ex-ample, if there is an excess of PTH or calcitriol (→A 2). Hyperoxalemia can be brought about by a metabolic defect in amino acid breakdown or by increased intestinal absorption (→A 3).
Hyperuricemia occurs as a result of an excessive supply, increased de novo synthesis, or in-creased breakdown of purines (→A 3). Xan-thine stones may occur when the formation of purines is greatly increased and the breakdown of xanthines to uric acid is inhibited. However, xanthine is much more soluble than uric acid and xanthine stones are therefore much less common.
Abnormal renal reabsorption is a frequent cause of increased renal excretion in
hypercal-ciuria and an invariable cause in cystinuria (→p. 104). The Ca2+concentration in blood is then maintained by the intestinal absorption and mobilization of bone minerals, while the cystine concentration is maintained by a re-duced breakdown. Urolithiasis may further be precipitated by decreased urinary excretion of citric acid due to enhanced proximal tubular reabsorption.
Release of ADH (in volume depletion, stress, etc.;→p. 282) increases the concentrations of stone-forming substances via enhanced urine concentration (→A 4).
The solubility of some substances depends on the pH of urine. Phosphates are easily dis-solved in an acidic urine, but poorly in an alka-line one. The inability to generate an acidic urine increases the incidence of urolithiasis in distal renal tubular acidosis. Phosphate stones are therefore, as a rule, only found in alkaline urine. Conversely, uric acid (urate) is more soluble when dissociated than undissociated, and uric acid stones are formed more readily in acidic urine. If the formation of NH3is re-duced, the urine has to be more acidic for acid to be eliminated, and this promotes the forma-tion of urate stones.
A significant factor is also how long crystals that have already formed actually remain in the supersaturated urine. The length of time de-pends on the diuresis and the flow conditions in the lower urinary tract that can, for example, lead to crystals getting caught (postrenal cause).
The effect of urolithiasis is that it blocks the lower urinary tract (→A 5). In addition, stretch-ing of the ureteric muscles elicits very painful contractions (renal colic). Obstruction to flow leads to ureteral dilation and hydronephrosis with cessation of excretion. Even after removal of a stone, damage to the kidney may persist.
The urinary obstruction also promotes growth of pathogens (urinary tract infection; pyelo-nephritis;→p. 116). Urea-splitting pathogens form NH3from urea, thus alkalinizing the urine.
This in turn, in a vicious circle, favors the forma-tion of phosphate stones. Even without bacteri-al colonization, intrarenbacteri-al deposition of uric acid (gouty kidney) or of calcium salts (nephro-calcinosis) can result in inflammation and de-struction of renal tissue.
5Kidney,SaltandWaterBalance
Plate5.16Urolithiasis
131 HPO42
H2O H+
Ca2+
NH3
Ca2+
CaHPO4
MgNH4PO4
HPO42
Ca2+
1
2
3
4
5
Infection Colics
Renal damage
Metastable solution Stagnant
urine
Absorption
Reduced reabsorption
Disordered metabolism
Xanthine Uric acid
Oxalate
ADH Hypovolemia
Stress
Precipitation pH Stone formation
Citrate etc.
pH Mobilization
Cystin
Cystine Xanthine Uric acid Calcitriol
Kidney stones
Urine concentration PTH
Calcium oxalate PTH