Factor VII deficiency
pH 7.4 PCO2
B. Glomerular Diseases
Disorders of Glomerular Permselectivity, Nephrotic Syndrome
The glomerular filter (fenestrated endothelium, basement membrane, slit membrane between podocytes,→A 1) is permselective, i.e., it pre-vents the passage of some blood components.
The filtration of molecules at the glomerular fil-ter depends on their size, shape, and charge.
Normally, macromolecules with a diameter of
> 4 nm cannot pass the basement membrane and the slit membrane. Negatively charged macromolecules (e.g., albumins) are repelled by the negative charge at the fenestrated endo-thelium (→A 1). The matrix of the basement membrane includes collagen type IV 3α, 4α, and 5α as well as lamina β2. genetic defects of 3α (IV), 4α (IV), or 5α (VI) (Alport syndrome and“thin basement membrane” disease) and of laminaβ2(Pierson syndrome) lead to glo-merulosclerosis. Antibodies against 3α (IV) are found in Goodpasture syndrome, an autoim-mune disease affecting the basement mem-brane, leading, among others, to glomerulo-nephritis.
The podocytes are connected to each other by nephrin, a transmembrane protein with a large extracellular domain. Nephrin binds the adaptor protein CD2AP (CD2-associated pro-tein) and the membrane protein podocin. Podo-cytes further express the Ca2+-permeable cat-ion channel TRPC6 (transient receptor potential channel 6), and the cytoskeletal proteins α-acti-nin-4 and NMMHC‑IIA (nonmuscle myosin heavy chain IIA). Regulation of gene expression in podocytes involves WT1, which suppresses the expression of several growth factors (→p. 16). Genetic defects of nephrin (nephrotic syndrome Finnish type), CD2AP, podocin (auto-somal recessive steroid resistant nephrotic syn-drome), TRPC6, α-actinin-4, NMMHC‑IIA or WT1 (Danys–Drash syndrome, Frasier syn-drome) may lead to glomerulosclerosis. Genetic defects are further responsible for the glomeru-lar lesions in the“Nagel–Patella” syndrome.
By far more frequent than the genetic de-fects affecting glomerular function are glomer-ular lesions due to glomerulonephritis or due to systemic disease, such as hypertension and diabetes mellitus (→p. 112).
If the integrity of the glomerular filter is dis-rupted, plasma proteins and even erythrocytes gain access to the Bowman space with resulting
proteinuria and hematuria. Electrophoresis re-veals that the defective filter preferably allows the passage of the small, negatively charged al-bumins (→A 3).
Even an intact glomerular filter allows the passage of small proteins, which are then reab-sorbed in the proximal tubule. The limited transport capacity of the tubular epithelium cannot cope, however, with the massive load of filtered proteins, if the glomerular filter is de-fective, which thus leads to proteinuria. A defec-tive reabsorption of proteins in the proximal tu-bule leads to excretion of moderate amounts of small sized proteins (tubular proteinuria).
Renal loss of proteins due to glomerular damage leads to hypoproteinemia. Serum elec-trophoresis demonstrates that it is largely due to a loss of albumin (→A 4). The reduced oncot-ic pressure in the vascular system leads to in-creased filtration of plasma water in the pe-riphery. Filtration in the peripheral capillaries is facilitated by damage to the capillary wall that may also be subject to inflammatory changes. As a result of protein filtration in the periphery, protein concentration and oncotic pressure rise in the interstitial spaces, so that the filtration balance shifts in favor of the inter-stitial space (→A 5). If the removal of proteins via the lymphatics is inadequate, edemas form (→A 7). The peripheral filtration increases the concentration of larger proteins, which are not filtered at the defective glomerular filter (e.g., lipoproteins).
If proteinuria, hypoproteinemia, and pe-ripheral edema occur together, this is termed nephrotic syndrome. The increase of the lipo-proteins result in hyperlipidemia and hyper-cholesterolemia (→A 6). The hyperlipidemia is confounded by decreased lipoprotein lipase ac-tivity.
Hypoproteinemia favors peripheral filtra-tion, the loss of plasma water into the intersti-tial space leads to hypovolemia which triggers thirst, release of ADH and, via renin and angio-tensin, of aldosterone (→p. 132). Increased wa-ter intake and increased reabsorption of sodi-um chloride and water provide what is needed to maintain the edemas. As aldosterone pro-motes renal excretion of K+and H+(→p. 106), hypokalemia and alkalosis develop.
114
5Kidney,SaltandWaterBalance
Plate5.8GlomerularPermselectivity:Disorders
115 1
6
7 2
5 3
4
p
Capsular space Glomerular capillary
Glomerular filter
Abnormal permselectivity of the glomerular filter
Tubular reabsorption Normal
Hypovolemia
ADH Aldosterone
Hyperlipidemia
Albumin
Urine electrophoresis
Serum electrophoresis
Albumin
Immuno- globulins Normal
Resorption Filtration
Lipoprotein lipase deficiency Lipoprotein
synthesis
Damage to peripheral capillaries Proteinuria
Hypoproteinemia
Oncotic pressure in the vascular system decreases
Edema
Alkalosis Hypokalemia
Pressure
P
Length of capillary
Glomerulonephritis
WT1 Nephrinb-catenin
Cadherin Podocin TRPC6
Laminin b2
CollagenIV Endothelium
Podocyte A. Abnormalities of Glomerular Permselectivity and Nephrotic Syndrome
Interstitial Nephritis
The term interstitial nephritis is applied to flammatory changes in the kidney if the in-flammation does not originate in the glomeru-li. Renal tissue is infiltrated by inflammatory cells (especially granulocytes) and the inflam-mation can lead to local destruction of renal tissue.
The most common form of interstitial ne-phritis is that caused by bacteria (pyelonephri-tis). Most often the infection originates in the urinary tract (bladder→ureter→kidney [as-cending pyelonephritis]); less often in the blood (descending pyelonephritis) (→A 1). The renal medulla is partially vulnerable, because its high acidity, tonicity, and ammonia concentra-tion weaken the bodyʼs defense mechanisms.
Flushing out the renal medulla thus lowers the danger of infection. Infection is promoted by an obstruction to urinary flow (urinary tract stone [→p. 130], pregnancy [→p. 126], prostatic hy-pertrophy, tumor) and by reduced immune de-fenses (e.g., diabetes mellitus [→p. 312]).
An interstitial nephritis can also cause the deposition of concrements (calcium salts, uric acid) in the renal medulla without any infec-tion (→A 2). Uric acid deposits in the kidney are principally caused by an excessive dietary intake of purines, which are broken down in the body into uric acid, as well as by a massive increase of endogenous uric acid production, as occurs in the leukemias and in rare cases of enzyme defects of uric acid metabolism (→p. 268). Calcium deposits are the conse-quence of hypercalciuria that occurs when in-testinal absorption of calcium is increased (e.g., in hypervitaminosis D) as well as with in-creased mobilization of calcium from bone (e.g., by tumors, immobilization; →p. 142).
Lastly, interstitial nephritis can result from toxic (e.g., phenacetin) or allergic (e.g., penicil-lin) factors, from radiation or as a rejection re-action in a transplanted kidney. The renal me-dulla is especially prone to hypoxia because O2
diffuses from the descending to the ascending limb of the vasa recta. In sickle cell anemia (→p. 40) deoxygenation therefore leads to ag-gregation of hemoglobin, especially in the re-nal medulla, and thus to vascular occlusion.
Massive administration of prostaglandin-synthesis inhibitors can damage the renal me-dulla by causing ischemia. In normal circum-stances renal medullary perfusion at low per-fusion pressure is maintained by the release of vasodilating prostaglandins. Inhibition of pros-taglandin synthesis stops this protective mech-anism, however.
In accordance with the site of the inflamma-tory processes, the first effects are caused by lesions in the segments of the nephron that lies within the renal medulla (loop of Henle and collecting duct). A relatively early occur-rence is reduced urinary concentration, caused by damage to the ascending part, by flushing out of the medulla as a result of inflammatory hyperemia as well as by a lack of ADH sensitiv-ity of the damaged distal nephron. The in-creased urine volume causes nocturnal di-uresis (nycturia). The decreased K+secretion into the collecting duct can cause hyperkale-mia, while reduced Na+reabsorption can result in hypovolemia (→A 3). However, the reduced Na+reabsorption in the loop of Henle can also result in an increased distal K+secretion with accompanying hypokalemia, especially when more aldosterone is released as the result of hypovolemia (→p. 288).
Renal acid excretion can be impaired, result-ing in formation of an alkaline urine and also in systemic acidosis.
Various functions of the proximal tubules (reabsorption of glucose and amino acids, se-cretion of PAH) and the glomeruli (GFR) are af-fected only in advanced pyelonephritis.
Infection by urea-splitting pathogens leads to a breakdown of urea into ammonia in the urine. As ammonia binds hydrogen ions (→A 4), an alkaline urine will result. This pro-motes the precipitation of phosphate-contain-ing concrements (→p. 130) that in turn can cause obstruction to urinary flow and thus the development of ascending pyelonephritis, i.e., a vicious circle is established.
116
5Kidney,SaltandWaterBalance
Plate5.9InterstitialNephritis
117 O
H2N
H+
Ca2+
Mg2+
CO2
NH2
NH3
HPO42
C
H2PO4
NH4+
Na+ K+ Ca2+
H+ 1
2
3
4 Descending
pathogens Deposition of concrements:
calcium salts, uric acid
Toxic damage, e.g. phenacetin Allergic reaction, e.g. penicillin Rejection reaction after transplantation Inhibitors of prostaglandin synthesis
Lesions of distal nephron Immune defense
Ischemia Interstitial nephritis
Impaired urinary concentration
Osmotic pressure in renal medulla Inurine
Precipitation of phosphate salts
Natriuresis Ascending pathogens
Outflow obstruction
Alkaline urine Na+ reabsorption
H+ secretion
K+ secretion Systemic
acidosis
Hyperkalemia A. Interstitial Nephritis
Acute Renal Failure
Diverse prerenal, intrarenal, and postrenal dis-orders can lead to sudden impairment of renal function (→A 1):
Obstruction of the urinary tract, for exam-ple, by urinary stones (→p. 130) can stop uri-nary excretion, even though the kidney re-mains intact—at least at first (postrenal).
Following hemolysis and the destruction of muscle cells (myolysis) hemoglobin or myobin, respectively, is filtered through the glo-meruli and precipitated in the acidic tubular lumen, especially because their tubular con-centration is increased by fluid absorption.
The resulting obstruction disrupts urine forma-tion. Similarly intrarenal precipitations of uric acid and calcium oxalate may obstruct tubules.
Renal function can also cease as a result of rap-idly progressing renal diseases (e.g., glomerulo-nephritis;→p. 112) or toxic damage to the kid-ney (intrarenal).
Loss of blood and fluid, compromised car-diac pump function, or peripheral vasodilation requires centralization of the circulation to maintain blood pressure (→p. 246). The activa-tion of the sympathetic nerve system with sub-sequent activation ofα-receptors thereby leads to renal vascular vasoconstriction, which may cause acute ischemic renal failure despite the release of vasodilating prostaglandins (prere-nal).
Several pathophysiological mechanisms can prevent the recovery of GFR or restoration of normal excretion of substances filtered by the glomeruli, even after the state of shock has been overcome and blood pressure has been normalized (→A 1):
◆Constriction of the vasa afferentia:
– Energy deficiency impairs Na+/K+-ATPase;
the resulting increase in intracellular con-centration of Na+also causes, via the 3Na+/ Ca2+exchanger, a rise in intracellular Ca2+ concentration (→p. 12, 114) and thus vaso-constriction.
– The ischemia promotes the release of renin both primarily and via an increased NaCl supply in the macula densa (reduced Na+ absorption in the ascending tubules) and thus the intrarenal formation of angioten-sin II, which has a vasoconstrictor action.
– If there is a lack of energy supply, adenosine
is generated from ATP. It acts on the kidney—
in contrast to the other organs—as a marked vasoconstrictor.
◆Obstruction of the glomerular filter by fibrin and erythrocyte aggregates.
◆Seeping away of filtered fluid in the dam-aged tubules.
◆Obstruction of the tubular lumen by des-quamated tubular cells, by crystals, or due to swelling of the tubular cells.
◆Intravascular stasis by thrombosis or adhe-sion of suicidal erythrocytes at the vascular wall (“sludge”). Thrombosis and erythrocyte death is fostered by injury to endothelial cells and subsequent decrease of NO formation. The blood cells cannot be flushed out of the net-work between renal medulla and cortex, even if the perfusion pressure rises. In humans, the enhanced formation of vasoconstrictory endo-thelin presumably plays only a minor role.
In the first three days of acute renal failure no urine (anuria) or only a little volume of poorly concentrated urine (oliguria) is excreted as a rule (oliguric phase;→A 2). However, uri-nary volume alone is a very poor indicator of the functional capacity of the kidney in acute renal failure, because the tubular transport processes are severely restricted and the reab-sorption of filtered fluid is thus reduced. Ac-cordingly, a relatively large fraction of filtered fluid is excreted.
Recovery after the oliguric phase will lead to a polyuric phase characterized by the gradual increase of the GFR while the reabsorption function of the epithelial nephron is still im-paired (salt-losing kidney;→A 3). If the renal tubules are damaged (e.g., by heavy metals), polyuric renal failure occurs as a primary re-sponse, i.e., large volumes of urine are excreted despite a markedly decreased GFR.
The dangers of acute renal failure lie in the inability of the kidney to regulate the water and electrolyte balance. The main threat in the oliguric phase is hyperhydration (especially with infusion of large volumes of fluid) and hy-perkalemia (especially with the simultaneous release of intracellular K+, as in burns, contu-sions, hemolysis, etc.). In the polyuric phase the loss of Na+, water, HCO3–, and especially of K+may be so large as to be life-threatening.
118
5Kidney,SaltandWaterBalance
Plate5.10AcuteRenalFailure
119 1
100 0
%
% 0 100
2 14 26
Reabsorption and GFR normalized GFR
Vasoconstriction Reduced renal perfusion, especially in shock Glomerular inflammation,
poisoning, etc.
Fibrin deposition
Adenosine
Renin Angiotensin Leak
[Ca2+] intracellular
GFR
GFR Ischemia
Days
Sludge Obstruction of tubular lumen
Hypothetic mechanism (see text)
Obstruction
Re-absorption
Re-absorption
Dehydration, hypokalemia Polyuria Oliguria
Hyperhydration, hyperkalemia, ascending pyelonephritis Urine volume
GFR
4 Recovery 2 Oliguric phase
3 Polyuric phase A. Acute Renal Failure
Chronic Renal Failure
A number of renal diseases (→p. 112 ff.), dia-betes mellitus (→p. 312) and/or hypertension (→p. 124, 222 ff.) can ultimately lead to the de-struction of renal tissue (→p. 112 ff., 124). If the residual renal tissue is not in a position to adequately fulfill its tasks, the picture of renal failure evolves.
Reduced renal excretion plays a decisive role for the course of the disease. The loss of neph-rons increases the filtration in the remaining glomerula. The decreased GFR leads to an in-versely proportional rise in the plasma level of creatinine (→A, top; see also p. 102). The plas-ma concentration of reabsorbed substances also rises, but less markedly, because renal tub-ular reabsorption is impaired in renal failure.
The reabsorption of Na+and water is inhibited in renal failure by a variety of factors, including natriuretic peptides and PTH (→p. 122). The reduced reabsorption of Na+in the proximal tubules also decreases the reabsorption of oth-er substances, such as phosphate, uric acid, HCO3–, Ca2+, urea, glucose, and amino acids.
The reabsorption of phosphate is also inhibited by PTH.
Reduced NaCl reabsorption in the ascending limb compromises the concentrating mecha-nism (→p. 108). The large supply of volume and NaCl from parts of the proximal nephron promotes the reabsorption of Na+distally and aids in the secretion of K+and H+in the distal nephron and in the collecting duct. As a result, the plasma concentration of electrolytes can remain practically normal even if GFR is mark-edly reduced (compensated renal insufficien-cy). Disorders occur only once GFR has fallen to less than a quarter of the normal level. How-ever, this compensation is carried out at the cost of the regulatory range, in that the dam-aged kidney is unable to adequately increase the excretion of water, Na+, K+, H+, phosphate, etc. (e.g., if oral intake is increased).
Uric acid can be precipitated at high concen-trations, especially in the joints, and thus cause gout (→p. 268). The renal retention of oxidants increases oxidative stress and inflammation.
Oxidative stress and decreased renal elimina-tion increase the plasma concentraelimina-tions of
“uremia toxins” (e.g., acetonine, dimethlyl-argi-nine, 2,3-butyleneglycol, hippurate,
guanidino-succinic acid, methylguanidine, methylglyoxal, indoles, phenols, dimethyl-arginine [ADMA], aliphatic and aromatic amines, homocysteine, etc.) as well as of“middle molecules” (lipids or peptides with a molecular weight of 300–
2000 Da). The substances exert their toxic ac-tion via different mechanisms. ADMA, for in-stance, inhibits the NO synthesis, the decreased formation leads to ischemia and blood pressure increase. Methylglyoxal triggers suicidal cell death and contributes to the pathophysiology of blood cells (accelerated degradation of erythrocytes and impairment of leukocyte function). High concentrations of urea can de-stabilize proteins and bring about cell shrink-age. But its effect is partly canceled by the cel-lular uptake of stabilizing osmolytes (especially betaine, glycerophosphorylcholine). The bacte-rial degradation of urea yields ammonia, which causes halitosis (foetor uraemicus), and con-tributes to the derangement of gastrointestinal function (nausea, peptic ulcer, diarrhea). Urea and several uremia toxins are products of pro-tein metabolism and their concentration can be decreased by dietary protein restriction.
The impaired renal production of erythro-poietin leads to the development of renal ane-mia (→p. 34 ff.), which leads to activation of the sympathetic nerve tone. The intrarenal for-mation of renin and of prostaglandins can be increased (e.g., in ischemia) or reduced (death of renin- or prostaglandin-producing cells). In-creased formation of renin promotes, while its reduced formation of renin or increased forma-tion of prostaglandins (→p. 318) inhibit the development of hypertension, a frequent oc-currence in renal failure (→p. 124 ff.). The hy-pertension contributes to further renal injury.
Accordingly, the progression of chronic renal failure is accelerated by genetic increase of an-giotensin converting enzyme.
The loss of renal inactivation of hormones (→p. 100) may slow hormonal regulatory cy-cles. Delayed elimination of insulin, for in-stance, may lead to hypoglycemia. Hyperprolac-tinemia inhibits the release of gonadotropins and thereby reduces the plasma levels of estro-gens (♀) and testosterone (♂). Consequences include amenorrhea (♀) and impotence (♂).
The reduced consumption of fatty acids by 120
"
5Kidney,SaltandWaterBalance
Plate5.11ChronicRenalFailureI
121 100
300 500 700
100 50 0
K+
Na+, K+ Ca2+
NaClH2O
PGE2
H+ V. V.
Glomeruar filtration rate (% of normal rate)
Anemia Erythropoietin
Renin
Ischemia GFR Decompensated renal failure
Plasma concentration (%)
Compensated renal failure
NH3 production
Urea Creatinine Normal kidney
GFR RPF
Uremia toxins
Middle molecules
Break-down of free fatty acids Retention of:
Phosphate
Acidosis Plasma-Ca2+
Hyperlipidemia Hypertension
Demineralization Neuropathy, gastroenteropathy,
susceptibility to infection, coagulopathies
HPO42, Mg2+
Uric acids
Uric acids Urea Abnormalities
electrolyteof balance
Pruritus, arthritis, gout
Calcitriol GFR RPF
Inactivation of hormones
Catabolism
PTH Sympathetic
nervous system