Hormones Produced By The Kidney
Introduction
As producers of hormones the kidneys are an endocrine organ. Hormones that are produced in the kidneys include ane,25-dihydroxyvitamin D3, renin and angiotensin, and erythropoietin. The kidney also contributes to the circulating pool of growth factors such equally insulin-like growth factor-1 (IGF-1). Moreover, the kidneys participate in the regulation of hormonal action by eliminating hormones from the apportionment, primarily polypeptide hormones. Renal emptying contributes significantly to the deposition of many peptide hormones and, to a lesser extent, catecholamines and some steroid hormones (Box 10.ii.1.1). Hence, in advanced renal failure the half-lives and serum levels of these hormones are altered. In addition, the kidneys are target organs for hormones. The nephron is a major or exclusive receptor-bearing site for some hormones, and several other hormones are important in the regulation of aspects of renal function (Box 10.ii.1.ii). Certain abnormalities in the levels and activities of some of these latter hormones play significant roles in chronic renal failure and the progression of renal disease, and inhibitory therapeutic interventions are important treatment strategies in some renal diseases.
Box 10.2.1.one
Renal emptying of hormones
◆
Peptide hormones
•
Atrial natriuretic peptide
◆
Steroid Hormones
•
Steroid hormone metabolites
Box ten.2.1.2
The nephron as an endocrine target organ
◆
Atrial natriuretic peptide
◆
Insulin-like growth gene-ane
◆
one,25-dihydroxyvitamin D3
Renal hormones
Erythropoietin and renal anaemia
Bilateral nephrectomy causes severe anaemia, and haematocrit levels fall to beneath 20%. Similarly, end stage renal disease (ESRD) in patients on maintenance dialysis is also associated with severe normochromic, normocytic anaemia, although haematocrit is on boilerplate slightly greater than in anephric haemodialysis patients. Chronic progressive renal failure is associated with declining red claret cell mass, although in that location is only a weak inverse correlation betwixt serum creatinine and haematocrit (Fig. x.2.1.1).
Fig. 10.2.i.1
(a) Relationship between haematocrit and plasma creatinine in lx patients with chronic renal failure of various degrees. (Modified from McGonigle R, Wallin J, Shadduck R, Fisher J. Erythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency. Kidney Int, 1984; 25: 437–44, by permission of the Nature Publishing Group.) (b) Response in patients with end-phase renal disease to therapy with recombinant human erythropoietin. Each gradient represents the mean value in 4 to five patients per dose-group. (Modified from Eschbach J, Egrie J, Downing M, Browne J, Adamson J. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined stage I and II clinical trial. N Engl J Med, 1987; 316: 73–eight, past permission of the Massachusetts Medical Gild.)
Erythropoietin (EPO) deficiency is the principal, but not the sole, cause of anaemia of chronic renal illness. Other mechanisms contributing to anaemia in chronic renal failure and finish stage renal disease are reduced cherry-red blood prison cell lifespan, chronic blood loss in the gastrointestinal tract, folic acid deficiency with haemodialysis procedures, and undefined uraemic toxins which suppress erythropoiesis.
In astute renal failure, at that place may be but balmy or no anaemia because the one-half-life of circulating red blood cells is relatively long compared to the transient reduction in renal EPO synthesis. In patients with renal cysts, specifically, inherited polycystic kidney affliction, who take advanced chronic renal failure, anaemia may be absent. Some patients may even present with erythrocytosis caused by increased erythropoietin production in cyst-lining cells. Erythropoiesis due to increased expression of EPO is sometimes found in patients with renal cell carcinoma and, less frequently, as paraneoplastic symptoms in liver carcinoma, cerebella haemangioblastoma, and cancerous tumours of the uterus, adrenal gland, ovary, prostate, lungs, and thymus.
Erythropoietin
EPO (molecular weight 30 kDa) is the result of express proteolysis and heavy glycosylation of the EPO gene production, proEPO. EPO circulates in normal serum as a mixture of α- and β-EPO. Both have the same amino acrid sequence (165 amino acid residues) and biological activity, but differ in their carbohydrate composition, and hence their half-life, due to differences in hepatic clearance.
During fetal development EPO gene expression initially occurs in the liver, simply renal peritubular interstitial (and probably proximal tubular) cells after become the chief site of EPO product. EPO is almost exclusively expressed in the kidney in normal adults, but modest amounts of extrarenal EPO probably stem from hepatocytes. EPO product is inversely regulated by oxygen tension, thus hypoxia stimulates EPO production and erythrocytosis is a common finding in patients with chronic obstructive pulmonary illness.
Erythropoietin receptors
EPO is a glycoprotein hormone which functions equally a mitogenic growth factor and induces proliferation of erythropoietin receptor-begetting cells. Erythropoietin receptors share homology with other growth factor receptors such as growth hormone, prolactin, and IL-6 receptors. The erythropoietin receptor consists of an extracellular, a transmembranous, and an intracellular domain, and a single EPO molecule binds to ii receptors on the cell surface. Initially, EPO receptors were thought to exist selectively expressed in cells of erythroid lineage such as burst-forming unit-erythroid (BFU-E) cells and colony forming unit-erythroid (CFU-E) cells in the os marrow, which is consistent with an outcome of EPO restricted to red blood cell production. Nonetheless, subsequent studies disclosed that erythropoietin receptors are more than widely expressed. Sites include the brain, retina, heart, skeletal musculus, kidney, and endothelial cells, raising the possibility of extrahaematopoietic effects of EPO (i). Analyses of mice harbouring a null mutation of the EPO or the EPO receptor gene have shown that EPO is indispensable, not only for cherry blood jail cell product but besides for normal development of brain, centre, and blood vessels. Recent studies too show that EPO has tissue protective effects in acute organ injuries such as acute ischaemic stroke, astute renal failure, and myocardial infarction.
Management of renal anaemia
Since the introduction of recombinant EPO (epoetin-α; Epogen) in the tardily 1980s, it became possible to care for anaemia without transfusion. Epoetin-α became the mainstay of therapy for anaemia of renal illness. There are currently three erythropoiesis-stimulating agents (ESAs) approved for the therapy of anaemia of chronic renal failure; epoetin-α (Epogen), darbepoetin-α (Aranesp), and continuous erythropoietin receptor activator (Micera).
Darbepoetin-α is closely related to EPO, but contains 2 additional N-linked oligosaccharide chains, which confers greater metabolic stability and half life than epoetin-α. CERA (continuous erythropoietin receptor activator) is a third generation ESA, which recently gained FDA blessing but is currently non available in the United states. CERA is a pegylated version or EPO, with an insertion of a methoxy-polyethyleneglycol polymer of about xxx kDa between two lysines within the EPO protein sequence. This about doubles the molecular size and considerably prolongs the circulating half-life, allowing for less frequent intravenous or subcutaneous injection (2). There are other therapeutic strategies for stimulating red blood cell product in patients with EPO deficiency, in diverse states of clinical development (3).
Detailed guidelines for ESA therapy have been recently published in the 'Dialysis Outcomes Quality Initiative (DOQI) on Anaemia of Chronic Renal Failure' by an skilful panel of the National Kidney Foundation of the United States (4, 5). Information technology is usually not necessary to measure serum EPO levels in patients with chronic renal failure. However, other reasons for anaemia should be ruled out, and baseline atomic number 26 studies (atomic number 26, ferritin, transferrin saturation, and total atomic number 26-bounden capacity) should be measured prior to initiating ESA therapy. If fe deficiency is present, patients should be treated with either oral or (preferably) intravenous atomic number 26. Intravenous assistants of iron is preferred in dialysis patients. At that place are limitations of the utility of atomic number 26 indices dialysis patients. Serum ferritin level reflects iron stores, only there is a poor correlation between ferritin levels and marrow iron stores in patients on dialysis. Serum transferrin, the iron send protein, which is unremarkably measured as total atomic number 26 binding capacity (TIBC), is a negative astute phase reactant and is decreased in ESRD patients (6). Transferrin saturation (TSAT) values of xx–30% in ESRD patients are comparable to values of 13–20% in normal patients. As a dominion, in dialysis patients undergoing ESA treatment, TSAT below xx% may reflect iron deficiency. Current DOQI guidelines for the treatment of renal anaemia recommend initiating ESAs when the haemoglobin value falls below 90 g/l. However, there has been considerable debate well-nigh the optimal target range of haemoglobin in patients with chronic renal failure. The recommended target haemoglobin level is in the range of < twenty g/l in dialysis and nondialysis patients with chronic kidney diseases (five). The DOQI guidelines also recommend avoiding haemoglobin levels above 130 g/l. Mortality and cardiovascular event rates were increased during ESA therapy in patients on chronic haemodialysis with higher vs lower haemoglobin levels (135 g/fifty vs 113 g/l and 130–150 g/l vs 105–115 g/fifty) in 2 recent clinical trials (7).
Hyporesponsiveness or resistance to ESA therapy is usually identified when the haemoglobin remains below 110 g/l despite increasing doses of ESA. The major causes include atomic number 26 deficiency due to the robust erythropoiesis or chronic blood loss, infection or inflammation, and underdialysis. Other possible aetiologies are haemorrhage or haemolysis, secondary hyperparathyroidism, aluminum toxicity, haemoglobinopathies, folate or vitamin B12 deficiency, carnitine deficiency, and primary bone marrow disorders.
The renin–angiotensin system
The renin–angiotensin system (RAS) is equanimous of its regulatory elements, all of which are expressed, although non exclusively, in the kidney. Renin is an aspartyl protease that cleaves angiotensinogen to generate the decapeptide angiotensin I. Angiotensinogen is produced primarily in the liver, but there are multiple extrahepatic sites including the vasculature and renal proximal tubules. Angiotensin I-converting enzyme is a dipeptidyl carboxypeptidase that generates angiotensin II from angiotensin I, and also degrades bradykinin. The angiotensin I-converting enzyme cistron is expressed ubiquitously in endothelia in all vascular beds, simply the enzyme is also present in the apical membranes of renal proximal tubules. Hyperthyroidism, sarcoidosis, and other lung diseases cause elevated serum angiotensin I-converting enzyme levels.
Angiotensin 2 acts through 2 receptors, known as angiotensin II blazon 1 and type two receptors (AT1 and AT2). AT1 receptors mediate most of the known functions of angiotensin II such as vasoconstriction, aldosterone secretion, jail cell growth, and proximal tubular sodium assimilation, and these receptors are blocked by angiotensin receptor blockers such as losartan.
The RAS regulates the activity of its active component, angiotensin Two. Renin is primarily expressed in the juxtaglomerular apparatus (Fig. x.ii.1.two), only is also produced in the intrarenal arteries and arterioles, proximal tubules, and the glomerular mesangium. The juxtaglomerular appliance is a true endocrine organ within the kidney, where renin is stored in secretory granules. Renin release is regulated by multiple signals (Table 10.2.ane.1). It is the rate-limiting regulator of angiotensin Two activity. The deportment of angiotensin II are determined by the distribution of AT1 receptors. In the kidney, angiotensin Two constricts both afferent and efferent glomerular arterioles, but the latter are more sensitive. Every bit a issue, the greater effect of efferent vasoconstriction raises glomerular capillary blood pressure, causing glomerular hypertension.
Plate 49
The juxtaglomerular apparatus. Renin is produced in specialized shine muscle cells of the afferent arteriole (juxtaglomerular cells) that are located in the glomerular vascular pole next to the macula densa of the distal tubule of the same nephron. Renin in juxtaglomerular cells is visualized by immunohistochemistry. Renin expression is upregulated past increased intravascular volume as well as by macula densa signals that are induced by increased distal tubular Cl- traffic. (Courtesy of Dr Luciano Barajas, Torrance, CA.) (Come across also Fig. ten.2.1.ii)
Table 10.two.ane.1
Signals regulating renin release
| Increases renin | Decreases renin |
|---|---|
| ◆ Intrarenal baroreception in juxtaglomerular appliance ◆ Renal nerve stimulation | ◆ Endothelin |
| ◆ Catecholamines | ◆ Distal tubular NaCl |
| ◆ Mg2+ | ◆ Ca2+ ◆ K+ ◆ ADH ◆ Angiotensin Two ◆ ANP (?) |
| Increases renin | Decreases renin |
|---|---|
| ◆ Intrarenal baroreception in juxtaglomerular apparatus ◆ Renal nerve stimulation | ◆ Endothelin |
| ◆ Catecholamines | ◆ Distal tubular NaCl |
| ◆ Mg2+ | ◆ Ca2+ ◆ K+ ◆ ADH ◆ Angiotensin II ◆ ANP (?) |
Angiotensin 2 likewise constricts the glomerular mesangium, which results in a decrease in the surface expanse available for glomerular ultrafiltration of water and modest solutes. In connecting and cortical collecting tubules, where all chief RAS components are coexpressed, angiotensin II promotes Na+ absorption.
Arterial stenosis, arteriolar stenosis, or vasoconstriction in the kidney, such every bit in renal artery stenosis, eclampsia, microangiopathies (haemolytic uraemic syndrome), and others are associated with severe hypertension. In primary hypertension, about sixty% of patients have normal renin and nigh 15% have high renin action. Still, patients with low-renin principal hypertension also respond to angiotensin I converting enzyme-inhibitors and AT1 receptor blockers. The role of polymorphism in RAS genes in human 'primary' hypertension is presently unclear, but is the field of study of ongoing genetic research.
The intrarenal renin–angiotensin axis
All elements leading to the recruitment of bioactive angiotensin II are expressed in connecting tubules. It is idea that angiotensin Ii from cells in this nephron segment is secreted through the apical membrane. Tubular fluid angiotensin II can actuate AT1 receptors which are located downstream in the upmost membrane of cortical collecting duct cells where signals are generated that actuate ENaC and hence, increase sodium absorption. Increased action of this intrarenal renin angiotensin axis is idea to be causative in some forms of primary hypertension (Fig 10.2.1.3). Clinically, this syndrome is characterized by low serum renin levels or plasma renin activity and normal aldosterone levels.
Fig. 10.two.1.3
Cartoon of the intra-renal renin-angiotensin-system (RAS) in the distal nephron. The genes encoding renin, angiotensinogen, and the angiotensin I converting enzyme are all expressed in distal convoluted tubular and connecting tubular cells generating angiotensin Two (AII), which is secreted through the upmost membrane. AII travels downstream post-obit tubular fluid menstruation and activates angiotensin II blazon 1 receptors (AT1) which are expressed in the apical membrane of cells in the cortical collecting duct. Signals from activated AT1 receptors increase the opening time of ENaC sodium channels, enhance Na+ (and water) absorption causing hypertension. It is idea that the intrarenal RAS is causative in some forms of primary hypertension, probably due to gain-of-functions in RAS genes.
Angiotensin Ii in chronic renal disease
The RAS and, specifically, angiotensin II play important roles in the progression of chronic renal failure and angiotensin II activity is an important therapeutic target. As indicated above, elevated renal angiotensin II activity causes increased glomerular capillary pressure level which, in turn, contributes to glomerular sclerosis. In proteinuric glomerular diseases, angiotensin I converting enzyme-inhibitors may reduce the caste of proteinuria. Moreover, angiotensin 2 induces increased expression of transforming growth cistron β and platelet-derived growth factor (PDGF) in glomerulus, tubules, and interstitium. Transforming growth factor β, in plow, increases the deposition of extracellular matrix proteins such as collagen type I, fibronectin, and laminin causing glomerular sclerosis and interstitial fibrosis, the hallmarks of progressive chronic renal failure in virtually all chronic renal diseases. The fundamental role of transforming growth factor β in renal scarring and progression of chronic renal failure has been demonstrated clearly in experimental animals. Hence, in chronic renal failure angiotensin I converting enzyme-inhibitors (and AT1 antagonists) are being used to decelerate the progression of chronic renal disease, reduce proteinuria, and to treat hypertension. Several prospective, randomized clinical trials accept demonstrated the utility of these drugs in chronic renal failure (8). Angiotensin I converting enzyme-inhibitors and/or AT1-blockers are the most important therapy in patients with diabetic nephropathy and should be employed early in the form, even in the absence of hypertension or renal failure (9).
Pseudoaldosteronism and renal blood pressure regulation
Syndromes associated with hyperaldosteronism typically present with hypokalaemia, metabolic alkalosis, and hypertension, although potassium depletion and hypokalaemia may be mild or absent until tardily in the course of the condition. Principal hyperaldosteronism is discussed in Affiliate 5.6. Hypertensive syndromes associated with secondary hyperaldosteronism, such equally hypertension due to suprarenal aortic stenosis or renal avenue stenosis, malignant hypertension, or reninoma, present with elevated plasma renin activity.
However, in that location has recently been an increased understanding of several (mostly monogenetic) syndromes that present with hypertension mimicking main hyperaldosteronism or those presenting with hypotension or normal claret force per unit area, which may be confused with Addison'southward disease.
Glucocorticoid-remediable aldosteronism (GRA)
GRA is acquired by an inherited chimeric gene equanimous of the regulatory elements of 11β-hydroxylase and the coding sequence of aldosterone synthase (Fig. ten.two.1.4). This syndrome is discussed in Chapter 5.vii.
Fig. 10.2.1.iv
Hypokalaemia and metabolic alkalosis associated with hypotension or depression-normal claret pressure (Gitelman's and Bartter'southward syndromes) or with hypertension (Liddle's syndrome; primary hyperaldosteronism; credible mineralocorticoid excess (AME); some forms of pregnancy-associated hypertension (progesterone-sensitive hypertension); glucocorticosteroid-remedial aldosteronism (GRA)). Genetic mutations in either the Na+/K+/2Cl−-cotransporter, K-channel (ROMK) or chloride aqueduct (ClCNKb) in the thick ascending limb of the loop of Henle cause urinary NaCl, K+, and fluid losses in the three different types of Bartter's syndrome. Genetic defects in the (thiazide-sensitive) NaCl cotransporter in apical membranes of distal tubules cause the urinary NaCl and fluid losses in Gitelman'due south syndrome. The syndromes are similar to cronic overdose with thiazide (Gitelman's) or loop diuretics (Bartter'southward). The increased Na+ delivery and assimilation in the cortical collecting duct besides every bit intravascular volume–contraction-induced secondary hyperaldosteronism drive potassium and proton secretion and urinary losses of these ions. Cortical collecting duct primary cells limited mineralocorticoid receptors which regulate Na/Thou, H-exchange in basolateral membranes. These receptors are over-activated in aldosteronism by increased aldosterone, in GRA by increased and ACTH-dependent aldosterone, and in AME by cortisol which is not sufficiently degraded due to a defect in the 11β-hydrocysteroid-dehydrogenase (DHG). This latter enzyme is also inhibited past glycerrhic acid, an ingredient of black liquorice. Epithelial sodium channels (ENaC) in apical membranes are of import determinants of distal tubular and collecting duct Na+ assimilation. Gain-of-role mutations in the Na-channel in Liddle's syndrome event in increased Na+ and fluid absorption (hypertension) which drives G+- and proton losses (hypokalaemic alkalosis). Loss-of-function mutations in ENaC cause urinary Na+ and fluid losses (hypotension) and reduces the tubule's ability to secrete Chiliad+ and protons causing hyperkaleamic acidosis in pseudohypoaldosteronism type I (PHA-ane). Certain mutations such equally MRL810S return the mineralocorticoid receptor (MR) sensitive for progesterone and cause familial forms of hypokalaemic hypertension and alkalosis during pregnancy (10). Pseudohypoaldosteronism type 2 (PHA-2, also called as familial hyperkalemic hypertension or Gordon's syndrome) is caused past mutations in either of two with-no-lysine-kinases, WNK1 or WNK4, leading to increased distal tubular NaCl absorption causing hypertension. The decreased Na+ delivery to downstream nephron elements reduces the ability of Grand+ and proton excretion leading to hyperkalaemia and metabolic acidosis.
Apparent mineralocorticoid excess (AME)
AME is caused past a defect in the 11β-hydroxysteroid dehydrogenase. This allows accumulated cortisol to activate mineralocorticoid receptors in distal tubules and cortical collecting ducts, causing increased activity of the Na/Thou-ATPase, and resulting in increased distal tubular Na+ retentiveness and Yard+ and H+ excretion (Fig. 10.ii.ane.iv). The syndrome is also discussed in particular in Affiliate 5.viii. Both AME and GRA respond to handling with an aldosterone adversary, spironolactone (although treatment of patients with GRA includes dexamethasone, to reduce ACTH-dependent expression of the chimeric gene).
Liddle'due south Syndrome
Patients with Liddle's syndrome present with the onset of symptoms of hyperaldosteronism during adolescence, demonstrate suppressed aldosterone and renin levels, and practise not respond well to spironolactone. The genetic defects in these patients are proceeds-of-function mutations in the amiloride-sensitive sodium aqueduct (ENaC) in the cortical collecting duct, which cause increased renal Na+ and water memory (Fig. ten.2.ane.4). The ENaC protein complex is composed of three subunits, each encoded by a dissimilar factor. The α-subunit is the conductance protein, and its translocation from the cytosol to the apical tubular prison cell membranes raises Na+ uptake from tubular fluid. The β- and γ-subunits regulate the translocation of the α-subunit into the upmost membrane. Liddle's syndrome is acquired by various mutations in either the β- or the γ-subunit of ENaC, causing increased opening fourth dimension of the Na+ channel. The increased Na+ uptake in the distal tubular and cortical collecting duct drives increased K+ and H+ loss, resulting in hypokalaemia and metabolic alkalosis, in addition to hypertension (Fig. 10.2.1.four). The treatment of hypertension in patients with Liddle's syndrome should include reduced dietary salt intake, amiloride, and/or triamterene.
Pregnancy-associated pseudohyperaldosteronism
Although blood pressure is normally reduced throughout pregnancy, almost half-dozen% of all pregnancies in the U.s.a. are complicated by the development of hypertension that increases maternal and fatal mortality. The causes of hypertension during pregnancy remain largely unknown; however, the recent discovery of a mutation in the mineralocorticoid receptor (MRL810s) provided an exact mechanism for the development of hypertension. Carriers of this mutation, MRL810S, are found to have an early-onset hypertension; females with this mutation peculiarly take hypertension, which is markedly exacerbated in pregnancy (ten). Progesterone, which typically lowers blood pressure and increases100 fold during pregnancy, is found to be a potent agonist for MRL810S and is thus responsible for pregnancy-associated hypertension (Fig. 10.2.i.4). In nonpregnant female and male carriers of this mutation, cortisone, the main metabolite of cortisol in the kidney, activates MRL810S and causes early-onset hypertension (11).
Gordon'due south syndrome
The genetic mechanisms of a peculiar form of familial hypertension called familial hyperkalaemic hypertension, likewise known as pseudohypoaldosteronism blazon two (PHA-two), or Gordon'southward syndrome, have recently been unravelled. The with-no-lysine-kinase WNK1 and WNK4 genes encode kinases that regulate electrolyte transport in the kidney. Some families acquit a gain-of-function mutation of WNK1 or loss-of-office mutation of WNK4. Both genes are expressed in the distal nephron (distal convoluted tubule and connecting tubule). WNK4 is an inhibitor of the Na+/Cl− cotransporter, and its loss-of-function increases salt (and water) absorption. Moreover, this reduces Na+ delivery to the cortical collecting duct, which is located downstream. Since at this nephron site Na+ levels determine K+ and proton secretion, hyperkalaemia and nonanion gap metabolic acidosis are present. WNK1 is an inhibitor of WNK4. Thus, a gain-of-role mutation of WNK1 causes the same clinical syndrome as loss-of-function of WNK4 (Fig 10.2.1.4).
Familial hypokalaemic, hypotensive metabolic alkalosis
Pseudohypoaldosteronism blazon I (PHA-1)
The recent discovery of the genetic defects underlying glucocorticosteroid-remedial aldosteronism and pseudohyperaldosteronism syndromes (AME and Liddle's syndrome) exemplifies the fundamental role of renal tubules in the genesis of hypertension. Perhaps all forms of hypertension, including primary hypertension, are in fact intrinsic kidney diseases, which share increased tubular Na+ reabsorption as a common mechanism. Similarly, some chronic hypotensive syndromes may too be intrinsic renal diseases which share defective renal tubular Na+ assimilation. The infinitesimal-to-minute accommodation of blood pressure level is regulated by cardiac output, which determines the distribution of intravascular volume betwixt the low pressure (venous pool) and high force per unit area (arteries) vasculature, and by vasoconstriction. 24-hour interval-to-day claret pressure level maintenance is regulated past Na+ and water status, and hence is a office of the kidneys. In PHA-ane, reduced Na+ absorption results from a loss-of-office mutation in one of the genes encoding ENaC, which leads to severe natriuresis in the postnatal period associated with astringent dehydration and hypotension, hyperkalaemia, and metabolic acidosis associated with hyperrenimic secondary hyperaldosteronism due to intravascular volume depletion (Fig. x.2.1.3) (12).
Gitelman'southward syndrome and the family unit of Bartter'southward syndromes
Both Gitelman's and Bartter'due south syndromes present with similar clinical features, including low normal blood pressure due to urinary Na+ loss, hypokalaemia, metabolic alkalosis, and secondary hyperaldosteronism (Fig. 10.2.i.4, Table x.2.1.ii). Bartter'south syndromes unremarkably manifest in childhood, in contrast to Gitelman's syndrome which is generally a disorder of adults.
Table 10.ii i.2
Clinical and laboratory findings in Gitelman's and Bartter'southward syndromes
| Gitelman'due south Syndrome | Bartter's Syndrome |
|---|---|
| Genetic defect ◆ NaCl-cotransporter | Genetic defect ◆ Yard-channel ◆ Na-One thousand-2Cl cotransporter ◆ Cl-channel |
| Site in nephron ◆ Distal tubule (apical membrane) | Site in nephron ◆ Thick ascending loop of Henle (apical membrane) |
| Clinical/laboratory findings ◆ Renal common salt wasting ◆ Hypotension (or normal blood pressure) ◆ Secondary hyperaldosteronism ◆ Hypokalemia ◆ Metabolic alkalosis ◆ Hypocalcaemia ◆ Hypomagnesaemia and hypermagnesuria | Clinical/laboratory findings ◆ Renal salt wasting ◆ Hypotension (or normal blood force per unit area) ◆ Secondary hyperaldosteronism ◆ Hypokalaemia ◆ Metabolic alkalosis ◆ Normo- or hypercalcaemia (± nephrocalcinosis) ◆ Hypomagnesaemia |
| Gitelman'due south Syndrome | Bartter's Syndrome |
|---|---|
| Genetic defect ◆ NaCl-cotransporter | Genetic defect ◆ K-channel ◆ Na-Chiliad-2Cl cotransporter ◆ Cl-aqueduct |
| Site in nephron ◆ Distal tubule (apical membrane) | Site in nephron ◆ Thick ascending loop of Henle (apical membrane) |
| Clinical/laboratory findings ◆ Renal salt wasting ◆ Hypotension (or normal blood pressure) ◆ Secondary hyperaldosteronism ◆ Hypokalemia ◆ Metabolic alkalosis ◆ Hypocalcaemia ◆ Hypomagnesaemia and hypermagnesuria | Clinical/laboratory findings ◆ Renal salt wasting ◆ Hypotension (or normal blood pressure) ◆ Secondary hyperaldosteronism ◆ Hypokalaemia ◆ Metabolic alkalosis ◆ Normo- or hypercalcaemia (± nephrocalcinosis) ◆ Hypomagnesaemia |
Gitelman's syndrome appears to event from an autosomal recessive defect in the cistron encoding the distal tubular thiazide-sensitive NaCl cotransporter (Fig. 10.2.one.4), explaining the renal salt wasting that appears to crusade its symptoms. Although the mechanisms causing renal magnesium wasting are not well understood, these patients accept hypomagnesaemia and hypocalciuria, dissimilar patients with Bartter's syndromes. Magnesium and potassium supplements are normally given to ameliorate symptoms, and these patients usually accept very good long-term prognosis.
Bartter'due south syndrome is also characterized past natriuresis, book contraction, hypotension (or depression normal blood pressure), hypokalaemia, and metabolic alkalosis, and is associated with secondary hyperaldosteronism. However, there are at least iii different variants, and iii different genetic abnormalities (13). All three cistron mutations identified thus far encode send proteins in the apical membrane of the thick ascending limb of the loop of Henle (Fig. 10.2.ane.4), resulting either in a loss-of-function of the (loop diuretic-sensitive) Na–K–2Cl (NKCC2) cotransporter, the ATP-dependent Yard channel (ROMK), or a chloride channel (ClC-Kb). Each of these defects will directly or indirectly causes urinary NaCl and K+ loss. Nearly patients also have hypercalciuria, due to reduced paracellular assimilation of Ca2+ in the loop of Henle, which may atomic number 82 to nephrocalcinosis and renal failure later in life (Tabular array 10.2.1.2). These patients often have a history of polyhydramnios during pregnancy and premature delivery. In some patients, increased urinary prostaglandin (PGE2) levels take been found and treatment with indomethacin sometimes improves hypokalaemia and other symptoms. Otherwise, therapy is symptomatic in nature with potassium replacement and saline infusion.
Vitamin D and the kidney
Calcitriol (1,25-dihydroxyvitamin D3)
1,25-dihydroxyvitamin D3 has generally gained hormonal status due to its regulatory interest on the parathyroid gland, serum calcium, and bone metabolism. The kidney plays an important role in the product of this most agile form of vitamin D. Vitamin D is the photolytic product of its forerunner, 7-dehydrocholesterol, or information technology is taken upward from diet. Hydroxylation in the carbon 25 position occurs in the liver, and generates 25-hydroxyvitamin D3. Serum levels of this intermediate are a useful mark for assessing vitamin D condition in patients with chronic renal failure. The precursor 25-hydroxyvitamin D3 is the substrate for the enzyme 25-hydroxyvitamin D1-hydroxylase, which is primarily expressed in renal proximal tubular cells and generates highly bioactive 1,25-dihydroxyvitamin D3 (calcitriol).
Calcitriol is a powerful regulator of calcium and phosphate homeostasis and raises serum calcium and phosphate levels. In turn, serum phosphate, (ionized) calcium, and parathyroid hormone (PTH) regulate calcitriol levels. In patients with normal renal function, hypocalcaemia increases and hypercalcaemia reduces renal α1-hydroxylase activity. Hypophosphataemia also raises calcitriol synthesis. The effects of insulin-similar growth factor 1 and growth hormone on renal phosphate assimilation, causing it to increase, are mostly independent of calcitriol synthesis.
Calcitriol acts through vitamin D receptors and increases the gastrointestinal absorption of calcium. It promotes bone mineralization past increasing the serum levels of Ca2+ and phosphate. Past these ways vitamin D contributes to the long-term homeostasis of calcium balance, whereas PTH regulates the minute-to-minute serum levels of ionized calcium. Calcitriol and PTH actions are interwoven, considering vitamin D blocks PTH release in parathyroid glands. The deportment of calcitriol on renal handling of Ca2+ are somewhat controversial.
Calcitriol in renal disease
Nephrotic syndrome
Much of the circulating calcitriol is jump to proteins, primarily vitamin D-binding protein and albumin. There are substantial renal losses of both of these proteins in the nephrotic syndrome. Although the agile form, free calcitriol, is maintained at a fairly constant level when the total vitamin D levels are decreased, even free calcitriol levels become decreased in severe poly peptide depletion. However, at that place is also depletion of 25-hydroxyvitamin D3 (Fig. x.ii.1.five), the forerunner for calcitriol synthesis. This is probably nigh important factor for reduced calcitriol bioactivity that occurs in longstanding and astringent nephrotic syndromes. Reduced vitamin D action reduces intestinal Caii+ absorption and decreases the serum levels of ionized Catwo+. Reduced calcitriol and ionized calcium levels lead to secondary hyperparathyroidism and enhanced os resorption. Glucocorticoids, when used chronically in high doses, inhibit abdominal vitamin D-dependent calcium absorption and cause osteomalacia.
Fig. 10.2.1.v
Dependence of 25-hydroxycholecalciferol levels on serum albumin. In the nephrotic syndrome, proteinuria causes urinary losses of albumin-bound 25-hydroxycholecalciferol. Since this course of vitamin D is the precursor for calcitriol synthesis, very depression levels of 25-hydroxycholecalciferol will issue in reduced action of calcitriol fifty-fifty in patients with normal renal part. (Reproduced from Goldstein D, Oda Y, Kurokawa Thousand, Massry Southward. Blood levels of 25-hydroxyvitamin D in nephrotic syndrome. Studies in 26 patients. Ann Intern Med, 1977; 87: 664–vii by permission of the American College of Physicians.)
Assistants of vitamin D or 25-hydroxyvitamin D3 (about 20 μg/day) corrects serum levels of 25-hydroxyvitamin D3 in patients with the nephrotic syndrome, with or without renal failure. Nonetheless, this handling will right calcitriol action, hyperparathyroidism, and disturbances in Ca2+ homeostasis just in patients with normal or nearly-normal renal function, merely will neglect in patients with advanced chronic renal failure. Thus, calcitriol replacement should be considered in advanced chronic renal failure patients.
Chronic renal failure
Secondary hyperparathyroidism in chronic renal failure and ESRD leads to renal os disease (renal osteodystrophy) and fractures. It may also contribute to anaemia, vascular sclerosis, coronary artery disease, and malignant tumours, all of which occur with increased incidence in ESRD, thus resulting in increased morbidity and mortality.
Secondary hyperparathyroidism in renal failure is a circuitous disorder, caused in role past a lack of PTH-inhibiting signals, due in plow to decreased i,25-dihydroxyvitamin D3 (Calcitriol) activity, reduced levels of ionized Ca2+, and hyperphosphataemia. Renal os disease is a group of diseases divers histologically, which include abnormally high (osteitis fibrosa cystica) likewise as low os turnover (adynamic bone illness). Renal bone illness can as well be caused (or contributed to) by aluminium degradation in os (from longstanding use of Al-containing phosphate binders). In both aluminium-related and adynamic bone illness, overly aggressive therapy of hyperparathyroidism tin be detrimental.
The 2003 Kidney Disease and Outcomes Quality Initiative (Thousand/DOQI) practice guidelines for the prevention of renal osteodystrophy draw the optimal management of secondary hyperparathyroidism and divalent ion metabolism abnormalities in patients with chronic renal failure (14). Earlier starting oral or intravenous calcitriol, hyperphosphataemia must be corrected with reduction of dietary phosphate intake and oral phosphate binders. Whereas aluminium hydroxide is the most effective phosphate binder, it should exist used for only a short catamenia of time (a few weeks) to prevent aluminum toxicity. The preferred long-term phosphate binders are calcium-containing agents such every bit CaCO3 and calcium acetate, or not-calcium containing agents like sevelamer hydrochloride (Renagel) and lanthanum carbonate (Fosrenol).
Calcitriol and other vitamin D metabolites are effective in controlling secondary hyperparathyroidism. However, these agents should not be used without documentation of secondary hyperparathyroidism and control of hyperphosphataemia. Calcitriol (0.25–1.0 µg/day orally or three times per calendar week intravenously in haemodialysis patients), doxercalciferol, 22-oxacalcitriol, and paricalcitol (19-nor-1,25-dihydroxyvitamin Dtwo) are used in clinical practice. A recent retrospective assay showed that there may be a survival advantage associated with paricalcitol compared to calcitriol in haemodialysis patients (xv). The causation remains elusive. Serum Caii+, phosphate, alkaline metal phosphatase, and intact PTH levels have to exist monitored closely. Calcitriol directly and indirectly (through ionized serum calcium) blocks PTH-release (Fig. 10.2.one.half-dozen).
Fig. 10.2.i.6
Effect of intravenous administration of calcitriol (1,25-dihydroxyvitamin D3, 0.five–4.0 μg three times per week) on secondary hyperparathyroidism in chronic haemodialysis patients. The initial decrease in serum PTH levels during the first week of therapy preceded the ascent in serum calcium, indicating a directly upshot of calcitriol in blocking PTH release from parathyroid glands. The subsequent farther decline in serum PTH levels results from direct effects of 1,25-dyhydroxyvitamin D3 and from increased serum Ca2+ levels that cake parathyroid glands through calcium-sensitive receptors. (Reproduced from Slatopolshy Due east, Weerts C, Thielan J, Horst R, Harter H, Martin Yard. Marked suppression of secondary hyperparathyroidism by intravenous assistants of 1,25-dihydroxy-cholecalciferol in uremic patients. J Clin Invest 1984; 74: 2136–43 by copyright permission of the American Society for Clinical Investigation).
Cinacalcet (Sensipar), a calcimimetic which targets the calcium-sensing receptor in the parathyroid gland and increases its sensitivity to calcium, is added to control refractory secondary hyperparathyroidism. Improver of cinacalcet to standard therapy helps to reach target levels of calcium, phosphates, and intact PTH in chronic haemodialysis patients (16).
Although effective medical therapy for secondary hyperparathyroidism has largely reduced the demand for parathyroidectomy, it is nonetheless indicated in patients with astringent tertiary hyperparathyroidism who cannot be managed with medicinal therapy or who have calciphylaxis.
The kidney as an endocrine target organ
The kidney is a primary target organ for a number of hormones. Aldosterone is discussed in Part five and ADH is addressed in Office two. Aspects of renin and angiotensin Two are reviewed earlier in this chapter. Several other hormones act through receptors that are as well expressed in the kidney and accept affect on kidney function.
Atrial natriuretic peptide
Increases in fundamental venous volume cause natriuresis. Upon volume expansion-induced stretch, atrial cardiomyocytes release the polypeptide hormone ANP from intracellular granules. ANP is a 28 amino acid peptide hormone that is not only induced by atrial stretch but likewise (directly or indirectly) by vasopressin, angiotensin II, and endothelin. Manoeuvres increasing the cardinal venous volume puddle induce ANP natriuresis, such every bit chronic volume expansion, head-out water immersion (swimming), supine posture, or lower extremity positive pressure. Atrial tachycardia as well increases ANP levels and activeness.
ANP receptors are primarily expressed in renal glomeruli and in the renal medullary and papillary collecting ducts. Extrarenal sites of action include the microvasculature, brain, and adrenal glands. In the resistance-regulating vasculature (arterioles), ANP is vasorelaxing and antagonizes angiotensin Ii deportment. In the brain, ANP reduces vasopressin release. In adrenal glands, ANP blocks release of aldosterone. All of these extrarenal deportment of ANP are consistent with and supportive of its natriuretic activity.
The main target for ANP is the kidney. Its renal effects include a moderate increment in glomerular filtration rate, due to an increase in both glomerular capillary filtration pressure and glomerular ultrafiltration coefficient. Its natriuretic furnishings result from inhibition of Na+ reabsorption in the inner medulla. Its diuretic effects are farther enhanced by inhibition of the deportment of vasopressin in the inner medullary collecting duct.
In patients with liver cirrhosis and portal hypertension, plasma ANP levels are normal or elevated, but there is resistance to the action of ANP. This may contribute to the renal Na+ and water retention and possibly to the intrarenal vasoconstriction that is observed in the hepatorenal syndrome.
It is unclear whether ANP plays a role in (master) hypertension. In most hypertensive patients ANP levels are elevated, probably reflecting increased Na+ and water retention. At that place is little evidence for renal resistance to ANP in principal hypertension.
A related peptide, urodilatin, is exclusively expressed in the kidney, and large amounts are excreted with urine, but the peptide is absent from plasma. Urodilatin acts through renal ANP receptors. It is believed that urodilatin is more potent and important compared to ANP in the regulation of renal Na+ excretion.
Experimental studies suggested that recombinant man (rh)ANP may have therapeutic utility in astute renal failure. Clinical trials have been performed to examine whether rhANP accelerates the recovery of renal function in patients with acute renal failure. Whereas pocket-size clinical studies suggested that rhANP improves consequence in these patients, a comprehensive, prospective, randomized controlled trial did non support this indication and rhANP is not marketed (17).
More recently performed minor clinical studies propose a potential office for recombinant urodilatin in the treatment of astute renal failure and severe congestive heart failure, although more comprehensive trials will exist necessary to make up one's mind on potential therapeutic uses for the recombinant form of this peptide hormone.
Growth hormone and insulin-similar growth factor-1
Growth hormone receptors are expressed in some segments of the nephron and growth hormone induces nephron growth (hypertrophy). About renal effects of growth hormone are mediated through local induction of IGF-1 (18). However, transgenic mice overexpressing growth hormone develop nephron hypertrophy, premature glomerular sclerosis, and renal failure, whereas IGF-1 transgenic mice only develop hypertrophy. There is preliminary evidence that the growth hormone-induced induction of glomerular sclerosis may be mediated by a separate class of receptors. However, now, therapeutic administration of growth hormone in children with short stature appears condom and there is no evidence that it may cause or advance renal failure (19). There has also been no study of increased incidence of renal failure in patients with acromegaly.
In normal subjects, IGF-1 and growth hormone (through IGF-1) increase glomerular filtration charge per unit by 15–20%. Experimental findings betoken that IGF-1 increases the renal expression of vasodilating prostaglandins as well equally nitric oxide causing a reduction in vascular resistance, a rise in renal blood period, and a ascent in the glomerular ultrafiltration surface surface area. IGF-1 besides increases renal tubular phosphate assimilation; this upshot is transmitted through IGF-one receptors and is independent of ane,25-dihydroxyvitamin D3 (Fig. ten.2.1.7). This is an of import machinery through which growth hormone maintains positive phosphate balance during adolescent growth.
Fig. ten.2.i.vii
Consequence of recombinant insulin-like growth gene-1 on tubular phosphate assimilation in normal subjects. Insulin-like growth factor-I was given subcutaneously on days 2, 3 and 4 and caused about a 50% decline in the fractional excretion of phosphate (FEPO4). (*p<0.01).
In chronic renal failure, serum growth hormone levels are elevated, but there is resistance to growth hormone and IGF-1 (xx). This may contribute to the reduced growth rate in children with renal failure, every bit well as to catabolism and malnutrition in developed patients with ESRD. Clearly, administration of recombinant human growth hormone accelerates growth in children with chronic renal failure and may increase adult height (nineteen, 21). There accept been several studies to examine whether recombinant growth hormone and/or IGF-i may improve nitrogen rest and nutritional status in patients with chronic renal failure. Although short-term administration of growth hormone and/or IGF-ane improves nitrogen residuum, it is unclear whether this is of long-term benefit in these patients. Moreover, the toll of such long-term therapy may be prohibitive.
As a mitogen growth factor, IGF-1 is involved in the natural process of healing after astute renal injury (acute tubular necrosis). This observation led to the study of recombinant human insulin-similar growth factor-I to prevent acute kidney injury (AKI) or to accelerate recovery of renal function in patients with AKI (22). Unfortunately, IGF-1 does not appear to have therapeutic use for this indication (Fig. ten.2.1.8).
Fig. 10.2.1.8
Prospective, randomized, blinded clinical trial of recombinant man insulin-like growth factor-one therapy in severely ill patients with acute kidney injury (by and large acute tubular necrosis). Recombinant human IGF-ane fails to accelerate the recovery of renal office (Hirschberg R, Kopple J, Lipsett P, Benjamin E, Minei J, Albertson T, et al. Multicenter clinical trial of recombinant human insulin-similar growth factor I in patients with acute renal failure. Kidney Int, 1999; 55: 2423–32 (22)).
Fibroblast growth factor 23
The kidney is one of the most important sites for phosphate homeostasis. Renal regulation of phosphate is a complex process influenced past numerous factors. Fibroblast growth factor 23 (FGF-23) is mainly produced by osteocytes, and plays pivotal roles in renal phosphate regulation. FGF-23 acts on the kidney through a specific receptor heterodimer composed of the enzyme Klotho and the FGF receptor (23). FGF-23 enhances the urinary excretion of phosphate via a mechanism similar to the activeness of PTH: by inhibiting sodium-dependent phosphate reabsorption in the proximal tubules, and suppressing renal α-hydroxylase activity, it thus decreases serum 1,25-dihydroxyvitamin D3 levels (24). FGF-23 was initially identified past positional cloning as a possible gene for inducing phosphate wasting in patients with autosomal dominant hypophosphataemic rickets (25). FGF-23 levels are increased in patients with oncogenic osteomalacia and 10-linked hypophosphataemia. The electric current treatment of these diseases is express to administration of phosphate and ane,25-dihydroxyvitamin D3. Nonetheless, new therapeutic agents that target FGF-23 may provide a novel approach in managing these hypophosphataemic disorders.
Renal metabolism of hormones
The kidney is an important site for the inactivation and elimination of hormones, primarily peptide hormones. Elimination of these peptide hormones from the circulation occurs mainly by glomerular ultrafiltration and subsequent tubular uptake, merely to a lesser extent also past tubular uptake from peritubular capillaries. This latter mode of elimination has been demonstrated for a number of peptides, including insulin and IGF-1.
Generally, tubular cells catabolize peptide hormones and individual amino acids are returned into the blood stream. The charge per unit-limiting cistron in the renal elimination of about peptide hormones is glomerular ultrafiltration, and hence molecule size. The glomerular sieving coefficient (Φ) is a ratio of the glomerular ultrafiltration of the peptide divided by the glomerular ultrafiltration of inulin (molecular weight five.0 kDa). The glomerular sieving coefficient may exist as great as 0.9 for small peptide hormones such equally insulin (molecular weight 5.8 kDa); for larger peptide hormones such equally growth hormone (molecular weight 22.0 kDa) it is around 0.vii or less. The sieving coefficient for small-scale peptides such every bit angiotensin II is probably about 1.0. Less than 5% of ultrafiltered peptide hormones are excreted intact with urine. Degradation by a variety of peptidases secreted by tubular cells may occur in tubular fluid. Uptake into tubular cells through the castor border occurs via bounden to scavenger receptors such as the insulin-like growth factor-II/mannose-vi-phosphate/megalin receptors and subsequent receptor endocytosis. In add-on to intracellular degradation, some hormones such as PTH may be transported intact across the prison cell and returned into the peritubular circulation. At that place is also prove for the binding of ultrafiltered peptide hormones to signaling receptors in apical membranes. By this means, peptides such as IGF-1and angiotensin Two may human activity on tubules.
The glomerular ultrafiltration of peptide hormones is increased in patients with the nephrotic syndrome due to the glomerular leakage of macromolecules. In this setting, there is likewise urinary loss of hormones that are bound in serum to binding proteins. In renal failure, the rate of glomerular ultrafiltration and peritubular uptake of peptide hormones is reduced, resulting in increased plasma levels of intact hormones or (agile or inactive) hormonal fragments.
Parathyroid hormone
Renal metabolism accounts for nearly 30% of PTH removal, and too for the removal of circulating C-terminal fragments. Intact PTH (molecular weight nine.five kDa) is ultrafiltered in normal glomeruli at pregnant rates. In patients with chronic renal failure, there is usually secondary hyperparathyroidism with increased levels of intact PTH due to hyperphosphataemia and 1,25-dihydroxyvitamin D3 deficiency. In these patients serum levels of C-terminal fragments are as well increased due to reduced renal elimination. Levels of Due north-terminal PTH fragments, however, are not increased in these patients due to their extrarenal elimination. Thus, increased serum levels of N-concluding PTH fragments in chronic renal failure are indicative of hyperparathyroidism. However, measurements of intact, or so-called mid-molecule, assays of serum PTH are preferred in patients with chronic renal failure to assess parathyroid status.
Calcitonin
Renal removal of calcitonin (molecular weight 3.five kDa) accounts for about 65% of its metabolism. Apical tubular membranes display calcitonin receptors and may transmit signals from ultrafiltered calcitonin. However, the primary mechanism of renal tubular action of calcitonin (enhancing urinary calcium and phosphate excretion) may exist transmitted through receptors in the basolateral membrane.
Prolactin
The kidneys are important sites for prolactin (molecular weight 23.0 kDa) elimination and degradation. In chronic renal failure there is usually hyperprolactinaemia, with varying severity, which is believed to contribute to amenorrhoea in females and hypospermia in males with stop phase renal failure.
Growth hormone and insulin-like growth gene-1
Renal emptying accounts for about one-half of the removal of growth hormone (molecular weight 22.0 kDa) from the circulation. Although the sieving coefficient (Φ) for costless growth hormone is about 0.7, approximately l% of circulating growth hormone is spring to growth hormone-binding poly peptide (the extracellular domain of growth hormone receptors), and the glomerular filtration rate of this relatively large protein complex is low.
More than than 99% of serum IGF-1(molecular weight 7.6 kDa) is bound in protein complexes of fifty–150 kDa, thus the glomerular ultrafiltration rate of IGF-one is very low. Withal, there is some basolateral tubular uptake and degradation of IGF-1 in proximal tubules. IGF-ane that is normally excreted in urine probably stems from synthesis and luminal secretion in medullary collecting ducts. However, in the nephrotic syndrome, IGF-1/IGF-bounden protein complexes undergo glomerular ultrafiltration and serum levels are reduced due to urinary losses (26).
In chronic renal failure, serum levels of IGF-one are normal, but growth hormone levels are elevated. However, this is associated with resistance to the action of growth hormone too as IGF-i.
Angiotensin Two
This peptide is produced in the kidney and has a very short (less than ane min) half-life. Renal emptying of this pocket-sized peptide (molecular weight i.iii kDa) occurs past glomerular ultrafiltration too as past filtration-independent pathways. Ultrafiltered angiotensin II may act specifically through upmost AT1 receptors, which are expressed in the loop of Henle. Through activation of these receptors, ultrafiltered angiotensin 2 contributes to the regulation of Na+, Cl− and bicarbonate reabsorption.
Atrial natriuretic peptide
Although circulating ANP (molecular weight 3.2 kDa) undergoes glomerular ultrafiltration and renal elimination, the importance of the kidney in regulation of ANP activity is questionable. The half-life is very short (less than iv min) and degradation occurs in many vascular beds. In renal failure, serum ANP levels are ofttimes elevated. This is probably caused by increased atrial ANP release, due to intravascular book expansion secondary to compromised renal Na+ and h2o excretion.
Insulin
Insulin is catabolized in musculus and liver. However, renal emptying accounts for up to one-half of the metabolism of insulin, and upward to 70% of the elimination of C-peptide from the circulation. Ultrafiltered insulin is absorbed in proximal tubules, and insulin is likewise extracted from serum past tubular jail cell uptake through basolateral membranes (27). Consequently, in diabetic patients with chronic renal failure, a dose reduction of insulin or oral antidiabetics is oft required to forbid hypoglycaemia.
Steroid hormones
Renal elimination of intact steroid hormones is unimportant, in function due to protein binding, and their primary site of metabolism is the liver. Yet, many steroid metabolites, which are largely not protein jump and usually inactive, undergo renal elimination.
Selected hormonal abnormalities in uraemia
In advanced chronic renal failure or ESRD, there are a multitude of hormonal abnormalities. Nevertheless, these abnormalities are oftentimes without practical or clinical consequences. Secondary hyperparathyroidism has been discussed before in this section.
Insulin resistance in renal failure
In chronic renal failure, in that location is resistance to several peptide hormones including growth hormone, IGF-1, and EPO.
Insulin has besides major furnishings on potassium homeostasis, because it stimulates the Na+/K+-pump. Insulin causes a shift of K+ from the extracellular to the intracellular compartment. This activity of insulin is independent of its activation of the glucose transporter, glut-four, and does not require enhanced cellular uptake of glucose. The insulin-induced intracellular K+ shift and resulting decline in serum K+ levels are associated with a significant increase in plasma renin activity and serum angiotensin Ii level. Aldosterone levels fall in response to hypokalaemia. Hypokalaemia tends to worsen claret force per unit area control in hypertensive patients, and there is an inverse relationship betwixt plasma Yard+ and systolic blood pressure level control in patients with primary hypertension.
Clinical studies in patients with main hypertension demonstrate that an octreotide-induced short-term reduction in serum insulin levels has no outcome on blood force per unit area. Similarly, a transient, acute rise in serum insulin (five times baseline) during a euglycaemic insulin clamp has no firsthand result on blood pressure in these subjects. Although these data do not disprove a (causative) relationship between hyperinsulinaemic insulin-resistant states and (chief) hypertension, they indicate that insulin does not regulate blood pressure acutely.
In that location is a relationship between glucagon, insulin, and catecholamines. Activation of α-receptors by catecholamines reduces insulin release. Simultaneously, catecholamines heighten glucagon secretion through β-receptors. These hyperglycaemic effects of catecholamines explain why pheochromocytomas tin can crusade diabetes. Thus, patients with a pheochromocytoma may present with insulinopenic/ hyperglucagonaemic (not insulin-resistant) diabetes.
In non-diabetic chronic renal failure patients, at that place is moderately reduced insulin sensitivity. Experimental evidence suggests that chronic renal failure induces a post-receptor signalling defect, probably by a reduction in insulin-receptor kinase action towards cellular substrates such as insulin receptor substrate 1 (IRS-1). This may be caused by an (unidentified) uraemic toxin. Elevations in counter-regulatory hormones may also reduce glycaemic response to insulin in chronic renal failure.
Thyroid hormones in renal failure
The incidence of principal thyroid disorders, such equally hypothyroidism, goitre, nodules, and thyroid carcinoma, is slightly college in patients with chronic renal failure than in the general population (28). It is postulated that the reduced renal excretion of iodine, resulting in increased thyroid iodine content could contribute to evolution of nodular goitre and hyperthyroidism. In patients with chronic renal failure, at that place are abnormalities in laboratory values that are used to evaluate the hypothalamic-pituitary-thyroid axis (29). These abnormalities may not reflect overt thyroid disease, just may precipitate false diagnosis and potentially harmful thyroid hormone therapy. In patients with chronic renal failure, total T4 and total and free Tthree serum levels are often reduced, simply these may not be reflective of thyroid disease.
Renal iodide excretion is the main road of iodide elimination. The renal clearance of iodide is nigh i-third of the glomerular filtration rate or that of creatinine clearance. Serum inorganic iodide is increased to several times normal levels in ESRD, and when the daily intake of iodine is high, iodine-induced hypothyroidism may occur in these patients fifty-fifty in the absence of credible underlying thyroid affliction (thirty). Radioactive 131I-therapy in dialysis patients with hyperparathyroidism requires downward adjustment of the dose and timing of haemodialysis, which removes the radioactive compound quite finer.
In euthyroid dialysis patients, the total Tfour and gratis T4 indices are often reduced, due to lowered bounden of T4 to thyroid hormone binding globulin, just free T4 (measured by equilibrium dialysis techniques) is normal. Elevated total T4 or free T4 values are rarely observed in euthyroid dialysis patients, and their presence suggests hyperthyroidism. T4 production in the thyroid gland appears to be normal in euthyroid patients with ESRD.
Similarly, the full Tiii and free T3 indices are besides unremarkably reduced. The primary cause for reduced T3 serum levels is a decrease in the rate of conversion mainly past impaired T4 uptake into hepatocytes rather than low hepatic blazon I deiodinase action (xxx)
TSH levels are usually normal in chronic renal failure despite often reduced levels of circulating T4 and T3. TSH levels likewise increase appropriately in chronic renal failure patients with primary hypothyroidism. Withal, in nearly euthyroid patients with ESRD, TSH values are greater than in a normal population, and range between five and 10 mU/l. The TSH response to thyrotropin-releasing hormone (TRH) is also oft blunted (29). In nearly dialysis patients with hypothyroidism, TSH values are usually above twenty mU/l, the response to TRH is brisk, and free T4 levels (past equilibrium dialysis methods) are elevated.
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Hormones Produced By The Kidney,
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