CLINICAL PATHOPHYSIOLOGY OF KIDNEY

Renal damage can impair renal perfusion as well as glomerular and/or tubular functions. In addition, abnormal urine composition can lead to precipitations (urolithiasis) that inhibit the free flow of urine. Abnormal renal function can be caused by reduced renal excretion of useless or harmful substances (e.g., uric acid, urea, creatinine, foreign substances, and so-called uremic toxins) whose plasma concentration then rises correspondingly. Conversely, a defective glomerular filter can lead to renal loss of protein, while impaired tubular reabsorption can result in the increased excretion of substances which are important for the body (electrolytes, minerals, bicarbonate, glucose, amino acids). Reduced renal excretory function affects the kidney’s decisive contribution to the regulation of the metabolism of water, electrolytes, minerals, and acid–base balance. Through its regulation of water and electrolyte metabolism the kidney is also important for long term blood pressure regulation.

The capacity of the kidney to regulate the composition of extracellular fluid is a function of volume, which, per unit time, is under the control of its epithelia. For substances that are not secreted by tubular cells, the controlled volume corresponds to the glomerular filtration rate (GFR). All substances that are dissolved in the filtrate can either be reabsorbed or excreted by the tubular epithelium. For substances that are secreted by the tubular epithelium (e.g., potassium), the controlled volume is ultimately the entire blood plasma that flows through the kidney (renal plasma flow [RPF]).

Renal excretion is regulated or governed by hormones (e.g., antidiuretic hormone [ADH] or [arginine] vasopressin [AVP], aldosterone, atrial natriuretic factor [ANF), parathyroid hormone [PTH], calcitriol [1,25(OH)₂ D₃], calcitonin, cortisol, prostaglandin E2, insulin, progestogens, estrogens, thyroxine, somatotropin) and is thus adapted to requirements. Thus, disorders of hormone release also impair renal excretory functions.

Normally the amount of filtered water and solutes is a multiple of what is actually excreted: all of the plasma water passes across the renal epithelia within 20 minutes; the total extracellular volume within three hours. The excretory capacity of the kidney is thus by no means exhausted. For this reason GFR, i.e., the volume controlled by the kidney, can be greatly impaired without there being any harmful effect on the body. However, a reduction in GFR will from the very beginning go hand in hand with a diminished regulatory range that will become apparent when there is an increased load.

The kidney is not only the target organ for hormones, but also, by forming hormones, it influences its own function as well as extrarenal elements of mineral metabolism (calcitriol) and blood pressure regulation (renin/angiotensin). The prostaglandins and kinins formed in the kidney primarily serve to regulate renal function. If the kidney is damaged, the effects of abnormal renal excretory function are added to those of abnormal renal excretion of hormones. The hormone erythropoietin, formed in the kidney, regulates erythropoiesis; its absence thus causes anemia.

Lastly, the kidney fulfills metabolic tasks. Thus, for example, in acidosis it splits ammonia from glutamate (ammonia is excreted as NH₄⁺) and forms glucose from the carbohydrate skeleton (gluconeogenesis). Glucose is also formed in the proximal tubules from absorbed lactate, and additionally fatty acids are broken down in the tubules. The kidney plays an important role in the inactivation of hormones. About 40% of insulin inactivation takes place in the kidney, which also breaks down steroid hormones. Filtered oligopeptides (e.g., hormones) are broken down in the tubular lumen and the amino acids are reabsorbed. Reduction of functional renal tissue necessarily impairs the above-mentioned metabolic tasks.

Pathophysiology of the Kidney

Abnormalities of Glomerular Function

The function of the glomeruli is to produce an adequate GFR, i.e., the volume of plasma water that is controlled by the renal epithelium. The selective permeability of this filter ensures the formation of a nearly protein-free filtrate. As all of the blood flowing through the kidney must pass through the glomerular vessels, the resistance of these vessels also determines RPF.

The GFR is determined by the effective filtration pressure (Peff), the hydraulic conductivity (Kf), and the filtering surface (F): GFR=Kf· F· Peff. The effective filtration pressure is made up of the hydrostatic (∆P) and the oncotic (∆π) pressure gradients across the filter: Peff = ∆P – ∆π. Even if the filter is defective, π within the capsular space of the glomerulus can be ignored, i.e., ∆π practically equals the plasma oncotic pressure (π cap). As a result of glomerular filtration, the protein concentration in plasma is increased and π cap as a rule comes close to the hydrostatic pressure gradient toward the end of the glomerular capillary loops (filtration equilibrium).

Reduced hydraulic conductivity or a reduced filtration surface decreases the GFR. No filtration equilibrium can be achieved; as a result of the reduced increase in π cap, Peff ultimately rises. But this does not compensate for the reduced conductivity.

Constriction of the vas afferens when systemic blood pressure remains constant reduces the filtration pressure and thus the proportion of filtered plasma water (filtration fraction= GFR/RPF). At the same time the renal blood flow and the GFR fall because of the increased resistance.

Constriction of the vas efferens raises the effective filtration pressure and thus also GFR/RPF. Simultaneously it reduces glomerular perfusion and thus GFR at any given filtration fraction. The constriction of the vas efferens (e.g., on infusion of angiotensin II) or obstruction of venous flow (e.g., by renal vein thrombosis) can thus ultimately reduce GFR.

The glomeruli can be damaged by inflammatory disease (glomerulonephritis). Among possible causes are soluble antigenantibody complexes that become entangled in the glomeruli and, via complement activation, produce local inflammation. This results in obstruction of the glomerular capillaries and destroys the filtering function (immune complex nephritis). Numerous drugs, allergens, and pathogens can act as antigens. Streptococci (group A, type 12) are very often responsible. Antibodies include IgG, IgM, and commonly IgA (IgA nephritis).

Masugi’s nephritis, caused by autoantibodies against the basement membrane, is muchless common than immune complex nephritis. The local inflammation initially results in hyperemia, accumulation of neutrophils (exudative phase), and damage to the often markedly thickened basement membrane. It is common for endothelial, mesangial, or capsular epithelial cells to proliferate and ultimately for excess mesangial matrix to form (sclerosing).

The glomeruli may also be damaged without any local inflammation, for example, by deposition of amyloid in amyloidosis, by a high concentration of filtrable proteins in plasma (e.g., in multiple myeloma), by high pressure in the glomerular capillaries (e.g., in arterial hypertension, renal vein thrombosis, venous back pressure in right heart failure, or hyperfiltration in diabetic nephropathy) as well as by reduced perfusion (e.g., in atherosclerosis, arteriosclerosis).

In glomerulonephritis, resistance in the vasa afferentia and efferentia is increased and the RPF is reduced despite filtration pressure usually being high. The reduced hydraulic conductivity prevents filtration equilibrium being achieved and lowers GFR. The reduced renal perfusion stimulates the release of rennin which, via angiotensin and aldosterone, raises blood pressure. In addition, the development of hypertension is aided by reduced excretion of NaCl and H₂O, brought about by the decrease in GFR.

Selective permeability is lost by damage to the glomerular filter, thus leading to proteinuria and edema.

Damage to the kidney can, for example, destroy erythropoietin-producing cells and thus result in the development of anemia.

Glomerular Filtration: Vascular Resistance and Hydraulic Conductivity

Disorders of Glomerular Permselectivity, Nephrotic Syndrome

The glomerular filter (fenestrated endothelium, basement membrane, slit membrane between podocytes) is not equally permeable for all blood constituents (selective permeability or permselectivity).

The glomerular filter

Molecules larger in diameter than the pores do not pass the filter at all. Molecules of clearly smaller diameter will in practice pass through, as will water, i.e., their concentration in the filtrate is approximately the same as that in plasma water. If these substances are not reabsorbed or secreted in the kidney, their clearance (C) is identical to the GFR, and the fractional excretion (C/GFR) is 1.0. If molecules are only slightly smaller in diameter than the diameter of the pores, only some of them can follow water through the pores, so that their concentration in the filtrate is lower than in plasma.

However, permeability is determined not only by the size, but also by the charge of the molecule. Normally, negatively-charged molecules can pass through much less easily than neutral or positively-charged molecules. This is due to negative fixed charges that make the passage of negatively-charged particles difficult.

In glomerulonephritis the integrity of the glomerular filter may be impaired, In glomerulonephritis the integrity of the glomerular filter may be impaired, and plasma proteins and even erythrocytes can gain access to the capsular space.

Red blood cell in the urine of the patient with glomerulonephritis (hematuria)

This results in proteinuria and hematuria. Close observation of proteinuria indicates that it is especially the permeability for negatively charged proteins that is increased. This behavior can be demonstrated most impressively by infusing differently charged polysaccharides, because polysaccharides—in contrast to proteins—are hardly reabsorbed by the tubules. Negatively-charged (–) dextrans are normally less well filtered than neutral (n) or cationic (+) dextrans. This selectivity is lost in glomerulonephritis and filtration of negatively-charged dextrans is massively increased. One of the causes of this is a breakdown of negatively-charged proteoglycans, for example, by lysosomal enzymes from inflammatory cells that split glycosaminoglycan. As has been shown by electrophoresis, it is especially the relatively small, markedly negatively-charged albumins that pass across the membrane. Even an intact glomerulus is permeable to a number of proteins that are then reabsorbed in the proximal tubules. The transport capacity is limited, though, and cannot cope with the excessive load of filtered protein at a defective glomerular filter. If tubular protein reabsorption is defective especially small proteins appear in the final urine (tubular proteinuria).

Renal loss of proteins leads to hypoproteinemia. Serum electrophoresis demonstrates that it is largely due to a loss of albumin, while the concentration of larger proteins actually tends to increase. This is because the reduced oncotic pressure in the vascular system leads to increased filtration of plasma water in the periphery and thus to a concentration of the other blood constituents. Filtration in the peripheral capillaries is facilitated not only by the reduced oncotic pressure, but also 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 interstitial space. If the removal of proteins via the lymphatics is inadequate, edemas form.

Nephrotic syndrome

If proteinuria, hypoproteinemia, and peripheral edema occur together, this is termed nephrotic syndrome. As the lipoproteins are not filtered even if the filter is damaged, but hypoproteinemia stimulates the formation of lipoproteins in the liver, hyperlipidemia results and thus also hypercholesterolemia. It remains debatable whether a loss of glomerular lipoprotein lipase contributes to the effect.

Hypoproteinemia favours peripheral filtration, the loss of plasma water into the interstitial space leads to hypovolemia which triggers thirst, release of ADH and, via renin and angiotensin, of aldosterone. Increased water intake and increased reabsorption of sodium chloride and water provide what is needed to maintain the edemas. As aldosterone promotes renal excretion of K+ and H+, hypokalemia and alkalosis develop.

Abnormalities of Glomerular Permselectivity and Nephrotic Syndrome

Edema of leds in the patient with nephrotic syndrome

ACUTE RENAL FAILURE

Numerous and diverse disorders can lead to more or less sudden impairment of renal function.

Acute Renal Failure – is a clinical syndrome of various ethiology, which is characterized by significant and acute decrease in glomerular filtration rate (GFR). Normal GFR – 100-140 ml/mines. Acute renal insufficiency develops, when GFR is reduced to 1-10 ml/mines. Osmotic active substances amount is derivated which is easily excrete in volume water of 1,5-2 l (daily diuresis) for one day with, the normal diet and normal metabolism out of organism. The minimum quantity liquid, from which they can still be excreted makes 500 ml. Acute renal insufficiency is characterized by such disorder renal functions when diuresis is reduced to 500 ml. This state is called as oliguria. If daily urine does not exceed 100 ml, takes place anuria.

Types of Acute Renal Failure:

Acute renal failure can be caused by several types of conditions, including a decrease in blood flow without ischemic injury; ischemic, toxic, or obstructive tubular injury; and obstruction of urinary tract outflow. The causes of acute renal failure commonly are categorized as prerenal (55% to 60%), postrenal (<5%), and intrinsic (35% to 40%).

Causes of Acute Renal Failure

Prerenal Failure

Prerenal failure, the most common form of acute renal failure, is characterized by a marked decrease in renal blood flow. It is reversible if the cause of the decreased renal blood flow can be identified and corrected before kidney damage occurs. Causes of prerenal failure include profound depletion of vascular volume (e.g., hemorrhage, loss of extracellular fluid volume), impaired perfusion caused by heart failure and cardiogenic shock, and decreased vascular filling because of increased vascular capacity (e.g., anaphylaxis or sepsis). Elderly persons are particularly at risk because of their predisposition to hypovolemia and their high prevalence of renal vascular disorders.

Some vasoactive mediators, drugs, and diagnostic agents stimulate intense intrarenal vasoconstriction and induce glomerular hypoperfusion and prerenal failure. Examples include hypercalcemia, endotoxins, and radiocontrast agents such as those used for cardiac catheterization. Many of these agents also cause acute tubular necrosis (discussed later). In addition, several commonly used classes of drugs impair renal adaptive mechanisms and can convert compensated renal hypoperfusion into prerenal failure. Angiotensin-converting enzyme (ACE) inhibitors reduce the effects of renin on renal blood flow; when combined with diuretics, they may cause prerenal failure in persons with decreased blood flow caused by large-vessel or small vessel renal vascular disease. Prostaglandins have a vasodilatory effect on renal blood vessels. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce renal blood flow through inhibition of prostaglandin synthesis. In some persons with diminished renal perfusion, NSAIDs can precipitate prerenal failure.

Normally, the kidneys receive 20% to 25% of the cardiac output. This large blood supply is required to remove metabolic wastes and regulate body fluids and electrolytes. Fortunately, the normal kidney can tolerate relatively large reductions in blood flow before renal damage occurs. As renal blood flow is reduced, the GFR drops, the amount of sodium and other substances that is filtered by the glomeruli is reduced, and the need for energy-dependent mechanisms to reabsorb these substances is reduced. As the GFR and urine output approach zero, oxygen consumption by the kidney approximates that required to keep renal tubular cells alive. When blood flow falls below this level, which is about 20% of normal, ischemic changes occur. Because of their high metabolic rate, the tubular epithelial cells are most vulnerable to ischemic injury. Improperly treated, prolonged renal hypoperfusion can lead to ischemic tubular necrosis with significant morbidity and mortality.

Acute renal failure is manifested by a sharp decrease in urine output and a disproportionate elevation of BUN in relation to serum creatinine levels. The kidney normally responds to a decrease in the GFR with a decrease in urine output. An early sign of prerenal failure is a sharp decrease in urine output. BUN levels also depend on the GFR. A low GFR allows more time for small particles such as urea to be reabsorbed into the blood. Creatinine, which is larger and nondiffusible, remains in the tubular fluid, and the total amount of creatinine that is filtered, although small, is excreted in the urine. Thus, there also is a disproportionate elevation in the ratio of BUN to serum creatinine to greater than 20:1 (normal, approximately 10:1).

Postrenal Failure

Postrenal failure results from obstruction of urine outflow from the kidneys. The obstruction can occur in the ureter (i.e., calculi and strictures), bladder (i.e., tumors or neurogenic bladder), or urethra (i.e., prostatic hypertrophy). Prostatic hyperplasia is the most common underlying problem. Because both ureters must be occluded to produce renal failure, obstruction of the bladder rarely causes acute renal failure unless one of the kidneys already is damaged or a person has only one kidney. The treatment of acute postrenal failure consists of treating the underlying cause of obstruction so that urine flow can be re-established before permanent nephron damage occurs.

Intrinsic Renal Failure

Intrinsic or intrarenal renal failure results from conditions that cause damage to structures within the kidney—glomerular, tubular, or interstitial. Injury to the tubules is most common and often is ischemic or toxic in origin. The major causes of intrarenal failure are ischemia associated with prerenal failure, toxic insult to the tubular structures of the nephron, and intratubular obstruction. Acute glomerulonephritis and acute pyelonephritis also are intrarenal causes of acute renal failure.

Intrinsic Renal Failure

Intrinsic or intrarenal renal failure results from conditions that cause damage to structures within the kidney—glomerular, tubular, or interstitial. Injury to the tubules is most common and often is ischemic or toxic in origin. The major causes of intrarenal failure are ischemia associated with prerenal failure, toxic insult to the tubular structures of the nephron, and intratubular obstruction. Acute glomerulonephritis and acute pyelonephritis also are intrarenal causes of acute renal failure.

Acute Tubular Necrosis. Acute tubular necrosis (ATN) is characterized by destruction of tubular epithelial cells with acute suppression of renal function.

It is the most common cause of intrinsic renal failure. ATN can be caused by a variety of conditions, including acute tubular damage caused by ischemia, the nephrotoxic effects of drugs, tubular obstruction, and toxins from a massive infection. The tubular injury that occurs in ATN frequently is reversible. The process depends on the recovery of the injured cells, removal of the necrotic cells and intratubular casts, and regeneration of renal cells to restore the normal continuity of the tubular epithelium. However, if the ischemia is severe enough to cause cortical necrosis, irreversible renal failure occurs.

Ischemic ATN occurs most frequently in persons who have major surgery, severe hypovolemia, overwhelming sepsis, trauma, and burns. Sepsis produces ischemia by provoking a combination of systemic vasodilation and intrarenal hypoperfusion. In addition, sepsis results in the generation of toxins that sensitize renal tubular cells to the damaging effects of ischemia. ATN complicating trauma and burns frequently is multifactorial in origin and caused by the combined effects of hypovolemia and myoglobin or other toxins released from damaged tissue. In contrast to prerenal failure, the GFR does not improve with the restoration of renal blood flow in acute renal failure caused by ischemic ATN.

Nephrotoxic ATN complicates the administration of or exposure to many structurally diverse drugs and other toxic agents. Nephrotoxic agents cause renal injury by inducing varying combinations of renal vasoconstriction, direct tubular damage, or intratubular obstruction. The kidney is particularly vulnerable to nephrotic injury because of its rich blood supply and ability to concentrate toxins to high levels in the medullary portion of the kidney. In addition, the kidney is an important site for metabolic processes that transform relatively harmless agents into toxic metabolites. Pharmacologic agents that are directly toxic to the renal tubule include antimicrobial agents such as the aminoglycosides, chemotherapeutic agents such as cisplatin and ifosfamide, and the radiocontrast agents used during cardiac catheterization and other diagnostic procedures. Radiocontrast media-induced nephrotoxicity is thought to result from direct tubular toxicity and renal ischemia. The risk of renal damage caused by radiocontrast media is greatest in elderly persons, in persons with diabetes mellitus, and in persons who, for various reasons, are susceptible to kidney disease. Heavy metals (e.g., lead, mercury) and organic solvents (e.g., carbon tetrachloride, ethylene glycol) are other nephrotoxic agents.

Myoglobin, hemoglobin, uric acid, and myeloma light chains are the most common cause of ATN attributable to intratubular obstruction. Deposits of immunoglobulins and urine acid crystals usually are seen in the setting of widespread malignancy or massive tumor destruction by therapeutic agents. Hemoglobinuria results from blood transfusion reactions and other hemolytic crises. Skeletal and cardiac muscles contain myoglobin, which accounts for their red color. Myoglobin corresponds to hemoglobin in function, serving as an oxygen reservoir in the muscle fibers. Myoglobin normally is not found in the serum or urine. Myoglobinuria most commonly results from muscle trauma but may result from extreme exertion, hyperthermia, sepsis, prolonged seizures, potassium or phosphate depletion, and alcoholism or drug abuse. Both myoglobin and hemoglobin discolor the urine, which may range from the color of tea to red, brown, or black.

Types of Acute Renal Failure

The course of acute renal failure can be divided into four phases: the onset or initiating phase, the oliguric phase, polyuric phase and the recovery or convalescent phase.

The onset or initiating phase, which lasts hours or days, is the time from the onset of the precipitating event (e.g., ischemic phase of prerenal failure or toxin exposure) until tubular injury occurs.

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). However, urinary 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 reabsorption of filtered fluid is thus reduced. Despite normal-looking urine volume, renal excretion of all those substances that must normally be excreted in the urine may be markedly impaired. Inthis case determination of the plasma and urine creatinine concentration provides information on the true functional state of the kidneys.

Pulmonary edema in acute renal failure

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 impaired (salt-losing kidney). If the renal tubules are damaged (e.g., by heavy metals), polyuric renal failure occurs as a primary response, 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 hyperkalemia (especially with the simultaneous release of intracellular K⁺, as in burns, contusions, 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.

Pathogenesis of acute renal failure

The recovery phase is the period during which repair of renal tissue takes place.

Because of the high morbidity and mortality rates associated with acute renal failure, identification of persons at risk is important to clinical decision making. Acute renal failure often is reversible, making early identification and correction of the underlying cause (e.g., improving renal perfusion, discontinuing nephrotoxic drugs) important. Treatment includes the judicious administration of fluids and dialysis or CRRT.

CHRONIC RENAL FAILURE

Unlike acute renal failure, chronic renal failure represents progressive and irreversible destruction of kidney structures. As recently as 1965, many patients with chronic renal failure progressed to the final stages of the disease and then died. The high mortality rate was associated with limitations in the treatment of renal disease and with the tremendous cost of ongoing treatment. In 1972, federal support began for dialysis and transplantation through a Medicare entitlement program. Technologic advances in renal replacement therapy (i.e., dialysis therapy and transplantation) have improved the outcomes for persons with renal failure. In the United States, there are approximately 400,000 persons with end-stage renal disease who are living today, a product of continued research and advances in treatment methods.

Chronic renal failure can result from a number of conditions that cause permanent loss of nephrons, including diabetes, hypertension, glomerulonephritis, and polycystic kidney disease. Typically, the signs and symptoms of renal failure occur gradually and do not become evident until the disease is far advanced. This is because of the amazing compensatory ability of the kidneys. As kidney structures are destroyed, the remaining nephrons undergo structural and functional hypertrophy, each increasing its function as a means of compensating for those that have been lost. It is only when the few remaining nephrons are destroyed that the manifestations of renal failure become evident.

Regardless of cause, chronic renal failure results in progressive deterioration of glomerular filtration, tubular reabsorptive capacity, and endocrine functions of the kidneys. All forms of renal failure are characterized by a reduction in the GFR, reflecting a corresponding reduction in the number of functional nephrons.

Stages of Progression

The rate of nephron destruction differs from case to case, ranging from several months to many years. The progression of chronic renal failure usually occurs in four stages: diminished renal reserve, renal insufficiency, renal failure, and end-stage renal disease.

The rate of nephron destruction differs from case to case, ranging from several months to many years. The progression of chronic renal failure usually occurs in four stages: diminished renal reserve, renal insufficiency, renal failure, and end-stage renal disease. The rate of nephron destruction differs from case to case, ranging from several months to many years. The progression of chronic renal failure usually occurs in four stages: diminished renal reserve, renal insufficiency, renal failure, and end-stage renal disease.

Renal Failure

Renal failure develops when the GFR is less than 20% of normal. At this point, the kidneys cannot regulate volume and solute composition, and edema, metabolic acidosis, and hyperkalemia develop. These alterations affect other body systems to cause neurologic, gastrointestinal, and cardiovascular manifestations.

End-Stage Renal Disease

End-stage renal disease (ESRD) occurs when the GFR is less than 5% of normal. Histologic findings of an end-stage kidney include a reduction in renal capillaries and scarring in the glomeruli. Atrophy and fibrosis are evident in the tubules. The mass of the kidneys usually is reduced. At this final phase of renal failure, treatment with dialysis or transplantation is necessary for survival.

Pathogenesis of syndromes in chronic renal failure

Clinical Manifestations

The clinical manifestations of renal failure include alterations in water, electrolyte, and acid-base balance; mineral and skeletal disorders; anemia and coagulation disorders; hypertension and alterations in cardiovascular function; gastrointestinal disorders; neurologic complications; disorders of skin integrity; and immunologic disorders. Uremia, which literally means “urine in the blood,” is the term used to describe the clinical manifestations of ESRD. Uremia differs from azotemia, which merely indicates the accumulation of nitrogenous wastes in the blood and can occur without symptoms.

There currently are four target populations that comprise the entire population of persons with chronic renal failure: persons with chronic renal insufficiency, those with ESRD being treated with hemodialysis, those being treated with peritoneal dialysis, and renal transplant recipients. The manifestations of renal failure are determined largely by the extent of renal function that is present (e.g., renal insufficiency, ESRD), coexisting disease conditions, and the type of renal replacement therapy the person is receiving.

Accumulation of Nitrogenous Wastes

The accumulation of nitrogenous wastes is an early sign of renal failure, usually occurring before other symptoms become evident. Urea is one of the first nitrogenous wastes to accumulate in the blood, and the BUN level becomes increasingly elevated as renal failure progresses. The normal concentration of urea in the plasma is usually less than 20 mg/dL. In renal failure, this level may rise to as high as 800 mg/dL.

Creatinine, a by-product of muscle metabolism, is freely filtered in the glomerulus and is not reabsorbed in the renal tubules. Creatinine is produced at a relatively constant rate, and any creatinine that is filtered in the glomerulus is lost in the urine, rather than being reabsorbed into the blood. Thus, serum creatinine can be used as an indirect method for assessing the GFR and the extent of renal damage that has occurred in renal failure. Because creatinine is a by-product of muscle metabolism, serum values vary with age and muscle mass. An increase in serum creatinine to three times its normal value suggests that there is a 75% loss of renal function, and with creatinine levels of 10 mg/dL or more, it can be assumed that 90% of renal function has been lost.

Disorders of Water, Electrolyte, and Acid-Base Balance

The kidneys function in the regulation of extracellular fluid volume. They do this by either eliminating or conserving sodium and water. Chronic renal failure can produce dehydration or fluid overload, depending on the pathology of the renal disease. In addition to volume regulation, the ability of the kidneys to concentrate the urine is diminished. With early losses in renal function, the specific gravity of the urine becomes fixed (1.008 to 1.012) and varies little from voiding to voiding. Polyuria and nocturia are common.

As renal function declines further, the ability to regulate sodium excretion is reduced. There is impaired ability to adjust to a sudden reduction in sodium intake and poor tolerance of an acute sodium overload. Volume depletion with an accompanying decrease in the GFR can occur with a restricted sodium intake or excess sodium loss caused by diarrhea or vomiting. Salt wasting is a common problem in advanced renal failure because of impaired tubular reabsorption of sodium. Increasing sodium intake in persons with chronic renal failure often improves the GFR and whatever renal function remains. In patients with associated hypertension, the possibility of increasing blood pressure or production of congestive heart failure often excludes supplemental sodium intake.

Approximately 90% of potassium excretion is through the kidneys. In renal failure, potassium excretion by each nephron increases as the kidneys adapt to a decrease in the GFR. As a result, hyperkalemia usually does not develop until renal function is severely compromised. Because of this adaptive mechanism, it usually is not necessary to restrict potassium intake in patients with chronic renal failure until the GFR has dropped below 5 mL/minute. In persons with ESRD, hyperkalemia often results from the failure to follow dietary potassium restrictions and ingestion of medications that contain potassium, or from an endogenous release of potassium, as in trauma or infection.

The kidneys normally regulate blood pH by eliminating hydrogen ions produced in metabolic processes and regenerating bicarbonate. This is achieved through hydrogen ion secretion, sodium and bicarbonate reabsorption, and the production of ammonia, which acts as a buffer for titratable acids. With a decline in renal function, these mechanisms become impaired, and metabolic acidosis results. In chronic renal failure, acidosis seems to stabilize as the disease progresses, probably as a result of the tremendous buffering capacity of bone. However, this buffering action is thought to increase bone resorption and contribute to the skeletal defects present in chronic renal failure.

Mineral Metabolism and Skeletal Disorders

Abnormalities of calcium, phosphate, and vitamin D occur early in the course of chronic renal failure. They involve the renal regulation of serum calcium and phosphate levels, activation of vitamin D, and regulation of parathyroid hormone (PTH) levels.

The regulation of serum phosphate levels requires a daily urinary excretion of an amount equal to that absorbed from the diet. With deteriorating renal function, phosphate excretion is impaired, and as a result, serum phosphate levels rise. At the same time, serum calcium levels fall because serum calcium is inversely regulated in relation to serum phosphate levels. The drop in serum calcium, in turn, stimulates PTH release, with a resultant increase in calcium resorption from bone. Most persons with ESRD develop secondary hyperparathyroidism, the result of chronic stimulation of the parathyroid glands. Although serum calcium levels are maintained through increased PTH function, this adjustment is accomplished at the expense of the skeletal system and other body organs.

The kidneys regulate vitamin D activity by converting the inactive form of vitamin D [25(OH) vitamin D₃] to its active form (1,25-OH₂ vitamin D₃). Decreased levels of active vitamin D lead to a decrease in intestinal absorption of calcium with a resultant increase in parathyroid hormone levels. Vitamin D also regulates osteoblast differentiation, thereby affecting bone matrix formation and mineralization.

Skeletal Disorders. The term renal osteodystrophy is used to describe the skeletal complications of ESRD. Several factors are thought to contribute to the development of renal osteodystrophy, including elevated serum phosphate levels, decreased serum calcium levels, impaired renal activation of vitamin D, and hyperparathyroidism. The skeletal changes that occur with renal failure have been divided into two major types of disorders: high-turnover and low-turnover osteodystrophy. Inherent to both of these conditions is abnormal reabsorption and defective remodeling of bone.

High–bone-turnover osteodystrophy, sometimes referred to as osteitis fibrosa, is characterized by increased bone resorption and formation, with bone resorption predominating. The disorder is associated with secondary hyperparathyroidism; altered vitamin D metabolism along with resistance to the action of vitamin D; and impaired regulation of locally produced growth factors and inhibitors. There is an increase in both osteoblast and osteoclast numbers and activity. Although the osteoblasts produce excessive amounts of bone matrix, mineralization fails to keep pace, and there is a decrease in bone density and formation of porous and coarse-fibered bone. Cortical bone is affected more severely than cancellous bone. Marrow fibrosis is another component of osteitis fibrosa; it occurs in areas of increased bone cell activity. In advanced stages of the disorder, cysts may develop in the bone, a condition called osteitis fibrosa cystica.

Low–bone-turnover osteodystrophy is characterized by decreased numbers of osteoblasts and low or reduced numbers of osteoclasts, a low rate of bone turnover, and an accumulation of unmineralized bone matrix. There are two forms of low-turnover osteodystrophy: osteomalacia and adynamic osteodystrophy. Osteomalacia, sometimes referred to as renal rickets, is characterized by a slow rate of bone formation and defects in bone mineralization. Until the 1980s, osteomalacia in ESRD resulted mainly from aluminum intoxication. Aluminum intoxication causes decreased and defective mineralization of bone by existing osteoblasts and more long-term inhibition of osteoblast differentiation. During the 1970s and 1980s, it was discovered that accumulation of aluminum from water used in dialysis and aluminum salts used as phosphate binders caused osteomalacia and adynamic bone disease. This discovery led to a change in the composition of dialysis solutions and substitution of calcium carbonate for aluminum salts as phosphate binders. As a result, the prevalence of osteomalacia in persons with ESRD is declining.

The second type of low-turnover osteodystrophy, adynamic osteodystrophy, is characterized by a low number of osteoblasts, the osteoclast number being normal or reduced. In persons with adynamic bone disease, bone remodeling is greatly reduced, and the bone surfaces become hypocellular. Adynamic bone disease is associated with an increased fracture rate. The disease is associated with a “relative hypothyroidism.” It has been suggested that hypersecretion of parathyroid hormone may be necessary to maintain normal rates of bone formation in persons with ESRD. Thus, this form of renal osteodystrophy is seen more commonly in persons with ESRD who do not have secondary hyperparathyroidism (i.e., those who have been treated with parathyroidectomy) or have been overtreated with calcium and vitamin D.

The symptoms of renal osteodystrophy, which occur late in the disease, include bone tenderness and muscle weakness. Proximal muscle weakness in the lower extremities is common, making it difficult to get out of a chair or climb stairs. Fractures are more common with low-turnover osteomalacia and adynamic renal bone disease.

Early treatment of hyperphosphatemia and hypocalcemia is important to prevent or slow long-term skeletal complications. Activated forms of vitamin D and calcium supplements often are used to facilitate intestinal absorption of calcium, increase serum calcium levels, and reduce parathyroid hormone levels. Milk products and other foods high in phosphorus content are restricted in the diet. Oral phosphate-binding agents such as calcium carbonate may be prescribed to decrease absorption of phosphate from the gastrointestinal tract. Aluminum-containing antacids can contribute to the development of osteodystrophy and their use should be avoided except in acute situations.

Hematologic Disorders

Chronic anemia is the most profound hematologic alteration that accompanies renal failure. Anemia first appears when the GFR falls below 40 mL/minute and is present in most persons with ESRD. Several factors contribute to anemia in persons with chronic renal failure, including a erythropoietin deficiency, uremic toxins, and iron deficiency. The kidneys are the primary site for the production of the hormone erythropoietin, which controls red blood cell production. The accumulation of uremic toxins further suppresses red cell production in the bone marrow, and the cells that are produced have a shortened life span. Iron is essential for erythropoiesis. Many persons receiving maintenance hemodialysis also are iron deficient because of blood sampling and accidental loss of blood during dialysis. Other causes of iron deficiency include factors such as anorexia and dietary restrictions that limit intake.

When untreated, anemia causes or contributes to weakness, fatigue, depression, insomnia, and decreased cognitive function. There is also increasing concern regarding the physiologic effects of anemia on cardiovascular function. The anemia of renal failure produces a decrease in blood viscosity and a compensatory increase in heart rate. The decreased blood viscosity also exacerbates peripheral vasodilatation and contributes to decreased vascular resistance. Cardiac output increases in a compensatory fashion to maintain tissue perfusion. Echocardiographic studies after initiation of chronic dialysis have shown ventricular dilatation with compensatory left ventricular hypertrophy. Anemia also limits myocardial oxygen supply, particularly in persons with coronary heart disease, leading to angina pectoris and other ischemic events. Thus, anemia, when coupled with hypertension, may be a major contributing factor to the development of left ventricular dysfunction and congestive heart failure in persons with ESRD.

A remarkable advance in medical management of anemia in persons with ESRD occurred with the availability of recombinant human erythropoietin (rhEPO). Secondary benefits of treating anemia with rhEPO, previously attributed to the correction of uremia, include improvement in appetite, energy level, sexual function, skin color, and hair and nail growth, and reduced cold intolerance. Frequent measurements of hematocrit are necessary. Worsening hypertension and seizures have occurred when the hematocrit was raised too suddenly. Because iron deficiency is common among persons with chronic renal failure, iron supplementation often is needed. Iron can be given orally or intravenously. Intravenous iron may be used for treatment of persons who are not able to maintain adequate iron status with oral iron. Bleeding disorders, which are manifested by epistaxis, menorrhagia, gastrointestinal bleeding, and bruising of the skin and subcutaneous tissues, are also common among persons with chronic renal failure. Although platelet production often is normal in ESRD, platelet function is impaired. Platelet function improves with dialysis but does not completely normalize, suggesting that uremia contributes to the problem. Anemia may accentuate the problem by changing the position of the platelets with respect to the vessel wall. Normally the red cells occupy the center of the bloodstream, and the platelets are in the skimming layer along the endothelial surface. In anemia, the platelets become dispersed, impairing the plateletendothelial cell adherence needed to initiate hemostasis.

Cardiovascular Disorders

Cardiovascular disorders, including hypertension, left ventricular hypertrophy, and pericarditis, are a major cause of morbidity and mortality in patients with ESRD. Hypertension commonly is an early manifestation of chronic renal failure. The mechanisms that produce hypertension in ESRD are multifactorial; they include an increased vascular volume, elevation of peripheral vascular resistance, decreased levels of renal vasodilator prostaglandins, and increased activity of the reninangiotensin system. Early identification and aggressive treatment of hypertension has been shown to slow the rate of renal impairment in many types of renal disease. Treatment involves salt and water restriction and the use of antihypertensive medications to control blood pressure. Many persons with renal insufficiency need to take several antihypertensive medications to control blood pressure.

The spectrum of heart disease includes left ventricular hypertrophy and ischemic heart disease. People with ESRD tend to have an increased prevalence of left ventricular dysfunction, both with a depressed left ventricular ejection fraction, as in systolic dysfunction, as well as impaired ventricular filling, as in diastolic failure. There are multiple factors that lead to development of left ventricular dysfunction, including extracellular fluid overload, shunting of blood through an arteriovenous fistula for dialysis, and anemia. These abnormalities, coupled with the hypertension that often is present, cause increased myocardial work and oxygen demand, with eventual development of heart failure. Coexisting conditions that have been identified as contributing to the burden of cardiovascular disease include anemia, diabetes mellitus, dyslipidemia, and coagulopathies. Anemia, in particular, has been correlated with the presence of left ventricular hypertrophy.

Pericarditis occurs in approximately 20% of persons receiving chronic dialysis. It can result from metabolic toxins associated with the uremic state or from dialysis. The manifestations of uremic pericarditis resemble those of viral pericarditis, with all its complications, including cardiac tamponade.

Gastrointestinal Disorders

Anorexia, nausea, and vomiting are common in patients with uremia, along with a metallic taste in the mouth that further depresses the appetite. Early-morning nausea is common. Ulceration and bleeding of the gastrointestinal mucosa may develop, and hiccups are common. A possible cause of nau sea and vomiting is the decomposition of urea by intestinal flora, resulting in a high concentration of ammonia. Parathyroid hormone increases gastric acid secretion and contributes to gastrointestinal problems. Nausea and vomiting often improve with restriction of dietary protein and after initiation of dialysis and disappear after kidney transplantation.

Disorders of Neural Function

Many persons with chronic renal failure have alterations in peripheral and central nervous system function. Peripheral neuropathy, or involvement of the peripheral nerves, affects the lower limbs more frequently than the upper limbs. It is symmetric and affects both sensory and motor function. Neuropathy is caused by atrophy and demyelination of nerve fibers, possibly caused by uremic toxins. Restless legs syndrome is a manifestation of peripheral nerve involvement and can be seen in as many as two thirds of patients on dialysis. This syndrome is characterized by creeping, prickling, and itching sensations that typically are more intense at rest. Temporary relief is obtained by moving the legs. A burning sensation of the feet, which may be followed by muscle weakness and atrophy, is a manifestation of uremia.

The central nervous system disturbances in uremia are similar to those caused by other metabolic and toxic disorders. Sometimes referred to as uremic encephalopathy, the condition is poorly understood and may result, at least in part, from an excess of toxic organic acids that alter neural function. Electrolyte abnormalities, such as sodium shifts, also may contribute. The manifestations are more closely related to the progress of the uremic disorder than to the level of the metabolic end-products. Reductions in alertness and awareness are the earliest and most significant indications of uremic encephalopathy. This often is followed by an inability to fix attention, loss of recent memory, and perceptual errors in identifying persons and objects. Delirium and coma occur late in the course; seizures are the preterminal event.

Disorders of motor function commonly accompany the neurologic manifestations of uremic encephalopathy. During the early stages, there often is difficulty in performing fine movements of the extremities; the gait becomes unsteady and clumsy with tremulousness of movement. Asterixis (dorsiflexion movements of the hands and feet) typically occurs as the disease progresses. It can be elicited by having the person hyperextend his or her arms at the elbow and wrist with the fingers spread apart. If asterixis is present, this position causes side-to-side flapping movements of the fingers.

Altered Immune Function

Infection is a common complication and cause of hospitalization and death of patients with chronic renal failure. Immunologic abnormalities decrease the efficiency of the immune response to infection. All aspects of inflammation and immune function may be affected adversely by the high levels of urea and metabolic wastes, including a decrease in granulocyte count, impaired humoral and cell-mediated immunity, and defective phagocyte function. The acute inflammatory response and delayed-type hypersensitivity response are impaired. Although persons with ESRD have normal humoral responses to vaccines, a more aggressive immunization program may be needed. Skin and mucosal barriers to infection also may be defective. In persons who are receiving dialysis, vascular access devices are common portals of entry for pathogens. Many persons with ESRD do not experience fever with infection, making the diagnosis more difficult.

Disorders of Skin Integrity

Skin manifestations are common in persons with ESRD. The skin often is pale because of anemia and may have a sallow, yellow-brown hue. The skin and mucous membranes often are dry, and subcutaneous bruising is common. Skin dryness is caused by a reduction in perspiration caused by the decreased size of sweat glands and the diminished activity of oil glands. Pruritus is common; it results from the high serum phosphate levels and the development of phosphate crystals that occur with hyperparathyroidism. Severe scratching and repeated needlesticks, especially with hemodialysis, break the skin integrity and increase the risk for infection. In the advanced stages of untreated renal failure, urea crystals may precipitate on the skin as a result of the high urea concentration in body fluids. The fingernails may become thin and brittle, with a dark band just behind the leading edge of the nail, followed by a white band. This appearance is known as Terry’s nails.

Sexual Dysfunction

Alterations in physiologic sexual responses, reproductive ability, and libido are common. The cause probably is multifactorial and may result from high levels of uremic toxins, neuropathy, altered endocrine function, psychological factors, and medications (e.g., antihypertensive drugs).

Impotence occurs in as many as 56% of male patients receiving dialysis. Derangements of the pituitary and gonadal hormones, such as decreases in testosterone levels and increases in prolactin and luteinizing hormone levels, are common and cause erectile difficulties and decreased spermatocyte counts. Loss of libido may result from chronic anemia and decreased testosterone levels. Several drugs, such as exogenous testosterone and bromocriptine, have been used in an attempt to return hormone levels to normal.

Impaired sexual function in women is manifested by abnormal levels of progesterone, luteinizing hormone, and prolactin. Hypofertility, menstrual abnormalities, decreased vaginal lubrication, and various orgasmic problems have been described. Amenorrhea is common among women who are receiving dialysis therapy.

Elimination of Drugs

The kidneys are responsible for the elimination of many drugs and their metabolites. Renal failure and its treatment can interfere with the absorption, distribution, and elimination of drugs. The administration of large quantities of phosphate binding antacids to control hyperphosphatemia and hypocalcemia in patients with advanced renal failure interferes with the absorption of some drugs. Many drugs are bound to plasma proteins, such as albumin, for transport in the body; the unbound portion of the drug is available to act at the various receptor sites and is free to be metabolized. A decrease in plasma proteins, particularly albumin, that occurs in many persons with ESRD results in less protein-bound drug and greater amounts of free drug.

Decreased elimination by the kidneys allows drugs or their metabolites to accumulate in the body and requires that drug dosages be adjusted accordingly. Some drugs contain unwanted nitrogen, sodium, potassium, and magnesium and must be avoided in patients with renal failure. For example, penicillin contains potassium. Nitrofurantoin and ammonium chloride add to the body’s nitrogen pool. Many antacids contain magnesium. Because of problems with drug dosing and elimination, persons with renal failure should be cautioned against the use of over-the-counter remedies.

Manifestations of renal failure

CLINICAL PATHOPHYSIOLOGY OF THE DIGESTIVE SYSTEM

Ulcer

The H⁺ ions in gastric juice are secreted by the parietal cells that contain H⁺/K⁺-ATPase in their luminal membrane, while the chief cells enrich the glandular secretion with pepsinogen. The high concentration of H⁺ (pH 1.0–2.0) denatures the food proteins and activates pepsinogens into pepsins which are endopeptidases and split certain peptide bindings in food proteins.

The regulation of gastric secretion is achieved through neural, endocrine, paracrine, and autocrine mechanisms. Stimulation is provided by acetylcholine, the postganglionic transmitter of vagal parasympathetic fibers (muscarinic M₁ receptors and via neurons stimulating gastrin release by gastrin-releasing peptide [GRP]), gastrin(endocrine) originating from the G cells of the antrum, and histamine (paracrine, H₂ receptor), secreted by the ECL cells and mast cells of the gastric wall. Inhibitors are secretin (endocrine) from the small intestine, somatostatin (SIH; paracrine) as well as prostaglandins (especially E₂ and I₂), transforming growth factor α (TGF-α) and adenosine (all paracrines and autocrines). The inhibition of gastric secretion by a high concentration of H⁺ ions in the gastric lumen is also an important regulatory mechanism.

Protection of the gastric and duodenal mucosa. Because the acid–pepsin mixture of gastric secretion denatures and digests protein, the protein-containing wall of the stomach and duodenum has to be protected from the harmful action of gastric juice. The following mechanisms are involved in this:

a) A gel-like mucus film, 0.1–0.5mm thick, protects the surface of the gastric epithelium. The mucus is secreted by epithelial cells (and depolymerized by the pepsins so that it can then be dissolved).

b) The epithelium secretes HCO₃ – ions that are enriched not only in the liquid layer directly over the epithelium, but also diffuse into the mucus film, where they buffer H⁺ ions that have penetrated from the gastric lumen. Prostaglandins are important stimulants of this HCO₃ – secretion.

c) In addition, the epithelium itself (apical cell membrane, tight junctions) has barrier properties that largely prevent the penetration of H⁺ ions or can very effectively remove those H⁺ ions that have already penetrated (Na⁺/H⁺ exchange carrier only basolaterally). These properties are regulated, among others, by the epidermal growth factor (EGF) contained in saliva and bound to receptors of the apical epithelial membrane. Glutathione-dependent, antioxidative mechanisms are also part of this cytoprotection.

d) Finally, good mucosal blood flow serves as the last “line of defense” that, among other actions, quickly removes H⁺ ions and provides a supply of HCO₃ – and substrates of energy metabolism.

Epithelial repair and wound healing. The following mechanisms repair epithelial defects that occur despite the protective factors listed above. The epithelial cells adjoining the defect are flattened and close the gap through sideward migration along the basal membrane. This restitution takes about 30 minutes.

Closing the gap by cell growth takes longer (proliferation; → p. 4). EGF, TGF-α, insulin-like growth factor (IGF-1), gastrin-releasing peptide (GRP), and gastrin stimulate this process. When the epithelium is damaged, especially those cell types proliferate rapidly that secrete an EGF-like growth factor.

If ultimately the basement membrane is also destroyed, acute wound healing processes are initiated: attraction of leukocytes and macrophages; phagocytosis of necrotic cell residua; revascularization (angiogenesis); regeneration of extracellular matrix as well as, after repair of the basement membrane, epithelial closure by restitution and cell division.

The danger of epithelial arrosion and subsequent ulcer formation exists whenever the protective and reparative mechanisms are weakened and/or the chemical attack by the acid–pepsin mixture is too strong and persists for too long. Gastric and duodenalulcers may thus have quite different causes.

Infection with Helicobacter pylori (H. pylori) is the most common cause of ulcer. As a consequence, administration of antibiotics has been shown to be the most efficacious treatment in most ulcer patients not receiving nonsteroidal anti-inflammatory drugs (NSAIDs; see below). H. pylori probably survives the acidic environment of the mucus layer because it possesses a special urease. The bacterium uses this to produce CO₂ and NH₃, and HCO₃ ^– and NH₄⁺, respectively, and can thus itself buffer H⁺ ions in the surroundings. H. pylori is transmitted from person to person, causing inflammation of the gastric mucosa. A gastic or duodenal ulcer is ten times more likely to develop in such cases than if a person does not suffer from gastritis of this kind. The primary cause of such an ulcer is a disorder in the epithelium’s barrier function, brought about by the infection.

It is likely that, together with this ulcer formation due to the infection, there is also an increased chemical attack, as by oxygen radicals that are formed by the bacteria themselves, as well as by the leukocytes and macrophages taking part in the immune response, or by pepsins, because H. pylori stimulates pepsinogen secretion.

Helicobacter pylori (H. pylori) is the most common cause of ulcer

The fact that infection of the gastric antrum also frequently leads to duodenal ulcer is probably related to gastrin secretion being increased by the infection. As a result, acid and pepsinogen liberation is raised and the duodenal epithelium is exposed to an increased chemical attack. This causes metaplasia of the epithelium, which in turn favors the embedding of H. pylori, leading to duodenitis and increased metaplasia, etc.

A further common cause of ulcer isthe intake of NSAIDs, for example, indomethacin, diclofenac, aspirin (especially in high doses). Their anti-inflammatory and analgesic action is based mainly on their inhibitory effect on cyclo-oxygenase, thus blocking prostaglandin synthesis (from arachidonic acid). An undesirable effect of NSAIDs is that they systemically block prostaglandin synthesis also in gastric and duodenal epithelia. This decreases HCO₃^– secretion, on the one hand, and stops inhibition of acid secretion, on the other. In addition, these drugs damage the mucosa locally by nonionic diffusion into the mucosal cells (pH of gastric juice << pKa’ of the NSAIDs). During intake of NSAIDs an acute ulcer may thus develop after days or weeks, the inhibitory action of these drugs on platelet aggregation raising the danger of bleeding from the ulcer.

Acute ulcers also occur if there is very severe stress on the organism (stress ulcer), as after major surgery, extensive burns, and multi-organ failure (“shock”). The main cause here is probably impaired blood flow through the mucosa correlated with high plasma concentrationsof cortisol.

Often psychogenic factors favor ulcer development. Strong emotional stress without an outward “safety valve” (high cortisol levels) and/or disturbed ability to cope with “normal” stress, for example, in one’s job, are the usual causes. Psychogenically raised secretion of gastric acid and pepsinogen, as well as stress-related bad habits (heavy smoking, antiheadache tablets [NSAIDs], high-proof alcohol) often play a part.

Smoking is a risk factor for ulcer development. A whole series of moderately effective single factors seem to add up here. Alcohol in large quantities or in high concentration damages the mucosa, while moderate drinking of wine and beer increases gastric secretion through their nonalcoholic components.

Rare causes of ulcer are tumors that autonomically secrete gastrin (gastrinoma, Zollinger–Ellison syndrome), systemic mastocytosis, or basophilia with a high plasma histamine concentration.

Apart from antibiotics (see above) and (rarely necessary) surgical intervention, the treatment of ulcer consists of lowering acid and pepsinogen secretion by blocking H₂ and M₁ receptors and/or of H⁺/K⁺ - ATPase. Treatment with antacids acts partly by buffering the pH in the lumen, but also has further, as yet not fully understood, effects on the mucosa.

Jaundice (Icterus)

Jaundice (i.e., icterus), which results from an abnormally high accumulation of bilirubin in the blood, is a yellowish discoloration to the skin and deep tissues.

The normal plasma concentration of bilirubin is maximally 17µmol/L. If it rises to more than 30 µmol/L, the sclera become yellow; if the concentration rises further, the skin turns yellow as well (jaundice [icterus]). Because normal skin has a yellow cast, the early signs of jaundice often are difficult to detect, especially in persons with dark skin. Bilirubin has a special affinity for elastic tissue. The sclera of the eye, which contains considerable elastic fibers, usually is one of the first structures in which jaundice can be detected.

The common causes of prehepatic, hepatic, and posthepatic jaundice

Several forms can be distinguished:

- Prehepatic jaundice is the result of increased bilirubin production, for example, in hemolysis (hemolytic anemia, toxins), inadequate erythropoiesis (e.g., megaloblastic anemia), massive transfusion (transfused erythrocytes are short-lived), or absorption of large hematomas. In all these conditions unconjugated (indirect reacting) bilirubin in plasma is increased.

The major cause of prehepatic jaundice is excessive hemolysis of red blood cells. Hemolytic jaundice occurs when red blood cells are destroyed at a rate in excess of the liver’s ability to remove the bilirubin from the blood. It may follow a hemolytic blood transfusion reaction or may occur in diseases such as hereditary spherocytosis, in which the red cell membranes are defective, or in hemolytic disease of the newborn. Neonatal hyperbilirubinemia results in an increased production of bilirubin in newborn infants and their limited ability to excrete it. Premature infants are at particular risk because their red cells have a shorter life span and higher turnover rate. In prehepatic jaundice, there is mild jaundice, the unconjugated bilirubin is elevated, the stools are of normal color, and there is no bilirubin in the urine.

- Intrahepatic jaundice is caused by a specific defect of bilirubin uptake in the liver cells (Gilbert syndrome Meulengracht), conjugation (neonatal jaundice, Crigler–Najjar syndrome), or secretion of bilirubin in the bile canaliculi (Dubin–Johnson syndrome, Rotor syndrome).

In the first two defects it is mainly the unconjugated plasma bilirubin that is increased; in the secretion type it is the conjugated bilirubin that is increased. All three steps may be affected in liver diseases and disorders,for example, in viral hepatitis, alcohol abuse, drug side effects (e.g., isoniazid, phenytoin, halothane), liver congestion (e.g., right heart failure), sepsis (endotoxins), or poisoning (e.g., the Amanita phalloides mushroom).

Intrahepatic or hepatocellular jaundice is caused by disorders that directly affect the ability of the liver to remove bilirubin from the blood or conjugate it so it can be eliminated in the bile. Liver diseases such as hepatitis and cirrhosis are the most common causes of intrahepatic jaundice. Intrahepatic jaundice usually interferes with all phases of bilirubin metabolism—uptake, conjugation, and excretion. Both conjugated and unconjugated bilirubin are elevated and the urine often is dark because of the presence of bilirubin.

- In posthepatic jaundice the extrahepatic bile ducts are blocked, in particular by gallstones, tumors (e.g., carcinoma of the head of the pancreas), or in cholangitis or pancreatitis. In these conditions it is particularly conjugated bilirubin that is increased.

Posthepatic or obstructive jaundice, also called cholestatic jaundice, occurs when bile flow is obstructed between the liver and the intestine. Among the causes of posthepatic jaundice are strictures of the bile duct, gallstones, and tumors of the bile duct or the pancreas. Conjugated bilirubin levels usually are elevated; the stools are clay colored because of the lack of bilirubin in the bile; the urine is dark; the levels of serum alkaline phosphatase are markedly elevated; and the aminotransferase levels are slightly increased. Blood levels of bile acids often are elevated in obstructive jaundice. As the bile acids accumulate in the blood, pruritus develops. A history of pruritus preceding jaundice is common in obstructive jaundice.

Jaundice

The types of Jaundice

Cholestasis

Cholestasis, blockage of bile flow, is due to either intrahepatic disorders, for example, cystic fibrosis, granulomatosis, drug side effects (e.g., allopurinol, sulfonamides), high estrogen concentration (pregnancy, contraceptive pill), graft versus host–reaction after transplantation, or, secondarily, extrahepatic bile duct occlusion.

In cholestasis the bile canaliculi are enlarged, the fluidity of the canalicular cell membrane is decreased (cholesterol embedding, bile salt effect), their brush border is deformed (or totally absent) and the function of the cytoskeleton, including canalicular motility, is disrupted. In addition, one of the two ATP-driven bile salt carriers, which are meant for the canalicular membrane, is falsely incorporated in the basolateral membrane in cholestasis. In turn, retained bile salts increase the permeability of the tight junctions and reduce mitochondrial ATP synthesis. However, it is difficult to define which of these abnormalities is the cause and which the consequence of cholestasis. Some drugs (e.g., cyclosporin A) have a cholestatic action by inhibiting the bile salt carrier, and estradiol, because it inhibits Na⁺-K⁺-ATPase and reduces membrane fluidity.

Most of the consequences of cholestasis are a result of retention of bile components: bilirubin leads to jaundice (in neonates there is a danger of kernicterus), cholesterol to cholesterol deposition in skin folds and tendons, as well as in the cell membranes of liver, kidneys, and erythrocytes (echinocytes, akanthocytes). The distressing pruritus (itching) is thought to be caused by retained endorphins and/or bile salts. The absence of bile in the intestine results in fatty stools and malabsorption. Finally, infection of accumulated bile leads to cholangitis, which has its own cholestatic effect.

Portal Hypertension

Venous blood from stomach, intestines, spleen, pancreas, and gallbladder passes via the portal vein to the liver where, in the sinusoids after mixture with oxygen-rich blood of the hepatic artery, it comes into close contact with the hepatocytes. About 15% of cardiac output flows through the liver, yet its resistance to flow is so low that the normal portal vein pressure is only 4–8 mmHg.

Obstruction of blood flow in the portal circulation, with portal hypertension and diversion of blood flow to

other venous channels, including the gastric and esophageal veins

If the cross-sectional area of the liver’s vascular bed is restricted, portal vein pressure rises and portal hypertension develops. Its causes can be an increased resistance in the following vascular areas, although strict separation into three forms of intrahepatic obstructions is not always present or possible:

- Prehepatic: portal vein thrombosis;

- Posthepatic: right heart failure, constrictive pericarditis, etc.;

- Intrahepatic:

– presinusoidal: chronic hepatitis, primary biliary cirrhosis, granuloma in schistosomiasis, tuberculosis, leukemia, etc.

– sinusoidal: acute hepatitis, damage from alcohol (fatty liver, cirrhosis), toxins, amyloidosis, etc.

– postsinusoidal: venous occlusive disease of the venules and small veins; BuddChiari syndrome (obstruction of the large hepatic veins).

Enlargement of the hepatocytes (fat deposition, cell swelling, hyperplasia) and increased production of etracellular matrix both contribute to sinusoidal obstructio n. As the extracellular matrix also impairs the exchange of substances and gases between sinusoids and hepatocytes, cell swelling is further increased. Amyloid depositions can ave a similar obstructive effect. Finally, in acute hepatitis and acute liver necrosis the sinusoidal space can also be obstructed by cell debris.

Mechanisms of disturbed liver function related to portal hypertension

Consequences of portal hypertension.

Wherever the site of obstruction, an increased portal vein pressure will lead to disorders in the preceding organs (malabsorption, splenomegaly with anemia and thrombocytopenia) as well as to blood flowing from abdominal organs via vascular channels that by pass the liver. These portal bypass circuits use collateral vessels that are normally thin-walled but are now greatly dilated (formation of varices; “haemorrhoids” of the rectal venous plexus; caput medusae

at the paraumbilical veins). The enlarged esophageal veins are particularly in danger of rupturing. This fact, especially together with thrombocytopenia (see above) and a deficiency in clotting factors (reduced synthesis in a damaged liver), can lead to massive bleeding that can be acutely life-threatening.

The vasodilators liberated in portal hypertension (glucagon, VIP, substance P, prostacyclins, NO, etc.) also lead to a fall in systemic blood pressure. This will cause a compensatory rise incardiac output, resulting in hyperperfusion of the abdominal organs and the collateral (bypass) circuits.

Liver function is usually unimpaired in prehepatic and presinusoidal obstruction, because blood supply is assured through a compensatory increase in flow from the hepatic artery. Still, in sinusoidal, postsinusoidal, and posthepatic obstruction liver damage is usually the cause and then in part also the result of the obstruction. As a consequence, drainage of protein-rich hepatic lymph is impaired and the increased portal pressure, sometimes in synergy with a reduction in the plasma’s osmotic pressure due to liver damage (hypoalbuminemia), pushes a protein-rich fluid into the abdominal cavity, i.e., ascites develops. This causes secondary hyperaldosteronism that results in an increase in extracellular volume.

As blood from the intestine bypasses the liver, toxic substances (NH₃, biogenicamines, short-chain fatty acids, etc.) that are normally extracted from portal blood by the liver cells reach the central nervous system, among other organs, so that portalsystemic (“hepatic”) encephalopathy develops.

Causes and Consequences of Portal Hypertension

Ascites. Ascites occurs when the amount of fluid in the peritoneal cavity is increased and is a late-stage manifestation of cirrhosis and portal hypertension. It is not uncommon for persons with advanced cirrhosis to present with an accumulation of 15 L or more of ascitic fluid. Those who gain this much fluid often experience abdominal discomfort, dyspnea, and insomnia.

Although the mechanisms responsible for the development of ascites are not completely understood, several factors seem to contribute to fluid accumulation, including an increase in capillary pressure caused by portal hypertension and obstruction of venous flow through the liver, salt and water retention by the kidney, and decreased colloidal osmotic pressure caused by impaired synthesis of albumin by the liver.

Treatment of ascites usually focuses on dietary restriction of sodium and administration of diuretics. Water intake also may need to be restricted. Because of the many limitations in sodium restriction, the use of diuretics has become the mainstay of treatment for ascites. Oral potassium supplements often are given to prevent hypokalemia. The upright position is associated with the activation of the renin-angiotensin-aldosterone system; therefore, bed rest may be recommended for persons with a large amount of ascites. Large-volume paracentesis (removal of 5 L or more of ascitic fluid) may be done in persons with massive ascites and pulmonary compromise.

Ascites

Splenomegaly.

The spleen enlarges progressively in portal hypertension because of shunting of blood into the splenic vein. The enlarged spleen often gives rise to sequestering of significant numbers of blood elements and development of a syndrome known as hypersplenism. Hypersplenism is characterized by a decrease in the life span and a subsequent decrease in all the formed elements of the blood, leading to anemia, thrombocytopenia, and leukopenia. The person with thrombocytopenia is subject to purpura, easy bruising, hematuria, and abnormal menstrual bleeding, and is vulnerable to bleeding from the esophagus and other segments of the gastrointestinal tract.

Liver Failure

Causes of acute liver failure are poisoning and inflammation, for example, fulminant cholangitis or viral hepatitis (especially in hepatitis B and E). The causes of chronic liver failure that is accompanied by fibrosis (cirrhosis) of the liver are:

– inflammation, for example, chronic persistent viral hepatitis;

– alcohol abuse, the most common cause;

– in susceptible patients, side effects of drugs, for example, folic acid antagonists, phenylbutazone;

– cardiovascular causes of impairment of venous return, for example, in right heart failure;

– a number of inherited diseases, for example, glycogen storage diseases, Wilson’s disease, galactosemia, hemochromatosis, α1-antitrypsin deficiency;

– intrahepatic or posthepatic cholestasis for prolonged periods, for example, in cystic fibrosis, a stone in the common bile duct, or tumors.

Alterations in liver function and manifestations of liver failure

The most serious consequences of liver failure are:

– Protein synthesis in the liver is reduced. This can lead to hypoalbuminemia that may result in ascites, i.e., an accumulation of extracellular fluid in the abdominal cavity, and other forms of edema. Plasma volume is reduced as a result, secondary hyperaldosteronism develops causing hypokalemia, which in turn encourages alkalosis. In addition, the reduced ability of the liver to synthesize causes a fall in the plasma concentration of clotting factors.

– Cholestasis occurs, producing not only liver damage but also aggravating any bleeding tendency, because the lack of bile salts decreases micellar formation and with it the absorption of vitamin K from the intestine, so that γ-carboxylation of the vitamin K-dependent clotting factors prothrombin (II), VII, IX, and X is reduced.

– Portal hypertension develops and may make the ascites worse because of lymphatic flow impairment. It may cause thrombocytopenia resulting from splenomegaly, and may lead to the development of clotting factors, thrombocytopenia, and varices are likely to cause severe bleeding. Finally, portal hypertension can cause an exudative enteropathy. This will increase the ascites due to loss of albumin from the plasma, while at the same time favoring bacteria in the large intestine being “fed” with proteins that have passed into the intestinal lumen, and thus increasing the liberation of ammonium, which is toxic to the brain.

– The hyperammonemia, which is partly responsible for the encephalopathy (apathy, memory gaps, tremor, and ultimately liver coma) is increased because.

1) gastrointestinal bleeding also contributes to an increased supply of proteins to the colon;

2) the failing liver is no longer sufficiently able to convert ammonium (NH₃NH₄⁺ ) to urea;

3) the above-mentioned hypokalemia causes an intracellular acidosis which activates ammonium formation in the cells of the proximal tubules and at the same time causes a systemic alkalosis. A respiratory component is added to the latter if the patient hyperventilates due to the encephalopathy.

Further substances that are toxic to the brain bypass the liver in portal hypertension and are therefore not extracted by it as would normally be the case. Those substances, such as amines, phenols, and short-chain fatty acids, are also involved in the encephalopathy. Lastly, the brain produces “false transmitters” (e.g., serotonin) from the aromatic amino acids, of which there are increased amounts in plasma when liver failure occurs. These transmitters probably play a part in the development of the encephalopathy.

Hepatic encephalopathy refers to the totality of central nervous system manifestations of liver failure. It is characterized by neural disturbances ranging from a lack of mental alertness to confusion, coma, and convulsions. A very early sign of hepatic encephalopathy is a flapping tremor called asterixis. Various degrees of memory loss may occur, coupled with personality changes such as euphoria, irritability, anxiety, and lack of concern about personal appearance and self. Speech may be impaired, and the patient may be unable to perform certain purposeful movements. The encephalopathy may progress to decerebrate rigidity and then to a terminal deep coma. Although the cause of hepatic encephalopathy is unknown, the accumulation of neurotoxins, which appear in the blood because the liver has lost its detoxifying capacity, is believed to be a factor. Hepatic encephalopathy develops in approximately 10% of persons with portosystemic shunts. One of the suspected neurotoxins is ammonia. A particularly important function of the liver is the conversion of ammonia, a by-product of protein and amino acid metabolism, to urea. The ammonium ion is produced in abundance in the intestinal tract, particularly in the colon, by the bacterial degradation of luminal proteins and amino acids. Normally, these ammonium ions diffuse into the portal blood and are transported to the liver, where they are converted to urea before entering the general circulation. When the blood from the intestine bypasses the liver or the liver is unable to convert ammonia to urea, ammonia moves directly into the general circulation and then into the cerebral circulation. Hepatic encephalopathy may become worse after a large pro-

tein meal or gastrointestinal tract bleeding.

Hematologic Disorders. Liver failure can cause anemia, thrombocytopenia, coagulation defects, and leukopenia. Anemia may be caused by blood loss, excessive red blood cell destruction, and impaired formation of red blood cells. A folic acid deficiency may lead to severe megaloblastic anemia. Changes in the lipid composition of the red cell membrane increase hemolysis. Because factors V, VII, IX, and X, prothrombin, and fibrinogen are synthesized by the liver, their decline in liver disease contributes to bleeding disorders. Malabsorption of the fat-soluble vitamin K contributes further to the impaired synthesis of these clotting factors.

Endocrine Disorders. The liver metabolizes the steroid hormones. Endocrine disorders, particularly disturbances in gonadal function, are common accompaniments of cirrhosis and liver failure. Women may have menstrual irregularities (usually amenorrhea), loss of libido, and sterility. In men, testosterone levels usually fall, the testes atrophy, and loss of libido, impotence, and gynecomastia occur. A decrease in aldosterone metabolism may contribute to salt and water retention by the kidney, along with a lowering of serum potassium resulting from increased elimination of potassium.

Skin Disorders. Liver failure brings on numerous skin disorders. These lesions, called variously vascular spiders, telangiectases, spider angiomas, and spider nevi, are seen most often in the upper half of the body. They consist of a central pulsating arteriole from which smaller vessels radiate. Palmar erythema is redness of the palms, probably caused by increased blood flow from higher cardiac output. Clubbing of the fingers may be seen in persons with cirrhosis. Jaundice usually is a late manifestation of liver failure.

Kidney function is impaired, giving rise to the hepatorenal syndrome. The hepatorenal syndrome refers to a

functional state of renal failure sometimes seen during the terminal stages of liver failure with ascites. It is characterized by progressive azotemia, increased serum creatinine levels, and oliguria. Although the basic cause is unknown, a decrease in renal blood flow is believed to play a part. Ultimately, when renal failure is superimposed on liver failure, azotemia and elevated levels of blood ammonia occur; this condition is thought to contribute to hepatic encephalopathy and coma.

Fibrosis and Cirrhosis of the Liver

Causes and Consequences of Liver Failure

Treatment.

The treatment of liver failure is directed toward eliminating alcohol intake when the condition is caused by alcoholic cirrhosis; preventing infections; providing sufficient carbohydrates and calories to prevent protein breakdown; correcting fluid and electrolyte imbalances, particularly hypokalemia; and decreasing ammonia production in the gastrointestinal tract by controlling protein intake. In many cases, liver transplantation remains the only effective treatment.