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CLINICAL PATHOPHYSIOLOGY OF KIDNEY

June 15, 2024

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)₂D₃], 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 thaeutral 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 (→ p. 102) 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 thaeutral (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

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. Myoglobiormally 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.

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-OH₂vitamin 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 maintaiormal 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