Before any discussion of the pathology of renal failure can begin, it is important to review the following functions that normal kidneys perform (Fig. 4-1):
• Elimination of metabolic wastes and other toxic materials
• Regulation of fluid volume
• Maintenance of electrolyte balance
• Regulation of blood pH
Figure 4-1 Longitudinal section of normal kidney.
In addition, the kidneys have several endocrine functions, including the following:
• Production of renin, which affects sodium, fluid volume, and blood pressure
• Formation of erythropoietin, which controls red cell production in the bone marrow
A normal kidney is also a receptor site for several hormones:
• Antidiuretic hormone (ADH), produced by the pituitary, reduces the excretion of water.
• Aldosterone, produced by the adrenal cortex, promotes sodium retention and enhances secretion of potassium and hydrogen ion.
• Parathyroid hormone increases phosphorus and bicarbonate excretion and stimulates conversion of vitamin D to the active 1,25-dihydroxycholecalciferol vitamin D3 form.
Renal physiology
How is blood supplied to the kidneys?
The kidneys are highly vascular organs that receive 20% to 25% of the resting cardiac output, which is greater than 1000 mL/min. Cardiac output is the volume of blood pumped per minute by each ventricle of the heart. Each kidney receives blood from a renal artery that originates from the abdominal aorta, and blood leaves the kidney through the renal vein. The renal artery branches out to form the afferent arterioles, which in turn form the glomerular capillaries of individual glomeruli. The glomerular capillaries then join to form the efferent arterioles, which in turn diffuse into peritubular capillaries and the vasa recta (Fig. 4-2).
Figure 4-2 The venous vessels of the kidney parallel the arterial vessels and are similarly named.
(From Copstead LC, Banasik JL: Pathophysiology, ed 4, St. Louis, 2010, Saunders.)
Blood flow to the kidney is dependent on hydration and cardiac output. Dehydration, blood loss, congestive heart failure, and myocardial infarction are examples of situations that would compromise blood flow to the kidney.
What is the difference between the peritubular capillaries and the vasa recta?
The peritubular capillaries surround the proximal and distal convoluted tubules and allow tubular secretion and reabsorption to occur. The vasa recta capillaries and branches surround the loops of Henle of the juxtamedullary nephrons and are located in the renal medulla. They play a major role in the concentration of urine as it moves through the tubules.
What is a nephron?
The nephron is the main functional unit of the kidney. There are more than a million such units in each of the two kidneys. Each nephron is a complex structure and has two main components: vascular and tubular. The vascular component consists of the afferent arteriole, glomerulus, efferent arteriole, and peritubular capillaries. The tubular portions of the nephron include Bowman’s capsule, proximal tubule, loop of Henle, and the distal tubule.
The glomerulus consists of a network of thin-walled capillaries supplied by the afferent arteriole and is closely surrounded by a pear-shaped epithelial membrane called Bowman’s capsule. The glomerulus and Bowman’s capsule combined are called the renal corpuscle. The space between the two layers of Bowman’s capsule opens into the proximal tubule, which makes a series of convolutions in the cortex of the kidney. It straightens out and then makes a U-turn, known as the loop of Henle, in the kidney medulla. It becomes convoluted again adjacent to its own glomerulus and finally joins other distal tubules to form a collecting duct to carry the freshly formed urine to the kidney pelvis (Fig. 4-3). Each kidney pelvis funnels the urine into its ureter, which connects with the urinary bladder. The urethra conveys the urine from the bladder to the exterior.
Figure 4-3 Diagram of nephron with afferent arteriole, glomerulus, efferent arteriole, and collecting duct.
What is the first step in urine formation?
Blood enters the glomerulus through an afferent arteriole. Because of the blood pressure in the capillaries and because of their thin walls, filtration of blood occurs. Water and dissolved solutes of molecular weight less than 68,000 Da (albumin) pass freely into Bowman’s space. This essentially protein-free fluid is the glomerular filtrate, and its rate of production is the glomerular filtration rate (GFR). The GFR is the amount of filtrate the kidneys produce each minute. A man of average size produces about 180 L of filtrate per day, or 125 mL/min. Ninety-nine percent of this filtrate is reabsorbed as it passes through the tubules.
Glomerular filtration is dependent on sufficient blood circulation to the glomerulus and maintenance of normal filtration pressures. The filtration of molecules depends on their shape, size, and ionic charge. As the molecular weight and size increase, the degree of filtration decreases. The glomerular basement membrane exerts a net negative charge. Substances carrying a negative charge will be repelled by the basement membrane, and its filtration will be prohibited.
What happens to the filtrate as it moves through the tubules?
The main function of the tubules is reabsorption and secretion. Tubular reabsorption is the process of the filtrate moving back into the blood of the peritubular capillaries or vasa recta (Fig. 4-4). This process is very selective and depends on the body’s needs at the time. Materials that are reabsorbed into the bloodstream are such ions as sodium, potassium, chloride, bicarbonate, and calcium.
Figure 4-4 Path of filtrate as it moves through different parts of a nephron.
(From Thibodeau GA, Patton KT: Anatomy & physiology, ed 7, St. Louis, 2010, Mosby.)
Of the 180 L of glomerular filtrate produced each day, about 2 L remain as the final urine. The rest of the water is reabsorbed along with glucose, amino acids, small proteins, and most electrolytes. The remaining filtrate becomes concentrated and begins to resemble the ultimate urine as it progresses down the tubule. Final adjustments of water-to-solute load occur in the distal tubule under the influence of ADH. The tubules conserve water and electrolytes by returning them to the blood. Hydrogen ions and metabolic wastes are excreted along with a volume of water appropriate to the total body need. The majority of reabsorption occurs in the proximal tubule; however, some reabsorption does occur in the distal tubule.
Tubular secretion adds materials to the filtrate from the blood. Tubular secretion helps to remove toxic substances from the blood and to restore blood pH by excreting excessive hydrogen ions. Substances secreted into the tubules include potassium, hydrogen, ammonia, creatinine, and some drugs.
Renal failure
What happens in kidney failure?
The normal urinary system maintains fluid volumes and the levels of many chemicals in the body. When the urinary system is not working properly, normal blood composition is disrupted and the patient will experience symptoms. Renal failure may be acute or chronic. In both types of renal failure there is enough loss of nephron function to upset the normal steady state of the body’s internal environment. Waste products of protein metabolism accumulate and will necessitate treatment of some kind.
This accumulation of waste products of protein metabolism is termed azotemia, indicating retention of nitrogenous products (azote = nitrogen). Azotemia is a major component of the uremic syndrome.
What is urea?
Urea is the waste product of protein metabolism and has a molecular weight of 60 Da. Urea is the most abundant organic waste and is freely filtered at the glomerulus. Most urea is produced during the breakdown of amino acids. Its normal value in the blood is 15 to 40 mg/dL. Blood urea level is influenced by many things, which is why it is not the best indicator of renal function or dysfunction. Increased levels may be seen with increased dietary consumption of protein, bleeding into the gastrointestinal tract, steroid use, and any hypercatabolic state. Decreased levels may be seen with a low dietary consumption of protein, liver disease, and overhydration.
What is creatinine?
Creatinine is a protein produced by muscle and released into the blood. The creatinine level in the blood is determined by the rate that creatinine is removed in the urine.
What is uremia?
Uremia, or the uremic syndrome, encompasses a complex of symptoms and findings resulting from disordered biochemical processes when kidney function fails.
Is retention of urea the cause of uremia?
Severity of the uremic symptoms roughly parallels the rise in blood urea. Urea clearly contributes to some of the symptoms—malaise, lethargy, anorexia, insomnia—but it is not the primary toxin of uremia. Numerous other substances are retained in the body when kidney function fails. More than 200 potential uremic toxins have been identified.
What is chronic kidney disease?
The National Kidney Foundation (NKF) defines chronic kidney disease (CKD) as either damage to the kidney or a GFR of less than 60 mL/min/1.73 m2 for more than three months. Kidney damage is further defined as pathologic irregularities or markers of damage, such as abnormalities in the blood, urine tests, or imaging studies. CKD stage 5 develops when the kidneys permanently lose most of their ability to remove waste and maintain fluid and chemical balances inside the body. This process can develop rapidly, within 2 to 3 months, or may develop slowly over 30 to 40 years.
CKD is defined according to the presence or absence of kidney damage and the level of kidney function, regardless of the type of kidney disease (diagnosis). Among individuals with CKD, the stages are defined based on the level of kidney function. Identifying the presence and stage of CKD in an individual is not a substitute for accurate assessment of the cause of kidney disease, extent of kidney damage, level of kidney function, comorbid conditions, complications of decreased kidney function, or risks for loss of kidney function or cardiovascular disease in that patient. Defining stages of CKD requires “categorization” of continuous measures of kidney function, and the “cut-off levels” between stages are inherently arbitrary. Nonetheless, staging of CKD will facilitate application of clinical practice guidelines, clinical performance measures, and quality improvement to manage the disease.
What is the course of chronic kidney disease?
Progressive and irreversible loss of kidney function occurs over many months or years. As the number of functioning nephrons decreases, each remaining unit must clear an increasing solute load. Eventually the limit to the amount of solute that can be cleared is reached, and the concentration in body fluids rises. Azotemia and clinical uremia result. Fortunately the slow rate of progression allows the body to adapt somewhat. Symptoms may be relatively mild proportionate to the chemical abnormalities.
What are the stages of chronic kidney disease?
CKD can be expressed in a series of stages from stage 1 to stage 5.
The stages of CKD are based on the GFR, which is widely recognized and accepted as the best overall measure of kidney function. The number of U.S. residents receiving treatment for CKD stage 5 was 506,256 in 2006, and the number of new cases that year was 110,854 (USRDS, 2008). The CKD stage 5 population represents only a small proportion of the total CKD population. The number of patients with CKD stages 1-4 far outnumber those who require maintenance dialysis or transplantation (Table 4-1).
Table 4-1 Chronic Kidney Disease (CKD) Population by Stage, Based on Estimated Glomerular Filtration Rate
|
Stage |
CKD Population |
|
5 |
n = 400,000 |
|
4 |
n = 400,000 |
|
3 |
n = 7,600,000 |
|
2 |
n = 5,300,000 |
|
1 |
n = 5,900,000 |
The NKF gives the following examples of potential etiologies in the causes of CKD: diabetes mellitus (types 1 and 2), systemic lupus erythematosus, human immunodeficiency virus (HIV), nephropathy, hepatitis B or C, hypertension, infection, stones, multiple myelomas, antibodies, and cystic diseases.
The NKF recommends that all individuals be assessed to see whether they are at an increased risk for developing CKD. The evaluation should include serum creatinine levels, assessment of proteinuria, and assessment of urinary sediment or urine dipstick for white or red blood cells. The best indicators, however, of level of kidney function are the estimates of the GFR. The goal is to delay or ameliorate the progression of the disease.
The recommendations from the NKF focus on stages and not on the disease etiology or pathology. The ultimate goal is to improve outcomes by maximizing opportunities for prevention (Table 4-2).
Table 4-2 Stages of Chronic Kidney Disease (CKD): Clinical Action Steps
What is end-stage renal disease?
End-stage renal disease is the name formerly used for CKD stage 5, or when the patient requires maintenance dialysis for survival. In the course of CKD, renal insufficiency often may be managed by diet, sodium restriction, phosphate control, and medication for a considerable time. As function falls to 10% to 15% of normal, the end is reached; dialysis or transplantation is necessary if the patient is to survive.
What places a person at risk for developing chronic kidney disease?
The NKF has identified older age, family history, and ethnic descent (African-American, American Indian, Latino, Asian, or Pacific Islander) as factors that increase susceptibility to kidney disease. High levels of proteinuria, hypertension, poor glycemic control in diabetes, and smoking are factors that can accelerate the progression of kidney disease. The most common causes of kidney failure in the United States are shown in Fig. 4-5. Early detection of proteinuria, a sensitive marker of kidney damage, will allow timelier introduction of therapy to slow the progression of disease. Early referral to a nephrologist, aggressive blood pressure control, and intensive management of blood glucose in diabetics may provide opportunities to delay the progression of CKD.
Figure 4-5 Primary causes of kidney failure.
(From United States Renal Data System, 2007 annual data report [website]: www.usrds.org/adr_2007.htm.)
What are some glomerular causes of chronic kidney disease?
Glomerular diseases damage the glomeruli and allow proteins and red blood cells to leak into the urine. Glomerular diseases fall into two major categories: glomerulonephritis and glomerulosclerosis.
Glomerulonephritis is an inflammatory disease affecting the glomeruli of the kidney. It either can be a primary disease of the kidney or may occur as a secondary complication of another disease, such as systemic lupus erythematosus, diabetes nephritis, or Goodpasture syndrome. The glomeruli become inflamed or damaged and allow red blood cells and significant amounts of proteins to pass into the urine. Glomerulonephritis may be caused by infection involving Streptococcus bacteria. The glomerular damage from the strep infection is not caused by the bacteria directly affecting the kidney but by the large production of antibodies that deposit in the glomeruli, causing the damage. As the immune system responds to infection, antigen-antibody complexes are formed. As the number of antigen-antibody complexes increase, they accumulate and block the glomeruli. The filtration capabilities of the glomerulus decline and the individual begins to experience such symptoms as a low serum albumin, hematuria, edema, hypertension, and decreased urine output.
Glomerulosclerosis describes the scarring or hardening of the blood vessels in the kidney. Systemic diseases, such as lupus and diabetes mellitus, cause the glomerular cells to produce scar material. The glomerular cells may produce growth factors that stimulate this scar tissue formation, or the growth factors can be brought to the glomerulus by the circulating blood volume that enters the glomerulus.
Diabetic nephropathy can occur with both type 1 diabetes mellitus (insulin-dependent diabetes [IDDM]) and type 2 diabetes mellitus (non–insulin-dependent diabetes). The glomerular basement membrane thickens with this nephropathy. Hyperglycemia increases the speed of blood flow to the kidney, which puts a strain on the glomeruli and elevates the blood pressure. As the glomeruli become damaged, their filtration capabilities become impaired. Diabetic nephropathy seldom develops before 10 years’ duration of type 1 diabetes and more likely occurs in people with 10- to 20-year tenure. The treatment, complications, and specific care needs of the patient with diabetic nephropathy are examined in Chapter 16.
Are there any genetic diseases that can cause chronic kidney disease?
Polycystic kidney disease (PKD) is the most common of all life-threatening genetic diseases in the United States and may also lead to renal failure. The pattern of inheritance is autosomal dominant. This means that both sexes are just as likely to be affected. Because the gene is dominant, only one affected gene is needed for the disease to develop. Consequently, the likelihood of passing the affected gene to a son or daughter is one in two, or 50%. PKD is a progressive disease and causes numerous cysts to form anywhere along the nephron. These fluid-filled cysts replace normal kidney tissue and begin to enlarge and compress the surrounding nephrons and renal vessels. The compressed renal issue eventually becomes fibrotic and causes kidney function to deteriorate. The kidneys can become quite enlarged as the cysts grow in size and number, causing the patient to experience a significant increase in abdominal girth. In some patients you will see an increased hematocrit due to increased secretion of erythropoietin. This occurs from compression of the kidneys, with increased erythropoietin being secreted from the cysts.
Symptoms vary by individual, as does the onset of kidney disease in family members. Cyst development is seen in 50% of all individuals by the age of 18. Low back pain or flank pain is one of the most common symptoms of PKD. Urinary tract infections, hematuria, severe hypertension, and decreased renal function are also seen. The cysts cause the patient to be susceptible to infection as bacteria become imbedded around the cysts, making it difficult for antibiotics to penetrate to the kidneys or cysts. Nephrectomy may need to be performed when the kidneys become very painful or chronically infected. The patient with PKD may develop cysts elsewhere, such as on the ovaries, testes, pancreas, liver, or spleen. PKD can occur in both adults and children, but not all of those affected will progress to CKD. Approximately 50% of those affected will require maintenance dialysis or a transplant while in their sixties.
What is amyloidosis?
Amyloidosis is a disorder that causes the body’s antibody-producing cells to produce abnormal protein fibers. These protein fibers join together and deposit in various organs in the body. Elevated levels of these protein fibers accumulate in tissues and organs and may cause renal failure when they accumulate in the kidneys. The symptoms of amyloidosis depend on the organ or body system affected. The heart, kidneys, nervous system, and gastrointestinal tract are the most often affected. A common symptom of kidney amyloidosis is proteinuria and hypertension. Amyloidosis may also occur as a result of CKD and is known as dialysis-related amyloidosis (DRA). DRA may manifest as carpal tunnel syndrome, bone cysts, and pathological fractures.
What is nephrosclerosis?
Nephrosclerosis is a term that translates as “hardening of the kidney” and describes the damage that occurs to the kidneys from prolonged, severe hypertension. Untreated hypertension leads to sclerosis of the renal arterioles, which decreases the blood supply to the nephrons. During the course of disease some glomeruli become sclerotic, resulting in hyperfiltration to compensate for the loss of renal function. Progressive scleroses of the glomeruli occur as a result. The renal vessels thicken and hypertrophy over time, and the kidneys lose their ability to produce renin, the function of which is to decrease blood pressure. Proteinuria, hematuria, and left ventricular hypertrophy may be found in the patient with nephrosclerosis. Aggressive attempts to control blood pressure are necessary to slow renal decline. Because hypertension is both a cause and a symptom of CKD, it is sometimes difficult to determine which came first.
What are some infectious causes of renal failure?
Pyelonephritis is an infection of the kidney and renal pelvis. Bacteria spread most commonly by ascending from the lower urinary tract. Pyelonephritis usually does not progress to CKD unless there is an underlying urinary tract problem, for example, obstruction. Organisms that normally colonize the bowel, such as gram-negative bacilli and enterococci, are usually those involved because they prosper in the urine and then ascend to the kidneys. Kidney damage occurs as a result of the inflammation, fibrosis, and scarring caused by the infection.
Renal tuberculosis is an infection caused by Mycobacterium tuberculosis. The urinary tract is the second most common site for infection after the lungs. Kidneys become damaged by lesions that cause inflammation and caseation. The infection spreads throughout the kidney and destroys the renal tissue. The kidneys become atrophied, scarred, and calcified. Tuberculosis of the kidney usually occurs secondary to pulmonary disease. Renal tuberculosis may remain dormant for many years after pulmonary infection. Symptoms include increased urination, suprapubic pain, hematuria, and fever.
What is nephrotic syndrome?
Nephrotic syndrome is not a specific renal disease but a disorder that occurs when glomeruli are damaged and protein leaks into the urine. Glomerulonephritis, diabetes mellitus, and lupus are examples of specific diseases that cause nephrotic syndrome. Other secondary conditions that may result in nephrotic syndrome include both viral and bacterial infections, such as streptococcus, mononucleosis, and hepatitis. Nephrotic syndrome, as it depletes the volume of protein in the blood, causes fluids to shift into the tissues, causing edema. Large volumes of protein being lost into the urine also cause the urine to become very foamy. No specific treatment exists for nephrotic syndrome other than decreasing the amount of salt in the diet to control the edema. Control of hypertension is very important.
Can a person develop cancer of the kidney?
Renal cell carcinoma or renal cell adenocarcinoma accounts for approximately 90% of kidney cancers and 3% of all adult malignancies. Renal cell carcinoma is found more frequently in men and has a high mortality rate when detected after metastases. The disease usually affects only one kidney, although equal incidence is seen in both right and left kidneys. Risk factors include tobacco use, analgesia abuse, and exposure to substances, such as asbestos and cadmium. The tumor may arise in any part of the kidney and compress renal tissue, which inevitably causes tissue necrosis and diminished blood flow. Metastasis often is seen in the lungs, lymph nodes, liver, and bones. The patient will most commonly exhibit hematuria, followed by flank pain, weight loss, fever, and hypertension. A mass in the flank or abdomen is sometimes palpable.
What is renal artery stenosis?
Renal artery stenosis is a condition in which there is a narrowing of the lumens of the arteries that supply the kidneys. A major reduction of blood flow to the kidneys occurs, damaging the renal parenchyma. The decreased renal perfusion leads to increased renin secretion, further damaging the kidneys.
How is acute renal failure defined?
Acute renal failure (ARF) is any sudden, severe impairment of kidney function. Onset is rapid, over hours or a few days. Classically there is oliguria (less than 400 mL of urine per 24 hours). However, nearly half of the cases are a nonoliguric variety. Nonoliguric renal failure is less fulminant and less difficult to manage than the oliguric form; dialysis is often not necessary. In 2004 an interdisciplinary group of nephrologists and critical care physicians formed to create the Acute Dialysis Quality Initiative (ADQI). Their goal was to achieve consensus on the definition of ARF and to propose uniform standards for diagnosing and staging acute kidney injury (AKI). The classification system defines three grades of increasing severity of AKI—risk, injury, and failure—and two outcome classes, loss and end-stage kidney disease (represented by the acronym RIFLE). This system has been proposed to classify AKI in a number of clinical settings and is based on changes in the patient’s baseline serum creatinine, GFR, or urine output (Table 4-3).
Table 4-3 RIFLE Criteria for Acute Renal Failure Classification
|
GFR Criteria |
Urine Output Criteria |
|
|
Risk |
↑ Serum Cr x 1.5 |
UO <0.5 mL/kg/hr x 6 hr |
|
Injury |
↑ Serum Cr x 2 |
UO <0.5 mL/kg/hr x 12 hr |
|
Failure |
↑ Serum Cr x 3 |
UO <0.3 mL/kg/hr x 12 hr |
|
Loss |
Dialysis-dependent AKI >4 wk |
|
|
ESKD |
Dialysis-dependent AKI >3 mo |
AKI, acute kidney injury; Cr, creatinine; ESKD, end-stage kidney disease; GFR, glomerular filtration rate.
From Clarkson, MR, Magee, MB, & Brenner, BM: The Kidney, ed 8, St. Louis, 2010, Mosby.
What causes acute renal failure?
There are three categories of causes for ARF, also known as AKI: (1) prerenal, (2) intrarenal (intrinsic), and (3) postrenal (see Box 18-1, pp. 248).
Prerenal causes involve reduced blood flow to the kidney that is sufficient to impair function. The most common causes include low extracellular fluid volume (as in severe dehydration), heart failure, and blockage of the renal arteries.
Postrenal causes involve blocked flow of urine leaving the kidney. Obstruction may be at the ureter, bladder, or urethral level.
Identification of prerenal and postrenal causes is important because often they may be corrected quickly, without residual damage to the kidneys.
Intrinsic ARF is caused by direct damage to kidney tissue. This might occur with an acute inflammation (rapidly progressive glomerulonephritis). Much more often it is the result of severely compromised blood flow (hemorrhagic shock) or direct toxicity to kidney parenchymal cells; this can come from some antibiotics, myoglobin, or ethylene glycol. The result is acute tubular necrosis (ATN), which causes 75% of all ARF. ATN is caused by injury to cells of the kidney tubules. The cell damage may be toxic (from chemicals or drugs) or ischemic (from severely reduced blood flow). Actual necrosis of cells does not always occur, but functional impairment is severe.
What brings on acute tubular necrosis?
The most frequent causes of ATN include surgery, trauma, sepsis, cardiovascular collapse, and nephrotoxic injury. Multisystem failure with sepsis is a frequent cause of ATN and is associated with high mortality.
Nephrotoxins include hemoglobin (from hemolysis of red blood cells) and myoglobin from muscle breakdown (rhabdomyolysis) as a result of crush injury, heatstroke, seizure, and so on. Many diagnostic and therapeutic agents, antibiotics (especially aminoglycosides), anesthetics, contrast media, cancer chemotherapy agents, and street drugs are toxic to the kidney in varying degrees.
How is acute renal failure recognized?
Most cases of ARF are found in hospital intensive care units. Monitoring of fluid intake/output, urine electrolytes, and serum solutes can furnish early clues. Serum creatinine may increase by 50 to 100 μmol/L, and urea may increase by 3.7 to 10.7 mmol/L each day. When tissue breakdown is extensive, serum potassium, phosphate, sulfate, and hydrogen ions rise rapidly.
What is the course of acute renal failure?
ARF from prerenal or postrenal causes reverses quickly when the precipitating factor is corrected. Most intrinsic renal failure, or ATN, is recoverable. However, other effects of the injury or the medical or surgical catastrophe that precipitated the renal failure may continue. These—with the complications of infection, sepsis, and hemorrhage—often have a very high mortality rate.