Chapter 17. Chronic Renal Failure & the Uremic Syndrome

• Abnormally elevated serum creatinine for 3 or more months.
• Calculated glomerular filtration rate (GFR) ≤60 mL/minute/1.73 m2 for 3 or more months.
• Clinical manifestations of the uremic syndrome in patients with advanced kidney failure.

The National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) has defined chronic kidney disease (CKD) as (1) kidney damage for 3 or more months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifested by either pathologic abnormalities or markers of kidney damage, including abnormalities in the composition of the blood or urine or in imaging tests; or (2) GFR ≤60 mL/minute/1.73 m2 for 3 or more months, with or without markers of kidney damage. The NKF-K/DOQI recommends using the equation derived from the Modification of Diet in Renal Disease (MDRD) to estimate GFR from the serum creatinine (eGFR) and has proposed a classification of CKD based on level of eGFR (Table 17–1).

CKD with decreased GFR (stages 2 through 5 of the NKF-K/DOQI classification), also known as chronic renal failure or chronic renal insufficiency in the literature prior to the NKF-K/DOQI classification, is a clinical syndrome that results from progressive decline of the GFR, typically over months to years, and is due to irreversible destruction of nephrons independent of the cause. In stage 2, the only manifestation of CKD may be a persistently decreased eGFR. As the GFR continues to decline (stages 3 and 4), other laboratory abnormalities begin to appear. The uremic syndrome refers to a constellation of symptoms and signs that occurs in patients with advanced kidney failure (typically GFR <10–15 mL/minute/1.73 m2) and reflects generalized organ dysfunction (stage 5). At this stage, kidney replacement therapy with dialysis or transplantation becomes necessary to sustain life. End-stage renal disease (ESRD) is an administrative term based on conditions for payment of health care by the Medicare ESRD program for patients treated by dialysis and/or transplantation in the United States.

It has been estimated that 8.3 million Americans have an eGFR ≤60 mL/minute/1.73 m2. Moreover, in the year 2002 alone, 100,359 patients began kidney replacement therapy and 431,284 were under active care in the United States. The prevalence and incidence rates of treated ESRD were 333 and 1435 cases per million population, respectively. Diabetes mellitus is the most common cause of ESRD, accounting for nearly 45% of cases; systemic hypertension is the second leading cause, and together with diabetes accounts for over two-thirds of the cases of ESRD. African-Americans are more susceptible to ESRD secondary to diabetes or hypertension.

The progressive nephron and GFR loss associated with progressive CKD leads to (1) abnormalities in water, electrolyte, and pH balance, (2) accumulation of waste products that are normally excreted by the kidney, and (3) abnormalities in the production and metabolism of certain hormones (ie, erythropoietin, active vitamin D). Fortunately, as the GFR declines, a number of compensatory mechanisms are activated, of which the most important is glomerular hyperfiltration in the remaining functioning nephrons. Due to this compensatory mechanism, a patient may be totally asymptomatic despite having lost 70% of kidney function. However, glomerular hyperfiltration is associated with the development of glomerulosclerosis in the remaining functioning nephrons, which contributes to further nephron loss. Other factors that contribute to nephron loss include (1) ongoing activity of the primary cause of CKD, (2) proteinuria, (3) development of tubulointerstitial lesions, (4) hyperlipidemia, and (5) acute superimposed renal insults (ie, contrast nephropathy, aminoglycoside toxicity, etc.).

Aggressive glucose and blood pressure control in diabetic and/or hypertensive patients reduces the risk of developing CKD. Screening individuals at high risk for CKD, particularly those with diabetes, hypertension, or a family history of diabetes, hypertension, or kidney disease, allows for early detection and implementation of interventions that prevent or slow the progression of CKD. Appropriate screening tests include a urinalysis, a first morning or a random “spot” urine sample for albumin or protein to creatinine ratio, serum creatinine level for estimation of GFR using an accepted prediction equation, and blood pressure measurement.

Symptoms and Signs

Patients are usually asymptomatic until kidney failure is advanced. When the GFR falls to approximately 10–15 mL/minute, nonspecific symptoms such as general malaise, weakness, insomnia, inability to concentrate, and nausea and vomiting begin to appear. Eventually other symptoms and signs that reflect generalized organ dysfunction develop as part of the uremic syndrome (Table 17–2).

Skin Manifestations

The skin is often pale (due to anemia) and hyperpigmented [due to increased production of β-melanocyte-stimulating hormone (β-MSH) and retention of carotenes and urochromes]. Pruritus is common and can be accompanied by scratching lesions. Ecchymoses and hematomas are often seen as a result of bleeding diathesis. Uremic frost is a fine white powder visible on the skin surface that results from crystallization of urea after sweat evaporates; it is now uncommon because of earlier initiation of dialysis. Other infrequent but clinically important abnormalities include skin necrosis due to vessel calcification (calciphylaxis) and bullous lesions.

Cardiovascular Manifestations

Cardiovascular manifestations are the most common cause of morbidity and mortality among patients with progressive CKD and include volume overload, edema, systemic hypertension, ischemic heart disease, left ventricular hypertrophy, heart failure, rhythm disturbances, and uremic pericarditis. Systemic hypertension is primarily due to volume overload; other contributing factors are hyperreninemia and erythropoietin therapy. Patients with chronic kidney failure (CKF) have accelerated atherosclerosis due to a high prevalence of “traditional” (ie, hypertension and hyperlipidemia) and “nontraditional” risk factors (those associated with the hemodynamic and metabolic abnormalities of CKF, such as volume overload, anemia, glucose intolerance, and hyperparathyroidism). Left ventricular hypertrophy is seen in 65–75% of patients with advanced CKF, and both arterial hypertension and anemia contribute to its development. Heart failure is usually multifactorial, with volume overload, hypertension, anemia, ischemic heart disease, and uremic cardiomyopathy as the main contributing factors. Rhythm disturbances are often precipitated by electrolyte abnormalities, metabolic acidosis, calcification of the conduction system, ischemia, and myocardial dysfunction. Uremic pericarditis occurs in 6–10% of patients with advanced uremia, just before initiation of dialysis or immediately after; it is associated with high blood urea levels (>60 mg/dL) and hemorrhagic pericardial effusion is seen in at least 50% of cases.

Neurologic Manifestations

Cerebrovascular accidents are common in these patients due to accelerated atherosclerosis. Uremic encephalopathy occurs in patients with advanced uremia and is characterized by insomnia, sleep pattern changes, inability to concentrate, memory loss, confusion, disorientation, emotional lability, anxiety, depression, and occasionally hallucinations. Without treatment, the encephalopathy progresses to generalized seizures, coma, and death. Other manifestations may include dysarthria, tremor, and myoclonic movements, and in advanced stages, hyperreflexia, clonus, and the Babinsky sign. The electroencephalogram shows diffuse slowing of cortical activity. Dialysis improves most of the manifestations of uremic encephalopathy. Another complication is peripheral neuropathy, which typically presents insidiously as a mixed symmetric polyneuropathy of the lower extremities. It may also affect the upper extremities but only after the lower extremities have been involved. Sensory abnormalities include the restless leg syndrome and a burning sensation on the feet, which may be severe enough to prevent ambulation. Motor abnormalities occur after the sensory abnormalities and include extremity weakness, unsteady gate, decreased deep tendon reflexes, and occasionally paraparesis and even paralysis. Autonomic nerves can also be affected, which may result in orthostatic hypotension, sweating abnormalities, impotence, and an abnormal response to the Valsalva maneuver.

Gastrointestinal Manifestations

Anorexia, nausea, and vomiting are typical manifestations of advanced kidney failure. Anorexia usually occurs earlier, can be intermittent, and is occasionally referred to some types of food such as meat. Nausea initially presents predominantly in the morning. The combination of these symptoms together with abnormalities in protein and energy metabolism, other comorbid conditions (ie, gastroparesis in diabetic patients), and side effects of medications often leads to malnutrition. Uremic fetor is a uriniferous odor of the breath that results from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste sensation. Other manifestations include a higher frequency of inflammatory and/or ulcerative lesions at all levels of the digestive tract and of gastrointestinal bleeding.

Hematologic Manifestations

A normochromic, normocytic anemia almost invariably develops in patients with CKF. It is mainly due to deficiency in the production of erythropoietin by the diseased kidneys. Other factors may also contribute, including hyporesponsiveness of progenitor cells to erythropoietin, accelerated hemolysis secondary to uremia, vitamin deficiencies (ie, folic acid), and iron losses associated predominantly with gastrointestinal bleeding. The white blood cell count is usually normal and increases in response to infections; however, leukocyte and immune system functions are abnormal, which predisposes to more frequent and severe infections. The platelet count is also normal, but function is abnormal, which results in a prolonged bleeding time and a tendency to bleed.

Bone Manifestations

The term renal osteodystrophy refers to various types of bone lesions that occur in patients with progressive CKD as a result of abnormalities in calcium and phosphorus metabolism. The lesions include secondary hyperparathyroidism, osteomalacia, adynamic bone disease, and growth retardation in children. Subcutaneous, vascular, joint, and visceral calcifications are also seen in patients with poorly controlled calcium-phosphate product. Although secondary hyperparathyroidism is the most common type of renal osteodystrophy, patients often have a predominant lesion or a combination of mixed lesions. Although close to 100% of patients have abnormalities in bone biopsy, radiologic abnormalities are found in only 40% of patients, and clinical manifestations, such as bone pain or fractures, in less than 10% of patients. Renal osteodystrophy can be prevented or attenuated with appropriate management of calcium and phosphate metabolism.

Endocrine and Metabolic Manifestations

Sexual dysfunction is common in patients with progressive CKD. Impotence, infertility, and decreased libido occur as a result of primary hypogonadism. Hyperprolactinemia also contributes to amenorrhea and galactorrhea in women. Total T4 and T3 and free T3 may be low, but free T4, reverse T3, and thyroid-stimulating hormone (TSH) are normal, suggesting a normal thyroid state. In early CKD, there is insulin resistance and glucose intolerance (azotemic pseudodiabetes), whereas in advanced CKD hypoglycemic episodes are common due to the longer half-life of insulin secondary to decreased renal catabolism and to decreased renal gluconeogenesis. Lipid abnormalities include elevated triglycerides and very low-density lipoprotein (VLDL) and decreased high-density lipoprotein (HDL); total cholesterol is normal and lipoprotein A may be elevated. Abnormalities of protein metabolism include decreased synthesis and increased catabolism.

Laboratory Findings

In addition to an elevated blood urea nitrogen (BUN) and serum creatinine, which are a reflection of a decreased GFR, patients with progressive CKD develop other laboratory abnormalities, particularly if they do not comply or are not given appropriate dietary instructions as the GFR declines. Typical abnormalities include hyponatremia (due to excessive water intake), hyperkalemia, hyperphosphatemia, hypocalcemia, hypermagnesemia, and hyperuricemia. Metabolic acidosis, usually with an elevated anion gap, is also common (Table 17–2). With the exception of hypocalcemia, these fluid and electrolyte disturbances result from an imbalance between intake and output by the progressively diseased kidneys.

Imaging Studies

Renal ultrasound is particularly helpful for diagnosing some cases of CKD [ie, polycystic kidney disease (PKD), obstructive uropathy] and for distinguishing acute from chronic kidney disease. The presence of symmetrically small (<8.5 cm) kidneys supports the diagnosis of CKD, whereas the occurrence of normal-sized kidneys favors an acute rather than a chronic process. There are exceptions, however, as some causes of CKD are associated with normal-sized or even enlarged kidneys, including diabetes, PKD, and amyloidosis. Other imaging studies may help determine the cause of CKD. Duplex Doppler ultrasound of the renal arteries, renal scintigraphy, and magnetic resonance angiography are useful in patients in whom renovascular ischemic disease is suspected. Voiding cystourethrography is helpful to rule out reflux nephropathy. Computed tomography allows for assessment of kidney stone activity and for evidence of papillary necrosis.

Special Tests

Kidney biopsy should be reserved for patients with near-normal kidney size, in whom a clear-cut diagnosis cannot be made by less invasive means, and when a potentially treatable cause is suspected.

Conservative treatment, usually with diet and medications, is indicated in all CKD stages. Kidney replacement therapy with dialysis or transplantation eventually becomes necessary in CKD stage 5. The goals of conservative treatment are to (1) treat the cause of CKD if possible and also to detect and treat any reversible cause of decreased kidney function, such as volume depletion, urinary tract infection, obstructive uropathy, use of nephrotoxic agents, accelerated or uncontrolled hypertension, and reactivation or flare of the original underlying etiologic disease process, (2) implement interventions to prevent or slow progression of CKD, (3) prevent or treat complications of CKD, (4) prevent or treat complications associated with other comorbid conditions, particularly diabetes and cardiovascular disease, and (5) prepare the patient and family for kidney replacement therapy (Figure 17–1). In addition, frequent review of medications is recommended; nephrotoxic agents should be avoided and dose adjustments should be made for drugs that are excreted by the renal route. Patients with CKD should be referred to a nephrologist when the eGFR is <30 mL/minute (stage 4), as this allows enough time for adequate preparation for kidney replacement therapy; for earlier stages of CKD, joint management between the primary care physician and the nephrologist is appropriate.

Interventions to Slow Progression of CKD

It has been shown that certain interventions slow the progression of CKD, including blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs), and glycemic control in diabetic patients. These interventions are most effective if they are implemented early in the course of CKD. Blood pressure control is essential not only to delay progression of CKD, but to reduce the risk of developing coronary artery disease and left ventricular hypertrophy. Treatment includes a low salt diet and antihypertensive medications. ACE inhibitors and ARBs are the antihypertensive agents of choice because they reduce glomerular hypertension by a dual mechanism: Lowering of systemic blood pressure and predominant vasodilation of the efferent arteriole; in addition, they improve glomerular membrane permeability and decrease production of fibrogenic cytokines. ARBs have fewer side effects than ACE inhibitors, such as cough or hyperkalemia; however, due to their higher cost, they are usually recommended for patients who do not respond to or tolerate ACE inhibitors. Recent studies suggest that the combination of ACE inhibitors and ARBs may be more effective to slow the progression of CKD than either agent alone. The recommended target blood pressure is <130/80 in patients with proteinuria of <1 g/day and <125/75 in those with proteinuria of >1 g/day. ACE inhibitors and ARBs have also been shown to be renoprotective in patients with normal blood pressure and proteinuria, particularly those with type 1 diabetes. Strict glycemic control is another intervention that reduces the risk of developing nephropathy, particularly if it is initiated early in the course of diabetes and/or of diabetic nephropathy (stage of normoalbuminuria or microalbuminuria). The benefit of strict glycemic control in patients with diabetes and overt nephropathy (proteinuria >300 mg/day) is less clear. Lastly, dietary protein restriction is another intervention that slows the progression of CKD.

Prevention and Treatment of Uremic Complications

As CKD becomes more severe, appropriate dietary changes must be made to prevent or treat water, electrolyte, and acid–base disorders. A low salt diet (2–3 g of sodium per day) and loop diuretics are recommended for volume overload. Thiazide diuretics are ineffective when the GFR is <30 mL/minute. Hyponatremia can be avoided by reducing water intake (for example, to 1.5 L/day). To prevent hyperkalemia, a low potassium diet (40–60 mEq/day) is recommended; in addition, exogenous sources of potassium should be avoided, including blood transfusions, salt substitutes, and certain medications (nonsteroidal anti-inflammatory drugs and potassium-sparing diuretics). Although ACE inhibitors and ARBs may cause hyperkalemia and acute kidney failure, they can be used in patients with progressive CKD because of their renoprotective effect, but with careful monitoring of serum potassium and creatinine. Hyperuricemia rarely leads to symptomatic gout, and thus treatment of this complication with low-dose allopurinol is not necessary unless it becomes a recurrent problem. To reduce the risk of developing hypermagnesemia, magnesium-containing antacids and cathartics should be avoided. Lastly, serum bicarbonate should be maintained at ≥22 mEq/L with administration of sodium bicarbonate, particularly in symptomatic patients and to prevent growth retardation in children.

Regarding cardiovascular complications, management of volume overload and hypertension includes a low salt diet, loop diuretics, and antihypertensive agents (see above). Risk factors for atherosclerotic complications should be aggressively treated. Uremic pericarditis is an indication for initiation of dialysis; a short course of nonsteroidal anti-inflammatory drugs is sometimes needed for pain control; pericardiocentesis is indicated if tamponade is present. Neurologic complications such as encephalopathy are an indication for initiation of dialysis; neuropathy also improves with dialysis and more consistently with kidney transplantation. Gastrointestinal complications such as anorexia, nausea, and vomiting improve with dialysis; in the evaluation of nausea and vomiting it is important to exclude nonuremic causes, for example, diabetic gastroparesis, peptic ulcer disease, or side effects of medications. Follow-up by a qualified dietician is recommended to avoid malnutrition; a protein and energy intake of 0.75 g/kg/day and 30–35 kcal/kg/day, respectively, is generally recommended. Treatment of platelet dysfunction is indicated in patients with active bleeding and before a surgical procedure; appropriate measures include (1) correction of anemia with erythropoietin or blood transfusion,(2) administration of desmopressin or cryoprecipitate for rapid correction, (3) conjugated estrogens for long-term correction, and (4) reduction of azotemia with dialysis if indicated.

Prevention and Treatment of Comorbid Conditions

Since cardiovascular complications are the main cause of death in patients with CKD, appropriate management of risk factors and of established cardiovascular disease is of the utmost importance. Diabetic complications should also be managed appropriately.

Preparation for Kidney Replacement Therapy

An adequate preparation for kidney replacement therapy includes (1) information on the different treatment modalities, (2) education regarding preservation of forearm veins for future vascular access placement for hemodialysis, (3) referral to social services to assess transportation needs to the dialysis unit, continuation of work in some cases, rehabilitation, and participation in support groups, and (4) placement of a permanent vascular access, preferably an arteriovenous fistula, when the creatinine clearance is <25 mL/minute, the serum creatinine is >4 mg/dL, or the estimated time before initiation of dialysis is 12 months; peritoneal dialysis catheters should be placed 2–4 weeks before dialysis initiation.

CKD is associated with high morbidity and mortality. Compared to the general population, the number of hospitalizations and of days spent in the hospital per year are three times higher in patients with CKD stages 2–4, and six to seven times higher in patients with ESRD receiving dialysis. One-, two-, and five-year survival for dialysis patients are 80, 65, and 38%, respectively. The expected remaining lifetimes of white dialysis patients are only one-fourth to one-sixth those of the general population. Lastly, cardiovascular mortality is 10–30 times higher in ESRD patients treated by dialysis compared with those in the general population. These poor outcomes underscore the importance of early detection and appropriate management of CKD long before dialysis is required.

• United States Renal Data System: http://www.usrds.org. Provides epidemiologic data on CKD and ESRD in the United States.
• National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI): http://www.kidney.org/professionals/kdoqi/index.cfm. Provides access to the GFR calculator and the NKF-K/DOQI Clinical Practice Guidelines.
• End-stage Renal Disease (ESRD) Program: http://www.cms.hhs.gov/esrd/3.asp. Provides information on the Medicare ESRD Program.