Chronic Kidney Disease : Pathophysiology, Etiology and Treatment

Chronic Kidney Disease

Chronic kidney disease (CKD) encompasses a spectrum of different pathophysiologic processes associated with abnormal kidney function, and a progressive decline in glomerular filtration rate (GFR). Table 274-1 provides a widely accepted classification, based on recent guidelines of the National Kidney Foundation [Kidney Dialysis Outcomes Quality Initiative (KDOQI)], in which stages of CKD are defined according to the estimated GFR.
Table 274-1 Classification of Chronic Kidney Disease (CKD)
GFR, mL/min per 1.73 m2
More than 90a
Less than 15
             aWith risk factors for CKD (see text).
             bWith demonstrated kidney damage (e.g., persistent proteinuria, abnormal urine sediment, abnormal blood and urine  
              chemistry, abnormal imaging studies).
Note: GFR, glomerular filtration rate.
Source: Modified from National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification and stratification. Am J Kidney Dis 39:suppl 1, 2002.

The term chronic renal failure applies to the process of continuing significant irreversible reduction in nephron number, and typically corresponds to CKD stages 3–5. The pathophysiologic processes and adaptations associated with chronic renal failure will be the focus of this chapter. The dispiriting term end-stage renal disease represents a stage of CKD where the accumulation of toxins, fluid, and electrolytes normally excreted by the kidneys results in the uremic syndrome. This syndrome leads to death unless the toxins are removed by renal replacement therapy, using dialysis or kidney transplantation. These latter interventions are discussed in Chaps. 275 and 276. End-stage renal disease will be supplanted in this chapter by the term stage 5 CKD.

Pathophysiology of Chronic Kidney Disease
The pathophysiology of CKD involves two broad sets of mechanisms of damage: (1) initiating mechanisms specific to the underlying etiology (e.g., immune complexes and mediators of inflammation in certain types of glomerulonephritis, or toxin exposure in certain diseases of the renal tubules and interstitium); and (2) a set of progressive mechanisms, involving hyperfiltration and hypertrophy of the remaining viable nephrons, that are a common consequence following long-term reduction of renal mass, irrespective of underlying etiology (Chap. 272). The responses to reduction in nephron number are mediated by vasoactive hormones, cytokines, and growth factors. Eventually, these short-term adaptations of hypertrophy and hyperfiltration become maladaptive as the increased pressure and flow predisposes to sclerosis and dropout of the remaining nephrons. Increased intrarenal activity of the renin-angiotensin axis appears to contribute both to the initial adaptive hyperfiltration and to the subsequent maladaptive hypertrophy and sclerosis, the latter, in part, owing to the stimulation of transforming growth factor  (TGF-). This process explains why a reduction in renal mass from an isolated insult may lead to a progressive decline in renal function over many years.

The Stages of CKD and Identification of at-Risk Populations
It is important to identify factors that increase the risk for CKD, even in individuals with normal GFR. Risk factors include hypertension, diabetes mellitus, autoimmune disease, older age, African ancestry, a family history of renal disease, a previous episode of acute renal failure, and the presence of proteinuria, abnormal urinary sediment, or structural abnormalities of the urinary tract.
In order to stage CKD, it is necessary to estimate the GFR. Two equations commonly used to estimate GFR are shown in Table 274-2, and incorporate the measured plasma creatinine concentration, age, sex, and ethnic origin. Many laboratories now report an estimated GFR, or "e-GFR," using one of these equations.
Table 274-2 Recommended Equations for Estimation of Glomerular Filtration Rate (GFR) Using Serum Creatinine Concentration (PCr), Age, Sex, Race, and Body Weight
1. Equation from the Modification of Diet in Renal Disease studya
     Estimated GFR (mL/min per 1.73 m2) = 1.86 x (PCr)–1.154 x (age)–0.203
     Multiply by 0.742 for women
     Multiply by 1.21 for African Americans
2. Cockcroft-Gault equation
Multiply by 0.85 for women
              aEquation is available in hand-held calculators and in tabular form.
               Adapted from AS Levey et al: Am J Kidney Dis 39 (Suppl 1): S1, 2002, with permission

The normal annual mean decline in GFR with age from the peak GFR (~120 mL/min per 1.73 m2) attained during the third decade of life is ~1 mL/min per year per 1.73 m2, reaching a mean value of 70 mL/min per 1.73 m2 at age 70. The mean GFR is lower in women than in men. For example, a woman in her 80s with a normal serum creatinine may have a GFR of just 50 mL/min per 1.73 m2. Thus, even a mild elevation in serum creatinine concentration [e.g., 130 mol/L (1.5 mg/dL)], often signifies a substantial reduction in GFR in most individuals.

Measurement of albuminuria is also helpful for monitoring nephron injury and the response to therapy in many forms of CKD, especially chronic glomerular diseases. While an accurate 24-h urine collection is the "gold standard" for measurement of albuminuria, the measurement of albumin-to-creatinine ratio in a spot first-morning urine sample is often more practical to obtain and correlates well, but not perfectly, with 24-h urine collections. Persistence in the urine of >17 mg of albumin per gram of creatinine in adult males and 25 mg albumin per gram of creatinine in adult females usually signifies chronic renal damage. Microalbuminuria refers to the excretion of amounts of albumin too small to detect by urinary dipstick or conventional measures of urine protein. It is a good screening test for early detection of renal disease, in particular, and may be a marker for the presence of microvascular disease in general. If a patient has a large amount of excreted albumin, there is no reason to perform an assay for microalbuminuria.

Stages 1 and 2 CKD are usually not associated with any symptoms arising from the decrement in GFR. However, there may be symptoms from the underlying renal disease itself, such as edema in patients with nephrotic syndrome or signs of hypertension secondary to the renal parenchymal disease in patients with polycystic kidney disease, some forms of glomerulonephritis, and many other parenchymal and vascular renal diseases, even with well-preserved GFR. If the decline in GFR progresses to stages 3 and 4, clinical and laboratory complications of CKD become more prominent. Virtually all organ systems are affected, but the most evident complications include anemia and associated easy fatigability; decreasing appetite with progressive malnutrition, abnormalities in calcium, phosphorus, and mineral-regulating hormones, such as 1,25(OH)2D3 (calcitriol) and parathyroid hormone (PTH); and abnormalities in sodium, potassium, water, and acid-base homeostasis. If the patient progresses to stage 5 CKD, toxins accumulate such that patients usually experience a marked disturbance in their activities of daily living, well-being, nutritional status, and water and electrolyte homeostasis, eventuating in the uremic syndrome. As discussed above, this state will culminate in death unless renal replacement therapy (dialysis or transplantation) is instituted.

Etiology and Epidemiology
It has been estimated from population survey data that at least 6% of the adult population in the United States has chronic kidney disease at stages 1 and 2. An unknown subset of this group will progress to more advanced stages of CKD. An additional 4.5% of the U.S. population is estimated to have stages 3 and 4 CKD. The most frequent cause of CKD is diabetic nephropathy, most often secondary to type 2 diabetes mellitus. Hypertensive nephropathy is a common cause of CKD in the elderly, in whom chronic renal ischemia as a result of small and large vessel renovascular disease may be underrecognized. Progressive nephrosclerosis from vascular disease is the renal correlate of the same processes that lead to coronary heart disease and cerebrovascular disease. The increasing incidence of CKD in the elderly has been ascribed, in part, to decreased mortality from the cardiac and cerebral complications of atherosclerotic vascular disease in these individuals, enabling a greater segment of the population to manifest the renal component of generalized vascular disease. Nevertheless, it should be appreciated that overwhelmingly the vast majority of those with early stages of renal disease, especially of vascular origin, will succumb to the cardiovascular and cerebrovascular consequences of the vascular disease before they can progress to the most advanced stages of CKD. The early stage of CKD, manifesting as albuminuria and even a minor decrement in GFR, is now recognized as a major risk factor for cardiovascular disease.
The striking interindividual variability in the rate of progression to CKD has an important heritable component, and a number of genetic loci that contribute to the progression of CKD have been identified. Similarly, it has been noted that women of reproductive age are relatively protected against progression of many renal diseases, and sex-specific responses to angiotensin II and its blockade have been identified.

Pathophysiology and Biochemistry of Uremia
Although serum urea and creatinine concentrations are used to measure the excretory capacity of the kidneys, accumulation of these two molecules themselves do not account for the many symptoms and signs that characterize the uremic syndrome in advanced renal failure. Hundreds of toxins that accumulate in renal failure have been implicated in the uremic syndrome. These include water-soluble, hydrophobic, protein-bound, charged, and uncharged compounds. Additional categories of nitrogenous excretory products include guanido compounds, urates and hippurates, products of nucleic acid metabolism, polyamines, myoinositol, phenols, benzoates, and indoles. Compounds with a molecular mass between 500 and 1500 Da, the so-called middle molecules, are also retained and contribute to morbidity and mortality. It is thus evident that the plasma concentrations of urea and creatinine should be viewed as being readily measured, but incomplete, surrogate markers for these compounds, and monitoring the levels of urea and creatinine in the patient with impaired kidney function represents a vast oversimplification of the uremic state.
The uremic syndrome and the disease state associated with advanced renal impairment involve more than renal excretory failure. A host of metabolic and endocrine functions normally undertaken by the kidneys are also impaired, and this results in anemia, malnutrition, and abnormal metabolism of carbohydrates, fats, and proteins. Furthermore, plasma levels of many hormones, including PTH, insulin, glucagon, sex hormones, and prolactin, change with renal failure as a result of urinary retention, decreased degradation, or abnormal regulation. Finally, progressive renal impairment is associated with worsening systemic inflammation. Elevated levels of C-reactive protein are detected along with other acute-phase reactants, while levels of so-called negative acute-phase reactants, such as albumin and fetuin, decline with progressive renal impairment. Thus, renal impairment is important in the malnutrition-inflammation-atherosclerosis/calcification syndrome, which contributes in turn to the acceleration of vascular disease and comorbidity associated with advanced renal disease.
In summary, the pathophysiology of the uremic syndrome can be divided into manifestations in three spheres of dysfunction: (1) those consequent to the accumulation of toxins normally undergoing renal excretion, including products of protein metabolism; (2) those consequent to the loss of other renal functions, such as fluid and electrolyte homeostasis and hormone regulation; and (3) progressive systemic inflammation and its vascular and nutritional consequences.

Clinical and Laboratory Manifestations of Chronic Kidney Disease and Uremia
Uremia leads to disturbances in the function of virtually every organ system. Chronic dialysis can reduce the incidence and severity of many of these disturbances, so that the overt and florid manifestations of uremia have largely disappeared in the modern health setting. However, as indicated in Table 274-3, even optimal dialysis therapy is not completely effective as renal replacement therapy, because some disturbances resulting from impaired renal function fail to respond to dialysis.

Table 274-3 Clinical Abnormalities in Uremiaa

Fluid and electrolyte disturbances
Volume expansion (I)
Hyponatremia (I)
Hyperkalemia (I)
Hyperphosphatemia (I)
Endocrine-metabolic disturbances
Secondary hyperparathyroidism (I or P)
Adynamic bone (D)
Vitamin D–deficient osteomalacia (I)
Carbohydrate resistance (I)
Hyperuricemia (I or P)
Hypertriglyceridemia (I or P)
Increased Lp(a) level (P)
Decreased high-density lipoprotein level (P)
Protein-energy malnutrition (I or P)
Impaired growth and development (P)
Infertility and sexual dysfunction (P)
Amenorrhea (I/P)
2-Microglobulin associated amyloidosis (P or D)
Neuromuscular disturbances
Fatigue (I)b
Sleep disorders (P)
Headache (P)
Impaired mentation (I)b
Lethargy (I)b
Asterixis (I)
Muscular irritability
Peripheral neuropathy (I or P)
Restless legs syndrome (I or P)
Myoclonus (I)
Seizures (I or P)
Coma (I)
Muscle cramps (P or D)
Dialysis disequilibrium syndrome (D)
Myopathy (P or D)
Cardiovascular and pulmonary disturbances
Arterial hypertension (I or P)
Congestive heart failure or pulmonary edema (I)
Pericarditis (I)
Hypertrophic or dilated cardiomyopathy (I, P, or D)
Uremic lung (I)
Accelerated atherosclerosis (P or D)
Hypotension and arrhythmias (D)
Vascular calcification (P or D)
Dermatologic disturbances
Pallor (I)b
Hyperpigmentation (I, P, or D)
Pruritus (P)
Ecchymoses (I)
Nephrogenic fibrosing dermopathy (D)
Uremic frost (I)
Gastrointestinal disturbances
Anorexia (I)
Nausea and vomiting (I)
Gastroenteritis (I)
Peptic ulcer (I or P)
Gastrointestinal bleeding (I, P, or D)
Idiopathic ascites (D)
Peritonitis (D)
Hematologic and immunologic disturbances
Anemia (I)b
Lymphocytopenia (P)
Bleeding diathesis (I or D)b
Increased susceptibility to infection (I or P)
Leukopenia (D)
Thrombocytopenia (D)

aVirtually all abnormalities in this table are completely reversed in time by successful renal transplantation. The response of these abnormalities to hemodialysis or peritoneal dialysis therapy is more variable. (I) denotes an abnormality that usually improves with an optimal program of dialysis and related therapy; (P) denotes an abnormality that tends to persist or even progress, despite an optimal program; (D) denotes an abnormality that develops only after initiation of dialysis therapy.
bImproves with dialysis and erythropoietin therapy.
Note: Lp(a), lipoprotein A.

Fluid, Electrolyte and Acid-Base Disorders

Sodium and Water Homeostasis
In most patients with stable CKD, the total-body content of sodium and water is modestly increased, although this may not be apparent on clinical examination. Normal renal function guarantees that the tubular reabsorption of filtered sodium and water is adjusted so that urinary excretion matches net intake. Many forms of renal disease (e.g., glomerulonephritis) disrupt this glomerulotubular balance such that dietary intake of sodium exceeds its urinary excretion, leading to sodium retention and attendant extracellular fluid volume (ECFV) expansion. This expansion may contribute to hypertension, which itself can accelerate the nephron injury. As long as water intake does not exceed the capacity for water clearance, the ECFV expansion will be isotonic and the patient will have a normal plasma sodium concentration and effective osmolality (Chap. 272). Hyponatremia is not commonly seen in CKD patients but, when present, can respond to water restriction. If the patient has evidence of ECFV expansion (peripheral edema, sometimes hypertension poorly responsive to therapy) he or she should be counseled regarding salt restriction. Thiazide diuretics have limited utility in stages 3–5 CKD, such that administration of loop diuretics, including furosemide, bumetanide, or torsemide, may also be needed. Resistance to loop diuretics in renal failure often mandates use of higher doses than those used in patients with near-normal kidney function. The combination of loop diuretics with metolazone, which inhibits the sodium-chloride co-transporter of the distal convoluted tubule, can help effect renal salt excretion. Ongoing diuretic resistance with intractable edema and hypertension in advanced CKD may serve as an indication to initiate dialysis.
In addition to problems with salt and water excretion, some patients with CKD may also have impaired renal conservation of sodium and water. When an extrarenal cause for fluid loss, such as gastrointestinal (GI) loss, is present, these patients may be prone to ECFV depletion because of the inability of the failing kidney to reclaim filtered sodium adequately. Furthermore, depletion of ECFV, whether due to GI losses or over-zealous diuretic therapy, can further compromise kidney function on a "pre-renal" basis, lead to acute-on-chronic kidney failure and result in overt uremia. In this setting, cautious volume repletion with normal saline may return the ECFV to normal and restore renal function to baseline without having to intervene with dialysis.

Potassium Homeostasis
In CKD, the decline in GFR is not necessarily accompanied by a parallel decline in urinary potassium excretion, which is predominantly mediated by aldosterone-dependent secretory events in the distal nephron segments. Another defense against potassium retention in these patients is augmented potassium excretion in the GI tract. Notwithstanding these two homeostatic responses, hyperkalemia may be precipitated in certain settings. These include increased dietary potassium intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, and metabolic acidosis. In addition, a host of medications can inhibit potassium entry into cells and renal potassium excretion. The most important medications in this respect include the angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and spironolactone and other potassium-sparing diuretics such as amiloride, eplerenone, and triamterene.
Certain causes of CKD can be associated with earlier and more severe disruption of potassium-secretory mechanisms in the distal nephron, out of proportion to the decline in GFR. These include conditions associated with hyporeninemic hypoaldosteronism, such as diabetes, and renal diseases that preferentially affect the distal nephron, such as obstructive uropathy and sickle cell nephropathy.
Hypokalemia is not common in CKD and usually reflects markedly reduced dietary potassium intake, especially in association with excessive diuretic therapy or concurrent GI losses. Hypokalemia can also occur as a result of primary renal potassium wasting in association with other solute transport abnormalities, such as Fanconi's syndrome, renal tubular acidosis, or other forms of hereditary or acquired tubulointerstitial disease. However, even with these conditions, as the GFR declines, the tendency to hypokalemia diminishes and hyperkalemia may supervene. Therefore, the use of potassium supplements and potassium-sparing diuretics should be constantly reevaluated as GFR declines.

Metabolic Acidosis
Metabolic acidosis is a common disturbance in advanced CKD. The majority of patients can still acidify the urine, but they produce less ammonia and, therefore, cannot excrete the normal quantity of protons in combination with this urinary buffer. Hyperkalemia, if present, further depresses ammonia production. The combination of hyperkalemia and hyperchloremic metabolic acidosis (known as type IV renal tubular acidosis, or hyporeninemic hypoaldosteronism) is often seen in patients with diabetic nephropathy or in those with predominant tubulointerstitial disease or obstructive uropathy; this is a non-anion-gap metabolic acidosis. Treatment of hyperkalemia may increase renal ammonia production, improve renal generation of bicarbonate, and improve the metabolic acidosis.
With worsening renal function, the total urinary net daily acid excretion is usually limited to 30–40 mmol, and the anions of retained organic acids can then lead to an anion-gap metabolic acidosis. Thus, the non-anion-gap metabolic acidosis that can be seen in earlier stages of CKD may be complicated by the addition of an anion-gap metabolic acidosis as CKD progresses. In most patients, the metabolic acidosis is mild; the pH is rarely less than 7.35 and can usually be corrected with oral sodium bicarbonate supplementation. Animal and human studies have suggested that even modest degrees of metabolic acidosis may be associated with the development of net protein catabolism, and it has been suggested that alkali supplementation be considered when the serum bicarbonate concentration falls below 20–23 mmol/L. The concomitant sodium load mandates careful attention to volume status and the potential need for diuretic agents.

Fluid, Electrolyte, and Acid-Base Disorders: Treatment
Adjustments in the dietary intake of salt and use of loop diuretics, occasionally in combination with metolazone, may be needed to maintain euvolemia. In contrast, overzealous salt restriction or diuretic use can lead to ECFV depletion and precipitate a further decline in GFR. The rare patient with salt-losing nephropathy may require a sodium-rich diet or salt supplementation. Water restriction is indicated only if there is a problem with hyponatremia. Otherwise, patients with CKD and an intact thirst mechanism may be instructed to drink fluids in a quantity that keeps them just ahead of their thirst. Intractable ECFV expansion, despite dietary salt restriction and diuretic therapy, may be an indication to start renal replacement therapy. Hyperkalemia often responds to dietary restriction of potassium, avoidance of potassium supplements (including occult sources, such as dietary salt substitutes) or potassium-retaining medications (especially ACE inhibitors or ARBs), or the use of kaliuretic diuretics. Potassium-binding resins, such as calcium resonium or sodium polystyrene, can promote potassium loss through the GI tract and may reduce the incidence of hyperkalemia in CKD patients. Intractable hyperkalemia is an indication (although uncommon) to consider institution of dialysis in a CKD patient. The renal tubular acidosis and subsequent anion-gap metabolic acidosis in progressive CKD will respond to alkali supplementation, typically with sodium bicarbonate. Recent studies suggest that this replacement should be considered when the serum bicarbonate concentration falls to 20 mmol/L to avoid the protein catabolic state seen with even mild degrees of metabolic acidosis.

Disorders of Calcium and Phosphate Metabolism
The principal complications of abnormalities of calcium and phosphate metabolism in CKD occur in the skeleton and the vascular bed, with occasional severe involvement of extraosseous soft tissues. It is likely that disorders of bone turnover and disorders of vascular and soft tissue calcification are related to each other (Fig. 274-1).

Figure 274-1
Flowchart for the development of bone, phosphate, and calcium abnormalities in chronic renal disease. PD, peritoneal dialysis.

Bone Manifestations of CKD
The major disorders of bone disease can be classified into those associated with high bone turnover with increased PTH levels (including osteitis fibrosa cystica, the classic lesion of secondary hyperparathyroidism) and low bone turnover with low or normal PTH levels (adynamic bone disease and osteomalacia).
The pathophysiology of secondary hyperparathyroidism and the consequent high-turnover bone disease is related to abnormal mineral metabolism through the following events: (1) declining GFR leads to reduced excretion of phosphate, and, thus phosphate retention; (2) the retained phosphate stimulates increased synthesis of PTH and growth of parathyroid gland mass; and (3) decreased levels of ionized calcium, resulting from diminished calcitriol production by the failing kidney as well as phosphate retention, also stimulate PTH production. Low calcitriol levels contribute to hyperparathyroidism, both by leading to hypocalcemia and also by a direct effect on PTH gene transcription.
In addition to increased production of PTH from the parathyroid cells, the mass of the parathyroid glands increases progressively with CKD. The cell mass may assume one of the following growth patterns: (1) diffuse hyperplasia (polyclonal), (2) nodular growth (monoclonal) within diffuse hyperplasia, or (3) diffuse monoclonal hyperplasia ("adenoma" or tertiary autonomous hyperparathyroidism). Patients with the monoclonal ("autonomous") hyperplasia are especially prone to develop resistant hypercalcemia and may require surgical parathyroidectomy.
The hyperparathyroidism stimulates bone turnover and leads to osteitis fibrosa cystica. Bone histology shows abnormal osteoid, bone and bone marrow fibrosis, and formation of bone cysts, sometimes with hemorrhagic elements so that they appear brown in color, hence the term brown tumor. Clinical manifestations of severe hyperparathyroidism include bone pain and fragility, the brown tumors, rare compression syndromes caused by brown tumors, and erythropoietin resistance in part related to the bone marrow fibrosis. Furthermore, PTH is a uremic toxin, and high levels are associated with muscle weakness, fibrosis of cardiac muscle, and nonspecific constitutional symptoms.
Low-turnover bone disease can be grouped into two categories—adynamic bone disease and osteomalacia. In the latter condition, there is accumulation of unmineralized bone matrix that may be caused by vitamin D deficiency, excess aluminum deposition, or even metabolic acidosis. Adynamic bone disease is increasing in prevalence, especially among diabetics and the elderly. It is characterized by reduced bone volume and mineralization and may result from excessive suppression of PTH production. The latter can result from the use of vitamin D preparations or from excessive calcium exposure in the form of calcium-containing phosphate binders or high-calcium dialysis solutions. Complications of adynamic bone disease include an increased incidence of fracture and an association with increased vascular and cardiac calcification.

Calcium, Phosphorus, and the Cardiovascular System
Recent epidemiologic evidence has shown a strong association between hyperphosphatemia and increased cardiovascular mortality in patients with stage 5 CKD and even in patients with earlier stages of CKD. Hyperphosphatemia and hypercalcemia are associated with increased vascular calcification, but it is unclear whether the excessive mortality is mediated by this mechanism. Studies using CT and electron-beam CT scanning show that CKD patients have calcification of coronary arteries and even heart valves that appear to be orders of magnitude greater than that in patients without renal disease. The magnitude of the calcification is proportional to age and hyperphosphatemia and is also associated with low PTH levels and low bone turnover. It is possible that in patients with advanced kidney disease, ingested calcium intake cannot be deposited in bones with low turnover and, therefore is deposited at extraosseous sites, such as the vascular bed and soft tissues. It is interesting in this regard that there is also an association between osteoporosis and vascular calcification in the general population. Finally, there is recent evidence indicating that hyperphosphatemia can induce a change in gene expression in vascular cells to an osteoblast-like profile.

Other Complications of Abnormal Mineral Metabolism
Calciphylaxis is a devastating condition seen almost exclusively in patients with advanced CKD. It is heralded by livedo reticularis and advances to patches of ischemic necrosis, especially on the legs, thighs, abdomen, and breasts (Fig. 274-2). Pathologically, there is evidence of vascular occlusion in association with extensive vascular calcification. It appears that this condition is increasing in incidence. Originally it was ascribed to severe abnormalities in calcium and phosphorus control in dialysis patients, usually associated with advanced hyperparathyroidism. However, more recently, calciphylaxis has been seen with increasing frequency in the absence of severe hyperparathyroidism. Other etiologies have been suggested, including the increased use of oral calcium as a phosphate binder. Warfarin is commonly used in hemodialysis patients, and one of the effects of warfarin therapy is to decrease the vitamin K–dependent regeneration of matrix GLA protein. This latter protein is important in preventing vascular calcification. Thus, warfarin treatment is considered a risk factor for calciphylaxis, and if a patient develops this syndrome, this medication should be discontinued and replaced with alternative forms of anticoagulation.

Figure 274-2
Calciphylaxis. This peritoneal dialysis patient was on chronic warfarin therapy for prophylactic anticoagulation for a mechanical heart valve. She slept with the dialysis catheter pressed between her legs. A small abrasion was followed by progressive skin necrosis along the catheter tract on her inner thighs. Despite treatment with hyperbaric oxygen, intravenous thiosulfate, and discontinuation of warfarin, she succumbed to systemic complications of the necrotic process.

Disorders of Calcium and Phosphate Metabolism: Treatment
The optimal management of secondary hyperparathyroidism and osteitis fibrosa is prevention. Once the parathyroid gland mass is very large, it is difficult to control the disease. Careful attention should be paid to the plasma phosphate concentration in CKD patients, who should be counseled on a low-phosphate diet as well as the appropriate use of phosphate-binding agents. These are agents that are taken with meals and complex the dietary phosphate to limit its GI absorption. Examples of phosphate binders are calcium acetate and calcium carbonate. A major side effect of calcium-based phosphate binders is total-body calcium accumulation and hypercalcemia, especially in patients with low-turnover bone disease. Sevelamer, a non-calcium-containing polymer, also functions as a phosphate binder; it does not predispose CKD patients to hypercalcemia, and may attenuate calcium deposition in the vascular bed.
Calcitriol exerts a direct suppressive effect on PTH secretion and also indirectly suppresses PTH secretion by raising the concentration of ionized calcium. However, calcitriol therapy may result in hypercalcemia and/or hyperphosphatemia through increased GI absorption of these minerals. Certain analogues of calcitriol are available (e.g., paricalcitol) that suppress PTH secretion with less attendant hypercalcemia.
Recognition of the role of the extracellular calcium-sensing receptor has led to the development of calcimimetic agents that enhance the sensitivity of the parathyroid cell to the suppressive effect of calcium. This class of drug produces a dose-dependent reduction in PTH and plasma calcium concentration in some patients.
Current KDOQI recommendations call for a target PTH level between 150 and 300 pg/mL, recognizing that very low PTH levels are associated with adynamic bone disease and possible consequences of fracture and ectopic calcification.

Cardiovascular Abnormalities
Cardiovascular disease is the leading cause of morbidity and mortality in patients at every stage of CKD. The incremental risk of cardiovascular disease in those with CKD compared to the age- and sex-matched general population ranges from 10- to 200-fold, depending on the stage of CKD. Between 30 and 45% of patients reaching stage 5 CKD already have advanced cardiovascular complications. As a result, most patients with CKD succumb to cardiovascular disease  before ever reaching stage 5 CKD. Thus, the focus of patient care in earlier CKD stages should be directed to prevention of cardiovascular complications.

Ischemic Vascular Disease
The presence of any stage of CKD is a major risk factor for ischemic cardiovascular disease, including occlusive coronary, cerebrovascular, and peripheral vascular disease. The increased prevalence of vascular disease in CKD patients derives from both traditional ("classic") and nontraditional (CKD-related) risk factors. Traditional risk factors include hypertension, hypervolemia, dyslipidemia, sympathetic overactivity, and hyperhomocysteinemia. The CKD-related risk factors comprise anemia, hyperphosphatemia, hyperparathyroidism, sleep apnea, and generalized inflammation. The inflammatory state associated with a reduction in kidney function is reflected in increased circulating acute-phase reactants, such as inflammatory cytokines and C-reactive protein, with a corresponding fall in the "negative acute-phase reactants," such as serum albumin and fetuin. The inflammatory state appears to accelerate vascular occlusive disease, and low levels of fetuin may permit more rapid vascular calcification, especially in the face of hyperphosphatemia. Other abnormalities seen in CKD may augment myocardial ischemia, including left ventricular hypertrophy and microvascular disease. Coronary reserve, defined as the increase in coronary blood flow in response to greater demand, is also attenuated. There is diminished availability of nitric oxide because of increased concentration of asymmetric dimethyl-1-arginine and increased scavenging by reactive oxygen species. In addition, hemodialysis, with its attendant episodes of hypotension and hypovolemia, may further aggravate coronary ischemia.

Heart Failure
Abnormal cardiac function secondary to myocardial ischemia, left ventricular hypertrophy, and frank cardiomyopathy, in combination with the salt and water retention that can be seen with CKD, often results in heart failure or even episodes of pulmonary edema. Heart failure can be a consequence of diastolic or systolic dysfunction, or both. A form of "low-pressure" pulmonary edema can also occur in advanced CKD, manifesting as shortness of breath and a "bat wing" distribution of alveolar edema fluid on the chest x-ray. This finding can occur even in the absence of ECFV overload and is associated with normal or mildly elevated pulmonary capillary wedge pressure. This process has been ascribed to increased permeability of alveolar capillary membranes as a manifestation of the uremic state, and it responds to dialysis. Other CKD-related risk factors, including anemia and sleep apnea, may contribute to the risk of heart failure.

Hypertension and Left Ventricular Hypertrophy
Hypertension is one of the most common complications of CKD. It usually develops early during the course of CKD and is associated with adverse outcomes, including the development of ventricular hypertrophy and a more rapid loss of renal function. Many studies have shown a relationship between the level of blood pressure and the rate of progression of diabetic and non-diabetic kidney disease. Left ventricular hypertrophy and dilated cardiomyopathy are among the strongest risk factors for cardiovascular morbidity and mortality in patients with CKD and are thought to be related primarily, but not exclusively, to prolonged hypertension and ECFV overload. In addition, anemia and the placement of an arteriovenous fistula for hemodialysis can generate a high cardiac output state and consequent heart failure.
The absence of hypertension may signify the presence of a salt-wasting form of renal disease, the effect of antihypertensive therapy, or volume depletion or may signify poor left ventricular function. Indeed, in epidemiologic studies of dialysis patients, low blood pressure actually carries a worse prognosis than does high blood pressure. This mechanism, in part, accounts for the "reverse causation" seen in dialysis patients, wherein the presence of traditional risk factors, such as hypertension, hyperlipidemia, and obesity, appear to portend a better prognosis. Importantly, these observations derive from cross-sectional studies of late-stage CKD patients and should not be interpreted to discourage appropriate management of these risk factors in CKD patients, especially at early stages. In contrast to the general population, it is possible that in late-stage CKD, low blood pressure, reduced body mass index, and hypolipidemia indicate the presence of a malnutrition-inflammation state, with poor prognosis.
The use of exogenous erythropoietic products can increase blood pressure and the requirement for antihypertensive drugs. Chronic ECFV overload is also a contributor to hypertension, and improvement in blood pressure can often be seen with the use of oral sodium restriction, diuretics, and fluid removal with dialysis. Nevertheless, because of activation of the renin-angiotensin-aldosterone axis and other disturbances in the balance of vasoconstrictors and vasodilators, some patients remain hypertensive despite careful attention to ECFV status.

Cardiovascular Abnormalities: Treatment
Management of Hypertension
There are two overall goals of therapy for hypertension in these patients: to slow the progression of the kidney disease itself, and to prevent the extrarenal complications of high blood pressure, such as cardiovascular disease and stroke. In all patients with CKD, blood pressure should be controlled to levels recommended by national guideline panels. In CKD patients with diabetes or proteinuria more than 1 g per 24 h, blood pressure should be reduced to 125/75, if achievable without prohibitive adverse effects. Salt restriction and diuretics should be the first line of therapy. When volume management alone is not sufficient, the choice of antihypertensive agent is similar to that in the general population. The ACE inhibitors and ARBs slow the rate of decline of kidney function, even in dialysis patients, but their use may be complicated by the development of hyperkalemia. Often the concomitant use of a kaliuretic diuretic, such as metolazone, can improve potassium excretion in addition to improving blood pressure control. Potassium-sparing diuretics should be used with caution or avoided altogether in most patients.

Management of Cardiovascular Disease
There are many strategies available to treat the traditional and nontraditional risk factors in CKD patients. While these have been proven effective in the general population, there is little evidence for their benefit in patients with advanced CKD, especially those on dialysis. Certainly hypertension, elevated serum levels of homocysteine, and dyslipidemia promote atherosclerotic disease and are treatable complications of CKD. Renal disease complicated by nephrotic syndrome is associated with a very atherogenic lipid profile and hypercoagulability, which increases the risk of occlusive vascular disease. Since diabetes mellitus and hypertension are the two most frequent causes of advanced CKD, it is not surprising that cardiovascular disease is the most frequent cause of death in dialysis patients. The role of "inflammation" may be quantitatively more important in patients with kidney disease, and the treatment of more traditional risk factors may result in only modest success. However, modulation of traditional risk factors may be the only weapon in the therapeutic armamentarium for these patients until the nature of inflammation in CKD and its treatment are better understood.
Lifestyle changes, including regular exercise, should be advocated but are not often implemented. Hyperhomocysteinemia may respond to vitamin therapy, including oral folate supplementation, but this therapy is of unproven benefit. Hyperlipidemia in patients with CKD should be managed according to national guidelines. If dietary measures are not sufficient, preferred lipid-lowering medications, such as statins, should be used. Again, the use of these agents has not been of proven benefit for patients with advanced CKD.

Pericardial Disease
Pericardial pain with respiratory accentuation, accompanied by a friction rub, is diagnostic of uremic pericarditis. Classic electrocardiographic abnormalities include PR-interval depression and diffuse ST-segment elevation. Pericarditis can be accompanied by pericardial effusion that is seen on echocardiography and can rarely lead to tamponade. However, the pericardial effusion can be asymptomatic, and pericarditis can be seen without significant effusion.
Pericarditis is observed in advanced uremia, and with the advent of timely initiation of dialysis, is not as common as it once was. It is now more often observed in underdialyzed, nonadherent patients than in those starting dialysis.

Pericardial Disease: Treatment
Uremic pericarditis is an absolute indication for the urgent initiation of dialysis or for intensification of the dialysis prescription in those already receiving dialysis. Because of the propensity to hemorrhage in pericardial fluid, hemodialysis should be performed without heparin. A pericardial drainage procedure should be considered in patients with recurrent pericardial effusion. Nonuremic causes of pericarditis and effusion include viral, malignant, tuberculous, and autoimmune etiologies. It may also be seen after myocardial infarction and as a complication of treatment with minoxidil.

Hematologic Abnormalities

A normocytic, normochromic anemia is observed as early as stage 3 CKD and is almost universal by stage 4. The primary cause in patients with CKD is insufficient production of erythropoietin (EPO) by the diseased kidneys. Additional factors include iron deficiency, acute and chronic inflammation with impaired iron utilization ("anemia of chronic disease"), severe hyperparathyroidism with consequent bone marrow fibrosis, and shortened red cell survival in the uremic environment. Less common causes include folate and vitamin B12 deficiency and aluminum toxicity. In addition, comorbid conditions such as hemoglobinopathy can worsen the anemia (Table 274-4).

Table 274-4 Causes of Anemia in CKD
-          Relative deficiency of erythropoietin
-          Diminished red blood cell survival
-          Bleeding diathesis
-          Iron deficiency
-          Hyperparathyroidism/bone marrow fibrosis
-          "Chronic inflammation"
-          Folate or vitamin B12 deficiency
-          Hemoglobinopathy
-          Comorbid conditions: hypo/hyperthyroidism, pregnancy, HIV-associated disease, autoimmune disease, immunosuppressive drugs
 The anemia of CKD is associated with a number of adverse pathophysiologic consequences, including decreased tissue oxygen delivery and utilization, increased cardiac output, ventricular dilatation, and ventricular hypertrophy. Clinical manifestations include angina, heart failure, decreased cognition and mental acuity, and impaired host defense against infection. In addition, anemia may play a role in growth retardation in children with CKD. While many studies in CKD patients have found that anemia and resistance to exogenous EPO are associated with a poor prognosis, it is unclear as to how much the low hematocrit itself versus inflammation leads to a poor outcome.

Anemia: Treatment
The availability of recombinant human EPO and modified EPO products, such as darbopoetin-alpha, has been one of the most significant advances in the care of renal patients since the introduction of dialysis and renal transplantation. The routine use of these products has obviated the need for regular blood transfusions in severely anemic CKD patients, thus dramatically reducing the incidence of transfusion-associated infections and iron overload. Frequent blood transfusions in dialysis patients also led to the development of alloantibodies that could sensitize the patient to donor kidney antigens and make renal transplantation more problematic.
Adequate bone marrow iron stores should be available before treatment with EPO is initiated. Iron supplementation is usually essential to ensure an adequate response to EPO in patients with CKD because the demand for iron by the marrow frequently exceeds the amount of iron that is immediately available for erythropoiesis (measured by percent transferrin saturation), as well as the amount in iron stores (measured by serum ferritin). For the CKD patient not yet on dialysis or the patient treated with peritoneal dialysis, oral iron supplementation should be attempted. If there is GI intolerance, the patient may have to undergo IV iron infusion, often during the dialysis session. In addition to iron, an adequate supply of other major substrates and cofactors for red cell production must be assured, including vitamin B12 and folate. Anemia resistant to recommended doses of EPO in the face of adequate iron stores may be due to some combination of the following: acute or chronic inflammation, inadequate dialysis, severe hyperparathyroidism, chronic blood loss or hemolysis, chronic infection, or malignancy. Patients with a hemoglobinopathy, such as sickle cell disease or thalassemia, will usually not respond normally to exogenous EPO; however, an increase in hemoglobin concentration is still seen in many of these patients. Blood transfusions may contribute to suppression of erythropoiesis in CKD; because they increase the risk of hepatitis, iron overload, and transplant sensitization, they should be avoided unless the anemia fails to respond to EPO and the patient is symptomatic.
Normalization of the hemoglobin concentration has not been demonstrated to be of incremental benefit to dialysis patients. Current practice is to target a hemoglobin concentration of 110 to 120 g/L.

Abnormal Hemostasis
Patients with later stages of CKD may have a prolonged bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption. Clinical manifestations include an increased tendency to bleeding and bruising, prolonged bleeding from surgical incisions, menorrhagia, and spontaneous GI bleeding. Interestingly, CKD patients also have a greater susceptibility to thromboembolism, especially if they have renal disease that includes nephrotic-range proteinuria. The latter condition results in hypoalbuminemia and renal loss of anticoagulant factors, which can lead to a thrombophilic state.

Abnormal Hemostasis: Treatment
Abnormal bleeding time and coagulopathy in patients with renal failure may be reversed temporarily with desmopressin (DDAVP), cryoprecipitate, IV conjugated estrogens, blood transfusions, and EPO therapy. Optimal dialysis will often correct a prolonged bleeding time.
Given the coexistence of bleeding disorders and a propensity to thrombosis that is unique in the CKD patient, decisions about anticoagulation that have a favorable risk-benefit profile in the general population may not be applicable to the patient with advanced CKD. One example is warfarin anticoagulation for atrial fibrillation: the decision to anticoagulate should be made on an individual basis in the CKD patient.
Certain anticoagulants, such as fractionated low-molecular-weight heparin, may need to be avoided or dose-adjusted in these patients, with monitoring of factor Xa activity where available. It is often more prudent to use conventional high-molecular-weight heparin, titrated to the measured partial thromboplastin time, in hospitalized patients requiring an alternative to warfarin anticoagulation.

Neuromuscular Abnormalities
Central nervous system (CNS), peripheral, and autonomic neuropathy as well as abnormalities in muscle structure and function are all well-recognized complications of CKD. Retained nitrogenous metabolites and middle molecules, including PTH, contribute to the pathophysiology of neuromuscular abnormalities. Subtle clinical manifestations of uremic neuromuscular disease usually become evident at stage 3 CKD. Early manifestations of CNS complications include mild disturbances in memory and concentration and sleep disturbance. Neuromuscular irritability, including hiccups, cramps, and fasciculations or twitching of muscles, becomes evident at later stages. In advanced untreated kidney failure, asterixis, myoclonus, seizures, and coma can be seen.
Peripheral neuropathy usually becomes clinically evident after the patient reaches stage 4 CKD, although electrophysiologic and histologic evidence occurs earlier. Initially, sensory nerves are involved more than motor, lower extremities more than upper, and distal parts of the extremities more than proximal. The "restless leg syndrome" is characterized by ill-defined sensations of sometimes debilitating discomfort in the legs and feet relieved by frequent leg movement. If dialysis is not instituted soon after onset of sensory abnormalities, motor involvement follows, including muscle weakness. Evidence of peripheral neuropathy without another cause (e.g., diabetes mellitus) is a firm indication for starting renal replacement therapy. Many of the complications described above will resolve with dialysis, although subtle nonspecific abnormalities may persist. Successful renal transplantation may reverse residual neurologic changes.

Gastrointestinal and Nutritional Abnormalities
Uremic fetor, a urine-like odor on the breath, derives from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste (dysgeusia). Gastritis, peptic disease, and mucosal ulcerations at any level of the GI tract occur in uremic patients and can lead to abdominal pain, nausea, vomiting, and GI bleeding. These patients are also prone to constipation, which can be worsened by the administration of calcium and iron supplements. The retention of uremic toxins also leads to anorexia, nausea, and vomiting.
Protein restriction may be useful to decrease nausea and vomiting; however, it may put the patient at risk for malnutrition and should be carried out, if possible, in consultation with a registered dietitian. Protein-energy malnutrition, a consequence of low protein and caloric intake, is common in advanced CKD and is often an indication for initiation of renal replacement therapy. In addition to diminished intake, these patients are resistant to the anabolic actions of insulin and other hormones and growth factors. Metabolic acidosis and the activation of inflammatory cytokines can promote protein catabolism. Assessment for protein-energy malnutrition should begin at stage 3 CKD. A number of indices are useful in this assessment and include dietary history, including diary and subjective global assessment; edema-free body weight; serum albumin concentration; and measurement of urinary protein nitrogen appearance. Dual-energy x-ray absorptiometry is now widely used to estimate lean body mass versus ECFV. Adjunctive tools include clinical signs, such as skinfold thickness, mid-arm muscle circumference, and additional laboratory tests such as serum pre-albumin and cholesterol levels. Nutritional guidelines for patients with CKD are summarized in the section below on "Principles of Treatment of CKD."

Endocrine-Metabolic Disturbances
Glucose metabolism is impaired in CKD, as evidenced by a slowing of the rate at which blood glucose levels decline after a glucose load. However, fasting blood glucose is usually normal or only slightly elevated, and the mild glucose intolerance does not require specific therapy. Because the kidney contributes to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic patients, both in the fasting and postprandial states. Because of this diminished renal degradation of insulin, patients on insulin therapy may need progressive reduction in dose as their renal function worsens. Many hypoglycemic agents require dose reduction in renal failure, and some, such as metformin, are contraindicated when the GFR is less than half of normal.
In women with CKD, estrogen levels are low, and menstrual abnormalities and inability to carry pregnancies to term are common. When the GFR has declined to ~40 mL/min, pregnancy is associated with a high rate of spontaneous abortion, with only ~20% of pregnancies leading to live births, and pregnancy may hasten the progression of the kidney disease itself. Men with CKD have reduced plasma testosterone levels, and sexual dysfunction and oligospermia may supervene. Sexual maturation may be delayed or impaired in adolescent children with CKD, even among those treated with dialysis. Many of these abnormalities improve or reverse with intensive dialysis or successful renal transplantation.

Dermatologic Abnormalities
Abnormalities of the skin are prevalent in progressive CKD. Anemic patients may be pale, and those with defective hemostasis may show multiple ecchymoses. Pruritus is quite common. In advanced CKD, even on dialysis, patients may become more pigmented, and this is felt to reflect the deposition of retained pigmented metabolites, or urochromes. Although many of the cutaneous abnormalities improve with dialysis, pruritus is often tenacious. The first lines of management are to rule out unrelated skin disorders, such as scabies, and to control phosphate concentration. EPO therapy was initially reported to improve uremic pruritus, although that is not always the case. Local moisturizers, mild topical glucocorticoids, oral antihistamines, and ultraviolet radiation have been reported to be helpful.
A skin condition called nephrogenic fibrosing dermopathy has recently been reported in which progressive subcutaneous induration, especially on the arms and legs, is described. The condition is similar to scleromyxedema and is seen in patients with CKD, most commonly on dialysis. Recent reports suggest that exposure to the magnetic resonance contrast agent, gadolinium, may precipitate this syndrome.

  • Initial Approach
    • History and Physical Examination

Symptoms and overt signs of kidney disease are often absent until renal failure supervenes. Thus, the diagnosis of kidney disease often surprises patients and may be a cause of skepticism and denial. Particular aspects of the history that are germane to renal disease include a history of hypertension (which can cause CKD or be a reflection of CKD), diabetes mellitus, abnormal urinalyses, and problems with pregnancy such as preeclampsia or early pregnancy loss. A careful drug history should be elicited: patients may not volunteer use of analgesics, for example. Other drugs to consider include nonsteroidal anti-inflammatory agents, gold, penicillamine, antimicrobials, antiretroviral agents, proton pump inhibitors, and lithium. In evaluating the uremic syndrome, questions about appetite, weight loss, nausea, hiccups, peripheral edema, muscle cramps, pruritus, and restless legs are especially helpful.
The physical examination should focus on blood pressure and target organ damage from hypertension. Thus, funduscopy and precordial examination (left ventricular heave, a fourth heart sound) should be carried out. Funduscopy is important in the diabetic patient, seeking evidence of diabetic retinopathy, which is associated with nephropathy. Other physical examination manifestations of CKD include edema and sensory polyneuropathy. The finding of asterixis or a pericardial friction rub not attributable to other causes usually signifies the presence of the uremic syndrome.

Laboratory Investigation
Laboratory studies should focus on a search for clues to an underlying causative or aggravating disease process and on the degree of renal damage and its consequences. If appropriate, tests for systemic lupus erythematosus and vasculitis should be performed. Serum and urine protein electrophoresis should be obtained in all patients  more than 35 years with unexplained CKD, especially if there is associated anemia and elevated, or even inappropriately normal, serum calcium concentration in the face of renal insufficiency. In the presence of glomerulonephritis, underlying infectious etiologies such as hepatitis B and C and HIV should be assessed. Serial measurements of renal function should be obtained to determine the pace of renal deterioration and ensure that the disease is truly chronic rather than subacute and hence potentially reversible. Serum concentrations of calcium, phosphorus, and PTH should be measured to evaluate metabolic bone disease. Hemoglobin concentration, iron, B12, and folate should also be evaluated. A 24-h urine collection may be helpful, as protein excretion more than 300 mg may be an indication for therapy with ACE inhibitors or ARBs.

Imaging Studies
            The most useful imaging study is a renal ultrasound, which can verify the presence of two kidneys, determine if they are symmetric, provide an estimate of kidney size, and rule out renal masses and evidence of obstruction. Since it takes time for kidneys to shrink as a result of chronic disease, the finding of bilaterally small kidneys supports the diagnosis of CKD of long-standing duration, with an irreversible component of scarring. If the kidney size is normal, it is possible that the renal disease is acute or subacute. The exceptions are diabetic nephropathy (where kidney size is increased at the outset of diabetic nephropathy before CKD with loss of GFR supervenes), amyloidosis, and HIV nephropathy, where kidney size may be normal in the face of CKD. Polycystic kidney disease that has reached some degree of renal failure will almost always present with enlarged kidneys with multiple cysts (Chap. 278). A discrepancy more than 1 cm in kidney length suggests either a unilateral developmental abnormality or disease process or renovascular disease with arterial insufficiency affecting one kidney more than the other. The diagnosis of renovascular disease can be undertaken with different techniques, including Doppler sonography, nuclear medicine studies, or CT or MRI studies. If there is a suspicion of reflux nephropathy (recurrent childhood urinary tract infection, asymmetric renal size with scars on the renal poles), a voiding cystogram may be indicated. However, in most cases by the time the patient has CKD, the reflux has resolved, and even if still present, repair does not improve renal function. Radiographic contrast imaging studies are not particularly helpful in the investigation of CKD. Intravenous or intraarterial dye should be avoided where possible in the CKD patient, especially with diabetic nephropathy, because of the risk of radiographic contrast dye–induced renal failure. When unavoidable, appropriate precautionary measures include avoidance of hypovolemia at the time of contrast exposure, minimization of the dye load, and choice of radiographic contrast preparations with the least nephrotoxic potential.

Renal Biopsy
In the patient with bilaterally small kidneys, renal biopsy is not advised because (1) it is technically difficult and has a greater likelihood of causing bleeding and other adverse consequences, (2) there is usually so much scarring that the underlying disease may not be apparent, and (3) the window of opportunity to render disease-specific therapy has passed. Other contraindications to renal biopsy include uncontrolled hypertension, active urinary tract infection, bleeding diathesis, and morbid obesity. Ultrasound-guided percutaneous biopsy is the favored approach, but a surgical or laparoscopic approach can be considered, especially in the patient with a single kidney where direct visualization and control of bleeding are crucial. In the CKD patient in whom a kidney biopsy is indicated (e.g., suspicion of a concomitant or superimposed active process, such as interstitial nephritis or accelerated loss of GFR), the bleeding time should be measured, and, if increased, desmopressin should be administered immediately prior to the procedure. A brief run of hemodialysis (without heparin) may also be considered prior to renal biopsy to normalize the bleeding time.

Establishing the Diagnosis and Etiology of CKD
The most important initial diagnostic step in the evaluation of a patient presenting with elevated serum creatinine is to distinguish newly diagnosed CKD from acute or subacute renal failure because the latter two conditions may respond to therapy specific to the disease. Previous measurements of plasma creatinine concentration are particularly helpful in this regard. Normal values from recent months or even years suggest that the current extent of renal dysfunction could be more acute, and hence reversible, than might otherwise be appreciated. In contrast, elevated plasma creatinine concentration in the past suggests that the renal disease represents the progression of a chronic process. Even if there is evidence of chronicity, there is the possibility of a superimposed acute process, such as ECFV depletion, supervening on the chronic condition. If the history suggests multiple systemic manifestations of recent onset (e.g., fever, polyarthritis, and rash) it should be assumed that renal insufficiency is part of the acute process.
Some of the laboratory tests and imaging studies outlined above can be helpful. Evidence of metabolic bone disease with hyperphosphatemia, hypocalcemia, and elevated PTH and bone alkaline phosphatase levels suggests chronicity. Normochromic, normocytic anemia suggests that the process has been ongoing for some time. The finding of bilaterally reduced kidney size (less than 8.5 cm in all but the smallest adults) favors CKD.
While renal biopsy can usually be performed in early CKD (stages 1–3), it is not always indicated. For example, in a patient with a history of type 1 diabetes mellitus for 15–20 years with retinopathy, nephrotic-range proteinuria, and absence of hematuria, the diagnosis of diabetic nephropathy is very likely and biopsy is not necessary. However, if there were some other finding not typical of diabetic nephropathy, such as hematuria or white blood cell casts, some other disease may be present and a biopsy may be indicated. Hypertensive nephrosclerosis and progressive ischemic nephropathy are usually diagnosed clinically by the presence of long-standing hypertension, evidence of ischemic disease elsewhere (e.g., cardiac or peripheral vascular disease), and the finding of only mild (less than 3g/d) proteinuria in the absence of urinary blood or red cell casts. It is important to consider progressive ischemic nephropathy because a small subset of these patients may respond to revascularization procedures, although this remains controversial.
In the absence of a clinical diagnosis, renal biopsy may be the only recourse to establish an etiology in early-stage CKD. However, as noted above, once the CKD is advanced and the kidneys are small and scarred, there is little utility and significant risk in attempting to arrive at a specific diagnosis.

Chronic Kidney Disease: Treatment
Treatments aimed at specific causes of CKD are discussed elsewhere. The optimal timing of therapy is usually well before there has been a measurable decline in GFR and certainly before CKD is established (Table 274-5). It is helpful to sequentially measure and plot the rate of decline of GFR in all patients. Any acceleration in the rate of decline should prompt a search for superimposed acute or subacute processes that may be reversible. These include ECFV depletion, uncontrolled hypertension, urinary tract infection, new obstructive uropathy, exposure to nephrotoxic agents [such as nonsteroidal anti-inflammatory drugs (NSAIDs) or radiographic dye], and reactivation or flare of the original disease, such as lupus or vasculitis

Table 274-5 Clinical Action Plan
GFR, mL/min per 1.73 m2
Kidney damage with normal or GFR
Diagnosis and treatment, treatment of comorbid conditions, slowing progression, CVD risk reduction
Kidney damage with mild GFR
Estimating progression
Moderate GFR
Evaluating and treating complications
Severe GFR
Preparation for kidney replacement therapy
Kidney failure
Less than 15 (or dialysis)
Kidney replacement (if uremia present)

aIncludes actions from preceding stages.
Note: CVD, cardiovascular disease.
Source: National Kidney Foundation: Am J Kidney Dis 39(2 Suppl 1):S1, 2002.

Slowing the Progression of CKD
There is variation in the rate of decline of GFR among patients with CKD. However, the following interventions should be considered in an effort to stabilize or slow the decline of renal function.
-          Protein Restriction
o   While protein restriction has been advocated to reduce symptoms associated with uremia, it may also slow the rate of renal decline at earlier stages of renal disease. This concept is based on clinical and experimental evidence that protein-mediated hyperfiltration contributes to ongoing decline in renal function in many different forms of renal disease. A number of studies have shown that protein restriction may be effective in slowing the progression of CKD, especially proteinuric and diabetic renal diseases. However, the Modification of Diet in Renal Disease study was unable to demonstrate a robust benefit in delaying progression to advanced stages of CKD with dietary restriction of protein intake. Nonetheless, restriction of dietary protein intake has been recommended for CKD patients. KDOQI clinical practice guidelines include a daily protein intake of between 0.60 and 0.75 g/kg per day, depending upon patient adherence, comorbid disease, presence of proteinuria, and nutritional status. It is further advised that at least 50% of the protein intake be of high biologic value. As patients approach stage 5 CKD, spontaneous protein intake tends to decrease, and patients may enter a state of protein-energy malnutrition. In these circumstances, a protein intake of up to 0.90 g/kg per day might be recommended, again, with an emphasis on proteins of high biologic value.
o   Sufficient energy intake is important to prevent protein-calorie malnutrition, and 35 kcal/kg is recommended. Monitoring of parameters of nutritional status must accompany the dietary intervention, using the parameters outlined above in the section on GI and nutritional abnormalities.
-          Reducing Intraglomerular Hypertension and Proteinuria
o   Increased intraglomerular filtration pressures and glomerular hypertrophy develop as a response to loss of nephron number from different kidney diseases. This response is maladaptive, as it promotes the ongoing decline of kidney function even if the inciting process has been treated or spontaneously resolved. Control of systemic and glomerular hypertension is at least as important as dietary protein restriction in slowing the progression of CKD. Therefore, in addition to reduction of cardiovascular disease risk, antihypertensive therapy in patients with CKD also aims to slow the progression of nephron injury by reducing intraglomerular hypertension. Elevated blood pressure increases proteinuria through its transmission to the glomerulus. Conversely, the renoprotective effect of antihypertensive medications is gauged through the consequent reduction of proteinuria. Thus, the more effective a given treatment is in lowering protein excretion, the greater the subsequent impact on protection from decline in GFR. This observation is the basis for the treatment guideline establishing 125/75 mmHg as the target blood pressure in proteinuric CKD patients.
o   ACE inhibitors and ARBs inhibit the angiotensin-induced vasoconstriction of the efferent arterioles of the glomerular microcirculation. This inhibition leads to a reduction in both intraglomerular filtration pressure and proteinuria. Several controlled studies have shown that these drugs are effective in slowing the progression of renal failure in patients with both diabetic and nondiabetic renal failure. This slowing in progression of CKD is strongly associated with their proteinuria-lowering effect. In the absence of an anti-proteinuric response with either agent alone, combined treatment with both ACE inhibitors and ARBs can be tried. Adverse effects from these agents include cough and angioedema with ACE inhibitors, anaphylaxis, and hyperkalemia with either class. A progressive increase in plasma creatinine concentration may suggest the presence of renovascular disease within the large or small arteries. Development of these side effects may mandate the use of second-line antihypertensive agents instead of the ACE inhibitors or ARBs. Among the calcium channel blockers, diltiazem and verapamil may exhibit superior anti-proteinuric and renoprotective effects compared to the dihydropyridines. At least two different categories of response can be considered: one in which progression is strongly associated with systemic and intraglomerular hypertension and proteinuria (e.g., diabetic nephropathy, glomerular diseases) and in which ACE inhibitors and ARBs are likely to be the first choice; and another in which proteinuria is mild or absent initially (e.g., adult polycystic kidney disease and other tubulointerstitial diseases) and hence the contribution of intraglomerular hypertension less prominent, for which reason other antihypertensive agents can be useful for control of systemic hypertension.
-          Slowing Progression of Diabetic Renal Disease
o   Diabetic nephropathy is now the leading cause of CKD requiring renal replacement therapy in many parts of the world, and its prevalence is increasing disproportionately in the developing world. Furthermore, the prognosis of diabetic patients on dialysis is poor, with survival comparable to many forms of cancer. Accordingly, it is mandatory to develop strategies whose aim is to prevent or slow the progression of diabetic nephropathy in these patients.
-          Control of Blood Glucose
o   Excellent glycemic control reduces the risk of kidney disease and its progression in both type 1 and type 2 diabetes mellitus. It is recommended that plasma values for preprandial glucose be kept in the 5.0–7.2 mmol/L (90–130 mg/dL) range and hemoglobin A1C should be less than 7%. As the GFR decreases with progressive nephropathy, the use and dose of oral hypoglycemics needs to be reevaluated. For example, chlorpropamide may be associated with prolonged hypoglycemia in patients with decreased renal function; metformin has been reported to cause lactic acidosis in the patient with renal impairment and should be discontinued when the GFR is reduced; and the thiazolidinediones (e.g., rosiglitazone, pioglitazone, and others), may increase renal salt and water absorption and aggravate volume-overloaded states. Finally, as renal function declines, renal degradation of administered insulin will also decline, so that less insulin may be required for glycemic control.
-          Control of Blood Pressure and Proteinuria
o   Hypertension is found in the majority of type 2 diabetic patients at diagnosis. This finding correlates with the presence of albuminuria and is a strong predictor of cardiovascular events and nephropathy. Microalbuminuria, the finding of albumin in the urine not detectable by the urine dipstick, precedes the decline in GFR and heralds renal and cardiovascular complications. Testing for microalbumin is recommended in all diabetic patients, at least annually. If the patient already has established proteinuria, then testing for microalbumin is not necessary. Antihypertensive treatment reduces albuminuria and diminishes its progression even in normotensive diabetic patients. In addition to treatment of hypertension in general, the use of ACE inhibitors and ARBs in particular is associated with additional renoprotection. These salutary effects are mediated by reducing intraglomerular pressure and inhibition of angiotensin-driven sclerosing pathways, in part through inhibition of TGF--mediated pathways.

Managing Other Complications of Chronic Kidney Disease

Medication Dose Adjustment
Although the loading dose of most drugs is not affected by CKD because no renal elimination is used in the calculation, the maintenance doses of many drugs will need to be adjusted. For those agents in which more than  70% excretion is by a nonrenal route, such as hepatic elimination, dose adjustment may not be needed. Some drugs that should be avoided include metformin, meperidine, and oral hypoglycemics that are eliminated by the kidney. NSAIDs should be avoided because of the risk of further worsening of kidney function. Many antibiotics, antihypertensives, and antiarrhythmics may require a reduction in dosage or change in the dose interval. For a comprehensive, detailed listing of the dose adjustments for most of the commonly used medications, see "Drug Prescribing in Renal Failure" published by the American College of Physicians (see

Preparation for Renal Replacement Therapy
Temporary relief of symptoms and signs of impending uremia, such as anorexia, nausea, vomiting, lassitude, and pruritus, may sometimes be achieved with protein restriction. However, this carries a significant risk of protein-energy malnutrition, and thus plans for more long-term management should be in place.
The institution of maintenance dialysis and kidney transplantation has extended the lives of hundreds of thousands of patients with CKD worldwide. Clear indications for initiation of renal replacement therapy for patients with CKD include pericarditis, encephalopathy, intractable muscle cramping, anorexia, and nausea not attributable to reversible causes such as peptic ulcer disease, evidence of malnutrition, and fluid and electrolyte abnormalities, principally hyperkalemia, that are refractory to other measures.
Recommendations for the optimal time for initiation of renal replacement therapy have been established by the National Kidney Foundation in their KDOQI Guidelines and are based on recent evidence demonstrating that delaying initiation of renal replacement therapy until patients are malnourished or have severe uremic complications leads to a worse prognosis on dialysis or with transplantation. Because of the interindividual variability in the severity of uremic symptoms and renal function, it is ill-advised to assign an arbitrary urea nitrogen or creatinine level to the need to start dialysis. Moreover, patients may become accustomed to chronic uremia and deny symptoms, only to find that they feel better with dialysis and realize in retrospect how poorly they were feeling before its initiation.
Previous studies suggested that starting dialysis before the onset of severe symptoms and signs of uremia was associated with prolongation of survival. This lead to the concept of "healthy" start and is congruent with the philosophy that it is better to keep patients feeling well all along, rather than allowing them to become ill with uremia before trying to return them to better health with dialysis. Although recent studies have not confirmed a clear association of early-start dialysis with improved patient survival, there is still merit in this approach. On a practical level, advanced preparation may help to avoid problems with the dialysis process itself (e.g., a poorly functioning fistula for hemodialysis or malfunctioning peritoneal dialysis catheter) and thus preempt the morbidity associated with resorting to the insertion of temporary hemodialysis access with its attendant risks of sepsis, bleeding, and thrombosis.

Patient Education
Social, psychological, and physical preparation for the transition to renal replacement therapy and the choice of the optimal initial modality are best accomplished with a gradual approach involving a multidisciplinary team. Along with conservative measures discussed in the sections above, it is important to prepare patients with an intensive educational program, explaining the likelihood and timing of initiation of renal replacement therapy and the various forms of therapy available. The more knowledgeable that patients are about hemodialysis (both in-center and home-based), peritoneal dialysis, and kidney transplantation, the easier and more appropriate will be their decisions. Patients who are provided with educational programs are more likely to choose home-based dialysis therapy. This approach is of societal benefit because home-based therapy is less expensive and is associated with improved quality of life. The educational programs should be commenced no later than stage 4 CKD so that the patient has sufficient cognitive function to learn the important concepts.
Exploration of social service support is also important. In those who may perform home dialysis or undergo preemptive renal transplantation, early education of family members for selection and preparation of a home dialysis helper or a related (or unrelated) kidney donor should occur long before the onset of symptomatic renal failure.
Kidney transplantation offers the best potential for complete rehabilitation, because dialysis replaces only a small fraction of the kidneys' filtration function and none of the other renal functions, including endocrine and anti-inflammatory effects. Generally, kidney transplantation follows a period of dialysis treatment, although preemptive kidney transplantation (usually from a living donor) can be carried out if it is certain that the renal failure is irreversible.

Implications for Global Health
In distinction to the natural decline and successful eradication of many devastating infectious diseases, there is rapid growth in the prevalence of hypertension and vascular disease in developing countries. Diabetes mellitus is becoming increasingly prevalent in these countries, perhaps due in part to change in dietary habits, diminished physical activity, and weight gain. Therefore, it follows that there will be a proportionate increase in vascular and renal disease. Healthcare agencies must plan for improved screening for early detection, prevention, and treatment plans in these nations and must start considering options for improved availability of renal replacement therapies.

Further Readings
  1. Go A et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351:1296, 2004 [PMID: 15385656]
  2. Ketteler M et al: Calcification and cardiovascular health: New insights into an old phenomenon. Hypertension 47:1027, 2006 [PMID: 16618842]
  3. Levey AS et al: CKD: Common, harmful and treatable—World Kidney Day 2007. Am J Kidney Dis 49(2), 2007
  4. National Kidney Foundation: Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Nutrition in Chronic Renal Failure. Am J Kidney Dis 35 (suppl 2): S1, 2000
  5. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification and stratification. Am J Kidney Dis 39 (suppl 1), 2000
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