|Key clinical recommendations||Label||References|
|The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends a target blood pressure of less than 130/80 mm Hg in patients with chronic kidney disease.||C||2|
|According to the evidence, ACE inhibitors are more effective than other antihypertensive drugs in preventing the progression of kidney disease in diabetic and nondiabetic patients.||A||12–15|
|Angiotensin-II receptor antagonists have been shown to reduce proteinuria and the occurrence of kidney failure.||A||17–21|
|To prevent progression of nephropathy in patients with diabetes mellitus, the American Diabetes Association recommends glycemic control, with the goal being an A1C concentration below 7 percent.||C||27|
|The most recent guidelines from the NKF K/DOQI recommend treating dyslipidemia aggressively in patients with chronic kidney disease. The goals are an LDL cholesterol level below 100 mg per dL (2.60 mmol per L) and a triglyceride level below 200 mg per dL (2.26 mmol per L).||C||33|
The National Kidney Foundation (NKF)1 defines chronic kidney disease as kidney damage or a glomerular filtration rate (GFR) of less than 60 mL per minute per 1.73 m2 (body surface area) for three months or more.1 This GFR rate corresponds with a serum creatinine concentration higher than 1.5 mg per dL (132.6 μmol per L) in men and higher than 1.3 mg per dL (114.9 μmol per L) in women.2,3 Chronic kidney disease also can be defined by the presence of urinary albumin in an excretion rate higher than 300 mg per 24 hours or in a ratio of more than 200 mg of albumin to 1 g of creatinine3 (Table 1).1,4,5
|Concentration measured||Urine collection method||Normal value||Microalbuminuria||Albuminuria or clinical proteinuria|
|Total protein||24-hour excretion (varies with method)||< 300 mg per 24 hours||—||> 300 mg per 24 hours|
|Spot urine dipstick||< 30 mg per dL||—||> 30 mg per dL|
|Spot urine protein-to-creatinine ratio (varies with method)||< 200 mg of protein to 1 g of creatinine||—||> 200 mg of protein to 1 g of creatinine|
|Albumin||24-hour urinary excretion||< 30 mg per 24 hours||30 to 300 mg per 24 hours||> 300 mg per 24 hours|
|Spot urine albumin-specific dipstick||< 3 mg per dL||> 3 mg per dL||—|
|Spot urine albumin-to- creatinine ratio (varies by sex*)||Men: < 17 mg of albumin to 1 g of creatinine||Men: 17 to 250 mg of albumin to 1 g of creatinine||Men: > 250 mg of albumin to 1 g of creatinine|
|Women: < 25 mg of albumin to 1 g of creatinine||Women: 25 to 355 mg of albumin to 1 g of creatinine||Women: > 355 mg of albumin to 1 g of creatinine|
Chronic kidney disease currently affects as many as 20 million Americans.3 The incidence and prevalence of the disease have doubled in the past decade, most likely because improved treatments for hypertension, diabetes mellitus, and coronary disease have increased longevity in affected patients and, therefore, their likelihood of developing chronic kidney disease. Estimated medical and other economic costs of chronic kidney disease are expected to approach $28 billion annually by 2010, with an additional $90 billion in annual costs related to associated increased cardiovascular disease, infections, and hospitalizations.3
Causes of chronic kidney disease include diabetes mellitus, hypertension, ischemia, infection, obstruction, toxins, and autoimmune and infiltrative diseases. Although it is important to identify the cause(s) of chronic kidney disease so that specific therapy can be instituted, the disease often progresses despite appropriate treatment. As kidney function deteriorates, patients develop complications related to fluid overload, electrolyte and acid-base imbalances, and the build-up of nitrogenous waste. To survive, some patients eventually need hemodialysis or kidney transplantation.
This article reviews the current recommendations and therapeutic strategies for preventing or delaying the progression of chronic kidney disease and the development of complications such as hypertension, hyperglycemia, hyperlipidemia, anemia, and renal osteodystrophy. Recommendations for nutrition and smoking cessation also are discussed.
CLASSIFICATION OF SEVERITY AND MONITORING OF DISEASE PROGRESSION
The GFR is used to assess the degree of kidney-function impairment and to monitor disease progression and treatment response. GFR is a measure of the overall filtration rate of all nephrons. In persons 30 years or younger, the normal GFR is approximately 125 mL per minute per 1.73 m2; after the age of 30 years, GFR declines by 1 mL per minute per 1.73 m2 per year.
Estimation of the GFR no longer requires a 24-hour urine collection for creatinine clearance but can be accomplished with similar accuracy using a mathematic formula.1 The most commonly used formulas for estimating GFR in patients with stable chronic kidney disease are the Modification of Diet in Renal Disease (MDRD) equation and the Cockcroft-Gault equation (Table 2).6–8
|Stage||Description||GFR (mL per minute per 1.73 m2)||Metabolic consequences|
|—||At increased risk||Higher than 60 (with risk factors for chronic kidney disease)||—|
|1||Kidney damage (early) with normal or elevated GFR||90 or higher||—|
|2||Kidney damage with mildly decreased GFR (early renal insufficiency)||60 to 89*||Parathyroid hormone level begins to rise (GFR of 60 to 80).|
|3||Moderately decreased GFR (moderate kidney failure)||30 to 59||Calcium absorption decreases (GFR below 50).|
|Lipoprotein activity declines.|
|There is onset of left ventricular hypertrophy and/or anemia (erythropoietin deficiency).|
|4||Severely decreased GFR (pre–end-stage kidney disease)||15 to 29||Triglyceride concentration begins to rise.|
|Hyperphosphatemia or metabolic acidosis develops.|
|There is a tendency toward hyperkalemia.|
|5||Kidney failure (end-stage kidney disease [uremia])||< 15 (or dialysis)||Azotemia develops.|
Hypertension is a frequent cause of chronic kidney disease. Systemic hypertension causes direct damage to small blood vessels in the nephron. The kidneys lose their ability to autoregulate glomerular filtration flow and pressure, with resultant hyperfiltration manifesting as albuminuria and proteinuria. When the proximal convoluted tubule reabsorbs the excess protein, secretion of vasoactive substances further damages the glomerular-tubular apparatus.9 Nephron damage activates the renin-angiotensin-aldosterone system, resulting in increased sympathetic tone and fluid overload, which compound the progression of hypertension and nephron loss.10
Several trials11–13 have demonstrated the benefit of strict blood pressure control in slowing the progression of kidney disease. Thus, the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends a target blood pressure of less than 130/80 mm Hg in patients with chronic kidney disease.2
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor antagonists preferentially lower intra-glomerular pressure and reduce proteinuria. Ample evidence shows that these agents are more effective than other anti-hypertensive drugs in preventing the progression of kidney disease.11,12,14–19
The Ramipril Efficacy in Nephropathy study15 found a significantly higher GFR and a lower rate of GFR decline in patients without diabetes who received the ACE inhibitor ramipril than in similar patients who were given placebo.
Angiotensin-II receptor antagonists have been shown to reduce the occurrence of kidney failure. Efficacy may be increased when these agents are given in combination with ACE inhibitors. In one study,20 combination therapy with candesartan (angiotensin-II receptor antagonist) and lisinopril (ACE inhibitor) was more effective than treatment with either drug alone in reducing blood pressure and microalbuminuria in patients with type 2 diabetes, hypertension, and microalbuminuria.
When ACE-inhibitor therapy is started, some patients with chronic kidney disease may have an initial decrease in GFR (usually less than 10 mL per minute per 1.73 m2), a mild increase in the serum creatinine concentration (less than 20 percent of the baseline value), and a mild increase in the potassium level (usually less than 0.5 mmol per L).21 Therefore, serum creatinine and potassium levels should be monitored one to two weeks after the initiation of therapy with an ACE inhibitor.
Diabetes mellitus is the most common cause of chronic kidney disease.22 Hyperglycemia is an independent risk factor for nephropathy.23 The pathophysiology of diabetic nephropathy is complex and most likely involves both hemodynamic and glucose-dependent factors, including the accumulation of advanced glycated products, endothelial dysfunction, and loss of intraglomerular blood pressure regulation.24 Studies have shown that the A1C level correlates with loss of renal function and that glycemic control reduces the progression of kidney disease.25,26
To prevent progression of nephropathy in patients with diabetes mellitus, the American Diabetes Association (ADA)27 recommends glycemic control, with the goal being an A1C concentration below 7 percent. The ADA also recommends yearly screening for microalbuminuria and blood pressure control with an ACE inhibitor or angiotensin-II receptor antagonist.
Dyslipidemia is a primary risk factor for cardiovascular disease and a common complication of progressive kidney disease. Most patients with chronic kidney disease have an abnormal lipid panel that increases their risk for atherogenesis. Dyslipidemia contributes to cardiovascular mortality, which is 10 to 20 times higher in dialysis patients than in the normal population even after adjustments are made for age, sex, and diabetes mellitus.28,29
The most noticeable lipid abnormality in chronic kidney disease is an elevated tri-glyceride level, possibly because of defective clearance.30,31 Patients with chronic kidney disease also have an elevated ratio of low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) cholesterol. LDL cholesterols, including lipoprotein(a), are pro-atherogenic, and levels are slightly elevated in patients with chronic kidney disease. Levels of oxidized LDL cholesterol also are elevated; these cholesterols activate pro-inflammatory pathways, thereby promoting atherogenesis and endothelial dysfunction. HDL cholesterol levels are decreased, indicating loss of anti-atherogenic effect.
Although no large randomized controlled trials have studied the effects of lipid reduction on the progression of kidney disease, animal models suggest that dyslipidemia worsens kidney function. A recent meta-analysis32 of 13 small studies showed that lipid reduction preserves GFR and reduces proteinuria. The most recent guidelines from the NKF K/DOQI33 recommend treating dyslipidemia aggressively in patients with chronic kidney disease. The goals are an LDL cholesterol level below 100 mg per dL (2.60 mmol per L) and a triglyceride level below 200 mg per dL (2.26 mmol per L).33
Fibrates are known to decrease triglyceride levels, but they may increase the risk for rhabdomyolysis in patients with chronic kidney disease. Statins can lower cholesterol levels safely and effectively in these patients, although research has not yet shown that treatment decreases cardiovascular mortality.34
The anemia of chronic renal disease is normocytic and normochromic. It occurs primarily because of lower production of erythropoietin by the decreased mass of functioning renal tubular cells.
Anemia results in fatigue, reduced exercise capacity, decreased cognition, and impaired immunity. Thus, it decreases quality of life. In addition, increased workload on the heart as a result of anemia can lead to left ventricular hypertrophy and maladaptive cardiomyopathy. These conditions increase the risk of death from heart failure or ischemic heart disease.35
Study results36,37 have shown that correction of anemia can limit the progression of chronic kidney disease and possibly decrease mortality. The NKF K/DOQI guidelines1 recommend a target hemoglobin concentration of 11 to 12 g per dL (110 to 120 g per L) in patients with chronic kidney disease. Patients with plasma ferritin concentrations below 100 ng per mL (100 mcg per L) should be given iron supplements.
Erythropoietin should be administered to predialysis patients who have anemia-dependent angina or severe anemia with a hemoglobin concentration below 10 g per dL (100 g per L).38 Hypertension and an increased risk for thrombotic events are potential adverse effects of treatment. Therefore, patients receiving erythropoietin must be monitored closely.
Changes in mineral metabolism and bone structure begin early in chronic kidney disease. These changes include osteitis fibrosa cystica (because of secondary hyperparathyroidism); less commonly, osteomalacia (defective mineralization); and adynamic bone disease (absence of cellular activity).39 Osteitis fibrosa cystica, the predominant bone defect, is characterized by an increase in bone turnover that leads to decreased cortical bone and impaired bone strength. Bone disease can result in pain and an increased risk of fracture.
Parathyroid hormone levels begin to rise when creatinine clearance falls below 60 mL per minute (1 mL per second).1 The development of hyperparathyroidism may be prevented by restricting dietary phosphate intake (e.g., colas, nuts, peas, beans, dairy products), using a calcium-based phosphate binder (antacid) with meals, and administering vitamin D (Rocaltrol) to suppress parathyroid hormone secretion.39 Vitamin D supplementation is safe and effective for lowering parathyroid hormone secretion in patients with elevated parathyroid hormone levels or hypocalcemia despite adequate correction of hyperphosphatemia.40
Even with appropriate medical therapy, some patients continue to have refractory hyperparathyroidism because of parathyroid gland hyperplasia. These patients should be referred for surgical treatment.
Patients with chronic kidney disease are at risk for malnutrition and hypoalbuminemia. Both of these conditions are associated with poor outcomes in patients who are beginning dialysis.41
The effect of dietary protein restriction on kidney disease is the subject of debate. Some studies suggest that dietary protein restriction slows the progression of kidney disease, particularly in patients with diabetes mellitus.41 However, these studies were confounded by the benefits of ACE-inhibitor therapy on the rate of disease progression.
The MDRD study42 attempted to determine a level of protein intake that might reduce the risk of kidney disease progression and also minimize the risk of malnutrition. The study evaluated three levels of dietary protein intake and found that a very-low-protein diet (0.28 g per kg per day) slightly decreased the rate of progression of proteinuria compared with diets with higher protein intake (0.56 g per kg per day and 1.3 g per kg per day). The very-low-protein diet did not result in malnutrition, but it also did not decrease progression to kidney failure or death.
Current recommendations from the NKF K/DOQI based on evidence from animal studies suggest a protein intake of 0.8 to 1.0 g per kg per day and a daily caloric intake of 30 to 35 kcal per kg per day in patients with chronic kidney disease.1 Patients with chronic kidney disease, particularly those requiring dialysis, need to be monitored closely every one to three months for serum albumin concentration and body weight so that appropriate interventions can be instituted to prevent malnutrition. Early referral to a nutritionist can help maintain optimal protein and caloric intake in these patients.
Smoking is a strong risk factor for cardiovascular mortality in patients at risk for chronic kidney disease.43 It also is strongly associated with the progression of nephropathy.43 The results of one small study44 showed that smoking cessation reduced the progression of kidney disease by 30 percent in patients with type 1 diabetes.
Smoking cessation should be strongly encouraged at each office visit. Patients should be offered nicotine-replacement therapies (e.g., patch, gum) and the antidepressant bupropion (Zyban).45
Despite optimal treatment, kidney function may continue to deteriorate. Ultimately, patients may develop uremia and kidney failure.46 Symptoms of uremia include anorexia, nausea, vomiting, malaise, asterixis, muscle weakness, platelet dysfunction, pericarditis, mental status changes, seizures and, possibly, coma. These symptoms result from the accumulation of several toxins in addition to urea; thus, no strict correlation exists between clinical presentation and plasma blood urea nitrogen and creatinine levels.
Acute uremia or uremia resulting from progressive disease is an indication for immediate dialysis. Patients with kidney failure should be evaluated for kidney transplantation.