Management of the Patient with Chronic Kidney Disease

Hasan Bazari

Since the early 2000s, new definitions and classifications of chronic kidney disease (CKD) have drawn attention to this increasingly serious clinical and public health problem. Over the next decade, the number of patients reaching end-stage renal disease in the United States is expected to double to more than 600,000 patients. While most patients with CKD do not progress to end-stage renal disease, they do experience increased risks for adverse cardiovascular events and all-cause mortality. Over the last two decades, a wealth of evidence has accumulated regarding optimal management of patients with CKD, leading to recommendations for better diagnosis and earlier implementation of potentially disease-modifying therapy.

Although care of persons with end-stage kidney disease usually resides with the nephrologist, diagnosis and management of earlier stages of CKD are typically responsibilities of the primary care physician and medical home team. Tasks include accurate diagnosis, early initiation of first-line therapy, and timely referral for nephrologic consultation. This chapter focuses on these tasks but also reviews measures used by the nephrologist for management of end-stage disease, since the primary care practice is often asked to participate in their implementation and monitoring.

DEFINITION, PATHOPHYSIOLOGY, CLINICAL PRESENTATION, AND COURSE (1, 2, 3, 4, 5, 6, 7, 8 and 9)

Pathophysiology

CKD can result from a multitude of etiologies, including diabetes mellitus, hypertension, vascular disease, glomerulonephritis, obstruction, and hereditary polycystic diseases, among others. However, among those who reach end-stage renal disease, diabetes mellitus and hypertension are the most common etiologies. CKD tends to be insidious and asymptomatic in the early stages. The clinical presentation can result from either the underlying disease or consequences of the kidney disease. In advanced stages of kidney disease, the symptoms are largely related to the development of uremia. Prognosis (including mortality and risk of progression to end-stage renal disease) and risks of complications increase as GFR declines, especially if it falls below 60 mL/min (see later discussion).

Hypertension

Hypertension can be a cause or consequence of CKD. Certain etiologies, such as renovascular disease and immunoglobulin A (IgA) nephropathy, can have severe hypertension as a presenting feature with headaches, palpitations, and dizziness. Hypertension in the context of CKD can be difficult to control and may require multiple agents.

Proteinuria

Proteinuria is fundamental to the pathogenesis of many types of renal disease not only as a characteristic feature of these diseases but also as a pathogenic mechanism in disease progression, as well as a target of therapy. In diabetes, microalbuminuria is the earliest clinical manifestation of diabetic nephropathy, usually occurring 6 to 7 years after onset of the diabetes in insulin-dependent diabetes mellitus. With time, the proteinuria becomes overt. Glomerular diseases are often characterized by heavy proteinuria, with patients not infrequently presenting with nephrotic syndrome including hypertension and edema. Other complications of nephrotic syndrome include deep venous thrombosis, pulmonary embolus, infections, and accelerated atherosclerosis from the accompanying hyperlipidemia. The degree of proteinuria often determines the rate of progression of the kidney disease but not in all renal diseases.

Fluid and Electrolyte Problems

Sodium and fluid retention generally occurs late in the course of kidney disease but can be a dominant feature with certain causes of CKD. Two particular causes stand out. Bilateral renal artery stenosis classically presents with the triad of hypertension, fluid overload, and azotemia. The degree of azotemia may be mild compared with other causes of renal failure. Glomerulonephritis can also lead to salt and water retention with near-normal renal function. IgA nephropathy, lupus nephritis, cryoglobulinemia, and poststreptococcal glomerulonephritis can present with predominantly fluid retention without end-stage renal disease. In patients with underlying congestive heart failure, the kidney disease can exacerbate salt and water retention.

Conversely, there are diseases in which tubular dysfunction predominates and salt wasting and metabolic acidosis may be key features. Reflux with nephropathy can induce salt wasting, and these patients are prone to volume depletion.

Hyperkalemia often occurs in the terminal stages of kidney disease. However, it can also be a severe problem in patients in relatively early stages with certain etiologies. Of particular importance are patients with diabetic nephropathy, who often have hyperkalemia as a consequence of hyporeninemic hypoaldosteronism. The therapy of diabetic nephropathy involves the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, both of which can worsen hyperkalemia.

Hypokalemia can also be a feature of early stages of CKD. High renin states in renal artery stenosis can induce kaliuresis and hypokalemia. Renal tubular acidosis can also induce renal potassium wasting.

Metabolic acidosis can be seen both early and late in kidney disease. Early, the acidosis is usually of the non-anion-gap type and is related to decreased ammoniagenesis or an associated renal tubular acidosis; late in kidney disease, it tends to be of the anion-gap type due to an inability to excrete organic acids.

Endocrine Problems

Often underappreciated is the importance of altered calcium and phosphate metabolism and its consequences.

Phosphate retention and decreased 1α-hydroxylation of vitamin D₂ (mediated in part by fibroblast growth factor-23 [FGF-23], a new described phosphatonin) trigger a cascade of derangements that can lead rather early in the course of CKD to secondary hyperparathyroidism. Hypocalcemia and hyperphosphatemia become clinically evident as the GFR falls below 40 mL/min. The vitamin 1,25 D deficiency and hyperphosphatemia combine to produce progressive hypocalcemia and worsening secondary hyperparathyroidism.

An important consequence of secondary hyperparathyroidism is the osteoporotic bone disease termed osteitis fibrosa cystica. In addition, uncontrolled phosphate levels and high calcium phosphate products can lead to premature vascular calcifications, vascular artery disease, and valvular calcifications causing aortic and mitral valvular disease. Hypocalcemia leads to muscle weakness and, rarely, tetany.

Anemia

Anemia is an important consequence of kidney disease. The predominant cause of the anemia is erythropoietin deficiency. Other contributing factors may include decreases in red cell survival, mucosal bleeding, and decreased iron absorption, as well as bone marrow resistance to erythropoietin. Anemia and high levels of FGF-23 can contribute to left ventricular hypertrophy in concert with uncontrolled hypertension. Left ventricular hypertrophy and anemia both contribute independently to poor prognosis in patients with CKD.

Cardiovascular Events

Risk of adverse cardiovascular events is markedly increased, both because of increase in occlusive coronary disease and risk of nonatherosclerotic complications such as arrhythmias, heart failure, and sudden death. During the early stages of CKD, risk equals that of persons with known coronary heart disease and increases by 40 to 50 times normal for persons undergoing dialysis. CKD is associated with a 3- to 4-fold increase in risk of stroke, which increases to 5.8 times normal for those with end-stage disease.

Depression

As with most serious chronic illnesses, depression is a frequent accompaniment of persons with CKD, especially as the condition progresses to more advanced stages. Prevalence estimates of major depressive disorder are to 20%. Prospective cohort study finds major depression to be an independent risk factor for poor prognosis, associated with significant increases in risk of hospitalization, need for dialysis, and death.

Clinical Presentation and Course

Patients with kidney failure often present with a common symptom complex regardless of the etiology of their renal disease. Fatigue, decreased exercise tolerance, anorexia, and nausea tend to dominate symptomatology. Pruritus related to elevated phosphate and uremic toxins is also common. Fluid overload and high-output congestive heart failure from anemia may initially be mistaken for primary cardiac dysfunction. Pericarditis can present with pleuritic and positional chest pain that can be worrisome for ischemic cardiac disease. Occasionally, this may progress to cardiac tamponade and present with hypotension, a globular heart, elevated neck veins, and a pulsus paradoxus. Mucosal bleeding can result from uremic platelet dysfunction. With the increased recognition of the need for optimal management of CKD, most patients transition to dialysis or transplantation much earlier than in the past. Hence, it is less common to see uremic encephalopathy. When it does occur, presentation may include cognitive decline, confusion, asterixis, myoclonus, and seizures. Seizures may also occasionally result from severe hypocalcemia.

The rate of progression of CKD can be predictable; the rate of decline in renal function, plotted as the inverse of serum creatinine, tends to be linear for chronic diseases such as diabetes and hypertension. On the other hand, inflammatory processes such as collagen vascular diseases are less predictable and are subject to both the intrinsic propensity of the disease in a particular patient and the influence of therapy.

DIAGNOSIS, STAGING, AND SCREENING (1,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22)

As noted, the consensus definition of CKD is largely a functional one, based on reduction in GFR to <60 mL/min. Diagnosis thus necessitates an accurate estimation of the GFR. A number of formulas have been developed to estimate this rate (most using age, sex, race, and serum creatinine).

Measurement of Renal Function: Estimation of Glomerular Filtration Rate

The serum creatinine by itself is a poor marker of renal function. Creatinine production is related to muscle mass and is about 15 mg/kg/d in women and 25 mg/kg/d in men. The fraction of creatinine that is secreted by tubules can vary from 10% to 50%, and this may play a more important role in patients with CKD, leading to an overestimation of the GFR. Consequently, formulas using the serum creatinine, but adjusting for age, sex, and racial differences, have been developed to provide a better estimation of renal function, as have measurement of other serum and urine markers. These include the following:

Insulin clearance: the gold standard; hard to implement and generally not available for clinical use
24-hour urine collection for creatinine clearance: traditionally touted as the standard method for measuring renal function, but inaccuracies reduce its reliability, and its usefulness has been questioned.
The Modification of Diet in Renal Disease (MDRD) equation: formulated in the context of a study of the effect of protein restriction and blood pressure control on the progression of CKD:

GFR (mL/min/1.73 m²) = 186(P_CR)-^1.154 (age)^-0.203 × 0.742 if female × 1.210 if African American (where P_CR is the plasma creatinine concentration (mg/dL), and age is in years)

In clinical practice, the MDRD equation has superceded previous formulas (e.g., the Cockcroft-Gault equation) for GFR estimation, correlating better with outcomes and more useful for risk stratification. However, concerns about its accuracy, especially with regard to a tendency to overclassify persons as having CKD, have led to development of further refinements in GFR estimation. Most notable is the CKD-EPI equation, which uses the same terms as the MDRD but has been found in meta-analytic review to classify fewer individuals as having CKD and more accurately predicting risks for mortality and end-stage renal disease. While not as widely used as the MDRD equation, the CKD-EPI equation holds promise for improved risk stratification, and its use is likely to increase over time.

Practical clinical application of these tools is available at http://nkdep.nih.gov/professionals/gfr_calculators/index.htm. Most laboratories in the United States now report an estimate of GFR based on the MDRD equation along with the serum creatinine.

Additional methods of measuring renal function, such as the measurement of cystatin C in conjunction with serum creatinine, show promise for still further enhancement of accuracy. At present, they remain under development but, in the near future, may offer a means of confirming the diagnosis of CKD suggested by use of a creatinine-based equation as a screening test.

Staging and Risk Stratification

Stages of Renal Failure

The National Kidney Foundation, through its Kidney Disease Outcomes Quality Initiative, offered new definitions of the stages of CKD in the early 2000s to improve detection, risk stratification, and research. Patients with stage 1 disease have intrinsic renal disease, such as autosomal dominant polycystic kidney disease or diabetes with microalbuminuria, but do not have a decrement in GFR. The definition is also inclusive of compromised renal function without structural renal damage, as in patients with severe heart failure. Data from NHANES III (the National Health and Nutrition Examination Survey) indicate that 11% of the US population, or 20 million people, have CKD and 0.1% have kidney failure. The stages of CKD are defined as follows:

Stage 1. Kidney damage with normal or increased GFR: GFR less than 90

Stage 2. Kidney damage with mild decreased GFR: GFR 60 to 89

Stage 3. Moderately decreased GFR: GFR 30 to 59

Stage 4. Severely decreased GFR: GFR 15 to 29

Stage 5. Kidney failure: GFR less than 15 (or dialysis)

Risks of progression to end-stage disease, development of cardiovascular complications, and mortality are largely a function of stage, as determined by GFR estimate. Additional independent predictors of risk have been sought to refine risk stratification because that which is based solely on GFR determination tends to overclassify persons into higher-risk groups. Adding degree of proteinuria (an independent risk factor) to the GFR estimate improves the accuracy of risk stratification. Similarly, the level of FGF-23 was found to independently correlate with risk for end-stage renal disease and predict mortality across the full spectrum of GFR. Serum levels of phosphate, parathyroid hormone, and calcium have been found to have little independent predictive value for death and cardiovascular disease, with the exception of a modest correlation between higher levels of serum phosphate and mortality.

Screening for Chronic Kidney Disease

In its last review, the U.S. Preventive Services Task Force found there is insufficient evidence on the harms and benefits of routine screening to offer a recommendation regarding screening for asymptomatic persons for early stages of CKD. Evidence was best for the beneficial effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs), but otherwise, there were too few good studies regarding important outcomes to serve as the basis for a recommendation. Nonetheless, much unintentional screening is taking place with the routine calculation and reporting of GFR accompanying most laboratory determinations of serum creatinine.

Diagnosis of the Underlying Condition(s)

Although at advanced stages of CKD, etiologic diagnosis is less important for management, outcomes for patients at earlier stages of disease may benefit from cause-specific therapy. Consequently, once diagnosis of an earlier stage of CKD is confirmed, the focus of the workup shifts to identification of underlying conditions. In adults, consideration of and treatment for diabetes (see Chapters 93 and 102), hypertension (see Chapters 14 and 26), atherosclerotic disease (see Chapters 15, 28, 31, and 54), and heart failure (see Chapter 32) are essential since they account for a substantial amount of the CKD burden, especially in older patients. Attention to medications with potentially adverse renal effects (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs)—see Chapter 156) is also essential. Other etiologies may be suggested by the presence of hematuria (see Chapter 129), proteinuria (see Chapter 130), or urinary retention (see Chapter 134) and should be pursued.

Monitoring

Monitoring renal function by GFR estimation can be done through periodic serum creatinine determination—an important priority. A close watch should also be kept on parameters relevant to complications, such as serum electrolytes, calcium, albumin, phosphate, parathyroid hormone, hematocrit, and vitamin D. In stages 3 and 4 CKD, monitoring of Vitamin D levels is conducted by measurement of 25-hydroxyvitamin D (Vitamin D₂) rather than those of 1,25 hydroxyvitamin D (which tend not to reflect total body vitamin D levels and often remain normal despite significant deficiency).