Chronic Kidney Disease

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Practice Essentials

Chronic kidney disease (CKD)—or chronic renal failure (CRF), as it was historically termed—is a term that encompasses all degrees of decreased renal function, from damaged–at risk through mild, moderate, and severe chronic kidney failure. CKD is a worldwide public health problem. In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes and high cost (see Epidemiology).

CKD is more prevalent in the elderly population. However, while  younger patients with CKD typically experience progressive loss of kidney function, 30% of patients over 65 years of age with CKD have stable disease.[1]

CKD is associated with an increased risk of cardiovascular disease and end-stage renal disease (ESRD). Kidney disease is the ninth leading cause of death in the United States.

The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation (NKF) established a definition and classification of CKD in 2002.[2] The KDOQI and the international guideline group Kidney Disease Improving Global Outcomes (KDIGO) subsequently updated these guidelines.[3] These guidelines have allowed better communication among physicians and have facilitated intervention at the different stages of the disease.

The guidelines define CKD as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for at least 3 months. Whatever the underlying etiology, once the loss of nephrons and reduction of functional renal mass reaches a certain point, the remaining nephrons begin a process of irreversible sclerosis that leads to a progressive decline in the GFR.[4]

Hyperparathyroidism is one of the pathologic manifestations of CKD. See the image below.



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Calciphylaxis due to secondary hyperparathyroidism.

Staging

The different stages of CKD form a continuum. The stages of CKD are classified as follows[3] :

By itself, measurement of GFR may not be sufficient for identifying stage 1 and stage 2 CKD, because in those patiernts the GFR may in fact be normal or borderline normal. In such cases, the presence of one or more of the following markers of kidney damage can establish the diagnosis[3] :

Hypertension is a frequent sign of CKD but should not by itself be considered a marker of it, because elevated blood pressure is also common among people without CKD.

In an update of its CKD classification system, the NKF advised that GFR and albuminuria levels be used together, rather than separately, to improve prognostic accuracy in the assessment of CKD.[3] More specifically, the guidelines recommended the inclusion of estimated GFR and albuminuria levels when evaluating risks for overall mortality, cardiovascular disease, end-stage kidney failure, acute kidney injury, and the progression of CKD. Referral to a kidney specialist was recommended for patients with a very low GFR (< 15 mL/min/1.73 m²) or very high albuminuria (> 300 mg/24 h).[3]

Patients with stages 1-3 CKD are frequently asymptomatic. Clinical manifestations resulting from low kidney function typically appear in stages 4-5 (see Presentation).

Signs and symptoms

Patients with CKD stages 1-3 are generally asymptomatic. Typically, it is not until stages 4-5 (GFR < 30 mL/min/1.73 m²) that endocrine/metabolic derangements or disturbances in water or electrolyte balance become clinically manifest.

Signs of metabolic acidosis in stage 5 CKD include the following:

Signs of alterations in the way the kidneys are handling salt and water in stage 5 include the following:

Anemia in CKD is associated with the following:

Other manifestations of uremia in ESRD, many of which are more likely in patients who are being inadequately dialyzed, include the following:

Screen adult patients with CKD for depressive symptoms; self-report scales at initiation of dialysis therapy reveal that 45% of these patients have such symptoms, albeit with a somatic emphasis.

See Presentation for more detail.

Diagnosis

Screening

American College of Physicians guidelines on screening for CKD include the following recommendations:

Laboratory studies

Laboratory studies used in the diagnosis of CKD can include the following:

Evidence of renal bone disease can be derived from the following tests:

In certain cases, the following tests may also be ordered as part of the evaluation of patients with CKD:

Imaging studies

Imaging studies that can be used in the diagnosis of CKD include the following:

Biopsy

Percutaneous renal biopsy is generally indicated when renal impairment and/or proteinuria approaching the nephrotic range are present and the diagnosis is unclear after appropriate workup.

See Workup for more detail.

Management

Early diagnosis and treatment of the underlying cause and/or institution of secondary preventive measures is imperative in patients with CKD. These may slow, or possibly halt, progression of the disease. The medical care of patients with CKD should focus on the following:

The pathologic manifestations of CKD should be treated as follows:

Indications for renal replacement therapy include the following:

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) issued a Clinical Practice Guideline for Nutrition in Chronic Renal Failure, as well as a revision of recommendations for Nutrition in Children with Chronic Kidney Disease.

See Treatment and Medication for more detail.

For a discussion of CKD in children, click here.

Pathophysiology

A normal kidney contains approximately 1 million nephrons, each of which contributes to the total glomerular filtration rate (GFR). In the face of renal injury (regardless of the etiology), the kidney has an innate ability to maintain GFR, despite progressive destruction of nephrons, as the remaining healthy nephrons manifest hyperfiltration and compensatory hypertrophy. This nephron adaptability allows for continued normal clearance of plasma solutes. Plasma levels of substances such as urea and creatinine start to show measurable increases only after total GFR has decreased 50%.

The plasma creatinine value will approximately double with a 50% reduction in GFR. For example, a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although still within the adult reference range, actually represents a loss of 50% of functioning nephron mass.

The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the reasons noted, has been hypothesized to represent a major cause of progressive renal dysfunction. The increased glomerular capillary pressure may damage the capillaries, leading initially to secondary focal and segmental glomerulosclerosis (FSGS) and eventually to global glomerulosclerosis. This hypothesis is supported by studies of five-sixths nephrectomized rats, which develop lesions identical to those observed in humans with chronic kidney disease (CKD).

Factors other than the underlying disease process and glomerular hypertension that may cause progressive renal injury include the following:

Thaker et al found a strong association between episodes of acute kidney injury (AKI) and cumulative risk for the development of advanced CKD in patients with diabetes mellitus who experienced AKI in multiple hospitalizations.[6] Any AKI versus no AKI was a risk factor for stage 4 CKD, and each additional AKI episode doubled that risk.[6]

Findings from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort, suggest that inflammation and hemostasis are antecedent pathways for CKD.[7] This study used data from 1787 cases of CKD that developed between 1987 and 2004.

Childhood renal function and CKD in children

In children, the GFR increases with age and is calculated with specific equations that are different than those for adults. Adjusted for body surface area, the GFR reaches adult levels by age 2-3 years.

Aspects of pediatric kidney function and the measure of creatinine are informative not only for children but also for adults. For example, it is important to realize that creatinine is derived from muscle and, therefore, that children and smaller individuals have lower creatinine levels independent of the GFR. Consequently, laboratory reports that do not supply appropriate pediatric normal ranges are misleading. The same is true for individuals who have low muscle mass for other reasons, such as malnutrition, cachexia, or amputation.

Another important note for childhood CKD is that physicians caring for children must be aware of normal blood pressure levels by age, sex, and height. Prompt recognition of hypertension at any age is important, because it may be caused by primary renal disease.

Fortunately, CKD during childhood is rare. Pediatric CKD is usually the result of congenital defects, such as posterior urethral valves or dysplastic kidney malformations. Another common cause is FSGS. Genetic kidney diseases are also frequently manifested in childhood CKD. Advances in pediatric nephrology have enabled great leaps in survival for pediatric CKD and end-stage renal disease (ESRD), including for children who need dialysis or transplantation.

Aging and renal function

The biologic process of aging initiates various structural and functional changes within the kidney.[8, 9] Renal mass progressively declines with advancing age, and glomerulosclerosis leads to a decrease in renal weight. Histologic examination is notable for a decrease in glomerular number of as much as 30-50% by age 70 years. The GFR peaks during the third decade of life at approximately 120 mL/min/1.73 m2; it then undergoes an annual mean decline of approximately 1 mL/min/y/1.73 m2, reaching a mean value of 70 mL/min/1.73 m2 at age 70 years.

Ischemic obsolescence of cortical glomeruli is predominant, with relative sparing of the renal medulla. Juxtamedullary glomeruli see a shunting of blood from afferent to efferent arterioles, resulting in redistribution of blood flow favoring the renal medulla. These anatomic and functional changes in renal vasculature appear to contribute to an age-related decrease in renal blood flow.

Renal hemodynamic measurements in aged humans and animals suggest that altered functional response of the renal vasculature may be an underlying factor in diminished renal blood flow and increased filtration noted with progressive renal aging. The vasodilatory response is blunted in the elderly when compared with younger patients.

However, the vasoconstrictor response to intrarenal angiotensin is identical in young and older human subjects. A blunted vasodilatory capacity with appropriate vasoconstrictor response may indicate that the aged kidney is in a state of vasodilatation to compensate for the underlying sclerotic damage.

Given the histologic evidence for nephronal senescence with age, a decline in the GFR is expected. However, a wide variation in the rate of GFR decline is reported because of measurement methods, race, gender, genetic variance, and other risk factors for renal dysfunction.

Genetics

Most cases of CKD are acquired rather than inherited, although CKD in a child is more likely to have a genetic or inherited cause. Well-described genetic syndromes associated with CKD include autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome. Other examples of specific single-gene or few-gene mutations associated with CKD include Dent disease, nephronophthisis, and atypical hemolytic uremic syndrome (HUS).

APOL1 gene

More recently, researchers have begun to identify genetic contributions to increased risk for development or progression of CKD. Friedman et al found that more than 3 million black persons with genetic variants in both copies of apolipoprotein L1 (APOL1) are at higher risk for hypertension-attributable ESRD and FSGS. In contrast, black individuals without the risk genotype and European Americans appear to have similar risk for developing nondiabetic CKD.[10]

FGF-23 gene

Circulating levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) are affected by variants in the FGF23 gene. Isakova et al reported that elevated FGF-23 levels are an independent risk factor for ESRD in patients who have fairly well-preserved kidney function (stages 2-4) and for mortality across the scope of CKD.[11]

Single-nucleotide polymorphisms

A review of 16 single-nucleotide polymorphisms (SNPs) that had been associated with variation in GFR found that development of albuminuria was associated mostly with an SNP in the SHROOM3 gene.[12] Even accounting for this variant, however, there is evidence that some unknown genetic variant influences the development of albuminuria in CKD. This study also suggests a separate genetic influence on development of albuminuria versus reduction in GFR.[12]

A genome-wide association study (GWAS) that included over 130,000 patients found 6 SNPs associated with reduced GFR, located in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80.[13] The SNP in SLC47A1 was associated with decreased GFR in nondiabetic individuals, whereas SNPs located in the DNAJC16 and CDK12 genes were associated with decreased GFR in individuals younger than 65 years.[13]

Immune-system and RAS genes

A number of genes have been associated with the development of ESRD. Many of these genes involve aspects of the immune system (eg, CCR3, IL1RN, IL4).[14]

Unsurprisingly, polymorphisms in genes involving the renin-angiotensin system (RAS) have also been implicated in predisposition to CKD. One study found that patients with CKD were significantly more likely to have the A2350G polymorphism in the ACE gene, which encodes the angiotensin-converting enzyme (ACE).[15] They were also more likely to have the C573T polymorphism in the AGTR1 gene, which encodes the angiotensin II type 1 receptor.[15]

Hyperkalemia

The ability to maintain potassium excretion at near-normal levels is generally maintained in CKD, as long as aldosterone secretion and distal flow are maintained. Another defense against potassium retention in patients with CKD is increased potassium excretion in the gastrointestinal tract, which also is under control of aldosterone.

Hyperkalemia usually does not develop until the GFR falls to less than 20-25 mL/min/1.73 m², at which point the kidneys have decreased ability to excrete potassium. Hyperkalemia can be observed sooner in patients who ingest a potassium-rich diet or have low serum aldosterone levels. Common sources of low aldosterone levels are diabetes mellitus and the use of ACE inhibitors, NSAIDs, or beta-blockers.

Hyperkalemia in CKD can be aggravated by an extracellular shift of potassium, such as occurs in the setting of acidemia or from lack of insulin.

Hypokalemia

Hypokalemia is uncommon but can develop in patients with very poor intake of potassium, gastrointestinal or urinary loss of potassium, or diarrhea or in patients who use diuretics.

Metabolic acidosis

Metabolic acidosis often is a mixture of normal anion gap and increased anion gap; the latter is observed generally with stage 5 CKD but with the anion gap generally not higher than 20 mEq/L. In CKD, the kidneys are unable to produce enough ammonia in the proximal tubules to excrete the endogenous acid into the urine in the form of ammonium. In stage 5 CKD, accumulation of phosphates, sulfates, and other organic anions are the cause of the increase in anion gap.

Metabolic acidosis has been shown to have deleterious effects on protein balance, leading to the following:

Hence, metabolic acidosis is associated with protein-energy malnutrition, loss of lean body mass, and muscle weakness. The mechanism for reducing protein may include effects on adenosine triphosphate (ATP)–dependent ubiquitin proteasomes and increased activity of branched-chain keto acid dehydrogenases.

Metabolic acidosis also leads to an increase in fibrosis and rapid progression of kidney disease, by causing an increase in ammoniagenesis to enhance hydrogen excretion.

In addition, metabolic acidosis is a factor in the development of renal osteodystrophy, because bone acts as a buffer for excess acid, with resultant loss of mineral. Acidosis may interfere with vitamin D metabolism, and patients who are persistently more acidotic are more likely to have osteomalacia or low-turnover bone disease.

Salt- and water-handling abnormalities

Salt and water handling by the kidney is altered in CKD. Extracellular volume expansion and total-body volume overload results from failure of sodium and free-water excretion. This generally becomes clinically manifested when the GFR falls to less than 10-15 mL/min/1.73 m², when compensatory mechanisms have become exhausted.

As kidney function declines further, sodium retention and extracellular volume expansion lead to peripheral edema and, not uncommonly, pulmonary edema and hypertension. At a higher GFR, excess sodium and water intake could result in a similar picture if the ingested amounts of sodium and water exceed the available potential for compensatory excretion.

Tubulointerstitial renal diseases represent the minority of cases of CKD. However, it is important to note that such diseases often cause fluid loss rather than overload. Thus, despite moderate or severe reductions in GFR, tubulointerstitial renal diseases may manifest first as polyuria and volume depletion, with inability to concentrate the urine. These symptoms may be subtle and require close attention to be recognized. Volume overload occurs only when GFR reduction becomes very severe.

Anemia

Normochromic normocytic anemia principally develops from decreased renal synthesis of erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell (RBC) production. The anemia starts early in the course of the disease and becomes more severe as viable renal mass shrinks and the GFR progressively decreases.

Using data from the National Health and Nutrition Examination Survey (NHANES), Stauffer and Fan found that anemia was twice as prevalent in people with CKD (15.4%) as in the general population (7.6%). The prevalence of anemia increased with stage of CKD, from 8.4% at stage 1 to 53.4% at stage 5.[16]

No reticulocyte response occurs. RBC survival is decreased, and bleeding tendency is increased from the uremia-induced platelet dysfunction. Other causes of anemia in CKD include the following:

Bone disease

Renal bone disease is a common complication of CKD. It results in skeletal complications (eg, abnormality of bone turnover, mineralization, linear growth) and extraskeletal complications (eg, vascular or soft-tissue calcification).

Different types of bone disease occur with CKD, as follows:

Bone disease in children is similar but occurs during growth. Therefore, children with CKD are at risk for short stature, bone curvature, and poor mineralization (“renal rickets” is the equivalent term for adult osteomalacia).

CKD–mineral and bone disorder (CKD-MBD) involves biochemical abnormalities related to bone metabolism. CKD-MBD may result from alteration in levels of serum phosphorus, PTH, vitamin D, and alkaline phosphatase.

Secondary hyperparathyroidism develops in CKD because of the following factors:

Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to PTH synthesis and secretion.

Hyperphosphatemia and hypocalcemia

Phosphate retention begins in early CKD; when the GFR falls, less phosphate is filtered and excreted, but because of increased PTH secretion, which increases renal excretion, serum levels do not rise initially. As the GFR falls toward CKD stages 4-5, hyperphosphatemia develops from the inability of the kidneys to excrete the excess dietary intake.

Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min/1.73 m². Increased phosphate concentration also affects PTH concentration by its direct effect on the parathyroid glands (posttranscriptional effect).

Hypocalcemia develops primarily from decreased intestinal calcium absorption because of low plasma calcitriol levels. It also possibly results from increased calcium-phosphate binding, caused by elevated serum phosphate levels.

Increased PTH secretion

Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been demonstrated to independently trigger PTH synthesis and secretion. As these stimuli persist in CKD, particularly in the more advanced stages, PTH secretion becomes maladaptive, and the parathyroid glands, which initially hypertrophy, become hyperplastic. The persistently elevated PTH levels exacerbate hyperphosphatemia from bone resorption of phosphate.

Skeletal manifestations

If serum levels of PTH remain elevated, a high ̶ bone turnover lesion, known as osteitis fibrosa, develops. This is one of several bone lesions, which as a group are commonly known as renal osteodystrophy and which develop in patients with severe CKD. Osteitis fibrosa is common in patients with ESRD.

The prevalence of adynamic bone disease in the United States has increased, and its onset before the initiation of dialysis has been reported in some cases. The pathogenesis of adynamic bone disease is not well defined, but possible contributing factors include the following:

Low-turnover osteomalacia in the setting of CKD is associated with aluminum accumulation. It is markedly less common than high-turnover bone disease.

Another form of bone disease is dialysis-related amyloidosis, which is now uncommon in the era of improved dialysis membranes. This condition occurs from beta-2-microglobulin accumulation in patients who have required chronic dialysis for at least 8-10 years. It manifests with cysts at the ends of long bones.

Etiology

Causes of chronic kidney disease (CKD) include the following:

Vascular diseases that can cause CKD include the following:

Primary glomerular diseases include the following:

Secondary causes of glomerular disease include the following:

Causes of tubulointerstitial disease include the following:

Urinary tract obstruction may result from any of the following:

Epidemiology

In the United States, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) reports that one in 10 American adults has some level of chronic kidney disease (CKD).[17] Kidney disease is the ninth leading cause of death in the United States.[18]

According to the NIDDK, the incidence of recognized CKD in people aged 20-64 years in the United States rose only slightly from 2000 – 2008 and remains less than 0.5%.[17] In contrast, the incidence in people aged 65 years or older more than doubled between 2000 and 2008, from approximately 1.8% to approximately 4.3%.[17]

The US prevalence of CKD increases dramatically with age (4% at age 29-39 y; 47% at age > 70 y), with the most rapid growth in people aged 60 years or older. In the National Health and Nutrition Examination Survey (NHANES) study, the prevalence of stage 3 CKD in this age group rose from 18.8% during the years 1988 ̶ 1994 to 24.5% during the years 2003 – 2006. During the same period, the prevalence of CKD in people aged 20-39 years remained consistently below 0.5%.[17]

According to 1999 – 2004 NHANES data, the estimated prevalence of CKD by stage was as follows[19] :

The US incidence of end-stage renal disease (ESRD) rose steadily from 1980-2001, but the rate subsequently leveled off at approximately 350 per 1 million population.[17] However, the percentage of patients older than 65 years has been the most rapidly growing segment of the ESRD population, having increased from 5% to 37% of this group.[17]

The US Surgeon General’s latest report on 10-year national objectives for improving the health of all Americans, Healthy People 2020, contains a chapter focused on CKD. For 2020, Healthy People lays out 14 objectives concerning reduction of the US incidence, morbidity, mortality, and health costs of CKD. Reducing renal failure will require additional public health efforts, including effective preventive strategies and early detection and treatment of CKD.

A systematic review and meta-analysis of observational studies estimating CKD prevalence in general populations worldwide found a consistent estimated global CKD prevalence of 11-13%. The majority of cases are stage 3.[20]

Race-related demographics

Although CKD affects all races, the incidence rate of ESRD among blacks in the United States is nearly 4 times that for whites.[17] Choi et al found that rates of ESRD among black patients exceeded those among white patients at all levels of baseline estimated glomerular filtration rate (GFR).[21] Risk of ESRD among black patients was highest at an estimated GFR of 45-59 mL/min/1.73 m2, as was the risk of mortality.

Schold et al found that among black kidney transplant recipients, rates of graft loss and acute rejection were higher than in white recipients, especially among younger patients.[22] Hicks et al looked at the connection between black patients with the sickle cell trait and their increased risk for kidney disease; the study found that sickle cell trait was not associated with diabetic or nondiabetic ESRD in a large sample of black patients.[23]

Important differences also exist in the frequency of specific causes of CKD among different races. In the Chronic Kidney Disease in Children (CKiD) Study, for example, glomerular disease was much more common among nonwhite persons.[24] Overall, FSGS in particular is more common among Hispanic Americans and black persons, as is the risk of nephropathy with diabetes or with hypertension; in contrast, IgA nephropathy is rare in black individuals and more common among those with Asian ancestry.[25]

Sex-related demographics

In NHANES, the distribution of estimated GFRs for the stages of CKD was similar in both sexes. In the United States Renal Data System (USRDS) 2011 Annual Data Report, however, the incident rate of ESRD cases at the initiation of hemodialysis in 2009 was higher for males, with 415.1 per million population compared with 256.6 for females.[26]

CKD in children is somewhat more common in boys, because posterior urethral valves, the most common birth defect leading to CKD, occur only in boys. Importantly, many individuals with congenital kidney disease such as dysplasia or hypoplasia do not clinically manifest CKD or ESRD until adulthood.

Prognosis

Patients with chronic kidney disease (CKD) generally experience progressive loss of kidney function and are at risk for end-stage renal disease (ESRD). The rate of progression depends on age, the underlying diagnosis, the implementation and success of secondary preventive measures, and the individual patient. Timely initiation of chronic renal replacement therapy is imperative to prevent the uremic complications of CKD that can lead to significant morbidity and death.

Tangri et al developed and validated a model in adult patients that uses routine laboratory results to predict progression from CKD (stages 3-5) to kidney failure.[27] They reported that lower estimated glomerular filtration rate (GFR), higher albuminuria, younger age, and male sex pointed to a faster progression of kidney failure. Also, a lower serum albumin, calcium, and bicarbonate level and a higher serum phosphate level were found to predict an elevated risk of kidney failure.[27]

Hospitalization

Unadjusted rates of hospitalization in the CKD popu­lation, reflecting its total disease burden, are 3-5 times higher than those of patients without CKD.[26] After adjustment for gender, prior hospitalizations, and comorbidity, rates for patients with CKD are 1.4 times higher. Rates of hospitalization for cardiovascular disease and bacterial infection are particularly elevated.[26]

In the United States in 2018, hospital admissions among patients with ESRD declined, to an average of 1.7 per patient per year. However, emergency department visits rose, to an average of 3 per patient per year.[28]

Dialysis

Hemodialysis performed 6 times per week significantly increased the risk of vascular access complications compared with a conventional 3-day regimen in one study.[29, 30] Of 125 patients who received hemodialysis 6 days per week, 48 experienced the composite primary endpoint event of vascular repair, loss, or related hospitalization, compared with only 29 of the 120 patients undergoing conventional treatment. Results indicated that overall risk for a first access event was 76% higher with daily hemodialysis than with the conventional regimen.[29, 30]

Mortality

The mortality rates associated with CKD are striking. After adjustment for age, gender, race, comorbidity, and prior hospitalizations, mortality in patients with CKD in 2009 was 56% greater than that in patients without CKD.[26] For patients with stages 4-5 CKD, the adjusted mortality rate is 76% greater.

Mortality rates are consistently higher for men than for women, and for black persons than for white individuals and patients of other races. For Medicare CKD patients aged 66 years and older, deaths per 1000 patient-years in 2009 were 75 for white patients and 83 for black patients.[26]

The highest mortality rate is within the first 6 months of initiating dialysis. Mortality then tends to improve over the next 6 months, before increasing gradually over the next 4 years. The 5-year survival rate for a patient undergoing long-term dialysis in the United States is approximately 35%, and approximately 25% in patients with diabetes.

A study by Sens found that the risk of mortality was elevated in patients with ESRD and congestive heart failure who received peritoneal dialysis compared with those who received hemodialysis.[31] Median survival time was 20.4 months in patients receiving peritoneal dialysis versus 36.7 months in the hemodialysis group.

At every age, patients with ESRD on dialysis have significantly increased mortality when compared with nondialysis patients and individuals without kidney disease. At age 60 years, a healthy person can expect to live for more than 20 years, whereas the life expectancy of a patient aged 60 years who is starting hemodialysis is closer to 4 years. Among patients aged 65 years or older who have ESRD, mortality rates are 6 times higher than in the general population.[26]

The most common cause of sudden death in patients with ESRD is hyperkalemia, which often follows missed dialysis or dietary indiscretion. The most common cause of death overall in the dialysis population is cardiovascular disease; cardiovascular mortality is 10-20 times higher in dialysis patients than in the general population.[32]

The morbidity and mortality of dialysis patients is much higher in the United States than in most other countries, which is probably a consequence of selection bias. Because of liberal criteria for receiving government-funded dialysis in the United States and the use of rationing (medical and economic) in most other countries, US patients receiving dialysis are on the average older and sicker than those in other countries.

In the National Health and Nutrition Examination Survey (NHANES) III prevalence study, hypoalbuminemia (a marker of protein-energy malnutrition and a powerful predictive marker of mortality in dialysis patients, as well as in the general population) was independently associated with low bicarbonate, as well as with the inflammatory marker C-reactive protein. A study by Raphael et al suggests that higher serum bicarbonate levels are associated with better survival and renal outcomes in African Americans.[33]

A study by Navaneethan et al found a connection between low levels of 25-hydroxyvitamin D (25[OH]D) and all-cause mortality in patients with nondialysis CKD.[34] Adjusted risk of mortality was 33% higher in patients whose 25(OH)D levels were below 15 ng/mL.

Morbidity and mortality among children with CKD and ESRD are much lower than among adults with these conditions, but they are strikingly higher than for healthy children. As with adults, the risk is highest among dialysis patients; consequently, transplantation is the preferred treatment for pediatric patients with ESRD.

Sexual and reproductive issues

Puberty is often delayed in boys and girls with significant CKD. Women with advanced CKD commonly develop menstrual irregularities, and those with ESRD are typically amenorrheic and infertile. However, pregnancy can occur and can be associated with accelerated renal decline, including in women with a kidney transplant. In advanced CKD and ESRD, pregnancy is associated with markedly decreased fetal survival.

Vitamin D

Many patients with CKD have low circulating levels of 25(OH)D. A study of 1099 patients (mostly men) with advanced CKD found that the lowest tertile of 1,25(OH)(2)D (< 15 pg/mL) was associated with death and initiation of long-term dialysis therapy compared with the highest tertile (> 22 pg/mL).[35] A retrospective cohort study in 12,763 non–dialysis-dependent patients with CKD found that 25(OH)D levels below 15 ng/mL were associated independently with all-cause mortality.[36]

Patient Education

Patients with chronic kidney disease (CKD) should be educated about the following:

Women of childbearing age who have end-stage renal disease (ESRD) should be counseled that although their fertility is greatly reduced, pregnancy can occur and is associated with higher risk than in women who do not have renal disease. In addition, many medications used to treat CKD are potentially teratogenic; in particular, women taking angiotensin-converting enzyme (ACE) inhibitors and certain immunosuppressive treatments require clear counseling.

History

Patients with chronic kidney disease (CKD) stages 1-3 (glomerular filtration rate [GFR] > 30 mL/min/1.73 m²) are frequently asymptomatic; in terms of possible “negative” symptoms related simply to the reduction in GFR, they do not experience clinically evident disturbances in water or electrolyte balance or endocrine/metabolic derangements.

Generally, these disturbances become clinically manifest with CKD stages 4-5 (GFR < 30 mL/min/1.73 m²). Patients with tubulointerstitial disease, cystic diseases, nephrotic syndrome, and other conditions associated with “positive” symptoms (eg, polyuria, hematuria, edema) are more likely to develop signs of disease at earlier stages.

Uremic manifestations in patients with CKD stage 5 are believed to be primarily secondary to an accumulation of multiple toxins, the full spectrum and identity of which is generally not known. Metabolic acidosis in stage 5 may manifest as protein-energy malnutrition, loss of lean body mass, and muscle weakness. Altered salt and water handling by the kidney in CKD can cause peripheral edema and, not uncommonly, pulmonary edema and hypertension.

Anemia, which in CKD develops primarily as a result of decreased renal synthesis of erythropoietin, manifests as fatigue, reduced exercise capacity, impaired cognitive and immune function, and reduced quality of life. Anemia is also associated with the development of cardiovascular disease, the new onset of heart failure, the development of more severe heart failure, and increased cardiovascular mortality.

Other manifestations of uremia in end-stage renal disease (ESRD), many of which are more likely in patients who are inadequately dialyzed, include the following:

Physical Examination

A careful physical examination is imperative. It may reveal findings characteristic of the condition that is underlying chronic kidney disease (CKD) (eg, lupus, severe arteriosclerosis, hypertension) or its complications (eg, anemia, bleeding diathesis, pericarditis). However, the lack of findings on physical examination does not exclude kidney disease. In fact, CKD is frequently clinically silent, so screening of patients without signs or symptoms at routine health visits is important.

Screening for depression

Forty-five percent of adult patients with CKD have depressive symptoms at initiation of dialysis therapy, as assessed using self-report scales. However, these scales may emphasize somatic symptoms—specifically, sleep disturbance, fatigue, and anorexia—that can coexist with chronic disease symptoms.

Hedayati et al reported that the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR[16]) and the Beck Depression Inventory (BDI) are effective screening tools and that scores of 10 and 11, respectively, were the best cutoff scores for identification of a major depressive episode in their study's patient population.[37] The study compared the BDI and QIDS-SR(16) with a gold-standard structured psychiatric interview in 272 patients with CKD stages 2-5 who had not been treated with dialysis.

Approach Considerations

Testing in patients with chronic kidney disease (CKD) typically includes a complete blood count (CBC), basic metabolic panel, and urinalysis, with calculation of renal function. Normochromic normocytic anemia is commonly seen in CKD. Other underlying causes of anemia should be ruled out.

The blood urea nitrogen (BUN) and serum creatinine levels will be elevated in patients with CKD. Hyperkalemia or low bicarbonate levels may be present. Serum albumin levels may also be measured, as patients may have hypoalbuminemia as a result of urinary protein loss or malnutrition. A lipid profile should be performed in all patients with CKD because of their risk of cardiovascular disease.

Serum phosphate, 25-hydroxyvitamin D, alkaline phosphatase, and intact parathyroid hormone (PTH) levels are obtained to look for evidence of renal bone disease. Renal ultrasonography and other imaging studies may be indicated.

Measurement of serum cystatin C levels is gaining a greater role in the estimation of kidney function.[38] Cystatin C is a small protein that is expressed in all nucleated cells, produced at a constant rate, and freely filtered by the glomerulus; it is not secreted but is instead reabsorbed by tubular epithelial cells and catabolized, so it does not return to the bloodstream. These properties make it a valuable endogenous marker of renal function.[39] A study that used cystatin C instead of creatinine to estimate glomerular filtration rate (GFR) concluded that cystatin C–based GFR equations outperform creatinine-based formulas in obese CKD patients, especially those with a body mass index (BMI) ≥35 kg/m2 and in obese women.[40]  

In certain cases, the following tests may be ordered as part of the evaluation of patients with CKD:

Screening

Evidence-based recommendations from the American College of Physicians (ACP) regarding the screening, monitoring, and treatment of adults with stage 1-3 CKD recommend against CKD screening for asymptomatic adults with no risk factors for kidney disease. The ACP’s position, however, has been disputed by the American Society of Nephrology (ASN).[41, 42, 43]

The ACP recommendations, issued in October 2013, are as follows[41, 43] :

The ASN, however, in response to the ACP recommendations, released a statement strongly advocating CKD screening even in patients without risk factors for CKD. The ASN pointed out that early CKD is usually asymptomatic and that catching and treating it early may slow its development.[42]

The nephrology society also disagreed with the ACP’s recommendation against testing for proteinuria, whether or not diabetes is present, in adults taking an ACE inhibitor or an ARB, emphasizing the importance of renal health assessment in adults on antihypertensive medication.[42]

The See Kidney Disease (SeeKD) targeted screening project identified a high proportion of individuals with risk factors for CKD and a high prevalence of unrecognized CKD. Participants with at least one risk factor for CKD (eg, diabetes, hypertension, vascular disease, family history of kidney problems) received a point-of-care creatinine measurement. Of the 5194 participants screened, 18.8% had unrecognized CKD (estimated GFR [eGFR] < 60 ml/min/1.73 m2); 13.8% had stage 3a CKD (eGFR 45-60 ml/min/1.73 m2).[44]

Urinalysis

In adult patients who are not at elevated risk for CKD, screening with total protein can be done with a standard urine dipstick, according to guidelines from the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI). If the dipstick test is positive (1+ or greater), patients should undergo testing for confirmation of proteinuria.[45]

Although 24-hour urine collection for total protein and creatinine clearance (CrCl) can be performed, spot urine collection for total protein–to-creatinine (P/C) ratio allows reliable approximation (extrapolation) of total 24-hour urinary protein excretion. In children, teenagers, and young adults in particular, a first morning urine specimen is preferable to a random specimen, as so-called orthostatic proteinuria (considered benign) can be excluded.

Patients with a P/C ratio above 200 mg/mg should undergo a full diagnostic evaluation.[45] A value of greater than 300-350 mg/mg is within the nephrotic range.

For screening patients at elevated risk, the KDOQI recommends using an albumin-specific dipstick; this is because albuminuria is a more sensitive marker than total protein for CKD from diabetes, hypertension, and glomerular diseases. A positive dipstick test should be followed by calculation of the albumin-to-creatinine ratio, with a ratio greater than 30 mg/mg followed by a full diagnostic evaluation.[45]

For monitoring proteinuria in adults with CKD, the KDOQI recommends measuring the P/C ratio in spot urine samples, using the albumin-to-creatinine ratio. However, a total P/C ratio is acceptable if the albumin-to-creatinine ratio is high (> 500 to 1000 mg/g).[45]

Dipstick proteinuria may suggest a glomerular or tubulointerstitial problem. The urine sediment finding of red blood cells (RBCs) and RBC casts suggests proliferative glomerulonephritis. Pyuria and/or white blood cell casts suggest interstitial nephritis (particularly if eosinophiluria is present) or urinary tract infection.

Renal Function Formulas

The Cockcroft-Gault formula for estimating creatinine clearance (CrCl) should be used routinely as a simple means to provide a reliable approximation of residual renal function in all patients with CKD. The formulas are as follows:

Alternatively, the Modification of Diet in Renal Disease (MDRD) Study equation could be used to calculate the glomerular filtration rate (GFR). This equation does not require a patient's weight.[46]

However, the MDRD underestimates the measured GFR at levels above 60 mL/min/1.73 m2. Stevens et al found that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is more accurate than the MDRD Study equation overall and across most subgroups and that it can report estimated GFRs that are at or above 60 mL/min/1.73 m2.[47]

However, a study by Silveiro et al found that both the CKD-EPI and MDRD equations underestimated GFR in patients with type 2 diabetes.[48] The measured GFR was 103 ± 23 mL/min/1.73 m², the CKD-EPI GFR was 83 ± 15 mL/min/1.73 m², and the MDRD GFR was 78 ± 17 mL/min/1.73 m². Accuracy was 67% for the CKD-EPI equation and 64% for the MDRD equation.[48]

Renal function calculation in pediatric patients

GFR in children is calculated using the Schwartz formula (see Chronic Kidney Disease in Children). Because this formula may currently overestimate GFR, likely due to a change in methods used to measure creatinine, Schwartz et al have proposed an updated equation that includes cystatin C.[49] However, the majority of dosing guidelines for medication adjustments due to reduced GFR use the original Schwartz equations.

Renal function calculation in elderly patients

Age is an important consideration with respect to estimated GFR. In a 70-kg man aged 25 years, a serum creatinine value of 1.2 mg/dL represents an estimated GFR of 74 mL/min/1.73m2, but in a 70-kg man aged 80 years, that same value represents an estimated GFR of 58 mL/min/1.73m2. Thus, in a 70-kg, 80-year-old man, a serum creatinine of 2 mg/dL actually represents severe renal impairment, with an estimated GFR of 32 mL/min/1.73 m2 as measured by the MDRD equation.

Therefore, in elderly patients an estimated GFR must be determined using a formula such as the MDRD equation, which includes age as a variable. This will allow appropriate adjustments of drug dosing and avoidance of nephrotoxins, in patients who have more extensive CKD than would be suggested by the serum creatinine value alone.

Renal Ultrasonography

Renal ultrasonography is useful to screen for hydronephrosis, which may not be observed in early obstruction, or involvement of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy. Small, echogenic kidneys are observed in advanced renal failure.

In contrast, kidneys usually are normal in size in advanced diabetic nephropathy, in which affected kidneys are initially enlarged from hyperfiltration. Structural abnormalities, such as those indicative of polycystic kidneys, also may be observed on ultrasonograms.

Renal ultrasonography is the initial imaging modality of choice for children. However, radiologists must have specific training to be able to recognize abnormal kidney size or development in pediatric patients.

Radiography

A retrograde pyelogram may be indicated if a high index of clinical suspicion for obstruction exists despite a negative finding on renal ultrasonography. Intravenous pyelography is not commonly performed, because of the potential for renal toxicity from the intravenous contrast; however, this procedure is often used to diagnose renal stones.

Plain abdominal radiography is particularly useful to look for radio-opaque stones or nephrocalcinosis, while a voiding cystourethrogram (VCUG) is the criterion standard for diagnosis of vesicoureteral reflux.

CT, MRI, and Radionuclide Scans

Computed tomography (CT) scanning can better define renal masses and cysts usually noted on ultrasonography. Also, CT scanning is the most sensitive test for identifying renal stones. Intravenous (IV) contrast–enhanced CT scans should be avoided in patients with renal impairment to avoid acute kidney injury; this risk significantly increases in patients with moderate to severe CKD. Dehydration also markedly increases this risk.

Magnetic resonance imaging (MRI) is very useful in patients who would otherwise undergo a CT scan but who cannot receive IV contrast. This imaging modality is reliable in the diagnosis of renal vein thrombosis, as are CT scanning and renal venography.

Magnetic resonance angiography (MRA) is becoming more useful for the diagnosis of renal artery stenosis, although renal arteriography remains the criterion standard. However, MRI contrast is problematic in patients with existing chronic kidney disease (CKD) because they have a low, but potentially fatal, risk of developing nephrogenic systemic fibrosis.

A renal radionuclide scan can be used to screen for renal artery stenosis when performed with captopril administration; it also quantitates differential renal contribution to total glomerular filtration rate (GFR). However, radionuclide scans are unreliable in patients with a GFR of less than 30 mL/min/1.73 m².

Renal Biopsy

Percutaneous renal biopsy is performed most often with ultrasonographic guidance and the use of a spring-loaded or other semi-automated needle. This procedure is generally indicated when renal impairment and/or proteinuria approaching the nephrotic range are present and the diagnosis is unclear after an appropriate workup.

Biopsies are also indicated to guide management in already-diagnosed conditions, such as lupus, in which the prognosis is highly dependent on the degree of kidney involvement. Biopsy is not usually indicated when renal ultrasonography reveals small, echogenic kidneys on ultrasonography, because this finding represents severe scarring and chronic, irreversible injury.

The most common complication of this procedure is bleeding, which can be life-threatening in a minority of cases. Surgical open renal biopsy can be considered when the risk of renal bleeding is felt to be great, occasionally with solitary kidneys, or when percutaneous biopsy is technically difficult to perform.

Renal histology in CKD reveals findings compatible with the underlying primary renal diagnosis. In some cases, a biopsy may show nonspecific changes, with the exact diagnosis remaining in doubt.

Screening

American College of Physicians guidelines on screening for CKD include the following recommendations:

Approach Considerations

Early diagnosis and treatment of the underlying cause and/or the institution of secondary preventive measures are imperative in patients with chronic kidney disease (CKD). These steps may delay, or possibly halt, progression of the disease. Early referral to a nephrologist is of extreme importance.

The medical care of patients with CKD should focus on the following:

In February 2014, the Canadian Society of Nephrology released new guidelines that recommend delaying dialysis in CKD patients without symptoms until their estimated glomerular filtration rate (eGFR) drops to 6 mL/min/1.73 m2 or until the first onset of a clinical indication (which includes uremia, fluid overload, and refractory hyperkalemia or acidemia).[50, 51] To ensure prompt recognition of that threshold, close monitoring should begin when eGFR reaches 15 mL/min/1.73 m2. Additional factors that may affect dialysis initiation include patient education and modality selection, the severity of existing uremic symptoms, and the rate of renal function decline.[50, 51]

Patients with CKD acutely presenting with indications for dialytic therapy should be transferred to a hospital center where acute dialysis can be performed.

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) has issued several clinical practice guidelines for managing all stages of CKD and related complications in adults.

Delaying or Halting Progression of Chronic Kidney Disease

Measures indicated to delay or halt the progression of chronic kidney disease (CKD) are as follows:

A prospective cohort study indicated that in patients with advanced CKD and stable hypertension, antihypertensive treatment with ACEIs or ARBs reduces the likelihood of long-term dialysis and lowers the mortality risk as well.[52, 53]

The study involved 28,497 predialysis patients with advanced CKD, hypertension, and anemia. Based on a median follow-up period of 7 months, the investigators found that in those patients who were treated with ACEIs or ARBs, the need for long-term dialysis was 6% lower than in patients who were not treated with these drugs, with the composite outcome of long-term dialysis or death also being 6% lower.

The rate of hyperkalemia-associated hospitalization was higher in the ACEI/ARB patients, but no significant increase was found in hyperkalemia-related predialysis mortality.

A retrospective simulation study found that in older patients with CKD, ACEIs and ARBs provided only marginal benefit in preventing progression to end-stage renal disease (ESRD). Among over 370,000 CKD patients aged 70 years and older, the number needed to treat (NNT) to prevent 1 case of ESRD was more than 100 for most patients (even with an exposure time of > 10 y). In younger patients, the the NNT ranged from 9-25. The investigators suggested that the reduced benefits  in older patients may reflect differences in baseline risk and life expectancy between older and younger patients.[54, 55]

Blood pressure control

Aggressive blood pressure control can help to delay the decline in renal function in patients with CKD. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) and the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) suggest a target blood pressure of less than 130/80 mm Hg.

Systolic blood pressure (SBP) control is considered more important than diastolic blood pressure control. However, SBP is also considered difficult to control in elderly patients with CKD.

In a diverse, community-based study by Peralta et al, high SBP appeared to account for most of the risk of progression to ESRD.[56] The risk began at an SBP of 140 mm Hg, as opposed to the current recommended goal of less than 130 mm Hg. The highest risk was found among patients with an SBP of at least 150 mm Hg. These researchers concluded that to improve blood pressure control in CKD, treatment approaches that lower SBP may be required.[56]

Use ACEIs or ARBs as tolerated, with close monitoring for renal deterioration and for hyperkalemia. With every dose change, serum creatinine levels need to be monitored. If serum creatinine levels increase more than 30% from baseline after adding RAS blockers, RAS blockers should be stopped. Avoid these agents in patients with advanced renal failure, bilateral renal artery stenosis, or renal artery stenosis in a solitary kidney.

The time of day at which patients take antihypertensive medications can affect circadian patterns of blood pressure, and this may translate into an effect on clinical outcome. Hermida et al reported, after a median follow-up of 5.4 years, that hypertensive patients with CKD who took at least 1 of their antihypertensive medications at bedtime had an adjusted risk for total cardiovascular events that was approximately one third that of patients who took all of their medications upon awakening.[57]

Management of protein

Data support the use of ACEIs or ARBs in diabetic kidney disease with or without proteinuria. However, in nondiabetic kidney disease, these agents are effective in retarding the progression of disease among patients with proteinuria of more than 500 mg/day.

In the Modification of Diet in Renal Disease (MDRD) Study, dietary protein restriction (0.58 g/kg/day, versus a usual-protein diet of 1.3 g/kg/day) did not significantly affect the mean change in glomerular filtration rate (GFR) over 3 years. Secondary analyses, however, suggested that a low-protein diet may slow the GFR decline in patients with the most rapidly declining GFR and reduce proteinuria.[58] A meta-analysis by Kasiske et al suggested that dietary protein restriction retards the rate of renal function decline, but the magnitude of the effect is relatively weak.[59]

National Kidney Foundation (NKF) guidelines advise that if a patient is started on protein restriction, the physician needs to closely monitor the patient's nutritional status.[45] Predialysis low serum albumin is associated with a poor outcome among dialysis patients. Protein restriction is not recommended in pediatric patients with CKD.

Vitamin D supplementation

Paricalcitol (Zemplar), a synthetic vitamin D analogue, is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of secondary hyperparathyroidism associated with CKD stage 5. However, a meta-analysis has found that paricalcitol also can safely reduce protein excretion in patients with CKD stages 2-5. Whether paricalcitol can slow the development of ESRD or reduce mortality is not yet known.[60]

In a prospective, controlled study, daily vitamin D supplementation decreased albuminuria in patients with stage 3-4 CKD who had low vitamin D levels and high parathyroid hormone (PTH) levels. The study population was composed of 50 CKD patients with hyperparathyroidism who were given 666 IU of oral cholecalciferol daily and 51 CKD patients without hyperparathyroidism who acted as controls.[61, 62]

At 6 months, cholecalciferol supplementation led to a mean increase in vitamin D (25(OH)D) levels of 53%. Urinary albumin-to-creatinine ratio decreased, from 284 to 167 mg/g, without alterations in other factors that could affect proteinuria. Control patients showed no change.

Changes in 25(OH)D levels were significantly and inversely associated with those in the urinary albumin-to-creatinine ratio , supporting a possible antiproteinuric effect of vitamin D receptor activation. Treated patients also had a mean drop of 13.8% in PTH, with a mild rise in phosphate and calcium-phosphate product. No change was seen in control patients.[61, 62]

Nephrotoxins

A study by Plantinga et al found that a great number of individuals with CKD may be unaware of their disease and thus may be at risk for further kidney injury through use of NSAIDs.[63] Persons who knew that they had CKD were less likely to use NSAIDs, suggesting that primary care physicians should be involved in communication regarding the risks of NSAIDs.[63]

However, despite the availability of guidelines and recommendations that include lists of medications that are relatively contraindicated and those that require renal dose adjustment, noncompliance with dosing guidelines and use of relatively contraindicated medications are common in patients with CKD. A cross-sectional study that included 373 adult patients with stage III/IV CKD found that 46.6% of them were prescribed at least one relatively contraindicated drug (acarbose, chlorpropamide, glyburide, nitrofurantoin, or any NSAID) during the 2-year study period; 34.0% were prescribed NSAIDs.[64]

Encourage smoking cessation, as smokers tend to reach ESRD earlier than nonsmokers. A large-population Norwegian study found that smoking cessation decreased the risk for future onset of kidney failure—especially in men, who tended to be heavier smokers than women in this cross-section.[65]

Subclinical hypothyroidism

In a study of 113 patients with CKD stages 2-4 and subclinical hypothyroidism, thyroid hormone replacement therapy (THRT) with L-thyroxine delayed the rate of decline in kidney function to ESRD.[66, 67] On average, before patients were treated with THRT, their estimated GFR declined by 4.31 ± 0.51 mL/min per 1.73 m2 each year; following treatment, the estimated GFR decline slowed to 1.08 ± 0.36 mL/min per 1.73 m2 each year.[66, 67]

Based on the slope of the decline in estimated GFR prior to THRT, linear regression analysis predicted that 53 of the 113 patients (46.9%) would reach stage 5 CKD—where they would require dialysis or a kidney transplant—within 10 years. However, using the altered slope of the decline of estimated GFR after patients received therapy, it was estimated that only 10 patients (8.8%) would reach this outcome in 10 years. Thus, THRT delayed reaching stage 5 CKD in 43 of the predicted 53 patients (81%).[66, 67]

Treating Pathologic Manifestations of Chronic Kidney Disease

Treat these pathologic manifestations of chronic kidney disease (CKD) as follows:

Anemia treatment

With erythropoietin treatment, the goal is a hemoglobin level of 10-12 g/dL, as normalization of hemoglobin in patients with CKD stages 4-5 has been associated with an increased risk of adverse outcomes. Before starting erythropoietin, patients should have their iron stores checked. The aim is to keep iron saturation at 30-50% and ferritin at 200-500 ng/mL.

A study by Shurraw et al showed that in people with non–hemodialysis-dependent CKD, a hemoglobin A1c (HbA1c) level higher than 9% is associated with worse clinical outcomes. Lower levels of HbA1c also seemed to be associated with excess mortality. Appropriate and timely control of the HbA1c level in people with diabetes mellitus and CKD may be more important than previously realized, but findings also suggest that intensive glycemic control may lead to increased mortality.[68]

Management of mineral and bone disorder

Treatment of abnormal mineral homeostasis in patients with CKD includes the following[69] :

The Kidney Disease: Improving Global Outcomes (KDIGO) Implementation Task Force updated its guidelines on the management of CKD–mineral and bone disorder in 2017.[69]  The guidelines, which were issued after weighing the quality and the depth of evidence, when available, propose a common-sense approach to the evaluation and treatment of mineral and bone disorder in different stages of CKD.

The National Kidney Foundation convened a work group to provide a US perspective on the KDOQI CKD-MBD guidelines. While agreeing with most of the KDIGO recommendations, the work group had some concerns about the suggestions related to hypocalcemia and hypercalcemia, phosphate-binder choice, and treatment of abnormal parathyroid hormone concentrations.[70]

Management of hyperphosphatemia

Definitive evidence on the benefit of lowering phosphate levels in CKD is lacking, and guideline recommendations vary. KDIGO  guidelines suggest lowering elevated phosphate levels toward the normal range in stages 3a-5d CKD.[69] United Kingdom National Institute for Health and Clinical Excellence (NICE) guidelines provide recommendations only for stages 4, 5, and 5d.[71]

Restricting dietary phosphate is one strategy for correcting hyperphosphatemia. However, because of its complexity and challenges, diet control by itself is insufficient and unreliable for keeping phosphate concentrations within the recommended range. Consequently, the use of phosphate binders (eg, calcium acetate, sevelamer carbonate, lanthanum carbonate) has been proposed as a means of reducing elevated phosphorus levels in patients with CKD.[72] Unfortunately, calculation of the cost-effectiveness of the various agents is complicated.[73]

KDIGO guidelines suggest that the choice of phosphate-binding agent for the treatment of hyperphosphatemia take into account CKD stage, presence of other components of CKD mineral and bone disorder, concomitant therapies, and side-effect profile.[69] For adult patients, NICE guidelines recommend calcium acetate as the first-line phosphate binder to control serum phosphate, in addition to dietary management.[71] For full discussion of management, see Hyperphosphatemia.

Block et al reported that in patients with CKD who have normal or near-normal serum phosphorus levels, these agents significantly reduce serum and urinary phosphorus and discourage secondary hyperparathyroidism progression. The investigators also reported, however, that phosphate binders encourage vascular calcification.[74]

These results are in contrast to those reported in previous experimental findings in animals with CKD and in human clinical trials, in which the use of phosphate binders did not reduce elevated phosphorus levels or decrease the progression to secondary hyperparathyroidism. Moreover, the effect of calcification is different among patients taking calcium-containing phosphate binders relative to those taking non–calcium-containing phosphate binders.

Furthermore, no randomized, controlled trials have shown improved mortality in dialysis patients who were treated with phosphate binders, activated vitamin D, or cinacalcet to manage moderate to severe hyperparathyroidism.

Management of metabolic acidosis

Limited but growing evidence suggests that correction of metabolic acidosis in patients with CKD may have beneficial effects on protein and bone metabolism. Experts recommend alkali therapy to maintain the serum bicarbonate concentration above 22 mEq/L.

De Brito-Ashurst et al found that patients with CKD who receive bicarbonate supplementation show a slower decline in renal function.[75] In this study, 134 adult patients with CKD (ie, creatinine clearance [CrCl], 15-30 mL/min/1.73 m2; serum bicarbonate, 16-20 mmol/L) were randomly assigned to receive oral sodium bicarbonate supplementation or standard care for 2 years. A slower decline in CrCl was observed in the bicarbonate group (1.88 mL/min/1.73 m2) than in the control group (5.93 mL/min/1.73 m2).[75]

Patients in the bicarbonate group were also less likely to experience rapid disease progression (9%) than were members of the control group (45%), and fewer patients who received bicarbonate supplementation developed ESRD than did controls (6.5% vs 33%, respectively).[75] In addition, nutritional parameters improved with bicarbonate supplementation.

Correction of acidosis with sodium bicarbonate was associated with significantly slower progression of CKD in the randomized, unblinded Use of Bicarbonate in Chronic Renal Insufficiency (UBI) trial. All 740 patients in UBI, most of whom had stage 3b or 4 CKD, received standard care; the 376 patients in the treatment group also received sodium bicarbonate. Achieving target serum bicarbonate levels (24-28 mmol/L) required an average of about 6 g/day of sodium bicarbonate—an admittedly significant pill burden of four to seven pills twice daily.[76]

At a mean follow-up of 32.9 months, serum creatinine had doubled in 25 patients in the treatment group and 62 patients in the control group (hazard ratio [HR], 0.36; P < 0.001). Dialysis had been initiated in 26 treatment group versus 45 control patients (HR, 0.5; P = 0.005), and death from any cause had occurred in 25 vs 12 patients, respectively (HR, 0.43; P = 0.01). Patients in the treatment group also showed a trend toward fewer hospitalizations. Fluid overload, uncontrolled blood pressure, and other unwanted effects were not seen in the treatment group.[76]

Management of cardiovascular risks

Guidelines issued in December 2013 by the Kidney Disease: Improving Global Outcomes (KDIGO) workgroup recommend wider statin use among patients with CKD. Specific recommendations include the following[77, 78] :

Patients with CKD may require anticoagulation for a variety of indications, such as atrial fibrillation, venous thromboembolism, or prevention of dialysis access thrombosis. A systematic review and meta-analysis of oral anticoagulation in adult patients with CKD concluded that in early-stage CKD, the benefit-risk profile of non–vitamin K oral anticoagulants (NOACs; ie, dabigatran, rivaroxaban, apixaban, edoxaban) was superior to that of vitamin K antagonists (eg, warfarin).[79]

In the study, which included 45 randomized trials of oral anticoagulation strategies in 34,082 patients with either chronic or dialysis-dependent kidney disease, NOACs provided better prevention of stroke and systemic embolism in CKD patients with atrial fibrillation and early-stage disease. In CKD patients with advanced or end-stage disease, however, the authors found insufficient evidence to recommend wide use of either class of anticoagulants to improve outcomes. Low-certainty evidence suggested lower risk of major bleeding with NOACs versus vitamin K antagonists.[79]

Renal Replacement Therapy

Indications for renal replacement therapy in patients with chronic kidney disease (CKD) include the following:

Timely planning for long-term renal replacement therapy

Consider the following:

Diet

Protein restriction

Protein restriction early in chronic kidney disease (CKD) as a means to delay a decline in the glomerular filtration rate (GFR) is controversial; however, as the patient approaches CKD stage 5, this strategy is recommended in adults (but not in children) to delay the onset of uremic symptoms.

Piccoli and colleagues observe that the choice of low-protein diets is extremely wide, and that moderate protein restriction may be feasible in the context of several traditional diets, such as the Mediterranean diet, which also address other therapeutic goals in CKD. However, these authors note that diet is deeply rooted in personal preferences and social habits, so the best compliance is probably obtained by personalization and comprehensive counseling.[80]

Patients with CKD who already are predisposed to becoming malnourished are at higher risk for malnutrition with overly aggressive protein restriction. Malnutrition is a well-established predictor of increased morbidity and mortality in the population with end-stage renal disease (ESRD) and must be avoided if possible.

Salt restriction

Reduction in salt intake may slow the progression of diabetic CKD, at least in part by lowering blood pressure. A meta-analysis found that dietary salt reduction significantly reduced blood pressure in type 1 and type 2 diabetes, with results comparable to those of single-drug therapy.[81] This finding is consistent with other evidence relating salt intake to blood pressure and albuminuria in hypertensive and normotensive patients. The dietary sodium recommendation for the general population in public health guidelines is less than 5-6 g daily.

Children and adults with tubulointerstitial diseases may experience salt wasting, and salt restriction would not usually be required in that situation.

A randomized, controlled trial by Slagman et al found that moderate dietary sodium reduction (approximately 2500 mg/day of Na+ or 6 g/day of NaCl) added to angiotensin-converting enzyme (ACE) inhibition compared with dual blockade (ACE inhibitor [ACEI] and angiotensin receptor blocker [ARB]) was more effective in reducing proteinuria and blood pressure in nondiabetic patients with modest CKD. Furthermore, a low-sodium diet added to dual blockade therapy yielded additional reductions in blood pressure and proteinuria .[82]

Vegter et al found that among patients with CKD but without diabetes, a high dietary salt intake (> 14 g/day) interfered with the antiproteinuric effect of ACEI therapy and increased the risk for ESRD.[83] The risk was independent of blood pressure control.

Other dietary restrictions

The following dietary restrictions may also be indicated:

Fruits and vegetables

A review of the potential health benefits of plant-based diets in patients with CKD found growing evidence, mostly observational, that in individuals with estimated GFR of 30–59 ml/min per 1.73 m2, plant-based diets (eg, Dietary Approaches to Stop Hypertension [DASH] diet, Mediterranean diet) may delay progression to ESRD and dialysis and may potentially improve survival.[84, 85]

A study by Goraya et al showed that increasing the amount of alkali-inducing fruits and vegetables in the diet may help to reduce kidney injury.[86] In this report, 30 days of a diet that included fruits and vegetables, in amounts calculated to reduce dietary acid by half, resulted in decreased urinary albumin, N-acetyl β-D-glucosaminidase, and transforming growth factor β in patients with moderately reduced estimated GFR as a result of hypertensive nephropathy.[86]

Nutritional guidelines

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) issued a clinical practice guideline for Nutrition in Chronic Renal Failure, as well as a 2008 revision of recommendations for Nutrition in Children with CKD. For adult patients on maintenance dialysis, the KDOQI guidelines recommend routine assessment of the following nutritional parameters:

Consultations and Long-Term Monitoring

Consultations for the management of patients with chronic kidney disease (CKD) may include the following:

Patients with CKD should be referred to a nephrologist early in the course of their disease and have continued nephrologic follow-up until initiation of chronic renal replacement therapy, during dialysis, and after kidney transplantation. Moreover, a multidisciplinary approach to care, including involvement of the nephrologist, primary care physician, renal dietitian, nurse, and social worker, should be initiated early in the course of CKD, with close patient follow-up.

Patients should be monitored for obstructive sleep apnea (OSA), which occurs with increased frequency in patients receiving dialysis. Sakaguchi et al also found a high incidence (65%) of OSA in Japanese patients with nondialysis CKD, with the OSA being moderate or severe in about one third of the patients who had it.[87] The study also found that a decreased glomerular filtration rate (GFR) was associated with an increased risk of OSA.[87]

Guidelines Summary

Guidelines on chronic kidney disease (CKD) have been issued by the following:

 

Medication Summary

In chronic kidney disease (CKD), doses and dosing intervals of drugs that are excreted or metabolized renally should be adjusted according to the residual glomerular filtration rate (GFR). Some drugs are contraindicated in moderate to severe renal impairment because of potentially serious effects from drug or metabolite accumulation. Routine consultation of the appropriate references should be undertaken when prescribing any new drug to a patient with CKD.

For patients undergoing dialysis, it is extremely important to carefully check dosing guides or monitor levels when possible. These modalities differ in their clearance of drugs. Hospitalized patients undergoing other types of continuous renal replacement therapy also require close monitoring. An experienced clinical pharmacist can be invaluable in assisting to design individualized dosing regimens.

Treatments for the pathologic manifestations of CKD include the following:

Calcium acetate (PhosLo, Eliphos, Phoslyra)

Clinical Context:  Calcium acetate is used for the treatment of hyperphosphatemia in end-stage renal disease (ESRD). It combines with dietary phosphorus to form insoluble calcium phosphate, which is excreted in feces.

Calcium carbonate (Caltrate 600, Tums)

Clinical Context:  Calcium carbonate is used for the treatment of hyperphosphatemia, normalizing phosphate concentrations in patients with CKD. It can also be used as a calcium supplement in these patients.

Calcium carbonate combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces. It is marketed in a variety of dosage forms and is relatively inexpensive.

Class Summary

Dietary phosphate binders promote the binding of phosphate in the gastrointestinal tract to reduce hyperphosphatemia.

Calcitriol (Rocaltrol, Calcijex, Vectical)

Clinical Context:  Calcitriol (1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3), the potent active metabolite of vitamin D, can be used to suppress PTH production and secretion in secondary hyperparathyroidism. In addition, calcitriol can alleviate hypocalcemia in CKD by increasing intestinal calcium absorption and helping to prevent secretion of calcium in the kidneys.

Doxercalciferol (Hectorol)

Clinical Context:  Doxercalciferol is a vitamin D analogue (1-alpha-hydroxyergocalciferol) that does not require activation by the kidneys. It is metabolized to the active form of vitamin D. Doxercalciferol is indicated for the treatment of secondary hyperparathyroidism in patients with CKD.

Paricalcitol (Zemplar)

Clinical Context:  Paricalcitol is a synthetic vitamin D analogue that binds and activates vitamin D receptors in the kidneys, parathyroid glands, intestines, and bones. It is used for the prevention and treatment of secondary hyperparathyroidism associated with CKD stages 3-4 and stage 5 patients on hemodialysis or peritoneal dialysis. It reduces PTH levels, improves calcium and phosphorus homeostasis, and stimulates bone mineralization.

Calcifediol (Rayaldee)

Clinical Context:  Extended-release formulation of calcifediol (25-hydroxyvitamin D3), a prohormone of the active form of vitamin D3. Calcifediol is converted to calcitriol by CYP27B1, also called 1-alpha hydroxylase, primarily in the kidney. Calcitriol binds to the vitamin D receptor in target tissues and activates vitamin D responsive pathways that result in increased intestinal absorption of calcium and phosphorus and reduced parathyroid hormone synthesis. It is indicated for secondary hyperparathyroidism associated with vitamin D insufficiency in patients with stage 3 or 4 chronic kidney disease (CKD) and serum total 25-hydroxyvitamin D levels

Class Summary

Vitamin D analogues are recommended in patients with CKD stages 3-5 who are not on dialysis and in whom the serum parathyroid hormone (PTH) level is elevated or has been persistently rising. Vitamin D increases the absorption of calcium in the intestines and helps to prevent secretion of calcium in the kidneys. By increasing calcium levels in serum, it helps to decrease phosphate and PTH levels, as well as bone resorption.

Lanthanum carbonate (Fosrenol)

Clinical Context:  Lanthanum carbonate is a noncalcium, nonaluminum phosphate binder indicated for the reduction of high phosphorus levels in patients with stage 5 kidney disease. It dissociates into ions in the upper gastrointestinal tract, and these ions directly bind to dietary phosphate, forming insoluble lanthanum phosphate complexes. It therefore inhibits phosphorus absorption.

Sevelamer (Renagel, Renvela)

Clinical Context:  Sevelamer is indicated for the reduction of serum phosphorus levels in patients with CKD on hemodialysis. This agent binds dietary phosphate in the intestine, thus inhibiting its absorption. In patients on hemodialysis, sevelamer treatment results in fewer hypercalcemic episodes than does calcium acetate therapy.

Sucroferric oxyhydroxide (Velphoro)

Clinical Context:  Sucroferric oxyhydroxide is an iron-based, calcium-free phosphate binder. When it is taken with meals, dietary phosphate is adsorbed in the GI tract and eliminated in the feces. It is indicated for control of serum phosphorus levels in patients with chronic kidney disease on hemodialysis.

Class Summary

Dietary phosphate binders promote the binding of phosphate in the gastrointestinal tract to reduce hyperphosphatemia.

Epoetin alfa (Epogen, Procrit)

Clinical Context:  Epoetin alfa stimulates the division and differentiation of committed erythroid progenitor cells. It induces the release of reticulocytes from the bone marrow into the bloodstream.

Darbepoetin (Aranesp)

Clinical Context:  Darbepoetin is an erythropoiesis-stimulating protein closely related to erythropoietin, a primary growth factor produced in the kidney that stimulates the development of erythroid progenitor cells. Its mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase red cell production.

Darbepoetin contains 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3 such chains. Darbepoetin has a longer half-life than epoetin alfa and may be administered weekly or biweekly.

Class Summary

Growth factors are used to treat anemia of CKD by stimulating red blood cell (RBC) production.

Ferrous sulfate (Feosol, Fer-In-Sol, Slow FE, Fer-iron, MyKidz Iron 10)

Clinical Context:  Ferrous sulfate is used as a building block for hemoglobin synthesis in patients with anemia of CKD who are being treated with erythropoietin.

Iron dextran complex (Dexferrum, INFed)

Clinical Context:  Iron dextran is used to treat microcytic, hypochromic anemia resulting from iron deficiency, and to replenish iron stores in individuals on erythropoietin therapy, when oral administration is infeasible or ineffective. A 0.5-mL (0.25 mL in children) test dose should be administered prior to starting therapy. This agent is available as 50 mg iron/mL (as dextran).

Iron sucrose (Venofer)

Clinical Context:  Iron sucrose is used to treat iron deficiency anemia (in conjunction with erythropoietin) in patients with dialysis- and non–dialysis-dependent CKD. Iron deficiency in these patients is caused by blood loss during the dialysis procedure, increased erythropoiesis, and insufficient absorption of iron from the gastrointestinal tract. There is a lower incidence of anaphylaxis with iron sucrose than with other parenteral iron products.

Ferric gluconate (Ferrlecit, Nulecit)

Clinical Context:  Ferric gluconate replaces the iron found in hemoglobin, myoglobin, and specific enzyme systems, allowing transportation of oxygen via hemoglobin.

Ferumoxytol (Feraheme)

Clinical Context:  Ferumoxytol is indicated for iron replacement in adults with CKD who have iron deficiency anemia. Iron is released from an iron-carbohydrate complex in reticuloendothelial system macrophages. The released iron is transported into storage pools or plasma transferrin, which allows the iron to be incorporated into hemoglobin.

Ferric pyrophosphate (Triferic)

Clinical Context:  Contains iron in the form of soluble ferric pyrophosphate citrate that is added to hemodialysate solution and administered to patients by transfer across the dialyzer membrane. Iron delivered into the circulation binds to transferrin for transport to erythroid precursor cells to be incorporated into hemoglobin.

Ferric carboxymaltose (Injectafer)

Clinical Context:  Ferric carboxymaltose is a non-dextran IV colloidal iron hydroxide in complex with carboxymaltose, a carbohydrate polymer that releases iron. It is indicated for iron deficiency anemia (IDA) in adults who have intolerance or an unsatisfactory response to oral iron. It is also indicated for IDA in adults with nondialysis- dependent chronic kidney disease.

Class Summary

Iron salts are nutritionally essential inorganic substances used to treat anemia.

Etelcalcetide (Parsabiv)

Clinical Context:  Calcimimetic agent that allosterically modulates the calcium-sensing receptor (CaSR) and enhances activation of the receptor by extracellular calcium. Activation of the CaSR on parathyroid chief cells decreases PTH secretion. It is indicated for secondary hyperparathyroidism in patients with CKD on dialysis.

Cinacalcet (Sensipar)

Clinical Context:  Cinacalcet directly lowers intact PTH levels by increasing the sensitivity to extracellular calcium of calcium-sensing receptors on chief cells of the parathyroid glands. It also results in a concomitant decrease in serum calcium. It is indicated for secondary hyperparathyroidism in patients with CKD on dialysis.

Class Summary

A calcimimetic mimics calcium at the parathyroid hormone (PTH) receptor and reduces PTH levels.

Which types of renal diseases are classified as chronic kidney disease (CKD)?How does the progression of chronic kidney disease (CKD) differ between younger patients and older patients?What risks are associated with chronic kidney disease (CKD)?How does the National Kidney Foundation (NKF) define chronic kidney disease (CKD)?What are the stages of chronic kidney disease (CKD)?Which markers of kidney damage can establish diagnosis of stage 1 and stage 2 chronic kidney disease (CKD)?How are glomerular filtration rate (GFR) and albuminuria levels used in the assessment of chronic kidney disease (CKD)?When do symptoms of chronic kidney disease (CKD) develop?How do symptoms vary by stage in chronic kidney disease (CKD)?What are the signs of metabolic acidosis in stage 5 chronic kidney disease (CKD)?Which disturbances in water or electrolyte balance are clinically evident in stage 5 chronic kidney disease (CKD)?Which symptoms are associated with anemia in chronic kidney disease (CKD)?Which extrarenal symptoms may be observed in end-stage renal disease (ESRD)?What are the American College of Physicians guidelines on screening for chronic kidney disease (CKD)?Which lab studies are used in the diagnosis of chronic kidney disease (CKD)?Which tests can be used to detect of renal bone disease?Which secondary tests may be ordered as part of the evaluation of chronic kidney disease (CKD)?Which imaging studies are used in the diagnosis of chronic kidney disease (CKD)?When is biopsy indicated for diagnosis of chronic kidney disease (CKD)?What is the focus of the medical care of patients with chronic kidney disease (CKD)?What is the treatment for anemia due to chronic kidney disease (CKD)?What is the treatment for hyperphosphatemia due to chronic kidney disease (CKD)?What is the treatment for hypocalcemia due to chronic kidney disease (CKD)?What is the treatment for hyperparathyroidism due to chronic kidney disease (CKD)?What is the treatment for volume overload due to chronic kidney disease (CKD)?What is the treatment for metabolic acidosis due to chronic kidney disease (CKD)?What is the treatment for uremic manifestations of chronic kidney disease (CKD)?What are the indications for renal replacement therapy in chronic kidney disease (CKD)?What is chronic kidney disease–mineral and bone disorder (CKD-MBD) and what causes it?How does the kidney maintain glomerular filtration rate (GFR) in the setting of renal injury?Which plasma values are affected by a decreased glomerular filtration rate (GFR)?What is hypothesized to be the negative effect of hyperfiltration and hypertrophy of nephrons in the setting of renal dysfunction?Which factors, other than the underlying disease process and glomerular hypertension, may cause progressive renal injury?What is the role of acute kidney injury (AKI) in the development of chronic kidney disease (CKD) in patients with diabetes mellitus?Which two factors have been suggested as antecedent pathways for chronic kidney disease (CKD)?When does the glomerular filtration rate (GFR) in children reach adult levels?Which patient attributes are factors in interpreting creatinine measurements in chronic kidney disease (CKD)?What are the causes of chronic kidney disease (CKD) in children?How does aging affect renal mass and the number of glomeruli in the kidney?Which anatomic and functional changes contribute to a decrease in renal blood flow over time?Does the vasoconstrictor response to intrarenal angiotensin vary at different ages?What is the role of age in the decline of the glomerular filtration rate (GFR)?Which genetic mutations and syndromes are associated with chronic kidney disease (CKD)?What is the role of the APOL1 gene in the risk for development or progression of chronic kidney disease (CKD)?What is the role of fibroblast growth factor 23 (FGF-23) in the risk for development or progression of chronic kidney disease (CKD)?Which genetic variations have been associated with the development of albuminuria in the setting of chronic kidney disease (CKD)?What is the role of the renin-angiotensin system (RAS) in predisposing a person to chronic kidney disease (CKD)?What factors may contribute to hyperkalemia and when does it typically occur in cases of chronic kidney disease (CKD)?What causes hypokalemia in cases of chronic kidney disease (CKD)?What causes metabolic acidosis in cases of chronic kidney disease (CKD)?What issues may arise from the negative effects of metabolic acidosis in cases of chronic kidney disease (CKD)?How does chronic kidney disease (CKD) affect the handling of salt and water in the kidney and what are the effects?How do tubulointerstitial renal diseases develop in cases of chronic kidney disease (CKD)?What are the causes of anemia and what is the prevalence in cases of chronic kidney disease (CKD)?What is the role of chronic kidney disease (CKD) in the development of bone disease?What are the effects of bone disease in children with chronic kidney disease (CKD)?Which factors are involved in the development of secondary hyperparathyroidism in cases of chronic kidney disease (CKD)?What are the causes and effects of hyperphosphatemia in chronic kidney disease (CKD)?What causes hypocalcemia in chronic kidney disease (CKD)?What conditions trigger elevated parathyroid hormone (PTH) levels in chronic kidney disease (CKD)?What is osteitis fibrosa and how does it relate to chronic kidney disease (CKD)?What causes adynamic bone disease and what is its prevalence in the US?What is associated with low-turnover osteomalacia in chronic kidney disease (CKD)?What is dialysis-related amyloidosis bone disease?What are causes of chronic kidney disease (CKD)?Which vascular diseases can cause chronic kidney disease (CKD)?Which conditions can be classified as a primary glomerular disease?What are the secondary causes of glomerular disease?What are the causes of tubulointerstitial disease?What are the causes of urinary tract obstruction?What is the prevalence of chronic kidney disease (CKD) in the US?What are the incidence and prevalence of chronic kidney disease (CKD) among different age groups in the US?What is the prevalence of chronic kidney disease (CKD) by stage in the US?How has the incidence of end-stage renal disease (ESRD) in the US changed over time?What efforts have been made to reduce the incidence and effects of renal failure in the US?What is the global prevalence of chronic kidney disease (CKD)?How does chronic kidney disease (CKD) affect black patients differently from white patients?What differences exist in the frequency of specific causes of chronic kidney disease (CKD) among different races?Is end-stage renal disease (ESRD) more common in males or females?What factors contribute to CKD in children occurring more frequently in boys than in girls?What factors affect the rate of progression of chronic kidney disease (CKD)?Which routine lab results can be used to predict the progression of chronic kidney disease (CKD) to kidney failure?What are the hospitalization rates for patients with chronic kidney disease (CKD)?What is the difference in hospitalization rates between patients with chronic kidney disease (CKD) treated with dialysis and those who receive a kidney transplant?What is the difference in vascular access complications rates between a 3-day dialysis regimen and a 6-day dialysis regimen in patients with chronic kidney disease (CKD)?What are the mortality rates associated with chronic kidney disease (CKD)?What is the most common cause of death related to end-stage renal disease (ESRD)?How does the morbidity and mortality of dialysis patients in the US compare to that in other countries?Which condition is associated with bicarbonate and C-reactive protein levels in patients treated with dialysis?How are 25-hydroxyvitamin D levels correlated with mortality in nondialysis chronic kidney disease (CKD)?How does morbidity and mortality in children with chronic kidney disease (CKD) compare with that in adults?How does chronic kidney disease (CKD) affect reproductive organs and fertility?How do 25(OH)D levels correlate with mortality risk in chronic kidney disease (CKD)?What educational information should be provided to patients with chronic kidney disease (CKD)?What educational information should be provided to women of childbearing age with end-stage renal disease (ESRD)?Which clinically evident symptoms are associated with the different stages of chronic kidney disease (CKD)?How does uremia manifest in chronic kidney disease (CKD) stage 5?How does anemia manifest in chronic kidney disease (CKD)?What are the manifestations of uremia in end-stage renal disease (ESRD)?What findings may be noted during the physical exam of a patient with chronic kidney disease (CKD)?Which depression screening tools are effective in the evaluation of adult patients with chronic kidney disease (CKD) and when should they be used?Which studies should be considered in the initial workup of suspected chronic kidney disease (CKD)?Which conditions are included in the differential diagnoses of chronic kidney disease (CKD)?What are the differential diagnoses for Chronic Kidney Disease?Which lab tests are typically included in the workup of chronic kidney disease (CKD)?Which lab findings are associated with chronic kidney disease (CKD)?Why should a lipid profile be included in the workup of chronic kidney disease (CKD)?Which lab tests may be ordered to evaluate for renal bone disease in chronic kidney disease (CKD)?What is the role of cystatin-C in determining the level of kidney function in chronic kidney disease (CKD)?Which tests may be used to screen for comorbidities in the evaluation of chronic kidney disease (CKD)?What are the evidence-based recommendations regarding screening, monitoring, and treatment of adults with stage 1-3 chronic kidney disease (CKD)?What is the prevalence of unrecognized chronic kidney disease (CKD) among individuals with one or more risk factors for CKD?Which screening test may be used to exclude chronic kidney disease (CKD) in adults who do not have risk factors for CKD?Which test can be used to determine total protein and creatinine clearance (CrCl) in the evaluation for chronic kidney disease (CKD), and when should it be administered?Which tests are used to screen patients at elevated risk for chronic kidney disease (CKD)?Which tests are recommended for monitoring proteinuria in adults with chronic kidney disease (CKD)?Which complications of chronic kidney disease (CKD) are associated with a positive dipstick result?What is the Cockcroft-Gault formula for estimating creatinine clearance (CrCl) and how is it used in patients with chronic kidney disease (CKD)?What equations calculate glomerular filtration rate (GFR) in patients with chronic kidney disease (CKD), and how accurate are they?What formula is used to calculate glomerular filtration rate (GFR) in children with chronic kidney disease (CKD)?What is the role of age in estimating glomerular filtration rate (GFR) in chronic kidney disease (CKD), and how is GFR calculated in elderly patients?What is the role of renal ultrasonography in the workup of chronic kidney disease (CKD)?What is the role of radiography in the workup of chronic kidney disease (CKD)?What is the role of CT scanning in the workup for chronic kidney disease (CKD)?What are the roles of MRI and MRA in the workup for chronic kidney disease (CKD)?What is the role of renal radionuclide scanning in the workup for chronic kidney disease (CKD)?When is percutaneous renal biopsy indicated in the workup for chronic kidney disease (CKD)?What is the most common complication of renal biopsy, and how is that risk mitigated?What is the role of renal histology in the workup of in chronic kidney disease (CKD)?What is the focus of medical care in chronic kidney disease (CKD)?According to the Canadian Society of Nephrology guidelines, what criteria are used to determine when dialysis should be initiated in chronic kidney disease (CKD)?What steps can be taken to delay or halt the progression of chronic kidney disease (CKD)?What is the benefit of treatment with ACE inhibitors or ARBs in advanced chronic kidney disease (CKD) and stable hypertension?What is the role of blood pressure control in chronic kidney disease (CKD) and what is the suggested target blood pressure?Is systolic blood pressure control or diastolic blood pressure control more important in chronic kidney disease (CKD)?What is the role of systolic blood pressure in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD)?Which serum levels should be monitored in chronic kidney disease (CKD) treated with ACE inhibitor and ARB antihypertensive medications?When are antihypertensive medications indicated for the treatment of proteinuria in diabetic and nondiabetic chronic kidney disease (CKD)?What is the effect of dietary protein restriction on glomerular filtration rate (GFR) in chronic kidney disease (CKD)?What is the role of paricalcitol (Zemplar) in chronic kidney disease (CKD)?What is the role of daily cholecalciferol (Vitamin D) in chronic kidney disease (CKD)?What risk is associated with NSAIDs in chronic kidney disease (CKD)?What is the effect of smoking on kidney failure?What is the role of thyroid hormone replacement therapy (THRT) in the treatment of chronic kidney disease (CKD)?What are the pathologic manifestations of chronic kidney disease (CKD) and how are they treated?What is the target hemoglobin level in patients undergoing erythropoietin treatment in the setting of chronic kidney disease (CKD)?What are the benefits of controlled hemoglobin A1c levels in chronic kidney disease (CKD)?What is the treatment for abnormal mineral homeostasis in chronic kidney disease (CKD)?What are the target phosphate levels in chronic kidney disease (CKD)?What strategies may be used to achieve recommended phosphorus levels in hyperphosphatemia and chronic kidney disease (CKD)?Which factors should be considered in the selection of a phosphate-binding agent for the treatment of hyperphosphatemia in chronic kidney disease (CKD)?What are the effects of phosphate-binding agents in chronic kidney disease (CKD)?What are the benefits and risks of correcting metabolic acidosis in chronic kidney disease (CKD)?What is the effect of bicarbonate supplementation on renal function in chronic kidney disease (CKD)?How are the cardiovascular risks associated with chronic kidney disease (CKD) managed?What are the indications for renal replacement therapy in chronic kidney disease (CKD)?What factors should be considered when planning for long-term renal replacement therapy in chronic kidney disease (CKD)?When is protein restriction recommended as a strategy to manage glomerular filtration rate (GFR) in chronic kidney disease (CKD)?What is the role of a low-protein diet in the treatment of chronic kidney disease (CKD)?What is the effect of protein restriction on nutritional status in chronic kidney disease (CKD)?What is the role of salt restriction in the treatment of diabetic chronic kidney disease (CKD)?What is the maximum recommended daily intake of sodium for the general population?Is salt restriction necessary in concomitant chronic kidney disease (CKD) and tubulointerstitial disease?What are the benefits of dietary sodium reduction in nondiabetic chronic kidney disease (CKD)?Which dietary restrictions, other than protein, may be indicated for chronic kidney disease (CKD)?What are the benefits of increasing dietary fruits and vegetables on kidney function?What organization has issued nutritional guidelines for children and adults with chronic kidney disease (CKD)?Which assessments may be used to monitor nutritional parameters in adult patients with chronic kidney disease (CKD) who are on maintenance dialysis?What consultations are indicated for the management of chronic kidney disease (CKD)?What is the association between obstructive sleep apnea (OSA) and chronic kidney disease (CKD)?What is the role of the glomerular filtration rate (GFR) in determining medication dosages in chronic kidney disease (CKD)?Why is it important to monitor medication dosages and levels in patients undergoing dialysis as well as hospitalized patients with chronic kidney disease (CKD)?What medication treatments and dietary adjustments can be used to treat the pathologic manifestations of chronic kidney disease (CKD)?Which medications in the drug class Calcimimetics are used in the treatment of Chronic Kidney Disease?Which medications in the drug class Iron Products are used in the treatment of Chronic Kidney Disease?Which medications in the drug class Hematopoietic Growth Factors are used in the treatment of Chronic Kidney Disease?Which medications in the drug class PO4 Scavengers are used in the treatment of Chronic Kidney Disease?Which medications in the drug class Vitamin D Analogues are used in the treatment of Chronic Kidney Disease?Which medications in the drug class Calcium Salts are used in the treatment of Chronic Kidney Disease?

Author

Pradeep Arora, MD, Assistant Professor of Medicine, University of Buffalo State University of New York School of Medicine and Biomedical Sciences; Attending Nephrologist, Veterans Affairs Western New York Healthcare System

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN, Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Disclosure: Nothing to disclose.

Acknowledgements

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation

Disclosure: Nothing to disclose.

Laura Lyngby Mulloy, DO, FACP Professor of Medicine, Chief, Section of Nephrology, Hypertension, and Transplantation Medicine, Glover/Mealing Eminent Scholar Chair in Immunology, Medical College of Georgia

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mauro Verrelli, MD, FRCP(C), FACP Assistant Professor, Department of Medicine, Section of Nephrology, University of Manitoba, Canada

Disclosure: Nothing to disclose.

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Calciphylaxis due to secondary hyperparathyroidism.

Calciphylaxis due to secondary hyperparathyroidism.