INTRODUCTION — All patients with kidney disease (whether acute or chronic) should undergo an assessment of kidney function by estimating the glomerular filtration rate (GFR) from the serum creatinine. This measurement is used clinically to evaluate the degree of kidney impairment, to follow the course of the disease, and to assess the response to therapy. An attempt must also be made to obtain a specific diagnosis. The first step is a careful urinalysis, looking for proteinuria, hematuria, and cellular casts. Further evaluation may include quantification of proteinuria, kidney ultrasound, referral to a nephrologist, and a kidney biopsy. Nephrology referral is especially indicated when there is a rapid decline in kidney function, an elevated albumin-to-creatinine ratio (>300 mg/g), or urinary red blood cell casts. (See "Assessment of kidney function" and "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Urinalysis in the diagnosis of kidney disease".)
An overview of the general issues involved in the management of the patient with chronic kidney disease (CKD), including modalities to slow the rate of progression, will be presented here. The specific therapy of patients with particular kidney diseases is discussed separately in the appropriate topic reviews.
NATURAL HISTORY OF KIDNEY DISEASE — The initial injury to the kidney may result in a variety of clinical manifestations, ranging from asymptomatic hematuria to kidney failure requiring dialysis. Many individuals fully recover and subsequently suffer from little or no sequelae. Poststreptococcal glomerulonephritis in children, for example, most frequently has a long-term benign prognosis. By comparison, some patients, such as those with lupus nephritis, experience repeated and chronic insults to the kidney, thereby resulting in lasting damage. Furthermore, others in whom the initial disease is either inactive or cured may still develop progressive kidney disease due to hemodynamic and other mechanisms.
In addition to variations in the activity of the individual diseases, these different manifestations are partly due to how the kidney responds to injury. The kidney adapts to damage by increasing the filtration rate in the undamaged nephrons, a process called adaptive hyperfiltration. As a result, the patient with mild kidney insufficiency often has a normal or near-normal serum creatinine concentration. Additional homeostatic mechanisms (most frequently occurring within the renal tubules) permit the serum concentrations of sodium, potassium, calcium, and phosphorous and the total body water to also remain within the normal range, particularly among those with mild to moderate kidney disease. (See "Assessment of kidney function".)
Adaptive hyperfiltration, although initially beneficial, eventually causes damage to the glomeruli of the remaining nephrons, which is manifest by proteinuria and progressive kidney failure. This process appears to be responsible for the development of kidney failure among those in whom the original illness is either inactive or cured . Estimates of single nephron glomerular filtration rate (SNGFR) in humans support hyperfiltration as a relevant pathophysiologic mechanism . An elevated SNGFR was associated with risk factors for progression, including obesity, a family history of end-stage kidney disease (ESKD), and a greater degree of glomerulosclerosis and arteriosclerosis, suggesting compensation in remaining nephrons to maintain total GFR. The institution of measures to help prevent this process, such as treatment with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, may slow progressive disease and even preserve kidney function . Benefit is more likely if treatment is initiated before much irreversible scarring has occurred. (See "Secondary factors and progression of chronic kidney disease".)
The gradual decline in function in patients with CKD is initially asymptomatic. However, different signs and symptoms may be observed with advanced kidney failure, including volume overload, hyperkalemia, metabolic acidosis, hypertension, anemia, and mineral and bone disorders (MBDs). The onset of ESKD results in a constellation of signs and symptoms referred to as uremia.
Manifestations of uremia include anorexia, nausea, vomiting, pericarditis, peripheral neuropathy, and central nervous system abnormalities (ranging from loss of concentration and lethargy to seizures, coma, and death). No direct correlation exists between the absolute serum levels of blood urea nitrogen (BUN), creatinine, or GFR and the development of these symptoms. Some patients have relatively low levels of BUN (eg, 60 mg/dL [21.4 mmol/L] in an older patient) but are markedly symptomatic, while others have marked elevations (eg, 140 mg/dL [50 mmol/L]) but remain asymptomatic. To continue life, uremic patients require kidney replacement therapy with hemodialysis, peritoneal dialysis, or kidney transplantation. (See "Uremic toxins".)
Not all individuals have progressive loss of kidney function. Some studies show a high rate of progression, while others report relatively stable disease [4-6]. The rate of progression of CKD from one major stage to another varies based upon the underlying disease, presence or absence of comorbid conditions, treatments, socioeconomic status, individual genetics, ethnicity, and other factors. Episodes of acute kidney injury (AKI) may cause more rapid progression to ESKD in individual patients. (See "Kidney and patient outcomes after acute kidney injury in adults".)
Using epidemiologic data, general estimates for the rate of transition from an estimated GFR (eGFR) between 15 to 60 mL/min/1.73 m2 to end-stage disease may be approximately 1.5 percent per year, while the rate of transition from an eGFR >60 to <60 mL/min/1.73 m2 is approximately 0.5 percent per year [7,8].
The combination of low eGFR plus dipstick-positive proteinuria is associated with a significantly increased risk of progressive kidney disease, compared with either abnormality alone. This was shown in a retrospective study of the association between these measures and the 25-year incidence of ESKD of middle-aged males originally studied in the Multiple Risk Factor Intervention Study (MRFIT) . The presence of 1+ dipstick proteinuria, 2+ dipstick proteinuria, eGFR <60 mL/min/1.73 m2, and a low eGFR plus 2+ proteinuria was associated with hazard ratios of 3.1, 15.7, 2.4, and 41, respectively, for the development of ESKD over a 25-year period.
DEFINITION AND CLASSIFICATION — CKD is defined as the presence of kidney damage (usually detected as urinary albumin excretion of ≥30 mg/day or equivalent) or decreased kidney function (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) for three or more months, irrespective of the cause. The persistence of the damage or decreased function for at least three months is necessary to distinguish CKD from acute kidney disease (AKI).
Classification, or staging, of CKD helps to guide management, including stratification of risk for progression and complications of CKD. Risk stratification is used to inform appropriate treatments and the intensity of monitoring and patient education. We agree with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines that state that, among patients who are diagnosed using the criteria described above, staging of CKD should be done according to the following (table 1) :
●Cause of disease
●Six categories of eGFR (G stages)
●Three categories of albuminuria (A stages)
Staging patients with CKD according to cause, eGFR, and albuminuria enhances risk stratification for the major complications of CKD (figure 1 and figure 2). As seen in these figures, increasing albuminuria is associated with a higher risk of adverse events at every level of eGFR.
A more detailed discussion of the definition and classification of CKD is provided separately. (See "Definition and staging of chronic kidney disease in adults".)
ASSOCIATION WITH CARDIOVASCULAR DISEASE, END-STAGE KIDNEY DISEASE, AND MORTALITY — There is a large body of evidence that patients with CKD have a substantial increase in cardiovascular risk that can be in part explained by an increase in traditional risk factors such as hypertension, diabetes, and the metabolic syndrome. CKD alone is also an independent risk factor for cardiovascular disease. Among patients with CKD, the risk of death, particularly due to cardiovascular disease, is much higher than the risk of eventually requiring dialysis. (See "Chronic kidney disease and coronary heart disease".)
The prevention and management of cardiovascular disease are critical for patients with CKD . As an example, the increased intake of calcium (which is commonly given to treat hyperphosphatemia and may result in a high calcium-phosphorus product) may enhance coronary arterial calcification. Although controversial, this may be associated with the development of coronary atherosclerosis and is related to the presence and/or consequences of elevated serum phosphorus, calcium, and parathyroid hormone (PTH) levels. (See 'Mineral and bone disorders (MBD)' below and "Vascular calcification in chronic kidney disease".)
These and other observations have suggested that CKD should be considered a coronary equivalent and that aggressive risk factor reduction should be part of standard therapy of patients with CKD. (See "Chronic kidney disease and coronary heart disease", section on 'CKD as a CHD risk equivalent' and "Chronic kidney disease and coronary heart disease", section on 'Reduction of CHD risk in patients with CKD'.)
Patients with CKD are also at increased risk for the development of end-stage kidney disease (ESKD) as well as all-cause mortality. The competing risks of cardiovascular and ESKD vary depending on the population of patients studied and factors such as age, proteinuria, and type of kidney disease. (See "Chronic kidney disease and coronary heart disease", section on 'Competing risks of cardiovascular and end-stage kidney disease'.)
GENERAL MANAGEMENT OF CHRONIC KIDNEY DISEASE — The general management of the patient with CKD involves the following issues :
●Treatment of reversible causes of kidney failure
●Preventing or slowing the progression of kidney disease
●Treatment of the complications of kidney failure
●Adjusting drug doses when appropriate for the level of estimated glomerular filtration rate (eGFR)
●Identification and adequate preparation of the patient in whom kidney replacement therapy will be required
Blood pressure control — Overall, the best evidence supports the following points (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of goal blood pressure on progression of CKD'):
●More intensive versus less intensive blood pressure lowering reduces the risk of end-stage kidney disease (ESKD) in patients with proteinuric chronic kidney disease (CKD), but not in patients with nonproteinuric CKD.
●However, more intensive blood pressure lowering may reduce mortality in patients with CKD (whether they have proteinuria or not), even though there is no benefit on kidney endpoints among patients without proteinuria. The mortality benefit from aggressive blood pressure lowering is most evident when patients are followed over the long term (ie, during posttrial follow-up), although an early reduction in mortality was noted in the Systolic Pressure Intervention Trial (SPRINT).
Hypertension is present in approximately 80 to 85 percent of patients with CKD . Treating hypertension can slow the progression of proteinuric CKD and reduce the rate of cardiovascular complications. (See "Chronic kidney disease and coronary heart disease", section on 'Blood pressure control' and "Overview of hypertension in acute and chronic kidney disease".)
The choice of antihypertensive therapy in patients with nondiabetic and diabetic CKD is discussed separately. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of hypertension in patients with diabetes mellitus".)
Patients with CKD are frequently hypervolemic and require diuretic therapy to attain goal blood pressure. In patients with advanced CKD and refractory edema, both loop diuretics and thiazide diuretics may be needed. (See "Thiazides versus loop diuretics in the treatment of hypertension", section on 'Patients with chronic kidney disease' and "Overview of hypertension in acute and chronic kidney disease" and "Causes and treatment of refractory edema in adults".)
The optimal blood pressure in hypertensive patients with CKD and its impact on the progression of CKD is presented at length elsewhere (table 2). (See "Goal blood pressure in adults with hypertension", section on 'Patients with chronic kidney disease'.)
Slowing the rate of progression — Studies in experimental animals and humans suggest that progression in CKD may be due at least in part to secondary factors that are unrelated to the activity of the initial disease. The major factors are thought to be intraglomerular hypertension and glomerular hypertrophy (which are primarily responsible for the adaptive hyperfiltration described above), leading to glomerular scarring (glomerulosclerosis). Additional causes may include systemic hypertension, hyperlipidemia, metabolic acidosis, and tubulointerstitial disease. (See "Secondary factors and progression of chronic kidney disease".)
The major histologic manifestation of hemodynamically mediated kidney injury is secondary focal segmental glomerulosclerosis . Thus, proteinuria typically is present in patients with progressive CKD, even in primary tubulointerstitial diseases such as reflux nephropathy.
Treating the underlying cause — Treatment of the underlying cause of CKD may halt or reduce the rate of its progression. The diagnostic evaluation of a patient with CKD to identify the cause is presented in detail separately. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)
Details of treatment of the underlying cause of CKD (by cause) are detailed elsewhere. As examples:
●Autosomal dominant polycystic kidney disease (See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment".)
●Diabetic kidney disease (See "Treatment of diabetic kidney disease".)
●Glomerular disease (See "IgA nephropathy: Treatment and prognosis" and "Membranoproliferative glomerulonephritis: Treatment and prognosis" and "Anti-GBM (Goodpasture) disease: Treatment and prognosis" and "Membranous nephropathy: Treatment and prognosis".)
●Viral infections (See "Kidney disease associated with hepatitis B virus infection", section on 'Treatment' and "Overview of kidney disease associated with hepatitis C virus infection", section on 'Treatment' and "HIV-associated nephropathy (HIVAN)", section on 'Overview of medical therapy'.)
●Hematological disorders (See "Renal amyloidosis" and "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis", section on 'Patients with chronic kidney disease'.)
●Cardiac or hepatic disorders (See "Cardiorenal syndrome: Prognosis and treatment", section on 'Management' and "Hepatorenal syndrome", section on 'Treatment'.)
Additional therapies — Patients with proteinuria, defined as measured or estimated albuminuria ≥300 mg/day or measured or estimated proteinuria ≥500 mg/day, should generally be prescribed specific agents to slow progression of CKD.
Patients with proteinuria — Therapy to slow the rate of progression in proteinuric patients with CKD, independent of treatment of the underlying disease, is centered on treating with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and attaining the blood pressure goal. In addition, such patients may benefit from treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors.
●ACE inhibitors or ARBs – Patients with proteinuric CKD should attain specific goals related to a reduction in urinary protein excretion to slow the rate of progression. Proteinuria goals and the use of ACE inhibitors or ARBs in such patients are discussed elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of hypertension in patients with diabetes mellitus".)
In contrast to their renoprotective effects in proteinuric CKD, ACE inhibitors and ARBs do not appear to be more beneficial than other antihypertensive agents in patients with nonproteinuric CKD. Recommendations for antihypertensive treatment in patients with nonproteinuric CKD are discussed elsewhere. (See "Overview of hypertension in acute and chronic kidney disease", section on 'Sequence of antihypertensive therapy in nonproteinuric CKD'.)
When used in patients with CKD, common side effects of angiotensin inhibition include a mild to moderate reduction in GFR and hyperkalemia. The decline in GFR occurs soon after the initiation of therapy or after an increase in dose. Hyperkalemia can occur soon after the initiation of therapy or later, if CKD is progressive. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers".)
●SGLT2 inhibitors – Patients who have proteinuric CKD (with or without diabetes) may benefit from treatment with SGLT2 inhibitors. The majority of studies demonstrating kidney protective benefits from these agents have been performed in patients with diabetic kidney disease. However, several large trials indicate that SGLT2 inhibitors are beneficial in proteinuric patients with nondiabetic kidney disease [15-18].
SGLT2 inhibitors act by blocking reabsorption of glucose in the proximal tubule through SGLT2, which lowers the renal glucose threshold and leads to substantial glycosuria. SGLT2 inhibitors have additional effects on the kidney that are likely independent of glycemic control. By blocking the cotransporter, they reduce sodium reabsorption. The resulting natriuresis reduces intravascular volume and blood pressure, but it also increases the delivery of sodium to the macula densa. Increased sodium delivery to the macula densa normalizes tubuloglomerular feedback and thereby reduces intraglomerular pressure (ie, reduces glomerular hyperfiltration) through constriction of the abnormally dilated afferent arteriole . This and other mechanisms may explain the benefits of SGLT2 inhibitors on kidney disease progression . (See "Diabetic kidney disease: Pathogenesis and epidemiology", section on 'Glomerular hyperfiltration'.)
The data supporting use of SGLT2 inhibitors among nondiabetic patients come from the following trials:
•In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial , 4304 individuals with eGFR 25 to 75 mL/min/1.73 m2 and urinary albumin to creatinine ratio of 200 to 5000 mg/g were randomly assigned to dapagliflozin (10 mg daily) or placebo. Approximately two-thirds of the participants had diabetes, and the cause of CKD in most of the remainder was either chronic glomerulonephritis or hypertensive nephrosclerosis . At a median follow-up of 2.4 years, dapagliflozin reduced all-cause mortality (4.7 versus 6.8 percent), the incidence of ESKD (5.1 versus 7.5 percent), and the risk of 50 percent or greater decline in eGFR (5.2 versus 9.3 percent). The beneficial effect of dapagliflozin was similar in patients with and without diabetes and also in patients with and without severe CKD (ie, eGFR <30 mL/min/1.73 m2) .
•In the Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) trial, 6609 patients with eGFR 20 to 44 mL/min/1.73 m2 (regardless of albuminuria) or 45 to 89 mL/min/1.73 m2 (if albumin-to-creatinine ratio was at least 200 mg/g) were randomly assigned to empagliflozin 10 mg daily or placebo . Less than half of participants had diabetes. At two years, empagliflozin reduced the incidence of ESKD (3.3 versus 4.8 percent), the incidence of a sustained decline in eGFR to <10 mL/min/1.73 m2 (3.5 versus 5.1 percent), and the incidence of a sustained decrease in eGFR of 40 percent or more (10.9 versus 14.3 percent) . The risks of all-cause mortality (4.5 versus 5.1 percent) and nonfatal cardiovascular events (4.3 versus 4.6 percent) were similar between the groups. Effects were similar in patients with and without diabetes and regardless of the eGFR at the start of the study. The benefit from empagliflozin was larger in patients with albumin-to-creatinine ratio ≥300 mg/g and substantially less in patients with lower albumin excretion.
In a meta-analysis of these two trials, SGLT2 inhibitors reduced the risk of kidney failure (defined as the need for maintenance dialysis, kidney transplantation, or a sustained decline in eGFR to <10 to 15 mL/min/1.73 m2) compared with placebo (4.6 versus 6.3 percent; hazard ratio 0.72, 95% CI 0.56-0.91) .
●Protein restriction − Protein restriction may slow the progression of CKD, although the optimal level and type of protein intake have not been determined. This issue is discussed elsewhere. (See "Dietary recommendations for patients with nondialysis chronic kidney disease".)
●Smoking cessation − Stopping smoking is associated with a slower rate of progression of CKD . In an increasing number of studies, smoking also appears to correlate with an enhanced risk of developing kidney disease (primarily nephrosclerosis) as well as increasing the rate of progression among those with existing CKD .
●Treatment of chronic metabolic acidosis with supplemental bicarbonate may slow the rate of kidney function loss. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease", section on 'Slowing of CKD progression'.)
●Glycemic control – Control of blood glucose can slow the development of albuminuria, the progression of microalbuminuria to overt proteinuria, and GFR loss in diabetic patients. Treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists may reduce the risk of kidney disease progression in patients with type 2 diabetes . (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Kidney outcomes' and "Treatment of diabetic kidney disease".)
Acute on chronic kidney disease — In addition to exacerbation of their original kidney disease, patients with CKD with a recent decrease in eGFR may be suffering from an underlying reversible process, which, if identified and corrected, may result in the recovery of function. This is sometimes termed "acute on chronic kidney disease."
Decreased kidney perfusion — Hypovolemia (such as vomiting, diarrhea, diuretic use, bleeding), hypotension (due to myocardial dysfunction or pericardial disease), infection (such as sepsis), and the administration of drugs that lower the eGFR (such as nonsteroidal antiinflammatory drugs [NSAIDs] and ACE inhibitors or ARBs) are common causes of potentially reversible declines in kidney function. In patients with CKD, hypovolemia should be diagnosed by history and physical examination rather than the urine sodium or fractional excretion of sodium. The kidney's normal response to hypoperfusion is to substantially lower the urine sodium concentration (<25 mEq/L) and the fractional excretion of sodium (<1 percent in patients with advanced kidney failure). However, the superimposition of a prerenal process among patients with CKD may not result in the expected low values, since the tubules in the diseased kidney are unable to reabsorb sodium so efficiently. If hypovolemia is suspected, a judicious trial of fluid repletion may result in the return of kidney function to the previous baseline. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury".)
Administration of nephrotoxic drugs — The administration of drugs or diagnostic agents is a frequent cause of worsening kidney function. Among patients with CKD, common offenders include aminoglycoside antibiotics (particularly with unadjusted doses), NSAIDs, and radiographic contrast material. The administration of such drugs should therefore be avoided or used with caution in patients with underlying CKD. (See "Manifestations of and risk factors for aminoglycoside nephrotoxicity" and "NSAIDs: Acute kidney injury" and "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management".)
Certain drugs also interfere with either creatinine secretion or the assay used to measure the serum creatinine. These include cimetidine, trimethoprim, cefoxitin, and flucytosine. In these settings, there will be no change in the true GFR; the clinical clue that this may have occurred is the absence of a concurrent elevation in the blood urea nitrogen (BUN). (See "Drugs that elevate the serum creatinine concentration".)
Urinary tract obstruction — Urinary tract obstruction should always be considered in the patient with unexplained worsening kidney function, although, in the absence of prostatic disease, it is much less common than decreased renal perfusion. Patients with slowly developing obstruction typically have no changes in the urinalysis, no symptoms referable to the kidney, and initially maintain their urine output. Kidney ultrasonography is often performed to exclude urinary tract obstruction in patients with an unexplained elevation in the serum creatinine. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis".)
Treatment of the complications of severe CKD — A wide range of disorders may develop as a consequence of the loss of kidney function. These include disorders of fluid and electrolyte balance, such as volume overload, hyperkalemia, metabolic acidosis, and hyperphosphatemia, as well as abnormalities related to hormonal or systemic dysfunction, such as anorexia, nausea, vomiting, fatigue, hypertension, anemia, malnutrition, hyperlipidemia, and bone disease.
One recommended diet, including suggestions for protein, fat, mineral, and water, is presented (table 3). This should be modified based upon the needs of the individual patient.
Volume overload — Sodium and intravascular volume balance are usually maintained until the eGFR falls below 10 to 15 mL/min/1.73 m2. However, the patient with mild to moderate CKD, despite being in relative volume balance, is less able to respond to rapid intake of sodium and is therefore prone to fluid overload.
Patients with CKD and volume overload generally respond to the combination of dietary sodium restriction and diuretic therapy, usually with a loop diuretic given daily. Some investigators have claimed that limiting sodium intake may also help decrease progression of CKD by lowering intraglomerular pressure . We agree with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines that sodium intake should be restricted to <2 g/day in adults with CKD, unless contraindicated . (See "Loop diuretics: Dosing and major side effects" and "Causes and treatment of refractory edema in adults".)
Hyperkalemia — The ability to maintain potassium excretion at near-normal levels is generally maintained in patients with kidney disease as long as both aldosterone secretion and distal flow are maintained [26,27]. Thus, hyperkalemia generally develops in the patient who is oliguric or who has an additional problem such as a high-potassium diet, increased tissue breakdown, or hypoaldosteronism (due in some cases to the administration of an ACE inhibitor or ARB) . Impaired cell uptake of potassium also may contribute to the development of hyperkalemia in advanced CKD. (See "Causes and evaluation of hyperkalemia in adults".)
Hyperkalemia due to ACE inhibitor or ARB therapy is most likely to occur in patients in whom the serum potassium concentration is elevated or in the high-normal range prior to therapy. This is discussed in detail separately. (See "Treatment and prevention of hyperkalemia in adults".)
There are several measures that may help prevent hyperkalemia in patients with CKD. These include ingestion of a low-potassium diet (eg, <40 to 70 mEq/day [1500 to 2700 mg/day]) and avoiding, if possible, the use of drugs that raise the serum potassium concentration, such as NSAIDs . Nonselective beta blockers may result in a postprandial rise in the serum potassium concentration but do not cause persistent hyperkalemia. (See "Causes and evaluation of hyperkalemia in adults", section on 'Beta blockers' and "Patient education: Low-potassium diet (Beyond the Basics)".)
Metabolic acidosis — CKD can lead to a progressive metabolic acidosis [30-32], with the serum bicarbonate concentration tending to stabilize between 12 and 20 mEq/L and rarely falling below 10 mEq/L [31,33]. Metabolic acidosis may be treated with bicarbonate supplementation, which requires careful monitoring of volume status because bicarbonate is administered with sodium. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease", section on 'Treatment of metabolic acidosis in CKD'.)
Mineral and bone disorders (MBD) — Hyperphosphatemia is a common complication of CKD. A tendency toward phosphate retention begins early in kidney disease due to the reduction in the filtered phosphate load. Although this problem is initially mild, with hyperphosphatemia being a relatively late event, phosphate retention is intimately related to the common development of secondary hyperparathyroidism. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
From the viewpoint of calcium and phosphate balance, the hypersecretion of parathyroid hormone (PTH) is initially appropriate since PTH can correct both hyperphosphatemia and hypocalcemia. As a result, phosphate balance and a normal serum phosphate concentration are generally maintained in patients with an eGFR of >30 mL/min/1.73 m2 . The price paid is secondary hyperparathyroidism and the development of renal osteodystrophy. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
Dietary phosphate restriction and oral phosphate binders may limit the development of secondary hyperparathyroidism in patients with CKD (table 4A-B). (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Nondialysis chronic kidney disease patients'.)
The increased intake of calcium may enhance coronary arterial calcification in this setting. This may predispose patients to coronary atherosclerosis and the presence and/or consequences of elevated serum phosphorus, calcium, and PTH levels (see "Vascular calcification in chronic kidney disease"). Relevant guidelines for managing MBD in CKD, as well as other KDIGO guidelines, can be accessed through the KDIGO website.
Changes in bone structure are an almost universal finding with progressive CKD . The principal types of renal bone disease include osteitis fibrosa, osteomalacia, and adynamic bone disease. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
Osteitis fibrosa results from secondary hyperparathyroidism. Although an exact relationship is unclear, PTH levels appear to increase when kidney function decreases beyond a certain threshold value, with evidence suggesting that hormone levels begin to rise when the creatinine clearance is <40 to 70 mL/min [36,37].
PTH levels should therefore be assessed among such patients as hormonal abnormalities are one of the earliest markers of abnormal mineral and bone metabolism with progressive CKD. Prevention and/or treatment of osteitis fibrosis in patients with predialysis CKD include dietary phosphate restriction, the administration of oral phosphate binders, and the administration of calcitriol (or vitamin D analogs) to suppress the secretion of PTH.
Circulating calcitriol (1,25-dihydroxyvitamin D), the most active metabolite of vitamin D, is principally synthesized in the kidney. Circulating calcitriol levels begin to fall when the eGFR is <40 mL/min/1.73 m2 and are typically markedly reduced in patients with ESKD. In addition to the loss of functioning kidney mass, calcitriol production is also reduced by phosphate retention. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
Calcimimetics are agents that allosterically increase the sensitivity of the calcium-sensing receptor in the parathyroid gland to calcium. The calcium-sensing receptor is the principal factor regulating parathyroid gland PTH secretion and hyperplasia. The separate target offers the potential to suppress PTH secretion by mechanisms complementary and potentially synergistic with vitamin D analogs that target the vitamin D receptor. Although not approved for patients with CKD not yet on dialysis, cinacalcet is an emerging option in the treatment of secondary hyperparathyroidism in patients with CKD who do not require dialysis.
Target serum levels for PTH, as well as the approach to the management of this issue, are discussed separately. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)
Anemia — The anemia of CKD is typically normocytic and normochromic and is due primarily to reduced production of erythropoietin by the kidney (a presumed reflection of the reduction in functioning kidney mass) and to shortened red cell survival . Anemia is a common feature in many patients with nondialysis-dependent CKD, with anemia becoming increasingly common as eGFRs decline below 30 mL/min/1.73 m2 [39,40], particularly among diabetics . As an example, based upon over 15,000 participants in the National Health and Nutrition Examination Survey (NHANES), the prevalence of anemia (hemoglobin [Hb] <12 g/dL in males and <11 g/dL in females) increased from 1 percent at an eGFR of 60 mL/min/1.73 m2 to 9 percent at an eGFR of 30 mL/min/1.73 m2 and to 33 to 67 percent at an eGFR of 15 mL/min/1.73 m2 . (See "Treatment of anemia in nondialysis chronic kidney disease".)
The 2012 KDIGO guidelines suggest that, among patients who do not have anemia, the Hb concentration should be checked when it is clinically indicated and at least yearly among all patients with stage 3 CKD (ie, eGFR 30 to 59 mL/min/1.73 m2), at least every six months among patients with stage 4 to 5 CKD (ie, eGFR ≤29 mL/min/1.73 m2), and at least every three months among patients who are on dialysis [10,42]. Among patients with known anemia who are not treated with erythropoiesis-stimulating agents (ESAs), Hb should be checked when it is clinically indicated and at least every three months among patients with stage 3 to 5 (ie, eGFR ≤59 mL/min/1.73 m2) who are not on hemodialysis (including patients who are on peritoneal dialysis); patients on hemodialysis should be monitored monthly. (See "Definition and staging of chronic kidney disease in adults", section on 'Staging of CKD'.)
As stated in the 2012 KDIGO guidelines, the evaluation of anemia in those with CKD should begin when the Hb level is <12 g/dL in females and <13 g/dL in adult males [10,42]. These values are consistent with the World Health Organization (WHO) definition of anemia . If untreated, the Hb level of patients with advanced CKD normally stabilizes at approximately 8 g/dL in the absence of bleeding or hemolysis.
The anemia observed with CKD is largely diagnosed by excluding nonrenal causes of anemia in the patient with a suitably decreased eGFR. The evaluation of patients should therefore include red blood cell indices, absolute reticulocyte count, serum iron, total iron-binding capacity, percent transferrin saturation, serum ferritin, white blood cell count and differential, platelet count, B12 and folate concentrations if the mean corpuscular volume (MCV) is increased, and testing for blood in stool. This work-up should be performed prior to administering ESA therapy. (See "Diagnostic approach to anemia in adults".)
The evaluation and treatment of iron deficiency in patients with CKD are presented elsewhere. (See "Diagnosis of iron deficiency in chronic kidney disease" and "Treatment of iron deficiency in dialysis patients" and "Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients".)
Although primarily used in patients with ESKD, ESAs such as erythropoietin and darbepoetin alfa also correct the anemia in those with CKD who do not require dialysis. (See "Treatment of anemia in nondialysis chronic kidney disease".)
The use of ESAs for the treatment of anemia in patients with CKD, including the 2012 KDIGO guideline recommendations, is discussed in detail separately. (See "Treatment of anemia in patients on dialysis".)
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs) are an emerging therapy for the treatment of anemia in patients requiring dialysis and those with nondialysis-requiring CKD. (See "Treatment of anemia in patients on dialysis", section on 'Investigational agents' and "Treatment of anemia in nondialysis chronic kidney disease", section on 'Investigational agents'.)
Dyslipidemia — Abnormal lipid metabolism is common in patients with kidney disease . The primary finding in CKD is hypertriglyceridemia, with the total cholesterol concentration usually being normal (perhaps due in part to malnutrition in some patients). All CKD patients should be evaluated and potentially treated for dyslipidemia. (See "Lipid management in patients with nondialysis chronic kidney disease", section on 'Treatment' and "Secondary prevention of cardiovascular disease in end-stage kidney disease (dialysis)", section on 'Lipid modification' and "Kidney transplantation in adults: Lipid abnormalities after kidney transplantation", section on 'Treatment'.)
Follow-up testing may be performed among patients who are age <50 years who are not already on a statin in order to assess cardiovascular risk and the need for statin therapy. Follow-up evaluation may also be performed to assess adherence to statin treatment, if there is a change in the modality of kidney replacement therapy, or if there is concern about new secondary causes of dyslipidemia (such as nephrotic syndrome, hypothyroidism, diabetes, excessive alcohol consumption, or liver disease).
The treatment of hypertriglyceridemia in CKD patients, including the 2013 KDIGO recommendations, is discussed elsewhere. (See "Lipid management in patients with nondialysis chronic kidney disease", section on 'Hypertriglyceridemia' and "Secondary prevention of cardiovascular disease in end-stage kidney disease (dialysis)", section on 'Hypertriglyceridemia' and "Kidney transplantation in adults: Lipid abnormalities after kidney transplantation", section on 'Treatment'.)
In the patient with hypercholesterolemia, a statin with or without ezetimibe can effectively and safely lower the plasma cholesterol concentration to or near acceptable levels. Given that CKD is associated with an adverse cardiovascular prognosis, CKD is considered a coronary heart disease equivalent . (See "Chronic kidney disease and coronary heart disease".)
The goal low-density lipoprotein cholesterol (LDL-C) is discussed elsewhere. (See "Lipid management in patients with nondialysis chronic kidney disease", section on 'Treatment'.)
Although some studies suggested that lipid lowering with statins could reduce proteinuria and slow progression of kidney disease, subsequent large trials found no beneficial effect on kidney outcomes [46-50]; therefore, statin therapy is not useful solely for kidney protection.
Sexual dysfunction — Significant abnormalities in sexual and reproductive function are frequently observed in patients with advanced kidney disease. As an example, >50 percent of uremic males complain of symptoms that include erectile dysfunction, decreased libido, and marked declines in the frequency of intercourse ; in addition, disturbances in menstruation and fertility are commonly encountered in females with CKD, usually leading to amenorrhea by the time the patient reaches ESKD. (See "Epidemiology and etiologies of male sexual dysfunction".)
An important clinical implication of these abnormalities is that pregnancy that is carried to term is uncommon in females with a plasma creatinine concentration of ≥3 mg/dL (265 micromol/L) . (See "Pregnancy in women with nondialysis chronic kidney disease".)
Treatment of complications of end-stage kidney disease — Once the patient has reached the stage of near ESKD (eGFR <15 mL/min/1.73 m2), signs and symptoms related to uremia begin to occur, such as malnutrition, anorexia, nausea, vomiting, fatigue, sexual dysfunction, platelet dysfunction, pericarditis, and neuropathy.
Malnutrition — Malnutrition is common in patients with advanced CKD because of a lower food intake (principally due to anorexia), decreased intestinal absorption and digestion, and metabolic acidosis [53-55]. Among participants age ≥60 years in the United States Third NHANES, an eGFR <30 mL/min/1.73 m2 was independently associated with malnutrition (odds ratio [OR] 3.6) . Many additional studies have shown a strong correlation between malnutrition and death in maintenance dialysis patients. (See "Indications for initiation of dialysis in chronic kidney disease".)
It is therefore desirable to monitor the nutritional status of patients with CKD. A low plasma concentration of albumin may be indicative of malnutrition. To best assess nutritional status, the serum albumin concentration and body weight should be measured serially; these should be measured approximately every one to three months for those with eGFRs <20 mL/min/1.73 m2 and more frequently, if necessary, for those with eGFRs ≤15 mL/min/1.73 m2 . (See "Assessment of nutritional status in patients on hemodialysis".)
The desire to maintain adequate nutrition among patients with CKD clearly competes with attempts to slow the progression of kidney failure with the use of a low-protein diet. This issue is discussed elsewhere. (See "Dietary recommendations for patients with nondialysis chronic kidney disease".)
Overall, the diet of most patients with CKD should provide approximately 30 to 35 kcal/kg per day . One recommended diet, including suggestions for protein, fat, mineral, and water, is presented in the table (table 3). The Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for nutrition in CKD, as well as other KDOQI guidelines, can be accessed through the National Kidney Foundation's website.
Uremic bleeding — An increased tendency to bleeding is present in patients with CKD. This appears to correlate most closely with prolongation of the bleeding time due primarily to impaired platelet function. (See "Uremic platelet dysfunction".)
No specific therapy is required in asymptomatic patients. However, correction of the platelet dysfunction is desirable in patients who are actively bleeding or who are about to undergo a surgical or invasive procedure (such as a kidney biopsy). A number of different modalities can be used in this setting, including the correction of anemia, the administration of desmopressin (DDAVP), cryoprecipitate, estrogen, and the initiation of dialysis. (See "Uremic platelet dysfunction".)
Pericarditis — Advances in management have decreased the incidence of pericarditis in patients with CKD, but this problem is still associated with significant morbidity and occasional mortality.
Fever, pleuritic chest pain, and a pericardial friction rub are the major presentations of uremic pericarditis. One relatively characteristic feature of uremic pericarditis is that the electrocardiogram does not usually show the typical diffuse ST and T wave elevation, presumably because this is a metabolic pericarditis, and epicardial injury is uncommon. Thus, the finding of these abnormalities suggests some other cause for the pericarditis. The occurrence of pericarditis in a patient with mild to moderate CKD is another clue that the kidney disease is probably not responsible.
The development of otherwise unexplained pericarditis in a patient with advanced kidney failure is an indication to institute dialysis (providing there is no circulatory compromise or evidence of impending tamponade) (see below). Most patients with uremic pericarditis respond rapidly to dialysis, with resolution of chest pain as well as a decrease in the size of the pericardial effusion.
Uremic neuropathy — Dysfunction of the central and peripheral nervous system including encephalopathy (impaired mental status progressing, if untreated, to seizures and coma), polyneuropathy, and mononeuropathy are important complications of ESKD. They have become much less common because of the tendency to earlier initiation of dialysis.
Sensory dysfunctions, characterized by the restless leg or burning feet syndromes, are frequent presentations of uremic neuropathy. These complications are usually absolute indications for the initiation of dialysis. The extent of recovery from uremic neuropathy is directly related to the degree and extent of dysfunction prior to the initiation of dialysis. (See "Uremic polyneuropathy".)
Thyroid dysfunction — The kidney normally plays an important role in the metabolism, degradation, and excretion of several thyroid hormones. It is not surprising, therefore, that impairment in kidney function leads to disturbed thyroid physiology. However, the overlap in symptomatology between the uremic syndrome and hypothyroidism requires a cautious interpretation of the tests of thyroid function.
It is usually possible to assess thyroid status accurately in CKD patients by physical diagnosis and thyroid function testing. Common findings include low serum-free and total T3 concentrations and normal reverse T3 and free T4 concentrations. The serum thyrotropin (TSH) concentration is typically normal, and most patients are euthyroid. (See "Thyroid function in chronic kidney disease".)
Infection and vaccination — Patients with CKD are at increased risk for infection [58-60]. The risk of bacterial infection (particularly pulmonary and genitourinary) increases with the decline in kidney function [59,61]. In one study, compared with an eGFR ≥90 mL/min/1.73 m2, eGFRs between 60 to 89, 45 to 59, and 15 to 44 mL/min/1.73 were associated with 16, 37, and 64 percent greater risks of all-cause infection related hospitalization, respectively .
Careful attention should be paid to preventive measures such as influenza and pneumococcal immunization [62,63].
We agree with the following 2012 KDIGO guidelines :
●Adults with all stages of CKD should be offered annual vaccination with influenza virus unless contraindicated.
●Adults with stage 4 and 5 CKD who are at high risk of progression of CKD should be immunized against hepatitis B and the response confirmed by immunologic testing.
●Adults with CKD stages 4 and 5 should be vaccinated with polyvalent pneumococcal vaccine unless contraindicated. Patients who have received pneumococcal vaccination should be offered revaccination within five years.
Specific recommendations are discussed elsewhere. (See "Pneumococcal vaccination in adults", section on 'Approach to vaccination'.)
Other — A comprehensive study of a patient with CKD or end-stage kidney disease (ESKD) should include examination of the external eye and direct ophthalmoscopy. Advanced kidney disease of any etiology induces eye findings that signal the need for initiation or intensification of therapy. These include conjunctival erythema (which may be noted when high plasma phosphate levels induce corneal and conjunctival precipitation of calcium pyrophosphate) [64-66].
Profound uremia may rarely be complicated by transient cortical blindness; this is termed uremic amaurosis, which occurs in association with preserved pupillary contraction on light exposure and normal funduscopic findings. This abnormality clears within 24 to 48 hours of initiating dialytic therapy .
REFERRAL TO NEPHROLOGISTS — Patients with CKD should be referred to a nephrologist when the estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m2 in order to discuss and potentially plan for kidney replacement therapy. There is less consensus about referral for patients with higher eGFRs although severely increased albuminuria and nephrotic-range albuminuria are generally considered to be indications for referral even when eGFR is normal. This issue and other indications for referral to a nephrologist are discussed elsewhere. (See "Definition and staging of chronic kidney disease in adults", section on 'Referral to a specialist'.)
Lower costs and/or decreased morbidity and mortality may be associated with early referral and care by nephrologists [68-78].
In most studies, referral to the nephrologist is considered late if it is within one to six months of the requirement for kidney replacement therapy . Such late referrals are extremely common in the United States [80-82]. In various studies, 25 to 50 percent of patients beginning chronic kidney replacement therapy in the United States required dialysis within one month of their first nephrology visit [80,81,83]; in addition, 22 to 49 percent of patients were first seen by a nephrologist less than four months prior to the initiation of dialysis [80,84]. Disturbingly, some patients received no medical care at all before the hospitalization leading to initiation of kidney replacement .
Similar patterns relating to late referral have been reported from other countries [86-88]. The proportion of dialysis patients who required dialysis within one month of the first visit to a nephrologist ranged from 25 percent in Paris, France  to 58 percent in Sao Paulo, Brazil . The prevalence of late referral can also have significant regional variation within a country; in the larger cities of Australia, the proportion of patients referred within three months of needing to start dialysis ranged from 14 to 44 percent .
Causes of late referral — Late referral to the nephrologist can be due to unavoidable causes, the referral biases of clinicians, patient factors, socioeconomic status of the patient, and/or the structure of the healthcare system(s) within a certain country [89-91].
Unavoidable causes — Unavoidable causes of late referral include end-stage kidney disease (ESKD) that follows acute kidney injury (AKI), "asymptomatic" kidney failure only presenting at an advanced stage, or a patient's refusal to seek help until symptoms occur.
Patients may resist referral to a nephrologist for a variety of reasons, including patient denial regarding the presence of kidney failure, lack of appropriate understanding of their condition, fear of dialysis procedures, fear of cost, distance from treatment center, or the desire to remain with the local clinician. The frequency of unavoidable late referral ranges from 12 to 60 percent [84,86,92,93].
Referral biases of clinicians — There are clear differences among clinicians in the rate of referral of patients with CKD to a nephrologist . Several factors might influence nephrology referral decisions by clinicians, including:
●Lack of training about guidelines regarding timing or indications for referral .
●Poor communication between referring clinicians and specialists, which has been implicated as a factor that adversely affects the quality and cost of patient care [81,95-97].
●Economic factors, including fear of losing patients and the loss of income from office visits, hospitalizations, or tests. In addition, nephrologists may subsequently refer patients to other specialists for nonrenal issues that can be handled by primary clinicians.
Structure of the health care system — In most resource-limited countries, patients have limited access to medical care, commonly resulting in the need for emergency dialysis upon presentation to the nephrologist. Unfortunately, this type of presentation is also common in resource-abundant countries such as the United States, where many patients have no direct, insured access to medical care .
The structural and economic constraints imposed upon referring clinicians by health care organizations may also dictate the frequency and timing of referral to the nephrologist:
●In the United Kingdom and Canada, and within certain health plans in the United States, a patient may be seen by a nephrologist only after referral from a primary care physician (PCP). Referrals from such physicians may be limited by some of the factors previously mentioned.
●Pressure to contain costs by avoiding subspecialty referral is a policy promoted by some health maintenance organizations (HMOs) in the United States.
Subsequently, certain payers have developed disease management organizations, which offer a continuum of care beginning with diseases that cause kidney failure through the requirement for kidney replacement therapy, and have placed the nephrologist at the center of the patient-care team . This development could potentially reverse earlier trends and channel patients to the nephrologist in larger numbers and in a more timely manner.
Patient factors — Socioeconomic patient characteristics are also associated with late referral in some studies. This was illustrated in a review of 460 patients starting dialysis over a four-year period, of whom 46, 37, and 17 percent presented less than one month, one to three months, and more than three months prior to initiating dialysis . Those presenting at less than one month were more likely to have an alcohol use disorder (34 percent), a substance use disorder (37 percent), or be homeless or unemployed (28 percent) compared with 10 percent or fewer among those presenting at more than three months.
Consequences of late referral — The clinical and economic consequences of late referral to the nephrologist have mostly been described from uncontrolled or retrospective studies. Comparison of study results is further hindered by differences in definition of early and late referral and duration of follow-up.
Metabolic and hematologic findings — Patients referred late to the nephrologist invariably present with biochemical indices of severe uremia and an imminent need for dialysis [83-87,100]. In most studies addressing this, compared with patients referred early, patients referred late also have a significantly greater degree of acidosis, anemia, hypocalcemia, hypoalbuminemia, and hyperphosphatemia.
As an example, in a study examining the predialysis care of 135 patients with CKD, compared with early referral, those referred late (referred less than four months before the initiation of dialysis) had a higher prevalence of hypoalbuminemia (80 versus 56 percent) and a hematocrit of less than 28 percent (55 versus 33 percent) .
Advanced metabolic abnormalities at the time of initiation of dialysis reflect suboptimal care of progressive CKD; this possibly contributes to the high morbidity and costs of initiation of dialysis.
Hospitalization and cost — The delayed referral of patients with CKD is associated with a greater likelihood of prolonged hospitalization around the time of initiation of dialysis, as well as with higher costs [76,101]. This was best shown in a 2007 meta-analysis of eight studies consisting of 3220 patients in which number of days in hospital was significantly higher for late- versus early-referral patients (25 versus 14 days, respectively) .
Late-referral patients are also hospitalized more frequently for the initiation of dialysis [76,81,85,86,92,102,103]. These adverse associations are probably due in part to a greater prevalence of uremic complications and other serious illnesses, such as uncontrolled hypertension and pulmonary edema. In addition, vascular access placement and the management of complications related to this aspect of dialysis care are a frequent cause of hospitalization and a large component of the cost of care [80,104,105].
Despite the pressure to control health care costs by avoiding hospitalization, a large proportion of patients with ESKD in the United States are hospitalized for initiation of dialysis [85,106]. This may in part be due to late referral, but perceptions of nephrologists that dialysis should be initiated in the hospital setting, as well as regional regulations requiring a first dialysis to be at an inpatient facility, may also have contributed. Multidisciplinary patient education and follow-up programs may decrease the likelihood of hospitalization for initiation of dialysis and lower the frequency of emergency initiation and time spent in hospital during the first month of dialysis .
Selection of dialysis modality, emergent first dialysis, and permanent access — Early referral to the nephrologist enables discussion of the preferred mode of kidney replacement therapy to suit the patient's lifestyle and timely placement of a permanent dialysis access. An informed decision on dialysis modality made under nonemergency circumstances reduces the likelihood of a subsequent change in dialysis modality [83,92]. Furthermore, patients referred late are less likely to receive a kidney transplant .
The majority of patients referred to the nephrologist in a timely manner tend to have a functioning permanent access at the start of dialysis compared with only a small minority of late referrals [84,85,87,88,92,108-110]. One study evaluated the clinical characteristics of 139 patients who, prior to the initiation of dialysis, received medical care provided by a nephrologist or a generalist or no medical care . Compared with the group cared for by generalists, patients treated by nephrologists were significantly less likely to have required a temporary venous catheter for the first dialysis (36 versus 89 percent). The late referral of patients has therefore resulted in a large number of dialysis patients without permanent vascular access at the time of initiation of dialysis. (See "Central venous catheters for acute and chronic hemodialysis access and their management".)
Late referrals may also affect the choice of chronic hemodialysis access. (See "Approach to the adult patient needing vascular access for chronic hemodialysis".)
Loss of kidney function and rehabilitation — Late referral to a nephrologist may not permit the timely institution of therapy aimed at decreasing the rate of loss of kidney function. Early institution of an angiotensin-converting enzyme (ACE) inhibitor and other renoprotective therapy such as strict blood pressure and glycemic control has its greatest impact when started early . The potential benefits of appropriate care were illustrated in a study of 726 patients newly referred to nephrology; the rate of decline in GFR decreased substantially from 5.4 mL/min/1.73 m2 per year during the five years prior to nephrology referral to a decline of 0.35 mL/min/1.73 m2 per year during the five years after nephrology referral . Protective therapy appears to have the greatest impact if it is initiated before the plasma creatinine concentration exceeds 1.5 to 2 mg/dL (132 to 176 micromol/L) or GFR is less than 60 mL/min/1.73 m2 . Waiting until the disease progresses further diminishes the likelihood of a successful response. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Dietary recommendations for patients with nondialysis chronic kidney disease" and "Treatment of diabetic kidney disease".)
Timely referral also permits the enrollment of patients into a multidisciplinary program that addresses the physical, logistic, social, emotional, and vocational problems encountered during life on dialysis. Participation in such predialysis educational programs has been associated with higher employment rates and delay in the need for initiation of kidney replacement therapy .
Mortality — Many studies have examined the association between timing of nephrology referral and deaths subsequent to initiation of dialysis, particularly during the first year of dialysis. To best assess this association, a 2007 meta-analysis evaluated this correlation among 20 studies that included over 12,000 patients . Compared with early referral, late referral was associated with a significantly increased risk of all-cause mortality (risk ratio [RR] 1.99, 95% CI 1.66-2.39) and one-year mortality (RR 2.08, 95% CI 1.31-3.31). However, significant heterogeneity was noted. Similar findings were noted in subsequent studies [101,115,116] and did not seem to vary with the cause of kidney disease (diabetic versus nondiabetic kidney disease) or whether patients were older . The positive impact of nephrology care on mortality was confirmed in a retrospective cohort study of 39,031 patients in the Department of Veteran's Health Affairs system . Patients with multiple nephrology visits during the year had a substantially lower mortality compared with patients who were not seen by a nephrologist or seen only once by a nephrologist, with adjusted hazard ratios of 0.80, 0.68, and 0.40 for two, three, and four nephrology visits, respectively.
Studies relating to mortality may suffer from lead-time bias. In general, such bias may be observed with early diagnosis and/or early initiation of treatment of a condition, resulting in the patient being expected to live longer from the time of diagnosis and/or initiation of treatment.
Future studies relating to the timing of initiation of dialysis may consider the effect of lead-time bias by adjusting for the estimated duration of time the patient would have remained off dialysis, which could be predicted using an estimated rate of decline of kidney function.
Comanagement with primary care provider — Comanagement of the patient with the primary care provider is a common strategy at early stages of CKD. Renoprotective therapy (eg, ACE inhibitor, angiotensin receptor blocker [ARB], and rigorous blood pressure control) should be instituted as early as possible after identifying the presence of progressive CKD. Protective therapy has the greatest impact if it is initiated before the plasma creatinine concentration exceeds 1.2 (106 micromol/L) and 1.5 mg/dL (133 micromol/L) in females and males, respectively, or when the eGFR is <60 mL/min/1.73 m2. At this point, most patients have already lost more than one-half of their eGFR. Waiting until the disease progresses further diminishes the likelihood of a successful response but still should be attempted. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and 'Slowing the rate of progression' above.)
Multidisciplinary chronic kidney disease clinic — The optimal medical care of CKD patients may be best provided by a team of health care professionals who practice at a single site (ie, a CKD clinic), following the principles of the chronic disease model of care . Such CKD clinics focus on guideline-driven nephrology care, management of comorbidities, lifestyle modification, and patient education in order to optimize patient outcomes. Observational and nonrandomized prospective studies have suggested that, compared with standard nephrology care, patients who attend a multidisciplinary CKD clinic have fewer hospitalizations, are more likely to have an arterial-venous fistula rather than graft or catheter, are more likely to start dialysis as an outpatient, are more likely to adhere to established CKD anemia or mineral and bone disease (MBD) goals, and may have improved survival [102,118-121].
Care management programs — The benefits of an outpatient care management program were demonstrated in a randomized, controlled trial that included 130 patients with GFR <30 mL/min/1.73 m2 . Patients were assigned to either standard care or to a "Healthy Transitions Program," which utilized nurse care managers supported by a protocol-driven informatics system that provided daily reports that identified incomplete process steps for each patient. Discussion and decision regarding kidney replacement modality (KRT) was identified as a critical process step, as were discussions regarding dietary education, medication reconciliation, and home safety.
The overall hospitalization rate was lower with the Healthy Transitions Program compared with a control standard care group (0.61 versus 0.92 per year, respectively), a result driven by a few patients with multiple hospitalizations in the control group. The most frequent cause of hospitalization was volume overload. Peritoneal dialysis was the initial KRT in more patients in the Healthy Transitions group compared with control (23 versus 3 percent, respectively). Hemodialysis was started without hospitalization in more patients in the Healthy Transitions group compared with control (58 versus 23 percent). Catheters were less common in the Healthy Transitions group compared with control (37 versus 69 percent respectively). Despite the small sample size, these data suggest better outcomes with a protocol-defined care management program.
The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) CKD guidelines suggest management of CKD patients in a multidisciplinary setting, with access to dietary counseling, kidney replacement therapies, transplant options, vascular access surgery, and ethical, psychological and social care .
PREPARATION FOR AND INITIATION OF KIDNEY REPLACEMENT THERAPY — It is important to identify patients who may eventually require kidney replacement therapy since adequate preparation can decrease morbidity and perhaps mortality. Early identification enables dialysis to be initiated at the optimal time with a functioning chronic access and may also permit the recruitment and evaluation of family members for the placement of a kidney allograft prior to the need for dialysis. In addition, the ability of the individual to psychologically accept the requirement of lifelong kidney replacement therapy is often diminished if inadequate time has elapsed between the time of recognition of end-stage kidney disease (ESKD) and the initiation of dialysis.
CKD progresses at a variable rate due to differences in the clinical course of the underlying diseases (particularly between individuals) and the recognition that the natural history of progressive kidney disease can be altered by various therapeutic interventions, particularly strict blood pressure control with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor (see 'Slowing the rate of progression' above). As a result, exactly if and when a patient may require dialysis or kidney transplantation is unclear. In addition, some patients refuse kidney replacement therapy until the onset of absolute indications, while others desire early initiation to avoid the complications of severe CKD, such as malnutrition.
Choice of kidney replacement therapy — Once it is determined that kidney replacement therapy will eventually be medically indicated, the patient should be counseled to consider the advantages and disadvantages of hemodialysis (in-center or at home), peritoneal dialysis (continuous or intermittent modalities), and kidney transplantation (living or deceased donor) [124,125]. The option of conservative management should also be discussed among patients who are unwilling or unable to undergo kidney replacement therapy. The 2015 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend that patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 should be educated concerning these issues . (See "Kidney palliative care: Conservative kidney management" and "Kidney palliative care: Withdrawal of dialysis" and "Kidney palliative care: Principles, benefits, and core components".)
Kidney transplantation is the treatment of choice for ESKD. A successful kidney transplant improves the quality of life and reduces the mortality risk for most patients when compared with maintenance dialysis. To facilitate early transplantation, a 2008 National Kidney Foundation (NKF)-KDOQI conference suggested early education and referral to a transplantation center plus the identification of potential living donors .
However, not all patients are appropriate candidates for a kidney allograft, because of absolute and/or relative contraindications to this procedure or the subsequent required medications. (See "Kidney transplantation in adults: Patient survival after kidney transplantation" and "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient".)
Living-donor transplants, if available, have the additional advantage of being performed with minimal delay, thereby permitting preemptive transplantation (transplantation prior to dialysis). Such patients appear to have improved graft survival compared with those who undergo a period of dialysis before transplantation . (See "Kidney transplantation in adults: Dialysis issues prior to and after kidney transplantation" and "Kidney transplantation in adults: Risk factors for graft failure".)
For these individuals and for those who are suitable transplant recipients, but must wait for an available kidney, the choice between hemodialysis or peritoneal dialysis is influenced by a number of considerations such as availability, convenience, comorbid conditions, home situation, age, and the ability to tolerate volume shifts. (See "Dialysis modality and patient outcome" and "Evaluating patients for chronic peritoneal dialysis and selection of modality".)
In the United States, the universal availability of kidney replacement therapy forces the nephrologist to consider its application in every patient in whom it might be indicated. However, the patient, particularly older adults and terminally ill, may decline kidney replacement therapy, a choice which is assuming more prominence as patients and clinicians grapple with the increasing use of advance directives and the laudable goals of death with dignity and life with quality. We agree with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines that conservative management of ESKD should be an option for such patients . (See 'Conservative management of kidney failure' below and "Kidney palliative care: Withdrawal of dialysis".)
Preparation for hemodialysis — Hemodialysis requires a stable access to the bloodstream to permit dialysis to be performed (see "Overview of the hemodialysis apparatus"). The access should generally be placed in the nondominant upper extremity because of the increased risk of infection and more severe consequences of arterial steal syndrome with lower extremity grafts. Venipuncture should therefore be restricted to the arm not chosen for eventual access placement so that the veins in the other arm will be preserved.
There are three major types of vascular access for maintenance hemodialysis: primary arteriovenous (AV) fistulas, AV grafts, and tunneled hemodialysis catheters. To facilitate placement of a permanent vascular access, we agree with the 2008 Society for Vascular Surgery (SVS) guidelines that recommend referral to an access surgeon when the patient has late stage 4 CKD, defined by an eGFR of <20 to 25 mL/min/1.73 m2 . (See "Approach to the adult patient needing vascular access for chronic hemodialysis".)
Arteriovenous fistulas — AV fistulas are the preferred form of vascular access given their significantly higher long-term patency rates and lower rate of complications. Since an AV fistula requires months to mature and is the access of choice, patients should be referred for surgery to attempt access construction when it is estimated that the patient is within one year of the anticipated need for dialysis, as manifested by an eGFR <25 mL/min/1.73 m2, a plasma creatinine concentration >4 mg/mL (354 micromol/L), or a rapid rate of progression. The 2006 KDOQI guidelines recommend that a fistula be placed at least six months prior to the anticipated start of hemodialysis . (See "Arteriovenous fistula creation for hemodialysis and its complications", section on 'Timing of AV fistula creation'.)
There are several types of AV fistulas, each of which is typically constructed with an end-to-side vein-to-artery anastomosis. The type chosen is based upon clinical evaluation and vascular mapping. AV fistulas have good long-term patency and infrequently develop infectious complications. A well-constructed radial cephalic fistula that functions for the first six months can be expected to function for up to 20 years. (See "Patient evaluation prior to placement of hemodialysis arteriovenous access" and "Arteriovenous fistula creation for hemodialysis and its complications", section on 'Types by anatomic location' and "Arteriovenous fistula creation for hemodialysis and its complications", section on 'Fistula creation'.)
The patient should be instructed in the care of the fistula. Such care includes routinely checking for a thrill and notifying the nephrologist if this is not present. The arm that has the fistula should not be used for blood drawing or for blood pressure checks. Patients should avoid sleeping on the access arm, avoid tight clothing on the access, and not carry anything that weighs more than 5 pounds with that arm. In addition, the fistula should be regularly examined by a clinician. (See "Overview of hemodialysis arteriovenous fistula maintenance and thrombosis prevention".)
Arteriovenous grafts — AV grafts are constructed by interposing a graft between an artery and vein, most commonly polytetrafluoroethylene (PTFE). AV grafts can provide excellent vascular access in patients who have inadequate vascular anatomy to support an AV fistula. PTFE has good surgical handling characteristics, and grafts of this material can usually be used two weeks after placement. However, AV grafts have a higher long-term complication rate (eg, infection, thrombosis) compared with primary fistulas. The 2006 KDOQI guidelines recommend that a synthetic graft be placed at least three to six weeks prior to the anticipated start of hemodialysis . (See "Arteriovenous graft creation for hemodialysis and its complications", section on 'Timing of AV graft creation'.)
As for a fistula, the patient should be instructed in the care of the AV graft. Such care includes routinely checking for a thrill and notifying the nephrologist if this is not present. The arm that has the graft should not be used for blood drawing or for blood pressure checks. Patients should avoid sleeping on the access arm, avoid tight clothing on the access, and not carry anything that weighs more than 5 pounds with that arm. The graft should be regularly examined by a clinician. (See "Overview of hemodialysis arteriovenous graft maintenance and thrombosis prevention".)
Tunneled hemodialysis catheters — Following placement, typically in the right internal jugular vein, tunneled hemodialysis catheters can be used immediately. (See "Central venous catheters for acute and chronic hemodialysis access and their management".)
Tunneled hemodialysis catheters are primarily used as intermediate-duration vascular access during maturation of AV fistulas. They can also provide acceptable long-term access in patients with contraindications to AV access or those who have exhausted all available sites. Nevertheless, tunneled hemodialysis catheters are inferior to AV access as long-term access since they provide lower flows and have higher rates of infection and other complications. (See "Approach to the adult patient needing vascular access for chronic hemodialysis".)
Preparation for peritoneal dialysis — Peritoneal dialysis catheters, which are placed into the abdominal cavity, can be used immediately after placement . However, to minimize the risk of fluid leak, it is preferable to wait at least 10 to 14 days before beginning dialysis. If dialysis is required less than 10 days following catheter placement, small volume exchanges performed in the recumbent position can be performed with little risk of leak. (See "Placement of the peritoneal dialysis catheter".)
Preparation for kidney transplantation — Preparation for kidney transplantation, which principally involves evaluation of the potential kidney transplant recipient and the living donor, is discussed in detail separately. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient" and "Kidney transplantation in adults: Living unrelated donors".)
Many patients, however, may not even be referred for evaluation for transplantation. Among 426,489 patients who started dialysis between 2005 and 2009, 12.5 percent had reportedly not been assessed for transplantation .
A number of studies have shown that females, Black patients, Hispanic patients, Native American patients, patients dialyzed in for-profit centers, and patients without private insurance are less likely to report having been assessed for transplantation, placed on a waitlist, or transplanted [131-141].
A living-donor kidney transplant program in which a home-based education approach is added to conventional, standard, clinic-based transplant may enhance kidney donation among African Americans. In a randomized study, this combined approach, compared with a clinic-alone education, resulted in significantly more living-donor inquires (77 versus 52 percent), living-donor evaluations (48 versus 17 percent), and eventual kidney transplantation (45 versus 14 percent) in African Americans .
In the United States, patients with higher education levels may have an advantage in obtaining kidney transplantation. In a study of 3245 incident dialysis patients, those with college degrees were approximately three times more likely than high school graduates to be waitlisted or undergo kidney transplantation . Although these results must be confirmed, it appears that education level contributes to the disparity in transplant referrals and operations .
Indications for kidney replacement therapy — There are several clinical indications to initiate dialysis in patients with CKD. These are discussed in detail elsewhere. (See "Indications for initiation of dialysis in chronic kidney disease".)
These include [125,145,146]:
●Pericarditis or pleuritis (urgent indication).
●Progressive uremic encephalopathy or neuropathy, with signs such as confusion, asterixis, myoclonus, wrist or foot drop, or, in severe, cases, seizures (urgent indication).
●A clinically significant bleeding diathesis attributable to uremia (urgent indication).
●Fluid overload refractory to diuretics.
●Hypertension poorly responsive to antihypertensive medications.
●Persistent metabolic disturbances that are refractory to medical therapy. These include hyperkalemia, hyponatremia, metabolic acidosis, hypercalcemia, hypocalcemia, and hyperphosphatemia.
●Persistent nausea and vomiting.
●Evidence of malnutrition.
Relative indications for the initiation of dialysis include decreased attentiveness and cognitive tasking, depression, persistent pruritus, or the restless leg syndrome.
We suggest that, among patients with progressive CKD, clinicians must be vigilant for the presence of symptoms and/or signs of uremia, and patients should also be fully informed of any symptoms of uremia to be able to contact their clinicians appropriately. Dialysis should be considered based upon clinical factors plus the eGFR. Dialysis should be initiated in the patient with symptoms and/or signs due to uremia. (See "Indications for initiation of dialysis in chronic kidney disease".)
Among asymptomatic patients with progressive CKD, the timing of initiation of dialysis is unclear, and there is no specific threshold eGFR level that has been established for the initiation of dialysis. The Initiating Dialysis Early and Late (IDEAL) study failed to demonstrate a difference between planned "early" and planned "late" dialysis initiation, although a limitation of this study was that patients crossed over between the two groups .The 2012 KDIGO guidelines suggest that dialysis be initiated when there are signs or symptoms attributable to kidney failure (such as serositis, acid-base or electrolyte disorders not easily corrected medically, pruritus); an inability to control volume status or blood pressure; a progressive deterioration in nutritional status that is refractory to dietary interventions; or cognitive impairment . The 2012 KDIGO guidelines state that such signs and symptoms often but not invariably occur when the eGFR is between 5 and 10 mL/min/1.73 m2.
All approaches require close follow-up, early nephrology referral, and adequate advanced dialysis planning (including the presence of a functioning peritoneal or vascular access and referral for transplantation). A detailed discussion of the indications for dialysis in the patient with CKD can be found elsewhere. (See "Indications for initiation of dialysis in chronic kidney disease".)
CONSERVATIVE MANAGEMENT OF KIDNEY FAILURE — Patients may elect to withhold dialysis [148-150]. We agree with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines that conservative management of end-stage kidney disease (ESKD) should be an option for all patients who decide not to pursue kidney replacement therapy . Conservative care includes the management of symptoms, advance-care planning, and provision of appropriate palliative care. (See "Kidney palliative care: Conservative kidney management" and "Kidney palliative care: Withdrawal of dialysis" and "Kidney palliative care: Principles, benefits, and core components".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Chronic kidney disease (The Basics)" and "Patient education: Peritoneal dialysis (The Basics)" and "Patient education: Dialysis and diet (The Basics)" and "Patient education: Bone problems caused by kidney disease (The Basics)" and "Patient education: Medicines for chronic kidney disease (The Basics)")
●Beyond the Basics topics (see "Patient education: Chronic kidney disease (Beyond the Basics)" and "Patient education: Dialysis or kidney transplantation — which is right for me? (Beyond the Basics)" and "Patient education: Hemodialysis (Beyond the Basics)" and "Patient education: Peritoneal dialysis (Beyond the Basics)" and "Patient education: Protein in the urine (proteinuria) (Beyond the Basics)" and "Patient education: Split urine collection for orthostatic proteinuria (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition of chronic kidney disease (CKD) – CKD is defined as the presence of kidney damage (usually detected as urinary albumin excretion of 30 mg/day or more, or equivalent) or decreased kidney function (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) for three or more months, irrespective of the cause. The persistence of the damage or decreased function for at least three months is necessary to distinguish CKD from acute kidney disease. Classification, or staging, of CKD provides a guide to management. (See 'Definition and classification' above.)
●Complications of CKD – CKD is associated with a higher risk of cardiovascular disease, end-stage kidney disease (ESKD), infection, malignancy, and mortality. (See 'Association with cardiovascular disease, end-stage kidney disease, and mortality' above and 'Infection and vaccination' above.)
Complications of the loss of kidney function include disorders of fluid and electrolyte balance, such as volume overload, hyperkalemia, metabolic acidosis, and hyperphosphatemia, as well as abnormalities related to hormonal or systemic dysfunction, such as anorexia, nausea, vomiting, fatigue, hypertension, anemia, malnutrition, hyperlipidemia, and bone disease. (See 'Treatment of the complications of severe CKD' above.)
●Overview of management – The management of CKD includes:
•Treatment of reversible causes of kidney dysfunction. (See 'Acute on chronic kidney disease' above.)
•Slowing the progression of kidney disease. This includes blood pressure control as well as additional therapies in patients with proteinuria, defined as measured or estimated albuminuria ≥300 mg/day or measured or estimated proteinuria ≥500 mg/day (see 'Slowing the rate of progression' above):
-Patients with proteinuria should be treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); this issue is discussed in detail elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD'.)
-In addition, in patients with proteinuria, we recommend treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor (Grade 1B).
•Medical management – Medical management is required for the complications of CKD (described above). (See 'Treatment of the complications of severe CKD' above.)
•Nephrology referral – Patients with CKD should be referred to a nephrologist when eGFR is <30 mL/min/1.73 m2 in order to discuss and potentially plan for kidney replacement therapy. Comanagement of the patient with the primary care provider is a common strategy at early stages of CKD. The optimal medical care of later-stage CKD patients may be best provided by a team of healthcare professionals who practice at a single site (ie, a CKD clinic), following the principles of the chronic disease model of care. (See 'Referral to nephrologists' above.)
•Planning for kidney replacement therapy – It is important to identify patients who may eventually require kidney replacement therapy since adequate preparation can decrease morbidity and perhaps mortality. Such patients should be counseled to consider the advantages and disadvantages of hemodialysis (in-center or at home), peritoneal dialysis (continuous or intermittent modalities), and kidney transplantation (living or deceased donor). The option of conservative management should also be discussed among patients who are unwilling or unable to undergo kidney replacement therapy. Early referral to a surgeon for evaluation and establishment of arteriovenous (AV) access is needed for patients choosing hemodialysis. (See 'Preparation for and initiation of kidney replacement therapy' above and 'Conservative management of kidney failure' above.)
•Indications for dialysis – Clinical indications to initiate dialysis in patients with CKD include (see 'Indications for kidney replacement therapy' above and "Indications for initiation of dialysis in chronic kidney disease"):
-Pericarditis or pleuritis (urgent indication).
-Progressive uremic encephalopathy or neuropathy (urgent indication).
-A clinically significant bleeding diathesis attributable to uremia (urgent indication).
-Fluid overload refractory to diuretics.
-Hypertension poorly responsive to antihypertensive medications.
-Persistent metabolic disturbances that are refractory to medical therapy.
-Persistent nausea and vomiting.
-Evidence of malnutrition.
-Decreased attentiveness and cognitive tasking (relative indication).
-Depression, persistent pruritus, or the restless leg syndrome (relative indications).
•Conservative kidney management – Conservative management of ESKD should be an option for all patients who decide not to pursue kidney replacement therapy. Conservative care includes the management of symptoms, advance-care planning, and provision of appropriate palliative care. (See 'Conservative management of kidney failure' above and "Kidney palliative care: Withdrawal of dialysis" and "Kidney palliative care: Principles, benefits, and core components".)