|
| A) | 21 to 39 years | ||
| B) | 40 to 59 years | ||
| C) | 60 to 74 years | ||
| D) | 65 years or older |
The overall prevalence of CKD in the United States adult general population was 14.0% in 2017–March 2020, with CKD stage 3 (5.1%) being the most prevalent. Overall, CKD prevalence has remained relatively stable during the last two decades [2]. Point prevalence of CKD increases with age, from 1.3% of individuals younger than 65 years of age, compared with 20.1% of individuals 65 years of age and older. Men have a slightly higher prevalence than women [2]. The prevalence of diabetes increased markedly from 2005–2008 to 2017–March 2020 among individuals with (35.6%) and without (9.5%) CKD; this is more than the number of CKD patients with hypertension or cardiovascular disease [2]. The greatest number of patients with CKD overall have stage 3 disease [2].
| A) | African American race is associated with faster disease progression. | ||
| B) | Hispanic patients have more severe CKD complications than non-Hispanics. | ||
| C) | Lower socioeconomic status carries increased odds of CKD development compared with higher socioeconomic status. | ||
| D) | All of the above |
There are socioeconomic differences in the prevalence of CKD. In the United States, White Americans in the lowest income quartile have 86% increased odds of having CKD compared to the highest income quartile [3]. Additionally, odds are increased by two times among unemployed African Americans and six times among unemployed Mexican Americans compared to their employed counterparts [4]. When controlling for race, high socioeconomic status still shows an inverse association with CKD, as demonstrated by a 2010 study involving only African American participants [5].
Homeless adults with CKD tend to be younger, disproportionately male, and suffer from higher rates of depression and substance abuse than non-homeless patients [6]. Homeless adults also experience significantly higher risk of ESRD and death and are more likely to use acute care services than non-homeless patients [7].
Geographic differences may also present emerging risk factors for CKD. It is hypothesized that ambient temperature can increase the risk of CKD by predisposing patients to kidney stones [8]. Living in a poorly built environment, such as one with exposure to pollution and low walkability, may emerge as a risk factor for CKD given its association with other risk factors, like obesity, diabetes, and hypertension [9]. A greater number of moves to various residences in a patient's lifetime is also associated with lower prevalence of albuminuria and reduced kidney function, though the mechanisms for these differences are unknown [9].
| A) | presence of glomerular disease on renal biopsy. | ||
| B) | the triad of hypertension, diabetes, and anemia. | ||
| C) | elevated serum creatinine on two separate samples taken one week apart. | ||
| D) | renal damage or decreased renal function persisting for at least three months. |
As noted, CKD is defined by the presence of renal damage or decreased function that persists longer than three months, according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines [19]. The diagnosis may be made by the use of blood or urine laboratory markers of kidney damage or abnormal renal function, by the demonstration of structural damage on imaging studies, or by pathologic change on renal biopsy. This includes:
Abnormalities of urinary sediment: Red blood cell casts (glomerular injury), white cell casts (interstitial/tubular injury)
Abnormal rate of albumin excretion (albuminuria) and/or reduced GFR
Radiographic imaging abnormalities: Change in size or contour of the kidneys, hydronephrosis, polycystic disease, papillary necrosis
Pathologic abnormalities on renal biopsy: Vascular disease, glomerulitis, tubulointer-stitial damage
| A) | pathologic changes on renal biopsy. | ||
| B) | demonstration of renal structural damage on imaging. | ||
| C) | blood or urine laboratory markers of kidney damage or abnormal renal function. | ||
| D) | Any of the above |
As noted, CKD is defined by the presence of renal damage or decreased function that persists longer than three months, according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines [19]. The diagnosis may be made by the use of blood or urine laboratory markers of kidney damage or abnormal renal function, by the demonstration of structural damage on imaging studies, or by pathologic change on renal biopsy. This includes:
Abnormalities of urinary sediment: Red blood cell casts (glomerular injury), white cell casts (interstitial/tubular injury)
Abnormal rate of albumin excretion (albuminuria) and/or reduced GFR
Radiographic imaging abnormalities: Change in size or contour of the kidneys, hydronephrosis, polycystic disease, papillary necrosis
Pathologic abnormalities on renal biopsy: Vascular disease, glomerulitis, tubulointer-stitial damage
| A) | The Cockcroft-Gault equation | ||
| B) | The CKD Epidemiology Collaboration (CKD-EPI) equation | ||
| C) | The Modification of Diet in Renal Disease (MDRD) equation | ||
| D) | No equation is preferred over the others. |
A GFR less than 60 mL/min/1.73 m2 is diagnostic of CKD. Various prediction equations are available to determine GFR; however, the Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) study equations are recommended by KDOQI, with the MDRD equation being preferred to Cockcroft-Gault (Table 1) [19]. More recently, the National Kidney Foundation has shown support for use of the CKD Epidemiology Collaboration (CKD-EPI) equation as the best and least expensive estimator of GFR and an improvement over the MDRD equation (Table 2) [20,21]. Both the MDRD and CKD-EPI equations account for age and gender and provide corrective factors for African American race. However, the CKD-EPI equation has been shown to be more accurate and precise than the MDRD equation, especially at higher GFR levels, and results in fewer false-positive diagnoses[20,22]. The KDIGO guidelines recommend the CKD-EPI equation as well, citing that it is less biased, more accurate, and more precise than the MDRD equation; this equation can use creatinine or cystatin C to estimate GFR[19].
| A) | BUN/creatinine ratio. | ||
| B) | albumin-to-creatinine ratio. | ||
| C) | glomerular filtration rate (GFR). | ||
| D) | Either B or C |
CKD is staged according to the severity of disease, as determined by the degree of reduced GFR and albuminuria, in combination with the specific cause of the kidney disease. In KDOQI staging, there are five stages of increasing severity as determined by GFR, with the fifth stage representing complete renal failure (Table 3)[1]. The KDIGO staging has separate classifications depending on whether the staging is by GFR or by degree of albuminuria, measured as either albumin-to-creatinine ratio or albumin excretion rate. If GFR is used to stage these patients, then the stages are annotated as G1–G5, corresponding to decreasing GFR and worsening severity[19]. If by albuminuria, the stages are A1–A3, corresponding to increasing albumin-to-creatinine ratio or albumin excretion rate (AER) and worsening severity[19]:
Stage A1: Normal to mildly increased (AER<30 mg/day)
Stage A2: Moderately increased (AER 30–300 mg/day)
Stage A3: Severely increased (AER >300 mg/day)
| A) | stage 1. | ||
| B) | stage 2. | ||
| C) | stage 3. | ||
| D) | stage 4. |
KDOQI STAGING OF CHRONIC KIDNEY DISEASE
| Stage | Description |
|---|---|
| 1 | Kidney damage with normal or elevated GFR (≥90 mL/min/1.73 m2) |
| 2 | Kidney damage with mild decrease in GFR (60–89 mL/min/1.73 m2) |
| 3 | Moderate decrease in GFR (30–59 mL/min/1.73 m2) |
| 4 | Severe decrease in GFR (15–29 mL/min/1.73 m2) |
| 5 | Kidney failure (<15 mL/min/1.73 m2 or requires dialysis) |
| A) | Diabetes | ||
| B) | Hypertension | ||
| C) | Age 60 years or older | ||
| D) | Infrequent nonsteroidal anti-inflammatory drug (NSAID) use |
The KDOQI guidelines recommend considering risk factors for CKD at routine health examinations when deciding whether to evaluate patients for CKD; however, it does not have strict screening guidelines in place, such as at what age to initiate testing and how often [19]. The KDOQI recognizes the following as risk factors that may indicate a need to screen for kidney disease [19]:
Diabetes
Hypertension
Autoimmune diseases
Family history of CKD
Age 60 years or older
Daily nonsteroidal anti-inflammatory drug (NSAID) and nephrotoxic drug use
African American or Hispanic race
| A) | Flaccidity of the arteries is a contributing mechanism. | ||
| B) | Post-renal obstruction is the most common cause of CKD. | ||
| C) | In patients with hypertension, CKD is most often due to the nephrotoxic effects of beta- blockers. | ||
| D) | CKD resulting from diabetic nephropathy is thought to be due largely to hyperglycemic end-organ damage to the glomerulus. |
The pathophysiology of CKD is dependent on the underlying cause, the most common of which are the disease processes of diabetes and hypertension. Diabetic nephropathy has various proposed hypotheses for mechanisms of kidney damage, though it is most often and broadly attributed to hyperglycemic end-organ damage to the glomerulus, eventually to the point of proteinuria. Experts have suggested that there may be disadvantaged nephron development in those born to mothers with diabetes, predisposing the offspring to CKD during their lives. Some also posit that hyperglycemia sensitizes end-organs to hypertensive damage, and because diabetes and hypertension often occur together, this has an additive deleterious effect on the kidney [4]. The initial manifestation is often albuminuria and hyperfiltration (i.e., an elevation in GFR) [18]. Over time, albuminuria increases to the point of overt nephropathy, accompanied by a decline in GFR. Hyperglycemia-mediated overactivation of protein kinase C is also thought to be involved in progressive renal parenchymal damage, resulting in the loss of selective permeability in the glomerulus and an increase in local inflammation [26]. In addition to glomerular damage, thickening of the basement membrane and afferent and efferent arterioles may be noted [26].
Hypertensive nephropathy is another common cause of CKD and induces renal damage through a variety of mechanisms. One mechanism is sympathetic nervous overactivity resulting in constriction of efferent arterioles and decreased outflow from the glomerulus, allowing for increased oncotic pressure in the nephron. Activation of the renin-angiotensin-aldosterone system (RAAS) may also occur as a response to sympathetic nerve activity. Arterial stiffness, a central component of hypertension, is a contributing mechanism as well. Impaired salt and water excretion from sympathetic nervous overactivity or from RAAS activation serves to increase hypertension and thereby increase renal damage.
| A) | initiate dialysis before reaching stage 3 CKD. | ||
| B) | treat comorbidities and slow progression of disease. | ||
| C) | identify damaged portions of kidney for surgical resection. | ||
| D) | increase daily water intake to improve renal blood flow and maintain urine production. |
The management of CKD is multifaceted, involving a series of tactical measures (including the effective management of comorbidities) designed to reduce the risk of further damage and slow the progression of kidney disease. The clinician should first seek to identify and treat reversible causes, such as lower urinary tract obstruction, which should be considered in any patient with unexplained deterioration in renal function. Optimal glucose control in the patient with diabetes and blood pressure control in those with hypertension, as well as initiation of ACE-I or ARB therapy, are important to limit progression [1,19,29]. Certain nephrotoxic agents should be avoided if at all possible, especially in the patient with diabetes or receiving loop diuretics. These include NSAIDs, aminoglycoside antibiotics, and radiographic contrast material. Additional measures to protect the kidney and slow progression include smoking cessation, statin therapy to control hyperlipidemia, dietary protein restriction, and satisfactory treatment of metabolic acidosis.
| A) | Insulin | ||
| B) | NSAIDs | ||
| C) | Aminoglycoside antibiotics | ||
| D) | Radiographic contrast medium |
The management of CKD is multifaceted, involving a series of tactical measures (including the effective management of comorbidities) designed to reduce the risk of further damage and slow the progression of kidney disease. The clinician should first seek to identify and treat reversible causes, such as lower urinary tract obstruction, which should be considered in any patient with unexplained deterioration in renal function. Optimal glucose control in the patient with diabetes and blood pressure control in those with hypertension, as well as initiation of ACE-I or ARB therapy, are important to limit progression [1,19,29]. Certain nephrotoxic agents should be avoided if at all possible, especially in the patient with diabetes or receiving loop diuretics. These include NSAIDs, aminoglycoside antibiotics, and radiographic contrast material. Additional measures to protect the kidney and slow progression include smoking cessation, statin therapy to control hyperlipidemia, dietary protein restriction, and satisfactory treatment of metabolic acidosis.
| A) | A first-generation sulfonylurea | ||
| B) | An ACE-I, an ARB, and aliskiren | ||
| C) | Either an ACE-I or an ARB but not both | ||
| D) | Both an ACE-I and an ARB concurrently |
Though they are known for their renoprotective benefits in patients with diabetes, ACE-Is and ARBs should not be used for primary prevention of diabetic kidney disease in normotensive and normoalbuminuric patients, as there has been little evidence of benefits. However, these drugs should be first-line therapy for hypertension when albuminuria is present; otherwise, a dihydropyridine calcium channel blocker or diuretic can be considered. All three classes of drugs often are needed to attain blood pressure targets [29]. Treatment with an ACE-I or ARB should be titrated to the highest approved dose that is tolerated. Patients should be monitored for changes in blood pressure, serum creatinine, and serum potassium within two to four weeks of initiation or an increase in the dose of an ACE-I or ARB. Treatment is continued unless serum creatinine rises by more than 30% within four weeks following initiation of treatment or an increase in dose. Hyperkalemia associated with the use of an ACE-I or ARB often can be managed by employing measures to reduce serum potassium levels rather than decreasing the dose or immediately stopping the ACE-I or ARB [29]. Data from the NEPHRON-D study show that combination therapy of ACE-I and ARB together should be avoided in patients with diabetic nephropathy due to high risk of adverse outcomes [29,33]. The addition of aliskiren, a direct renin inhibitor, to either ACE-I or ARB therapy in patients with diabetes and CKD does not improve outcomes and may actually increase adverse events; thus, it should be avoided [29,34].
| A) | reducing all-cause mortality. | ||
| B) | improving kidney disease outcomes. | ||
| C) | slowing progression to end-stage disease. | ||
| D) | reducing the risk of a major atherosclerotic event. |
Because dyslipidemia is common in people with diabetes and CKD, reducing low-density lipoprotein cholesterol (LDL-C) with statins is essential for reducing the risk of major atherosclerotic events [19]. The use of statins has been shown to reduce the risk of cardiovascular-related kidney disease [29]. There is, however, no evidence that treatment of dyslipidemia improves kidney disease outcomes, progression to ESRD, or all-cause mortality [36]. Statins should not be started in patients on dialysis.
| A) | ACE-Is should be avoided in these patients. | ||
| B) | Sodium should be restricted to a goal of <4.5 g/day. | ||
| C) | Direct renin inhibitors such as aliskiren should be used in conjunction with an ACE-I/ARB to improve outcomes. | ||
| D) | Potassium-sparing diuretics should be used with caution in patients who are currently on ACE-I or ARB therapy due to the risk for hyperkalemia. |
Certain antihypertensive medications are preferred and should be used when appropriate. Renin-angiotensin-system (RAS) inhibitors, ACE-Is, and ARBs are preferred in patients with hypertension, CKD, and severely increased proteinuria without diabetes, and may be started in those with hypertension, CKD, and moderately increased proteinuria without diabetes. It is important to avoid any combination of ACE-I, ARB, and RAS therapy in patients with CKD, with or without diabetes [40]. Most patients should also be treated with diuretics. Thiazide diuretics are recommended for patients with stage 1 through 3 disease, while loop diuretics are recommended for patients with stage 4 or 5 disease [40]. Potassium-sparing diuretics should be used cautiously in patients who are concurrently on ACE-I or ARB therapy due to the risk for hyperkalemia [40]. Dietary sodium should be reduced to less than 2 grams per day according to KDIGO guidelines [19,40]. All patients should be considered on an individual basis and have a treatment plan suited to their health status, disease severity, and comorbidities. Patient education is important in ensuring appropriate self-management and adherence [40].
Evidence shows that a low-sodium diet, well known as an intervention for hypertension, is beneficial for reducing proteinuria in patients with CKD. In one study, sodium restriction plus ACE-I was shown to be superior to ACE-I plus ARB for reduction of proteinuria and blood pressure [44].
Data from a large cohort study show that only 46.1% of patients with CKD and hypertension were controlled to a blood pressure <130/80 mm Hg [45]. In addition, 32% of these patients required four or more antihypertensive medications, thus highlighting the difficulty of controlling blood pressure in this patient population.
In its 2013 guidelines, the American College of Physicians (ACP) also recommends the use of either an ACE-I or ARB in patients with hypertension and CKD [25]. They state that these medications reduce the risk of progression to ESRD, the risk of doubling serum creatinine, and the progression from microalbuminuria to macroalbuminuria [25]. While these medications are effective, they should be avoided in combination with each other or with aliskiren when used in patients with diabetes [46,47,48]. The ACP guideline also cites evidence that reveals no difference in ESRD or mortality between strict blood pressure control (128–133/75–81 mm Hg) and standard control (134–141/81–87 mm Hg) [25].
| A) | stroke. | ||
| B) | anuria. | ||
| C) | atrial fibrillation. | ||
| D) | vitamin D deficiency. |
Data show that ESA therapy may not be entirely safe in some patients. In one study, patients with CKD, anemia, and type 2 diabetes who received darbepoetin alfa did not experience reduced risk of death or CVD compared to placebo; however, they did experience a two-fold greater risk of stroke [52]. Additionally, high doses of ESA are associated with increased rates of hypertension and thrombotic events [53].
| A) | 200 mg/day. | ||
| B) | 1,000 mg/day. | ||
| C) | 2,000 mg/day. | ||
| D) | 4,000 mg/day. |
All patients with CKD should have serum calcium, phosphorus, and PTH levels measured. Frequency of measurement is dependent on staging; stage 3 patients should have serum calcium and phosphate levels checked every 6 to 12 months; the frequency for PTH measurement should be based on baseline level and CKD progression. In CKD stage 4, serum calcium and phosphate levels should be checked every 3 to 6 months, and PTH every 6 to 12 months. In CKD stage 5, serum calcium and phosphate levels should be checked every one to three months, and PTH should be checked every three to six months [16]. In patients who are not on hemodialysis, serum phosphorus should be kept between 2.7 mg/dL and 4.6 mg/dL [54,55]. Dietary phosphorus should be restricted to 800–1,000 mg/day, and serum phosphorus should be monitored monthly after initiation of dietary phosphorus restriction [56].
| A) | Sodium intake should be reduced to <2 g/day. | ||
| B) | Dietary intake of phosphorus rarely needs to be restricted. | ||
| C) | Guidelines recommend eliminating protein from the diet entirely. | ||
| D) | Hypokalemia has a high prevalence in patients with CKD, thus warranting potassium supplementation. |
Patients with CKD derive significant benefit from careful diet and regular physical activity. Nutrition is especially important in these patients, and they should receive expert dietary consultation to guide their transitions to an appropriate diet [19]. The KDIGO recommends reducing protein intake in order to limit the accumulation of harmful toxins, (e.g., uremic toxins) in the body [19]. Of note, the first large-scale study of dietary protein intake in patients with CKD—the MDRD study—did not show conclusive evidence regarding the efficacy of a protein-restricted diet in slowing the progression of CKD [63]. However, secondary analyses that have emerged since the publication of the initial results show potential benefit from a protein-restricted diet [64]. Guidelines recommend dietary protein restriction to 0.8 g/kg/day in adults with GFR <30 mL/min/1.73 m2; further protein restriction beyond this level offers no advantage [19]. High protein intake, defined as more than 1.3 g/kg/day, should be avoided in adults with CKD at risk for progression [19]. High total protein intake, especially high intake of non-dairy animal protein, may speed the decline in renal function in patients with CKD [19]. Protein should come from various alternative sources, including vegetable sources, as these are associated with decreased production of uremic toxins, are low in phosphorus, and may lead to lower production of endogenous acid compared to animal protein [65]. The efficacy of protein restriction, however, remains a topic of debate.
The KDIGO also recommends reducing sodium intake to <2 g per day in adults, citing that sodium excretion is already impaired in patients with CKD and that high intakes can worsen hypertension and proteinuria and blunt the response to the RAAS blockade [19]. A 2013 randomized controlled trial of 20 patients found that sodium restriction resulted in statistically significant reductions in blood pressure, extracellular fluid volume, albuminuria, and proteinuria in patients with stage 3 or 4 CKD [51]. A 2015 Cochrane Review, and a 2021 update of the review, found that sodium reduction in people with CKD reduced blood pressure and consistently reduced proteinuria, but whether such reductions could be maintained long term was not determined [66,67]. Further studies with larger sample sizes will be needed to expand on these findings in the future.
Dietary phosphorus is commonly restricted in patients with CKD. As discussed, impaired phosphorus metabolism can have serious implications, particularly in regards to mineral and bone disease. Higher serum phosphorus levels have been shown to be associated with increased mortality in patients with CKD [68]. Additionally, studies in rats demonstrate that uremic rats fed a low-phosphorus diet had slower progression of kidney disease than those on a non-restricted diet [69].
Restriction of dietary potassium is based on concern for hyperkalemia in patients with CKD not only because of reduced renal function but also because of concurrent diabetes or use of medications that can raise potassium levels, such as ACE-Is or ARBs [27]. Severely elevated potassium levels can put these patients at significant risk for ventricular arrhythmias. The prevalence of hyperkalemia is high in patients with CKD before they start dialysis, with one study reporting serum potassium ≥5.0 mEq/L in 54.2% of patients and ≥5.5 mEq/L in 31.5% of patients [70]. While a low-potassium diet may be encouraged, hypokalemia is also associated with increased risk of ESRD [71]. One possible risk of a low-potassium diet is that many potassium-containing foods, often fruits and vegetables, are also rich in fiber, and thus patients may risk missing out on important sources of fiber by excluding these foods. Fiber supplementation may be useful in these patients [72].
| A) | Increases rate of progression to ESRD | ||
| B) | Destroys normally functioning glomeruli | ||
| C) | Improves blood pressure and glycemic control and aids in weight loss | ||
| D) | Improves fluid balance through sweating to compensate for reduced urine production |
Patients with CKD should partake in physical activity to benefit their cardiovascular health and maintain a healthy weight [19]. Obesity is associated with glomerular hyperfiltration, increased kidney venous pressure, and glomerular hypertrophy, suggesting that obesity may be a risk factor for CKD [72]. Weight loss leads to improved blood pressure control, glycemic control, reduction of hyperfiltration, and proteinuria, suggesting that it can be an effective strategy in slowing the progression of kidney disease [72].
In the CKD population, exercise training has been shown to improve physical performance and functioning [75]. Many studies also support the role of exercise in improving hypertension, inflammation, oxidative stress, and other cardiovascular risk factors in patients with CKD, with no evidence of a harmful effect on renal function [76]. Referral to physical therapy or cardiac rehabilitation may be appropriate to safely increase physical activity in these patients [76]. A Cochrane Review found evidence for significant benefit of regular exercise on physical fitness, walking capacity, cardiovascular dimensions, health-related quality of life, and some nutritional parameters in adults with CKD [77]. A study of rats that had CKD induced by doxorubicin administration demonstrated that exercise ameliorated CKD by regulating renal cell apoptotic pathways; a greater beneficial effect was shown in rats that exercised for 60 minutes compared to 30 minutes, suggesting a duration-dependent benefit [78]. A randomized controlled trial of 90 patients with CKD undergoing either standard care or exercise intervention demonstrated significant improvements in the exercise patients [79]. These patients took part in a combined aerobic and resistance training program for 12 months. Cardiorespiratory fitness (measured as peak oxygen consumption [VO2 max]), body composition, and diastolic function all improved significantly in this time period [79]. An extended program may produce further benefits.
| A) | oliguria for more than three days. | ||
| B) | oliguria for more than five days. | ||
| C) | a 5 mL/min/1.73 m2 or greater decline in GFR in one year. | ||
| D) | a 5 mL/min/1.73 m2 or greater decline in GFR in three years. |
Primary care physicians often have questions about monitoring patients with CKD. The KDIGO guidelines recommend at least annual testing for reassessment of GFR and albuminuria in patients with CKD to monitor for progression of disease; those at higher risk for progression should be assessed more frequently [19]. Though small fluctuations in GFR may occur, a decline in an entire GFR category or a ≥25% decrease in GFR from baseline is cause for concern and signifies disease progression [19]. A 5 mL/min/1.73 m2 or greater decline in GFR per year is considered rapid progression [19]. As mentioned, prognosis is generally informed by factors associated with CKD progression, including cause of CKD, level of GFR, level of albuminuria, age, sex, race/ethnicity, elevated blood pressure, hyperglycemia, dyslipidemia, smoking, obesity, CVD, and exposure to nephrotoxic agents [19]. The American College of Physicians recommends against testing for proteinuria in adults with or without diabetes who are taking an ACE-I or ARB, citing no additional benefit with testing [25]. Patients who have significant complications of CKD, such as anemia and mineral and bone disease, should have these monitored, as discussed.
| A) | Unexplained hematuria | ||
| B) | High-grade albuminuria | ||
| C) | Difficulty determining the cause of kidney disease | ||
| D) | All of the above |
Referral of the patient with CKD to a nephrologist is dependent on a number of considerations, including the stage of kidney disease and severity of illness, the primary care physician's experience managing CKD, and practice patterns and access to subspecialty service in the given geographic locale. In general, all patients with severe disease—late stage 3 or early stage 4 (GFR in the range of 30–35 mL/min)—should be referred, as most patients with this degree of renal dysfunction are known to have progressive kidney disease and are at risk for progressing soon to ESRD. Indications for earlier referral include the presence of high-grade albuminuria (AER >300 mg/day), difficulty determining the cause of kidney disease, unexplained hematuria, and the presence of resistant comorbidities or complications such as hypertension, anemia, hyperkalemia, and problems of calcium-phosphate metabolism.