#48763: Diagnosis and Management of Chronic Kidney Disease in Primary Care

Chronic kidney disease (CKD) is an increasingly common condition that has the potential to become a public health threat. CKD is defined as kidney damage or a decrease in kidney function for at least three months [1]. While it was once prevalent in 12.3% of the population, it is now seen in 14.0% [2]. In 2020, Medicare costs for the care of patients with CKD accounted for 25% of total expenditures [2]. Significant comorbidities include diabetes, hypertension, and cardiovascular disease (CVD). Caring for these patients and their comorbidities can be complex, especially with efforts concentrated toward preventing progression of CKD to end-stage renal disease (ESRD). Primary care physicians are often at the forefront of this care, whether as the physician initially diagnosing and managing the CKD or as the coordinator of specialist efforts. Guidelines for the management of patients with CKD are constantly evolving, and new data are frequently being published. The purpose of this course is to present current data on the diagnosis and management of CKD in the primary care setting.

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].

The prevalence of stage 3 CKD in Black Americans (7.6%) was higher than that among White Americans (5.9%) [2]. Regarding comorbidities, 21.5% of NHANES participants with CKD also had diagnosed hypertension and 38.0% had diagnosed diabetes [2].

The average Medicare cost per patient with CKD per year exceeded $25,920 in 2020 [2]. Those who had diabetes and CHF concurrent with CKD reached a cost of $36,578 per patient [2]. Comparatively, the average cost to care for a Medicare patient without diabetes, CHF, or CKD is $12,232 per year [2]. The economic burden to society is significant.

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].

Regarding racial differences, a large cohort study showed that Hispanic patients with CKD had twice the prevalence of low income and low educational attainment compared to White patients [10]. They also had significantly higher rates of self-reported diabetes and hypertension than Black or White patients. Mean glomerular filtration rate (GFR) at the time of the study was lower in Hispanic patients than Black or White patients, while median proteinuria was higher [11]. This study found Hispanic patients to have disproportionately lower socioeconomic status, less angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACE-I/ARB) use, poorer blood pressure control, and more severe CKD complications than non-Hispanics [11].

Poor CKD outcomes in Hispanics may be attributable to a number of factors. Low levels of education and health literacy and limited access to health care are common culprits in ethnic disparities in care, and these can apply to other ethnic minorities as well [12]. Furthermore, Hispanic patients may have difficulty understanding physician instructions regarding lifestyle modifications, medications, and many other aspects of care depending on their fluency in English or access to a healthcare provider who is fluent in Spanish [13]. Additionally, unique cultural characteristics, such as adherence to a traditional Hispanic diet that is high in potassium and phosphorus, may not be targeted by physicians as areas for directed patient education or may not be things that patients are willing to change [13].

African American race also carries associations with CKD status. In particular, there is an association between African American race and faster disease progression; African Americans experience 3.2 greater odds of a significant decline in GFR per year compared to White Americans [14,15,16]. The prevalence of advanced CKD is also higher in African American patients [16,17]. As mentioned, the odds of prevalent CKD are significantly lower in high-income African American patients compared to low-income patients [18]. Many of the typical precipitating factors are suspected to be the sources of these disparities, including unemployment, low level of education, limited access to healthy foods, and poor access to healthcare services [16].

All-cause hospitalization rates for Medicare patients with CKD are higher than for those without CKD [2]. This rate also increases with later stages of disease, as patients with stage 4 or 5 CKD have a 34% all-cause hospitalization rate compared to patients with stage 1 or 2 disease. Cardiovascular admissions are 56% higher in patients with stage 4 or 5 CKD compared to stage 1 or 2. In addition, 21.5% of patients with CKD were rehospitalized within 30 days of discharge in 2020; all-cause rehospitalization occurred at a higher rate (34%) in stage 4 and 5 patients compared to stage 1 or 2 (18.2%) [2]. Rehospitalization in patients with CKD is also higher in African Americans than White Americans, though African Americans and White Americans have similar rates of mortality [2]. The unadjusted mortality rate for patients with CKD who are 66 years of age and older declined more than 20% over a decade, from 144.9 per 1,000 patient years in 2010 to 115.1 per 1,000 patient years in 2019, with an increase in 2020 to 127.4 per 1,000 patient years at risk [2]. Mortality is higher in men than women. Among those with later stage CKD, mortality is 3.9% higher in Black Americans than White Americans [2].

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:

The simplest, most reliable, and recommended method to detect renal damage is by testing for albuminuria. Excessive albumin excretion is a reflection of primary kidney disease or renal involvement by a systemic vascular disorder such as follows long-standing hypertension, diabetes, and atherosclerosis. In select patients, screening could be initiated by urinalysis dipstick testing for proteinuria, which if positive would need to be confirmed by some measure of the albumin excretion rate. In adults at risk for CKD, urinary albumin dipstick testing and the measurement of the urinary albumin-to-creatinine ratio should be used[1]. The guidelines provided by the international Kidney Disease: Improving Global Outcomes (KDIGO) group recommend that an albumin-to-creatinine ratio >30 mg/g be used as the standard for establishing the diagnosis of CKD[19].

Another way to diagnose CKD, and the preferred method for detecting and monitoring abnormal kidney function, is the measure or estimation of GFR[19]. A determination of GFR should be made in all patients with renal disease or signs of impaired renal function. The GFR indicates the degree of renal functional impairment, is a useful guide to dosage adjustment of drugs cleared by the kidney, and can be used to follow the course of kidney disease and to assess the response to therapy.

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].

Serum creatinine alone, while adequate for assessment of acute kidney injury, should not be used to assess kidney function in CKD [19]. An estimated 83% of laboratories report an estimated GFR along with reporting serum creatinine results [23].

As noted, threshold abnormalities of albumin excretion and GFR are diagnostic of CKD only when demonstrated to have been present for longer than three months, thereby excluding the patient who may be in the recovery phase of an acute, reversible kidney injury. The presence of chronicity can be confirmed by follow-up testing or inferred from known structural abnormalities on renal imaging or by review of past records that permit estimation of GFR at an earlier date.

Although the presence of CKD can be established on the basis of albuminuria and reduced GFR, proper diagnosis also includes identifying the underlying cause, as this may have important therapeutic and other management implications. A host of etiologies can be responsible for renal damage and diminished function, including hypertension, diabetes, autoimmune diseases, glomerulonephritis, drug-induced nephritis, and lower urinary tract obstructive disorders [19]. Consultation with a nephrologist is appropriate in most cases to determine the underlying cause of CKD [19].

As of 2023, the U.S. Preventive Services Task Force (USPSTF) does not recommend regular screening for CKD in the general population [24]. Instead, the USPSTF concludes that the evidence is insufficient to assess the balance of benefits and harms of routine screening for chronic kidney disease in asymptomatic adults.

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]:

In 2013, the American College of Physicians released practice guidelines for CKD that recommend against screening asymptomatic patients without risk factors, owing to insufficient evidence that there is a benefit in screening these patients [25]. This group recommends against testing for proteinuria in adults with or without diabetes who are currently taking an ACE-I or an ARB.

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.

Other underlying causes of the renal damage leading to CKD are generally associated with unique mechanisms, including immune complex deposition and interstitial damage from prolonged use of nephrotoxic drugs. Acute kidney injury (AKI) may also lead to CKD if the initial insult has not been removed or if the initial injury has not been completely reversed. Even in cases of full recovery after AKI, the risk of developing CKD is increased [7]. Renal ischemia-reperfusion injury may also cause lasting damage [9].

Many of the complications and comorbidities associated with CKD stem from this initial damage and begin to manifest as renal damage progresses. Hypertension, a common comorbidity of CKD, can cause renal damage as well as be exacerbated by it, as discussed. Anemia is a common complication of CKD and is likely due to reduced renal production of erythropoietin, though other factors, such as uremia-induced inhibition of erythropoiesis, shortened erythrocyte survival, and disordered iron homeostasis, also play a role [11]. A study of patients with stage 3 CKD determined that renal anemia is associated with rapid progression to stage 4 and a higher risk of CVD and hospitalization [13].

Alterations in bone and mineral metabolism are commonly seen in patients with CKD, starting in early-stage disease. Hypocalcemia is common in these patients, often leading to parathyroid hyperplasia and secondary hyperparathyroidism [16]. The hypocalcemia is likely attributable to phosphate retention, skeletal resistance to parathyroid hormone (PTH), altered vitamin D metabolism, or a combination of these factors [27]. In line with altered vitamin D metabolism, patients with CKD also have defective intestinal calcium absorption. Hyperphosphatemia is also common, and the resultant elevation in the plasma calcium-phosphate product often leads to precipitation of calcium phosphate in soft tissues and to calcific changes in the walls of arterioles and small arteries [27]. These electrolyte derangements are largely attributable to intrarenal damage and hormonal abnormalities, both of which affect electrolyte excretion and reabsorption. Activation of fibroblast growth factor 23 (FGF-23) and PTH is implicated in the regulation of phosphate reabsorption in the tubules. FGF-23 also inhibits vitamin D production and promotes catabolism of vitamin D stores [28].

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.

For cases of CKD that do progress to late-stage kidney disease, it is also important to anticipate and prepare patients for renal replacement therapy [19]. The KDOQI guidelines recommend timely referral for planning renal replacement therapy in people with progressive CKD in whom the risk of kidney failure within one year is 10% to 20% or higher [19]. Patients with a GFR less than 30 mL/min/1.73 m² should be referred to a nephrologist to make preparations for impending end-stage disease and renal replacement therapy [19]. It is well to keep in mind, however, that acute, intercurrent declines in GFR are often due to reversible factors such as volume depletion, radiographic contrast or nephrotoxic drug use, and urinary tract obstruction; efforts should be made to correct these in order to appropriately address declines in GFR and determine whether true progression of the disease has occurred [19].

An intensive and multifactorial management approach is required for patients with renal disease in order to address all risk determinants. The mainstays of treatment are management of complications and/or comorbidities, lifestyle modification, and dialysis for patients with severe or late-stage disease. Some patients may be candidates for kidney transplant, although the wait for a non-related donor can be long. Psychosocial issues and patient education (primarily to ensure compliance with the established treatment plan) are important as well.

MANAGEMENT OF COMORBIDITIES

Diabetes

The KDOQI Work Group recommends an individualized hemoglobin A1c target ranging from <6.5% to <8.0% in patients with diabetes and CKD not treated with dialysis.

(https://www.kidney.org/sites/default/files/docs/diabetes-ckd-update-2012.pdf Last Accessed: September 14, 2020)

Level of Evidence: 1C (Most patients should receive the recommended course of action based on low-quality evidence.)

As described, diabetes is a common comorbidity in patients with CKD and, in some cases, can be responsible for the renal damage leading to the diagnosis of CKD. Numerous studies have shown that intensive glycemic control reduces albuminuria in patients with diabetes [26,30,31]. Hemoglobin A1c (HbA1c) should be kept to a target of 7% to prevent or delay microvascular complications, including diabetic kidney disease, except in those who are at risk for hypoglycemia with intensive glucose control [19,32]. A lower HbA1c target (e.g., <6.5% or <7%) may be selected for patients for whom there are more significant concerns regarding onset and progression of moderately increased albuminuria and nonfatal myocardial infarction, and for patients who are able to achieve such targets easily and without hypoglycemia [29].

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].

Due to decreased renal function, some antihyperglycemic medications are not adequately cleared and should be dosed appropriately to prevent hypoglycemia [35]. First-generation sulfonylureas should be avoided altogether in the patient with CKD; glipizide or glimepiride, second-generation sulfonylureas, is preferred and does not require dosage adjustment [35,36,37]. Adjustment of insulin dosage is not required for the usual patient but may become necessary toward the advent of ESRD. Metformin, a commonly used antihyperglycemic that can reportedly cause lactic acidosis when levels accumulate, was previously contraindicated in patients with serum creatinine ≥1.4 mg/dL [36]. However, in 2016, the U.S. Food and Drug Administration (FDA) expanded its labeling for metformin products to include patients with an estimated GFR of 45 mL/min/1.73 m² [38]. The KDOQI guidelines recommend metformin for patients with an eGFR ≥30 mL/min/1.73 m² and increased monitoring when eGFR is <60 mL/min/1.73 m². Dose adjustment is needed when the eGFR is <45 mL/min/1.73 m², and for some patients when the eGFR is 45–59 mL/min/1.73 m². When treated with metformin for more than four years, patients should be monitored for vitamin B12 deficiency [29].

KDOQI guidelines recommend treating patients with type 2 diabetes, CKD, and an eGFR ≥20 mL/min/1.73 m² with a sodium-glucose cotransporter 2 (SGLT2) inhibitor [29]. This recommendation is for kidney and cardiovascular protection. SGLT2 inhibitors have been shown to have safety and benefit in patients with CKD. If patients are already being treated with other glucose-lowering agents, an SGLT2 inhibitor can be added to the current treatment regimen. The choice of an SGLT2 inhibitor should prioritize agents with documented kidney or cardiovascular benefits and take eGFR into account [29]. In 2021, the FDA expanded approval of the SGLT2 inhibitor dapagliflozin to reduce the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression [39]. Though this agent is typically used to treat type 2 diabetes, benefits were consistently demonstrated regardless of the presence diabetes.

Dyslipidemia

In adults with newly identified CKD (including those treated with chronic dialysis or kidney transplantation), the KDOQI Work Group recommends evaluation with a lipid profile (i.e., total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides).

(https://kdigo.org/wp-content/uploads/2017/02/KDIGO-2013-Lipids-Guideline-English.pdf Last Accessed: September 11, 2023)

Level of Evidence: IC (Most patients should receive the recommended course of action based on low quality evidence.)

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.

Hypertension

Hypertension is both a cause and complication of CKD [40]. Approximately 50% to 75% of patients with CKD also have hypertension, and poorly controlled hypertension is associated with increased mortality, cardiovascular risk, and disease progression [1,41]. Data show that blood pressure control is often suboptimal in patients with hypertension and stage 3 CKD, especially in those at the highest risk of adverse outcomes due to diabetes or albuminuria [42]. Furthermore, the prevalence of treatment-resistant hypertension is high in patients with CKD, ranging from 12.1% to 48.3% depending on stage [43]. Treatment-resistant hypertension in patients with CKD is associated with Black race, male gender, larger waist circumference, diabetes, lower GFR, and higher albumin-to-creatinine ratio.

Regarding the evaluation and management of the patient with hypertension and CKD, KDIGO guidelines recommend that standardized office blood pressure measurement (in preference to routine office measurement) be obtained at every health encounter. Standardized office measurements are those obtained using recommended preparations and techniques in contrast to routine or "casual" measurements, which do not employ these preparations and techniques [40]. Out-of-office measurements with ambulatory blood pressure monitoring should be used to complement standardized office readings [40]. Clinicians should take into account the patient's CKD stage, CVD risk factors, comorbid conditions, adherence and barriers to lifestyle modification and drug therapy, and complications of antihypertensive therapy. Appropriate steps should be taken to determine the cause of hypertension, and if there is suspicion for renal artery disease as the cause, noninvasive imaging and referral to a nephrologist are recommended [40]. The goals of antihypertensive therapy should be to lower blood pressure, reduce the risk of CVD, and slow the progression of kidney disease. An appropriate blood pressure goal is <120/80 mm Hg, when tolerated, using standardized office blood pressure measurement [40]. KDIGO recommends that those who have a urine albumin excretion <30 mg/day and whose office blood pressure is consistently >140/90 mm Hg should be treated to ≤140/90 mm Hg [19].

In patients with diabetes, hypertension, and albuminuria, the Department of Veterans Affairs Guideline Panel recommends the use of an ACE-I or ARB to slow the progression of CKD, unless there is documentation of intolerance.

(https://www.healthquality.va.gov/guidelines/CD/ckd/VADoDCKDCPG2014.pdf Last Accessed: August 14, 2020)

Strength of Recommendation: Strong for

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].

Anemia

Anemia is a common finding in patients with CKD, associated with reduced quality of life and increased CVD, hospitalizations, and mortality [49]. Testing for hemoglobin should be carried out at least annually in all patients with CKD [49,50]. Men with hemoglobin <13.0 g/dL and women with hemoglobin <12.0 g/dL are considered anemic and warrant further evaluation with a complete blood count including red blood cell indices, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell count, differential, and platelet count [49,50]. Absolute reticulocyte count, serum ferritin, and transferrin saturation should also be obtained [49,50].

Anemic patients with CKD can be treated with erythropoiesis-stimulating agents (ESAs), which supplement the production of erythropoietin. Patients on ESA therapy should have their hemoglobin checked at least monthly [49,50]. ESA therapy should be dosed individually according to the patient's hemoglobin concentration, body weight, and clinical circumstances [50]. The frequency of administration should be based on CKD stage, treatment setting, efficacy considerations, patient tolerance and preference, and type of ESA [50]. Those who are not on dialysis can be administered ESA subcutaneously, while dialyzed patients may get ESA intravenously [49,50]. Patients receiving dialysis should also receive intravenous iron, though non-dialysis patients may receive iron orally. Iron should be administered monthly during initial ESA therapy and at least every three months after ESA treatment is stable [49,50].

Goals of treatment include a transferrin saturation >20% and serum ferritin >200 ng/mL in dialyzing patients and >100 ng/dL in non-dialyzing patients [50]. In those receiving ESA therapy, anemia should be corrected to a target hemoglobin of 11.0–12.0 g/dL [36]. The target hemoglobin should not exceed 13.0 g/dL, as no benefit has been demonstrated beyond this level [51].

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].

Vitamin and Mineral Imbalance

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].

In people with GFR <45 mL/min/1.73 m², the optimal PTH level is not known. If PTH levels cannot be controlled, it is appropriate to start phosphate binder therapy [16]. In patients with CKD stages 3–5, decisions about phosphate-lowering treatment should be based on progressively or persistently elevated serum phosphate. For patients receiving phosphate-lowering treatment, the KDIGO recommends restricting the dose of calcium-based phosphate binders [16]. Data from a 2013 review suggest that non-calcium-based phosphate binders are associated with lower all-cause mortality rates compared to calcium-based phosphate binders [46].

After kidney function has deteriorated to ESRD, maintaining normal serum phosphorus requires dietary restrictions, phosphate-binding medications, and dialysis. Even so, normal serum phosphorus remains elusive in many patients with stage 5 kidney disease. Researchers are testing novel targets that may inhibit intestinal transport of phosphorus to achieve better phosphate control [56].

Hypocalcemia is a classical feature of untreated CKD, in part secondary to diminished gastrointestinal uptake of calcium due to vitamin D deficiency. Because hypocalcemia contributes to the pathogenesis of secondary hyperparathyroidism and renal osteodystrophy, the KDIGO recommends maintaining serum calcium in the normal range, including the correction of hypocalcemia. While a retrospective analysis of a large dialysis cohort confirmed an association between hypocalcemia and mortality risk, two other observations raised doubts about the generalizability of the need to correct hypocalcemia [16]. The first observation is the potential harm for some adults with a positive calcium balance. (Note: serum calcium levels do not necessarily reflect calcium balance.) The second is that the prevalence of hypocalcemia may have increased after the introduction of calcimimetics in patients on dialysis. Retaining the original KDIGO recommendation (from 2009) on this issue supports the concept that patients developing hypocalcemia during calcimimetic treatment require aggressive calcium treatment. Given the unproven benefits of this treatment and the potential for harm, the 2017 KDIGO Work Group emphasizes an individualized approach to the treatment of hypocalcemia rather than recommending the correction of hypocalcemia for all patients, with the understanding that significant or symptomatic hypocalcemia should still be addressed [16].

The KDIGO recommends that vitamin D deficiency and insufficiency be corrected using treatment strategies recommended for the general population [16,19]. Routine prescribing of vitamin D supplements or analogs is not recommended in the absence of suspected or documented deficiency to suppress elevated PTH concentrations in people with CKD not on dialysis [19]. In patients with stage 5 CKD who require PTH-lowering therapy, calcimimetics, calcitriol, or vitamin D analogs, or a combination of calcimimetics with calcitriol or vitamin D analogs, is recommended [16].

Vitamin D insufficiency is independently related to impaired GFR and correlated with mortality risk in patients with CKD [47,57]. A meta-analysis of 10 prospective studies showed that higher vitamin D levels are associated with significantly improved survival in patients with CKD [42]. A 2013 meta-analysis of 20 observational studies shows that vitamin D treatment is associated with decreased risk of all-cause and CV mortality in patients with CKD who are not undergoing dialysis [58]. Vitamin D supplementation in patients with CKD can also reduce left atrial volume index, which is associated with decreased cardiovascular morbidity and mortality [59]. However, the ability to improve other markers of cardiac function with vitamin D supplementation is lacking evidence. Randomized controlled trials show that although paricalcitol supplementation can reduce PTH levels, it does not appear to improve left ventricular structure or function or diastolic dysfunction [60,61]. Additionally, data from a prospective study indicate that bisphosphonate treatment in female patients with CKD is associated with lower risk of death, although not with lower risk of cardiovascular events [62].

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.

Adequate treatment of CKD is multidimensional and involves lifestyle modification as well as pharmacologic interventions, making adherence to treatment of particular concern. Patients with CKD have been shown to have similarly poor medication adherence as patients without CKD in a large study of antihypertensive adherence [80]. Compliance may be complicated by high rates of resistant hypertension requiring multiple medications for adequate blood pressure control [61].

An analysis of 2,288 NHANES III participants with CKD assessed adherence to lifestyle modifications by assigning healthy lifestyle scores to each participant based on factors like smoking, BMI, physical activity, and diet [64]. Those who were non-smokers experienced the greatest reduction in all-cause mortality. Regular exercisers also experienced a 20% reduction mortality compared to non-exercisers. Those with a healthy BMI (18.5–22 kg/m²) had a 30% decrease in mortality [64].

A study of older adults with CKD revealed that they typically take more than five medications, often prescribed by multiple physicians [72]. Interviews with these subjects also revealed that patients have assigned priorities to their medications that may not be in agreement with physicians' priorities. While most subjects expressed a desire to be adherent to medication, many admitted to regularly skipping medications that they perceived as less important, even if that view was not consistent with physicians' recommendations. Many patients also reported reluctance in addressing their concerns with physicians and finding these discussions unsatisfying. Improved communication between patients and physicians can improve understanding of medication importance and thus adherence.

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.

Timely referral of the patient with severe, progressive CKD is important for patient and physician alike, in order to ensure sufficient time to prepare for the eventually of dialysis or organ transplantation. The best preparation, in terms of choice, efficiency, safety, and cost, requires weeks to months. For the patient, it involves discussions of the rationale, requirements, needed lifestyle alterations, and technical aspects of dialysis and transplantation. For physicians, in anticipation that the patient will likely need to undergo dialysis, timely preparation requires planning for the optimal time to establish peritoneal or vascular access [85].

Due to the high prevalence of CKD in relation to the number of nephrologists, much of CKD care is dispensed by primary care physicians. However, this care tends to be suboptimal, characterized by underuse of important medications, failure to reach therapeutic blood pressure goals, and late referral to nephrologists [87]. A national study of primary care providers and nephrologists revealed that primary care clinicians were less likely to recognize CKD, differed from nephrologists in recommendations for diagnostic testing, and recommended referral less [88]. A study of patients with CKD treated by primary care physicians showed that only 54% achieved KDOQI blood pressure goals, 70% did not have annual urine testing, and 26% were prescribed nephrotoxic drugs [89]. Lack of awareness of published clinical practice guidelines and lack of available clinical and administrative resources were cited as barriers to care [89]. Patients who are referred late to nephrologists have significantly higher mortality compared to those who are referred early, and late referrals also result in increased early hospitalization for CKD [70].

There is a need for primary care in the identification and treatment of CKD. Evaluation of risk factors and diagnostic testing can easily be done in this setting. Primary care physicians can also provide valuable counseling on lifestyle modifications and are often adept in the treatment of diabetes and hypertension, both of which are cornerstones of treatment in CKD [90]. Early recognition of CKD and early initiation of ACE-I or ARB therapy can provide significant benefit in slowing the progression of CKD [90].

Overcoming barriers to treatment by primary care providers involves many possible strategies. Widespread education on clinical practice guidelines would provide marked benefit, though there may still be difficulty translating these into practice [91]. Routine reporting of GFR when reporting serum creatinine has also shown promise as an effective strategy for early recognition of CKD [74]. Clinical decision support tools may provide benefit and comfort in caring for patients with CKD in the primary care setting [76]. Technologic advances such as telemedicine also improve primary care access to the latest information and guidelines on CKD [92]. Finally, overall reorganization of healthcare delivery that emphasizes multidisciplinary care and the role of primary care, such as the patient-centered medical home model, may produce rewarding results in CKD care [90].