Nephrology

Severe renal arteriosclerosis was associated with a ninefold increased risk of atherosclerotic cardiovascular disease in patients with lupus nephritis, based on data from an observational study of 189 individuals.

Mohammed Haneefa Nizamudeen/Getty Images

Atherosclerotic cardiovascular disease (ASCVD) has traditionally been thought to be a late complication of systemic lupus erythematosus (SLE), but this has been challenged in recent population-based studies of patients with SLE and lupus nephritis (LN) that indicated an early and increased risk of ASCVD at the time of diagnosis. However, it is unclear which early risk factors may predispose patients to ASCVD, Shivani Garg, MD, of the University of Wisconsin, Madison, and colleagues wrote in a study published in Arthritis Care & Research.

In patients with IgA nephropathy and renal transplantation, previous studies have shown that severe renal arteriosclerosis (r-ASCL) based on kidney biopsies at the time of diagnosis predicts ASCVD, but “a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence,” possibly because of underreporting of r-ASCL. Dr. Garg and colleagues also noted the problem of underreporting of r-ASCL in their own previous study of its prevalence in LN patients at the time of diagnosis.

To get a more detailed view of how r-ASCL may be linked to early occurrence of ASCVD in LN patients, Dr. Garg and coauthors identified 189 consecutive patients with incident LN who underwent diagnostic biopsies between 1994 and 2017. The median age of the patients was 25 years, 78% were women, and 73% were white. The researchers developed a composite score for r-ASCL severity based on reported and overread biopsies.

Overall, 31% of the patients had any reported r-ASCL, and 7% had moderate-severe r-ASCL. After incorporating systematically reexamined r-ASCL grades, the prevalence of any and moderate-severe r-ASCL increased to 39% and 12%, respectively.

Based on their composite of reported and overread r-ASCL grade, severe r-ASCL in diagnostic LN biopsies was associated with a ninefold increased risk of ASCVD.

The researchers identified 22 incident ASCVD events over an 11-year follow-up for an overall 12% incidence of ASCVD in LN. ASCVD was defined as ischemic heart disease (including myocardial infarction, coronary artery revascularization, abnormal stress test, abnormal angiogram, and events documented by a cardiologist); stroke and transient ischemic attack (TIA); and peripheral vascular disease. Incident ASCVD was defined as the first ASCVD event between 1 and 10 years after LN diagnosis.

The most common ASCVD events were stroke or TIA (12 patients), events related to ischemic heart disease (7 patients), and events related to peripheral vascular disease (3 patients).

Lack of statin use

The researchers also hypothesized that the presence of gaps in statin use among eligible LN patients would be present in their study population. “Among the 20 patients with incident ASCVD events after LN diagnosis in our cohort, none was on statin therapy at the time of LN diagnosis,” the researchers said, noting that current guidelines from the American College of Rheumatology and the European League Against Rheumatism (now known as the European Alliance of Associations for Rheumatology) recommend initiating statin therapy at the time of LN diagnosis in all patients who have hyperlipidemia and chronic kidney disease (CKD) stage ≥3. “Further, 11 patients (55%) met high-risk criteria (hyperlipidemia and CKD stage ≥3) to implement statin therapy at the time of LN diagnosis, yet only one patient (9%) was initiated on statin therapy.” In addition, patients with stage 3 or higher CKD were more likely to develop ASCVD than patients without stage 3 or higher CKD, they said.

The study findings were limited by several factors including the majority white study population, the ability to overread only 25% of the biopsies, and the lack of data on the potential role of chronic lesions in ASCVD, the researchers noted. However, the results were strengthened by the use of a validated LN cohort, and the data provide “the basis to establish severe composite r-ASCL as a predictor of ASCVD events using a larger sample size in different cohorts,” they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Severe renal arteriosclerosis was associated with a ninefold increased risk of atherosclerotic cardiovascular disease in patients with lupus nephritis, based on data from an observational study of 189 individuals.

Mohammed Haneefa Nizamudeen/Getty Images

Atherosclerotic cardiovascular disease (ASCVD) has traditionally been thought to be a late complication of systemic lupus erythematosus (SLE), but this has been challenged in recent population-based studies of patients with SLE and lupus nephritis (LN) that indicated an early and increased risk of ASCVD at the time of diagnosis. However, it is unclear which early risk factors may predispose patients to ASCVD, Shivani Garg, MD, of the University of Wisconsin, Madison, and colleagues wrote in a study published in Arthritis Care & Research.

In patients with IgA nephropathy and renal transplantation, previous studies have shown that severe renal arteriosclerosis (r-ASCL) based on kidney biopsies at the time of diagnosis predicts ASCVD, but “a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence,” possibly because of underreporting of r-ASCL. Dr. Garg and colleagues also noted the problem of underreporting of r-ASCL in their own previous study of its prevalence in LN patients at the time of diagnosis.

To get a more detailed view of how r-ASCL may be linked to early occurrence of ASCVD in LN patients, Dr. Garg and coauthors identified 189 consecutive patients with incident LN who underwent diagnostic biopsies between 1994 and 2017. The median age of the patients was 25 years, 78% were women, and 73% were white. The researchers developed a composite score for r-ASCL severity based on reported and overread biopsies.

Overall, 31% of the patients had any reported r-ASCL, and 7% had moderate-severe r-ASCL. After incorporating systematically reexamined r-ASCL grades, the prevalence of any and moderate-severe r-ASCL increased to 39% and 12%, respectively.

Based on their composite of reported and overread r-ASCL grade, severe r-ASCL in diagnostic LN biopsies was associated with a ninefold increased risk of ASCVD.

The researchers identified 22 incident ASCVD events over an 11-year follow-up for an overall 12% incidence of ASCVD in LN. ASCVD was defined as ischemic heart disease (including myocardial infarction, coronary artery revascularization, abnormal stress test, abnormal angiogram, and events documented by a cardiologist); stroke and transient ischemic attack (TIA); and peripheral vascular disease. Incident ASCVD was defined as the first ASCVD event between 1 and 10 years after LN diagnosis.

The most common ASCVD events were stroke or TIA (12 patients), events related to ischemic heart disease (7 patients), and events related to peripheral vascular disease (3 patients).

Lack of statin use

The researchers also hypothesized that the presence of gaps in statin use among eligible LN patients would be present in their study population. “Among the 20 patients with incident ASCVD events after LN diagnosis in our cohort, none was on statin therapy at the time of LN diagnosis,” the researchers said, noting that current guidelines from the American College of Rheumatology and the European League Against Rheumatism (now known as the European Alliance of Associations for Rheumatology) recommend initiating statin therapy at the time of LN diagnosis in all patients who have hyperlipidemia and chronic kidney disease (CKD) stage ≥3. “Further, 11 patients (55%) met high-risk criteria (hyperlipidemia and CKD stage ≥3) to implement statin therapy at the time of LN diagnosis, yet only one patient (9%) was initiated on statin therapy.” In addition, patients with stage 3 or higher CKD were more likely to develop ASCVD than patients without stage 3 or higher CKD, they said.

The study findings were limited by several factors including the majority white study population, the ability to overread only 25% of the biopsies, and the lack of data on the potential role of chronic lesions in ASCVD, the researchers noted. However, the results were strengthened by the use of a validated LN cohort, and the data provide “the basis to establish severe composite r-ASCL as a predictor of ASCVD events using a larger sample size in different cohorts,” they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Severe renal arteriosclerosis was associated with a ninefold increased risk of atherosclerotic cardiovascular disease in patients with lupus nephritis, based on data from an observational study of 189 individuals.

Mohammed Haneefa Nizamudeen/Getty Images

Atherosclerotic cardiovascular disease (ASCVD) has traditionally been thought to be a late complication of systemic lupus erythematosus (SLE), but this has been challenged in recent population-based studies of patients with SLE and lupus nephritis (LN) that indicated an early and increased risk of ASCVD at the time of diagnosis. However, it is unclear which early risk factors may predispose patients to ASCVD, Shivani Garg, MD, of the University of Wisconsin, Madison, and colleagues wrote in a study published in Arthritis Care & Research.

In patients with IgA nephropathy and renal transplantation, previous studies have shown that severe renal arteriosclerosis (r-ASCL) based on kidney biopsies at the time of diagnosis predicts ASCVD, but “a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence,” possibly because of underreporting of r-ASCL. Dr. Garg and colleagues also noted the problem of underreporting of r-ASCL in their own previous study of its prevalence in LN patients at the time of diagnosis.

To get a more detailed view of how r-ASCL may be linked to early occurrence of ASCVD in LN patients, Dr. Garg and coauthors identified 189 consecutive patients with incident LN who underwent diagnostic biopsies between 1994 and 2017. The median age of the patients was 25 years, 78% were women, and 73% were white. The researchers developed a composite score for r-ASCL severity based on reported and overread biopsies.

Overall, 31% of the patients had any reported r-ASCL, and 7% had moderate-severe r-ASCL. After incorporating systematically reexamined r-ASCL grades, the prevalence of any and moderate-severe r-ASCL increased to 39% and 12%, respectively.

Based on their composite of reported and overread r-ASCL grade, severe r-ASCL in diagnostic LN biopsies was associated with a ninefold increased risk of ASCVD.

The researchers identified 22 incident ASCVD events over an 11-year follow-up for an overall 12% incidence of ASCVD in LN. ASCVD was defined as ischemic heart disease (including myocardial infarction, coronary artery revascularization, abnormal stress test, abnormal angiogram, and events documented by a cardiologist); stroke and transient ischemic attack (TIA); and peripheral vascular disease. Incident ASCVD was defined as the first ASCVD event between 1 and 10 years after LN diagnosis.

The most common ASCVD events were stroke or TIA (12 patients), events related to ischemic heart disease (7 patients), and events related to peripheral vascular disease (3 patients).

Lack of statin use

The researchers also hypothesized that the presence of gaps in statin use among eligible LN patients would be present in their study population. “Among the 20 patients with incident ASCVD events after LN diagnosis in our cohort, none was on statin therapy at the time of LN diagnosis,” the researchers said, noting that current guidelines from the American College of Rheumatology and the European League Against Rheumatism (now known as the European Alliance of Associations for Rheumatology) recommend initiating statin therapy at the time of LN diagnosis in all patients who have hyperlipidemia and chronic kidney disease (CKD) stage ≥3. “Further, 11 patients (55%) met high-risk criteria (hyperlipidemia and CKD stage ≥3) to implement statin therapy at the time of LN diagnosis, yet only one patient (9%) was initiated on statin therapy.” In addition, patients with stage 3 or higher CKD were more likely to develop ASCVD than patients without stage 3 or higher CKD, they said.

The study findings were limited by several factors including the majority white study population, the ability to overread only 25% of the biopsies, and the lack of data on the potential role of chronic lesions in ASCVD, the researchers noted. However, the results were strengthened by the use of a validated LN cohort, and the data provide “the basis to establish severe composite r-ASCL as a predictor of ASCVD events using a larger sample size in different cohorts,” they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors during acute COVID-19 illness raises the risk for euglycemic diabetic ketoacidosis (euDKA), a new case series suggests.

Five patients with type 2 diabetes who were taking SGLT2 inhibitors presented in DKA despite having glucose levels below 300 mg/dL. The report was published online last month in AACE Clinical Case Reports by Rebecca J. Vitale, MD, and colleagues at Brigham and Women’s Hospital, Boston.

“A cluster of euglycemic DKA cases at our hospital during the first wave of the pandemic suggests that patients with diabetes taking SGLT2 inhibitors may be at enhanced risk for euDKA when they contract COVID-19,” senior author Naomi D.L. Fisher, MD, said in an interview.

Dr. Fisher, an endocrinologist, added: “This complication is preventable with the simple measure of holding the drug. We are hopeful that widespread patient and physician education will prevent future cases of euDKA as COVID-19 infections continue to surge.”

These cases underscore recommendations published early in the COVID-19 pandemic by an international panel, she noted.

“Patients who are acutely ill with nausea, vomiting, abdominal pain, or diarrhea, or who are experiencing loss of appetite with reduced food and fluid intake, should be advised to hold their SGLT2 inhibitor. This medication should not be resumed until patients are feeling better and eating and drinking normally.”  

On the other hand, “If patients with asymptomatic or mild COVID-19 infection are otherwise well, and are eating and drinking normally, there is no evidence that SGLT2 inhibitors need to be stopped. These patients should monitor [themselves] closely for worsening symptoms, especially resulting in poor hydration and nutrition, which would be reason to discontinue their medication.” 
 

Pay special attention to the elderly, those with complications

However, special consideration should be given to elderly patients and those with medical conditions known to increase the likelihood of severe infection, like heart failure and chronic obstructive pulmonary disease, Dr. Fisher added.

The SGLT2 inhibitor class of drugs causes significant urinary glucose excretion, and they are also diuretics. A decrease in available glucose and volume depletion are probably both important contributors to euDKA, she explained.

With COVID-19 infection the euDKA risk is compounded by several mechanisms. Most cases of euDKA are associated with an underlying state of starvation that can be triggered by vomiting, diarrhea, loss of appetite, and poor oral intake.

In addition – although not yet known for certain – SARS-CoV-2 may also be toxic to pancreatic beta cells and thus reduce insulin secretion. The maladaptive inflammatory response seen with COVID-19 may also contribute, she said.  

The patients in the current case series were three men and two women seen between March and May 2020. They ranged in age from 52 to 79 years.

None had a prior history of DKA or any known diabetes complications. In all of them, antihyperglycemic medications, including SGLT2 inhibitors, were stopped on hospital admission. The patients were initially treated with intravenous insulin, and then subcutaneous insulin after the DKA diagnosis.

Three of the patients were discharged to rehabilitation facilities on hospital days 28-47 and one (age 53 years) was discharged home on day 11. The other patient also had hypertension and nonalcoholic steatohepatitis.

A version of this article first appeared on Medscape.com.

Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors during acute COVID-19 illness raises the risk for euglycemic diabetic ketoacidosis (euDKA), a new case series suggests.

Five patients with type 2 diabetes who were taking SGLT2 inhibitors presented in DKA despite having glucose levels below 300 mg/dL. The report was published online last month in AACE Clinical Case Reports by Rebecca J. Vitale, MD, and colleagues at Brigham and Women’s Hospital, Boston.

“A cluster of euglycemic DKA cases at our hospital during the first wave of the pandemic suggests that patients with diabetes taking SGLT2 inhibitors may be at enhanced risk for euDKA when they contract COVID-19,” senior author Naomi D.L. Fisher, MD, said in an interview.

Dr. Fisher, an endocrinologist, added: “This complication is preventable with the simple measure of holding the drug. We are hopeful that widespread patient and physician education will prevent future cases of euDKA as COVID-19 infections continue to surge.”

These cases underscore recommendations published early in the COVID-19 pandemic by an international panel, she noted.

“Patients who are acutely ill with nausea, vomiting, abdominal pain, or diarrhea, or who are experiencing loss of appetite with reduced food and fluid intake, should be advised to hold their SGLT2 inhibitor. This medication should not be resumed until patients are feeling better and eating and drinking normally.”  

On the other hand, “If patients with asymptomatic or mild COVID-19 infection are otherwise well, and are eating and drinking normally, there is no evidence that SGLT2 inhibitors need to be stopped. These patients should monitor [themselves] closely for worsening symptoms, especially resulting in poor hydration and nutrition, which would be reason to discontinue their medication.” 
 

Pay special attention to the elderly, those with complications

However, special consideration should be given to elderly patients and those with medical conditions known to increase the likelihood of severe infection, like heart failure and chronic obstructive pulmonary disease, Dr. Fisher added.

The SGLT2 inhibitor class of drugs causes significant urinary glucose excretion, and they are also diuretics. A decrease in available glucose and volume depletion are probably both important contributors to euDKA, she explained.

With COVID-19 infection the euDKA risk is compounded by several mechanisms. Most cases of euDKA are associated with an underlying state of starvation that can be triggered by vomiting, diarrhea, loss of appetite, and poor oral intake.

In addition – although not yet known for certain – SARS-CoV-2 may also be toxic to pancreatic beta cells and thus reduce insulin secretion. The maladaptive inflammatory response seen with COVID-19 may also contribute, she said.  

The patients in the current case series were three men and two women seen between March and May 2020. They ranged in age from 52 to 79 years.

None had a prior history of DKA or any known diabetes complications. In all of them, antihyperglycemic medications, including SGLT2 inhibitors, were stopped on hospital admission. The patients were initially treated with intravenous insulin, and then subcutaneous insulin after the DKA diagnosis.

Three of the patients were discharged to rehabilitation facilities on hospital days 28-47 and one (age 53 years) was discharged home on day 11. The other patient also had hypertension and nonalcoholic steatohepatitis.

A version of this article first appeared on Medscape.com.

Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors during acute COVID-19 illness raises the risk for euglycemic diabetic ketoacidosis (euDKA), a new case series suggests.

Five patients with type 2 diabetes who were taking SGLT2 inhibitors presented in DKA despite having glucose levels below 300 mg/dL. The report was published online last month in AACE Clinical Case Reports by Rebecca J. Vitale, MD, and colleagues at Brigham and Women’s Hospital, Boston.

“A cluster of euglycemic DKA cases at our hospital during the first wave of the pandemic suggests that patients with diabetes taking SGLT2 inhibitors may be at enhanced risk for euDKA when they contract COVID-19,” senior author Naomi D.L. Fisher, MD, said in an interview.

Dr. Fisher, an endocrinologist, added: “This complication is preventable with the simple measure of holding the drug. We are hopeful that widespread patient and physician education will prevent future cases of euDKA as COVID-19 infections continue to surge.”

These cases underscore recommendations published early in the COVID-19 pandemic by an international panel, she noted.

“Patients who are acutely ill with nausea, vomiting, abdominal pain, or diarrhea, or who are experiencing loss of appetite with reduced food and fluid intake, should be advised to hold their SGLT2 inhibitor. This medication should not be resumed until patients are feeling better and eating and drinking normally.”  

On the other hand, “If patients with asymptomatic or mild COVID-19 infection are otherwise well, and are eating and drinking normally, there is no evidence that SGLT2 inhibitors need to be stopped. These patients should monitor [themselves] closely for worsening symptoms, especially resulting in poor hydration and nutrition, which would be reason to discontinue their medication.” 
 

Pay special attention to the elderly, those with complications

However, special consideration should be given to elderly patients and those with medical conditions known to increase the likelihood of severe infection, like heart failure and chronic obstructive pulmonary disease, Dr. Fisher added.

The SGLT2 inhibitor class of drugs causes significant urinary glucose excretion, and they are also diuretics. A decrease in available glucose and volume depletion are probably both important contributors to euDKA, she explained.

With COVID-19 infection the euDKA risk is compounded by several mechanisms. Most cases of euDKA are associated with an underlying state of starvation that can be triggered by vomiting, diarrhea, loss of appetite, and poor oral intake.

In addition – although not yet known for certain – SARS-CoV-2 may also be toxic to pancreatic beta cells and thus reduce insulin secretion. The maladaptive inflammatory response seen with COVID-19 may also contribute, she said.  

The patients in the current case series were three men and two women seen between March and May 2020. They ranged in age from 52 to 79 years.

None had a prior history of DKA or any known diabetes complications. In all of them, antihyperglycemic medications, including SGLT2 inhibitors, were stopped on hospital admission. The patients were initially treated with intravenous insulin, and then subcutaneous insulin after the DKA diagnosis.

Three of the patients were discharged to rehabilitation facilities on hospital days 28-47 and one (age 53 years) was discharged home on day 11. The other patient also had hypertension and nonalcoholic steatohepatitis.

A version of this article first appeared on Medscape.com.

Background: Chronic kidney disease (CKD) is both a prothrombotic state and a condition with an elevated bleeding risk that increases in a linear fashion as estimated glomerular filtration rate (eGFR) decreases. These features of the disease along with the exclusion of patients with CKD from most anticoagulation trials have resulted in uncertainty about overall risks and benefits of anticoagulant use in this population.

The most compelling data were seen in the management of atrial fibrillation in early-stage CKD (five studies representing 11,332 patients) in which high-dose DOACs were associated with a lower risk for stroke or systemic embolism (risk ratio, 0.79; 95% confidence interval, 0.66-0.92), hemorrhagic stroke (RR, 0.48; 95% CI, 0.30-0.76), and all-cause death (RR, 0.88; 95% CI, 0.78-0.99). Overall stroke reduction was primarily hemorrhagic, and DOACs were equivalent to vitamin K antagonists (VKAs) for ischemic stroke risk.

The analysis also suggests that, in CKD, DOACs may reduce major bleeding when compared with VKAs across a variety of indications, though that finding was not statistically significant.

Efficacy of DOACs, compared with VKAs, in treatment of venous thromboembolism was uncertain, and patients with end-stage kidney disease and advanced CKD (creatinine clearance, less than 25 mL/min) were excluded from all trials comparing DOACs with VKAs, with limited overall data in these populations.

Bottom line: For patients with atrial fibrillation and early-stage CKD, direct oral anticoagulants show a promising risk-benefit profile when compared with vitamin K antagonists. Very few data are available on the safety and efficacy of anticoagulants in patients with advanced CKD and end-stage kidney disease.

Citation: Ha JT et al. Benefits and harms of oral anticoagulant therapy in chronic kidney disease. Ann Intern Med. 2019 Aug 6;171(3):181-9.

Dr. Herrle is a hospitalist at Maine Medical Center in Portland and at Stephens Memorial Hospital in Norway, Maine.

Background: Chronic kidney disease (CKD) is both a prothrombotic state and a condition with an elevated bleeding risk that increases in a linear fashion as estimated glomerular filtration rate (eGFR) decreases. These features of the disease along with the exclusion of patients with CKD from most anticoagulation trials have resulted in uncertainty about overall risks and benefits of anticoagulant use in this population.

The most compelling data were seen in the management of atrial fibrillation in early-stage CKD (five studies representing 11,332 patients) in which high-dose DOACs were associated with a lower risk for stroke or systemic embolism (risk ratio, 0.79; 95% confidence interval, 0.66-0.92), hemorrhagic stroke (RR, 0.48; 95% CI, 0.30-0.76), and all-cause death (RR, 0.88; 95% CI, 0.78-0.99). Overall stroke reduction was primarily hemorrhagic, and DOACs were equivalent to vitamin K antagonists (VKAs) for ischemic stroke risk.

The analysis also suggests that, in CKD, DOACs may reduce major bleeding when compared with VKAs across a variety of indications, though that finding was not statistically significant.

Efficacy of DOACs, compared with VKAs, in treatment of venous thromboembolism was uncertain, and patients with end-stage kidney disease and advanced CKD (creatinine clearance, less than 25 mL/min) were excluded from all trials comparing DOACs with VKAs, with limited overall data in these populations.

Bottom line: For patients with atrial fibrillation and early-stage CKD, direct oral anticoagulants show a promising risk-benefit profile when compared with vitamin K antagonists. Very few data are available on the safety and efficacy of anticoagulants in patients with advanced CKD and end-stage kidney disease.

Citation: Ha JT et al. Benefits and harms of oral anticoagulant therapy in chronic kidney disease. Ann Intern Med. 2019 Aug 6;171(3):181-9.

Dr. Herrle is a hospitalist at Maine Medical Center in Portland and at Stephens Memorial Hospital in Norway, Maine.

Background: Chronic kidney disease (CKD) is both a prothrombotic state and a condition with an elevated bleeding risk that increases in a linear fashion as estimated glomerular filtration rate (eGFR) decreases. These features of the disease along with the exclusion of patients with CKD from most anticoagulation trials have resulted in uncertainty about overall risks and benefits of anticoagulant use in this population.

The most compelling data were seen in the management of atrial fibrillation in early-stage CKD (five studies representing 11,332 patients) in which high-dose DOACs were associated with a lower risk for stroke or systemic embolism (risk ratio, 0.79; 95% confidence interval, 0.66-0.92), hemorrhagic stroke (RR, 0.48; 95% CI, 0.30-0.76), and all-cause death (RR, 0.88; 95% CI, 0.78-0.99). Overall stroke reduction was primarily hemorrhagic, and DOACs were equivalent to vitamin K antagonists (VKAs) for ischemic stroke risk.

The analysis also suggests that, in CKD, DOACs may reduce major bleeding when compared with VKAs across a variety of indications, though that finding was not statistically significant.

Efficacy of DOACs, compared with VKAs, in treatment of venous thromboembolism was uncertain, and patients with end-stage kidney disease and advanced CKD (creatinine clearance, less than 25 mL/min) were excluded from all trials comparing DOACs with VKAs, with limited overall data in these populations.

Bottom line: For patients with atrial fibrillation and early-stage CKD, direct oral anticoagulants show a promising risk-benefit profile when compared with vitamin K antagonists. Very few data are available on the safety and efficacy of anticoagulants in patients with advanced CKD and end-stage kidney disease.

Citation: Ha JT et al. Benefits and harms of oral anticoagulant therapy in chronic kidney disease. Ann Intern Med. 2019 Aug 6;171(3):181-9.

Dr. Herrle is a hospitalist at Maine Medical Center in Portland and at Stephens Memorial Hospital in Norway, Maine.

Is gouty nephropathy real? It’s a question that has been posed often in rheumatology over the last several decades.

HYWARDS/Getty Images

A new study found 36% of patients with untreated gout at a medical center in Vietnam have diffuse hyperechoic renal medulla as seen on ultrasound, which could indicate the presence of microcrystalline nephropathy. However, the results, published in Kidney International, may raise more questions than answers about the existence of gouty nephropathy and its relation to chronic kidney disease (CKD).

In their study, Thomas Bardin, MD, of the department of rheumatology at Lariboisière Hospital in Paris and colleagues evaluated 502 consecutive patients from Vien Gut Medical Center in Ho Chi Minh City, Vietnam, using B-mode renal ultrasound. The patients were mostly men with a median age of 46 years, body mass index of 25 kg/m², estimated disease duration of 4 years, and uricemia of 423.2 micromol/L (7.11 mg/dL). Patients had a median estimated glomerular filtration rate (eGFR) of 78 mL/min per 1.73 m². There was a history of hypertension in 112 patients (22.3%), type 2 diabetes in 58 patients (11.5%), renal lithiasis in 28 patients (5.6%), and coronary heart disease in 5 patients (1%).

While 39% of patients had previously used allopurinol for “a generally short period,” patients were not on urate-lowering therapy at the time of the study. Clinical tophi were present in 279 patients (55.6%), urate arthropathies in 154 patients (30.7%), and 43 patients (10.4%) used steroids daily.

B-mode renal ultrasound showed 181 patients (36%; 95% confidence interval, 32%-40%) had “hyperechoic pattern of Malpighi pyramids compared with the adjacent cortex,” which was “associated with twinkling artifacts” visible on color Doppler ultrasound. There was a significant association between renal medulla hyperechogenicity and patient age, disease duration, use of steroids, clinical tophi, and urate arthropathy (P less than .0001 for all). A significant association was also seen between renal medulla hyperechogenicity and decreased eGFR (P < .0001), proteinuria (P = .0006), leukocyturia (P = .0008), hypertension (P = .0008), hyperuricemia (P = .002), and coronary heart disease (P = .006).

In a multivariate analysis, there was a significant association between renal medulla hyperechogenicity and clinical tophi (odds ratio, 7.27; 95% CI, 3.68–15.19; P < .0001), urate arthropathy (OR, 3.46; 95% CI, 1.99–6.09; P < .0001), estimated gout duration (OR, 2.13; 95% CI, 1.55–2.96; P < .0001), double contour thickness (OR, 1.45; 95% CI, 1.06–1.97; P < .02), and eGFR (OR, 0.30; 95% CI, 0.09–0.89; P < .034).

“The finding was observed mainly in tophaceous gout, which involved a large proportion of our patients who had received very little treatment with urate-lowering drugs and was associated with moderately impaired renal function and urinary features compatible with tubulointerstitial nephritis,” Dr. Bardin and colleagues wrote in the study. The researchers also found “similar features” in 4 of 10 French patients at the Paris Necker Hospital in Paris, and noted that similar findings have been reported in Japan and Korea, which they said may mean hyperechoic medulla “is not unique to Vietnamese patients.”
 

Relation to CKD still unclear

In a related editorial, Federica Piani, MD, and Richard J. Johnson, MD, of the division of renal diseases and hypertension at the University of Colorado at Denver, Aurora, explained that gout was considered by some clinicians to be a cause of CKD in a time before urate-lowering therapies, because as many as 25% of patients with gout went on to experience kidney failure and about half experienced lower kidney function.

The association between gout and CKD was thought to be attributable to “frequent deposition of urate crystals in the tubular lumens and interstitium in the outer medulla of these patients,” but the concept was later challenged because “the crystals were generally found focally and did not readily explain the kidney damage.”

But even as interest in rheumatology moved away from the concept of gouty nephropathy to how serum uric acid impacts CKD, “the possibility that urate crystal deposition in the kidney could also be contributing to the kidney injury was never ruled out,” according to Dr. Piani and Dr. Johnson.

Kidney biopsies can sometimes miss urate crystals because the crystals dissolve if alcohol fixation is not used and because the biopsy site is often in the renal cortex, the authors noted. Recent research has identified that dual-energy CT scans can distinguish between calcium deposits and urate crystals better than ultrasound, and previous research from Thomas Bardin, MD, and colleagues in two patients noted a correlation between dual-energy CT scan findings of urate crystals and hyperechoic medulla findings on renal ultrasound.

The results by Dr. Bardin and associates, they said, “have reawakened the entity of urate microcrystalline nephropathy as a possible cause of CKD.”

Robert Terkeltaub, MD, professor of medicine at the University of California, San Diego, and section chief of Rheumatology at the San Diego VA Medical Center, said in an interview that he also believes the findings by Dr. Bardin and associates are real. He cited a study by Isabelle Ayoub, MD, and colleagues in Clinical Nephrology from 2016 that evaluated kidney biopsies in Germany and found medullary tophi were more likely to be present in patients with CKD than without.

“Chronic gouty nephropathy did not disappear. It still exists,” said Dr. Terkeltaub, who was not involved in the study by Dr. Bardin and colleagues.

The prospect that, if “you look hard enough, you’re going to see urate crystals and a pattern that’s attributed in the renal medulla” in patients with untreated gout is “very provocative, and interesting, and clinically relevant, and merits more investigation,” noted Dr. Terkeltaub, who is also president of the Gout, Hyperuricemia and Crystal-Associated Disease Network.

If verified, the results have important implications for patients with gout and its relationship to CKD, Dr. Terkeltaub said, but they raise “more questions than answers.

“I think it’s a really good wake-up call to start looking, doing good detective work here, and looking especially in people who have gout as opposed to just people with chronic kidney disease,” he said.

The authors reported no relevant conflicts of interest. Dr. Johnson, who coauthored an accompanying editorial, reported having equity in XORTX Therapeutics, serving as a consultant for Horizon Pharma, and having equity in Colorado Research Partners LLC. Dr. Terkeltaub reported receiving a research grant from AstraZeneca in the field of hyperuricemia and consultancies with AstraZeneca, Horizon, Sobi, Selecta Biosciences.

Is gouty nephropathy real? It’s a question that has been posed often in rheumatology over the last several decades.

HYWARDS/Getty Images

A new study found 36% of patients with untreated gout at a medical center in Vietnam have diffuse hyperechoic renal medulla as seen on ultrasound, which could indicate the presence of microcrystalline nephropathy. However, the results, published in Kidney International, may raise more questions than answers about the existence of gouty nephropathy and its relation to chronic kidney disease (CKD).

In their study, Thomas Bardin, MD, of the department of rheumatology at Lariboisière Hospital in Paris and colleagues evaluated 502 consecutive patients from Vien Gut Medical Center in Ho Chi Minh City, Vietnam, using B-mode renal ultrasound. The patients were mostly men with a median age of 46 years, body mass index of 25 kg/m², estimated disease duration of 4 years, and uricemia of 423.2 micromol/L (7.11 mg/dL). Patients had a median estimated glomerular filtration rate (eGFR) of 78 mL/min per 1.73 m². There was a history of hypertension in 112 patients (22.3%), type 2 diabetes in 58 patients (11.5%), renal lithiasis in 28 patients (5.6%), and coronary heart disease in 5 patients (1%).

While 39% of patients had previously used allopurinol for “a generally short period,” patients were not on urate-lowering therapy at the time of the study. Clinical tophi were present in 279 patients (55.6%), urate arthropathies in 154 patients (30.7%), and 43 patients (10.4%) used steroids daily.

B-mode renal ultrasound showed 181 patients (36%; 95% confidence interval, 32%-40%) had “hyperechoic pattern of Malpighi pyramids compared with the adjacent cortex,” which was “associated with twinkling artifacts” visible on color Doppler ultrasound. There was a significant association between renal medulla hyperechogenicity and patient age, disease duration, use of steroids, clinical tophi, and urate arthropathy (P less than .0001 for all). A significant association was also seen between renal medulla hyperechogenicity and decreased eGFR (P < .0001), proteinuria (P = .0006), leukocyturia (P = .0008), hypertension (P = .0008), hyperuricemia (P = .002), and coronary heart disease (P = .006).

In a multivariate analysis, there was a significant association between renal medulla hyperechogenicity and clinical tophi (odds ratio, 7.27; 95% CI, 3.68–15.19; P < .0001), urate arthropathy (OR, 3.46; 95% CI, 1.99–6.09; P < .0001), estimated gout duration (OR, 2.13; 95% CI, 1.55–2.96; P < .0001), double contour thickness (OR, 1.45; 95% CI, 1.06–1.97; P < .02), and eGFR (OR, 0.30; 95% CI, 0.09–0.89; P < .034).

“The finding was observed mainly in tophaceous gout, which involved a large proportion of our patients who had received very little treatment with urate-lowering drugs and was associated with moderately impaired renal function and urinary features compatible with tubulointerstitial nephritis,” Dr. Bardin and colleagues wrote in the study. The researchers also found “similar features” in 4 of 10 French patients at the Paris Necker Hospital in Paris, and noted that similar findings have been reported in Japan and Korea, which they said may mean hyperechoic medulla “is not unique to Vietnamese patients.”
 

Relation to CKD still unclear

In a related editorial, Federica Piani, MD, and Richard J. Johnson, MD, of the division of renal diseases and hypertension at the University of Colorado at Denver, Aurora, explained that gout was considered by some clinicians to be a cause of CKD in a time before urate-lowering therapies, because as many as 25% of patients with gout went on to experience kidney failure and about half experienced lower kidney function.

The association between gout and CKD was thought to be attributable to “frequent deposition of urate crystals in the tubular lumens and interstitium in the outer medulla of these patients,” but the concept was later challenged because “the crystals were generally found focally and did not readily explain the kidney damage.”

But even as interest in rheumatology moved away from the concept of gouty nephropathy to how serum uric acid impacts CKD, “the possibility that urate crystal deposition in the kidney could also be contributing to the kidney injury was never ruled out,” according to Dr. Piani and Dr. Johnson.

Kidney biopsies can sometimes miss urate crystals because the crystals dissolve if alcohol fixation is not used and because the biopsy site is often in the renal cortex, the authors noted. Recent research has identified that dual-energy CT scans can distinguish between calcium deposits and urate crystals better than ultrasound, and previous research from Thomas Bardin, MD, and colleagues in two patients noted a correlation between dual-energy CT scan findings of urate crystals and hyperechoic medulla findings on renal ultrasound.

The results by Dr. Bardin and associates, they said, “have reawakened the entity of urate microcrystalline nephropathy as a possible cause of CKD.”

Robert Terkeltaub, MD, professor of medicine at the University of California, San Diego, and section chief of Rheumatology at the San Diego VA Medical Center, said in an interview that he also believes the findings by Dr. Bardin and associates are real. He cited a study by Isabelle Ayoub, MD, and colleagues in Clinical Nephrology from 2016 that evaluated kidney biopsies in Germany and found medullary tophi were more likely to be present in patients with CKD than without.

“Chronic gouty nephropathy did not disappear. It still exists,” said Dr. Terkeltaub, who was not involved in the study by Dr. Bardin and colleagues.

The prospect that, if “you look hard enough, you’re going to see urate crystals and a pattern that’s attributed in the renal medulla” in patients with untreated gout is “very provocative, and interesting, and clinically relevant, and merits more investigation,” noted Dr. Terkeltaub, who is also president of the Gout, Hyperuricemia and Crystal-Associated Disease Network.

If verified, the results have important implications for patients with gout and its relationship to CKD, Dr. Terkeltaub said, but they raise “more questions than answers.

“I think it’s a really good wake-up call to start looking, doing good detective work here, and looking especially in people who have gout as opposed to just people with chronic kidney disease,” he said.

The authors reported no relevant conflicts of interest. Dr. Johnson, who coauthored an accompanying editorial, reported having equity in XORTX Therapeutics, serving as a consultant for Horizon Pharma, and having equity in Colorado Research Partners LLC. Dr. Terkeltaub reported receiving a research grant from AstraZeneca in the field of hyperuricemia and consultancies with AstraZeneca, Horizon, Sobi, Selecta Biosciences.

Is gouty nephropathy real? It’s a question that has been posed often in rheumatology over the last several decades.

HYWARDS/Getty Images

A new study found 36% of patients with untreated gout at a medical center in Vietnam have diffuse hyperechoic renal medulla as seen on ultrasound, which could indicate the presence of microcrystalline nephropathy. However, the results, published in Kidney International, may raise more questions than answers about the existence of gouty nephropathy and its relation to chronic kidney disease (CKD).

In their study, Thomas Bardin, MD, of the department of rheumatology at Lariboisière Hospital in Paris and colleagues evaluated 502 consecutive patients from Vien Gut Medical Center in Ho Chi Minh City, Vietnam, using B-mode renal ultrasound. The patients were mostly men with a median age of 46 years, body mass index of 25 kg/m², estimated disease duration of 4 years, and uricemia of 423.2 micromol/L (7.11 mg/dL). Patients had a median estimated glomerular filtration rate (eGFR) of 78 mL/min per 1.73 m². There was a history of hypertension in 112 patients (22.3%), type 2 diabetes in 58 patients (11.5%), renal lithiasis in 28 patients (5.6%), and coronary heart disease in 5 patients (1%).

While 39% of patients had previously used allopurinol for “a generally short period,” patients were not on urate-lowering therapy at the time of the study. Clinical tophi were present in 279 patients (55.6%), urate arthropathies in 154 patients (30.7%), and 43 patients (10.4%) used steroids daily.

B-mode renal ultrasound showed 181 patients (36%; 95% confidence interval, 32%-40%) had “hyperechoic pattern of Malpighi pyramids compared with the adjacent cortex,” which was “associated with twinkling artifacts” visible on color Doppler ultrasound. There was a significant association between renal medulla hyperechogenicity and patient age, disease duration, use of steroids, clinical tophi, and urate arthropathy (P less than .0001 for all). A significant association was also seen between renal medulla hyperechogenicity and decreased eGFR (P < .0001), proteinuria (P = .0006), leukocyturia (P = .0008), hypertension (P = .0008), hyperuricemia (P = .002), and coronary heart disease (P = .006).

In a multivariate analysis, there was a significant association between renal medulla hyperechogenicity and clinical tophi (odds ratio, 7.27; 95% CI, 3.68–15.19; P < .0001), urate arthropathy (OR, 3.46; 95% CI, 1.99–6.09; P < .0001), estimated gout duration (OR, 2.13; 95% CI, 1.55–2.96; P < .0001), double contour thickness (OR, 1.45; 95% CI, 1.06–1.97; P < .02), and eGFR (OR, 0.30; 95% CI, 0.09–0.89; P < .034).

“The finding was observed mainly in tophaceous gout, which involved a large proportion of our patients who had received very little treatment with urate-lowering drugs and was associated with moderately impaired renal function and urinary features compatible with tubulointerstitial nephritis,” Dr. Bardin and colleagues wrote in the study. The researchers also found “similar features” in 4 of 10 French patients at the Paris Necker Hospital in Paris, and noted that similar findings have been reported in Japan and Korea, which they said may mean hyperechoic medulla “is not unique to Vietnamese patients.”
 

Relation to CKD still unclear

In a related editorial, Federica Piani, MD, and Richard J. Johnson, MD, of the division of renal diseases and hypertension at the University of Colorado at Denver, Aurora, explained that gout was considered by some clinicians to be a cause of CKD in a time before urate-lowering therapies, because as many as 25% of patients with gout went on to experience kidney failure and about half experienced lower kidney function.

The association between gout and CKD was thought to be attributable to “frequent deposition of urate crystals in the tubular lumens and interstitium in the outer medulla of these patients,” but the concept was later challenged because “the crystals were generally found focally and did not readily explain the kidney damage.”

But even as interest in rheumatology moved away from the concept of gouty nephropathy to how serum uric acid impacts CKD, “the possibility that urate crystal deposition in the kidney could also be contributing to the kidney injury was never ruled out,” according to Dr. Piani and Dr. Johnson.

Kidney biopsies can sometimes miss urate crystals because the crystals dissolve if alcohol fixation is not used and because the biopsy site is often in the renal cortex, the authors noted. Recent research has identified that dual-energy CT scans can distinguish between calcium deposits and urate crystals better than ultrasound, and previous research from Thomas Bardin, MD, and colleagues in two patients noted a correlation between dual-energy CT scan findings of urate crystals and hyperechoic medulla findings on renal ultrasound.

The results by Dr. Bardin and associates, they said, “have reawakened the entity of urate microcrystalline nephropathy as a possible cause of CKD.”

Robert Terkeltaub, MD, professor of medicine at the University of California, San Diego, and section chief of Rheumatology at the San Diego VA Medical Center, said in an interview that he also believes the findings by Dr. Bardin and associates are real. He cited a study by Isabelle Ayoub, MD, and colleagues in Clinical Nephrology from 2016 that evaluated kidney biopsies in Germany and found medullary tophi were more likely to be present in patients with CKD than without.

“Chronic gouty nephropathy did not disappear. It still exists,” said Dr. Terkeltaub, who was not involved in the study by Dr. Bardin and colleagues.

The prospect that, if “you look hard enough, you’re going to see urate crystals and a pattern that’s attributed in the renal medulla” in patients with untreated gout is “very provocative, and interesting, and clinically relevant, and merits more investigation,” noted Dr. Terkeltaub, who is also president of the Gout, Hyperuricemia and Crystal-Associated Disease Network.

If verified, the results have important implications for patients with gout and its relationship to CKD, Dr. Terkeltaub said, but they raise “more questions than answers.

“I think it’s a really good wake-up call to start looking, doing good detective work here, and looking especially in people who have gout as opposed to just people with chronic kidney disease,” he said.

The authors reported no relevant conflicts of interest. Dr. Johnson, who coauthored an accompanying editorial, reported having equity in XORTX Therapeutics, serving as a consultant for Horizon Pharma, and having equity in Colorado Research Partners LLC. Dr. Terkeltaub reported receiving a research grant from AstraZeneca in the field of hyperuricemia and consultancies with AstraZeneca, Horizon, Sobi, Selecta Biosciences.

The U.S. Food and Drug Administration has expanded the indication for belimumab (Benlysta) to adults with active lupus nephritis who are receiving standard therapy.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Roughly 40% of patients with systemic lupus erythematosus (SLE) develop lupus nephritis (LN), which causes inflammation in the kidneys and can lead to end-stage kidney disease.

“Benlysta is the first medicine approved to treat systemic lupus and adults with active lupus nephritis, an important treatment advance for patients with this incurable autoimmune disease,” Hal Barron, MD, GlaxoSmithKline’s chief scientific officer and president of research and development, said in a company news release.

Belimumab IV infusion was first approved in the United States in March 2011 for adults with SLE. The FDA approved belimumab IV infusion for use in children as young as age 5 years with SLE in 2019.

Both the IV and subcutaneous formulations are now indicated in the United States for adults with SLE and LN.

Belimumab is a B-lymphocyte stimulator protein inhibitor that is thought to decrease the amount of abnormal B cells; the latter are thought to play a role in lupus.

The expanded indication for belimumab for patients with LN is based on findings from the BLISS-LN phase 3 trial, published in The New England Journal of Medicine in September.

“Neutralizing B-cell activating factor and down-regulating autoreactive B-cell function in kidneys” represents a “compelling therapeutic approach to lupus nephritis,” the lead investigator of BLISS-LN, Richard Furie, MD, told the online annual Perspectives in Rheumatic Diseases meeting recently.

“In the 4 decades I have been caring for people with lupus, we have not been able to achieve remission in more than just one-third of patients with lupus nephritis, and despite all of our efforts, 10%-30% of patients with lupus kidney disease still progress to end-stage kidney disease,” Dr. Furie, who is chief of the division of rheumatology at Northwell Health, notes in the GSK statement.

“The data from the BLISS-LN study show that Benlysta added to standard therapy not only increased response rates over 2 years, but it also prevented worsening of kidney disease in patients with active lupus nephritis, compared to standard therapy alone,” he added.

BLISS-LN study: Belimumab effect seen mostly in those on MMF

BLISS-LN enrolled 448 adults with biopsy-confirmed active LN. Half were randomly allocated to receive IV belimumab (10 mg/kg) plus standard therapy (mycophenolate mofetil for induction and maintenance or cyclophosphamide for induction followed by azathioprine for maintenance, with steroids) and half to receive placebo plus standard therapy.

At 2 years, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval, 1.0- 2.3; P = .03).

This primary endpoint was defined as a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate that was no worse than 20% below the value before the renal flare or ≥60 mL per minute per 1.73 m² of body surface area, without use of rescue therapy.

The risk for a renal-related event or death was also significantly lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; P = .001). The safety profile of belimumab was consistent with that observed in prior studies.

But in a commentary that accompanied the publication of BLISS-LN, editorialists noted that “most of the treatment effect was seen in patients who had received mycophenolate mofetil. No benefit was present in the subgroup of patients who received cyclophosphamide-azathioprine.”

In addition, induction treatment was not randomly assigned, editorialists Michael Ward, MD, MPH, and Maria Tektonidou, MD, PhD, noted.

“If patients with more severe nephritis were preferentially treated with cyclophosphamide, a likely inclination among most physicians, the trial may be telling us that belimumab enhances responses only among less severely affected patients,” observed Dr. Ward, who is with the National Institutes of Health, and Dr. Tektonidou, of the National and Kopodistrian University, in Athens.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has expanded the indication for belimumab (Benlysta) to adults with active lupus nephritis who are receiving standard therapy.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Roughly 40% of patients with systemic lupus erythematosus (SLE) develop lupus nephritis (LN), which causes inflammation in the kidneys and can lead to end-stage kidney disease.

“Benlysta is the first medicine approved to treat systemic lupus and adults with active lupus nephritis, an important treatment advance for patients with this incurable autoimmune disease,” Hal Barron, MD, GlaxoSmithKline’s chief scientific officer and president of research and development, said in a company news release.

Belimumab IV infusion was first approved in the United States in March 2011 for adults with SLE. The FDA approved belimumab IV infusion for use in children as young as age 5 years with SLE in 2019.

Both the IV and subcutaneous formulations are now indicated in the United States for adults with SLE and LN.

Belimumab is a B-lymphocyte stimulator protein inhibitor that is thought to decrease the amount of abnormal B cells; the latter are thought to play a role in lupus.

The expanded indication for belimumab for patients with LN is based on findings from the BLISS-LN phase 3 trial, published in The New England Journal of Medicine in September.

“Neutralizing B-cell activating factor and down-regulating autoreactive B-cell function in kidneys” represents a “compelling therapeutic approach to lupus nephritis,” the lead investigator of BLISS-LN, Richard Furie, MD, told the online annual Perspectives in Rheumatic Diseases meeting recently.

“In the 4 decades I have been caring for people with lupus, we have not been able to achieve remission in more than just one-third of patients with lupus nephritis, and despite all of our efforts, 10%-30% of patients with lupus kidney disease still progress to end-stage kidney disease,” Dr. Furie, who is chief of the division of rheumatology at Northwell Health, notes in the GSK statement.

“The data from the BLISS-LN study show that Benlysta added to standard therapy not only increased response rates over 2 years, but it also prevented worsening of kidney disease in patients with active lupus nephritis, compared to standard therapy alone,” he added.

BLISS-LN study: Belimumab effect seen mostly in those on MMF

BLISS-LN enrolled 448 adults with biopsy-confirmed active LN. Half were randomly allocated to receive IV belimumab (10 mg/kg) plus standard therapy (mycophenolate mofetil for induction and maintenance or cyclophosphamide for induction followed by azathioprine for maintenance, with steroids) and half to receive placebo plus standard therapy.

At 2 years, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval, 1.0- 2.3; P = .03).

This primary endpoint was defined as a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate that was no worse than 20% below the value before the renal flare or ≥60 mL per minute per 1.73 m² of body surface area, without use of rescue therapy.

The risk for a renal-related event or death was also significantly lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; P = .001). The safety profile of belimumab was consistent with that observed in prior studies.

But in a commentary that accompanied the publication of BLISS-LN, editorialists noted that “most of the treatment effect was seen in patients who had received mycophenolate mofetil. No benefit was present in the subgroup of patients who received cyclophosphamide-azathioprine.”

In addition, induction treatment was not randomly assigned, editorialists Michael Ward, MD, MPH, and Maria Tektonidou, MD, PhD, noted.

“If patients with more severe nephritis were preferentially treated with cyclophosphamide, a likely inclination among most physicians, the trial may be telling us that belimumab enhances responses only among less severely affected patients,” observed Dr. Ward, who is with the National Institutes of Health, and Dr. Tektonidou, of the National and Kopodistrian University, in Athens.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has expanded the indication for belimumab (Benlysta) to adults with active lupus nephritis who are receiving standard therapy.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Roughly 40% of patients with systemic lupus erythematosus (SLE) develop lupus nephritis (LN), which causes inflammation in the kidneys and can lead to end-stage kidney disease.

“Benlysta is the first medicine approved to treat systemic lupus and adults with active lupus nephritis, an important treatment advance for patients with this incurable autoimmune disease,” Hal Barron, MD, GlaxoSmithKline’s chief scientific officer and president of research and development, said in a company news release.

Belimumab IV infusion was first approved in the United States in March 2011 for adults with SLE. The FDA approved belimumab IV infusion for use in children as young as age 5 years with SLE in 2019.

Both the IV and subcutaneous formulations are now indicated in the United States for adults with SLE and LN.

Belimumab is a B-lymphocyte stimulator protein inhibitor that is thought to decrease the amount of abnormal B cells; the latter are thought to play a role in lupus.

The expanded indication for belimumab for patients with LN is based on findings from the BLISS-LN phase 3 trial, published in The New England Journal of Medicine in September.

“Neutralizing B-cell activating factor and down-regulating autoreactive B-cell function in kidneys” represents a “compelling therapeutic approach to lupus nephritis,” the lead investigator of BLISS-LN, Richard Furie, MD, told the online annual Perspectives in Rheumatic Diseases meeting recently.

“In the 4 decades I have been caring for people with lupus, we have not been able to achieve remission in more than just one-third of patients with lupus nephritis, and despite all of our efforts, 10%-30% of patients with lupus kidney disease still progress to end-stage kidney disease,” Dr. Furie, who is chief of the division of rheumatology at Northwell Health, notes in the GSK statement.

“The data from the BLISS-LN study show that Benlysta added to standard therapy not only increased response rates over 2 years, but it also prevented worsening of kidney disease in patients with active lupus nephritis, compared to standard therapy alone,” he added.

BLISS-LN study: Belimumab effect seen mostly in those on MMF

BLISS-LN enrolled 448 adults with biopsy-confirmed active LN. Half were randomly allocated to receive IV belimumab (10 mg/kg) plus standard therapy (mycophenolate mofetil for induction and maintenance or cyclophosphamide for induction followed by azathioprine for maintenance, with steroids) and half to receive placebo plus standard therapy.

At 2 years, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval, 1.0- 2.3; P = .03).

This primary endpoint was defined as a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate that was no worse than 20% below the value before the renal flare or ≥60 mL per minute per 1.73 m² of body surface area, without use of rescue therapy.

The risk for a renal-related event or death was also significantly lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; P = .001). The safety profile of belimumab was consistent with that observed in prior studies.

But in a commentary that accompanied the publication of BLISS-LN, editorialists noted that “most of the treatment effect was seen in patients who had received mycophenolate mofetil. No benefit was present in the subgroup of patients who received cyclophosphamide-azathioprine.”

In addition, induction treatment was not randomly assigned, editorialists Michael Ward, MD, MPH, and Maria Tektonidou, MD, PhD, noted.

“If patients with more severe nephritis were preferentially treated with cyclophosphamide, a likely inclination among most physicians, the trial may be telling us that belimumab enhances responses only among less severely affected patients,” observed Dr. Ward, who is with the National Institutes of Health, and Dr. Tektonidou, of the National and Kopodistrian University, in Athens.

A version of this article first appeared on Medscape.com.

For 2021, the American Diabetes Association offers new guidance on assessing patients’ financial and social barriers to care, especially given the COVID-19 pandemic, individualizing treatment of patients with type 2 diabetes, and use of diabetes technology.

As it does every year, the annual update incorporates new clinical information that has become available since the last guideline, with occasional revisions during the year as needed. “Standards of Medical Care in Diabetes – 2021,” was published online as a supplement to Diabetes Care.

The new standards advise that patients be assessed for food and housing insecurity, social support, and “cost-related medication nonadherence,” and those found to have difficulty referred to appropriate community resources.

“Clinicians need to be sensitive to the fact that patients may have very good reasons for not taking their medication, [as in] if they can’t afford it,” ADA chief science & medical officer Robert A. Gabbay, MD, PhD, said in an interview.

Dr. Gabbay noted that “a heightened awareness” of social determinants of health is weaved throughout the 2021 standards because of the pandemic, with information on the topic derived from a July 2020 joint consensus statement in Diabetes Care, endorsed by a number of other societies, as well as a November publication also in Diabetes Care.

“We made several recommendations that speak to social determinants of health, placing an emphasis on engaging in conversations around this subject and screening for related issues such as food insecurity that weren’t there previously,” he said.

“Screening tools are suggested. It helped us to have an in-depth scientific review of the literature to know the prevalence of this in people with diabetes. ... Having the science to put it in was a key step,” Dr. Gabbay noted.
 

Consider kidney, heart disease in type 2 treatment individualization

Recent data from trials such as CREDENCE and DAPA-HF, among others, have been added to inform the choice of pharmacologic treatment in patients with type 2 diabetes with comorbid diabetic kidney disease and chronic heart failure.

“ADA has been advocating individualization of treatment based on comorbidities for a while, but we’ve taken more steps in that direction. Beyond lifestyle for all individuals with type 2 diabetes, clinicians want to think early on about which comorbidities patients have and then think about the appropriate treatment based on that,” Dr. Gabbay said.

And for the third year in a row, the section on cardiovascular disease and risk management has been endorsed by the American College of Cardiology.

“All the things in that section are very much aligned with ACC and that’s been a great partnership,” Dr. Gabbay said.

Now, ADA is in discussions with other professional societies representing relevant specialties to create further such unified messages.

“What we all want to avoid is having multiple different guidelines. We want to speak with one voice and find common ground as much as possible. … It makes it much easier for clinicians to know what to do. That’s the goal of all this,” he noted.
 

Diabetes technology: The rise of CGM during pandemic and beyond

New information about continuous glucose monitoring (CGM) has been added to the diabetes technology section. Use of CGM is now recommended for anyone with diabetes who takes multiple daily injections or uses an insulin pump, regardless of age or diabetes type. The document provides expanded advice on use of time in range data for glycemic monitoring, particularly during the COVID-19 pandemic when remote monitoring is preferable.

Insurers are increasingly covering CGM for patients on insulin, but it’s far from universal. While the ultimate goal is to ensure access to CGM for everyone with diabetes, those treated with multiple daily insulin doses are the priority for now.

“Our hope is that as there’s greater evidence there will be more movement towards coverage. There are still so many people for whom it’s quite clear they would benefit because they’re on insulin but don’t have access to it. That’s an important area that ADA is advocating for, and it’s reflected in the standards of care,” Dr. Gabbay said.

In another technology-related revision, the term “blinded” CGM has been replaced with “professional CGM,” because clinic-based use of the devices can be “blinded” to the patient or monitored in real-time by both the patient and clinician. Also, a new recommendation has been added to address skin reactions associated with diabetes technology use.

Information about use of CGM in hospital settings during the COVID-19 pandemic has also been added in the technology section.

The COVID-19 pandemic comes up again in the section on vaccines.

“We mention that people with diabetes should be considered high priority [for COVID-19 vaccines], and that’s something that ADA is strongly advocating for because 40% of COVID-19 deaths have been in people with diabetes,” Dr. Gabbay said.

Dr. Gabbay reported being on the advisory boards of Onduo, Health Reveal, Vida Health, Lark, and Form Health.

A version of this article originally appeared on Medscape.com.

For 2021, the American Diabetes Association offers new guidance on assessing patients’ financial and social barriers to care, especially given the COVID-19 pandemic, individualizing treatment of patients with type 2 diabetes, and use of diabetes technology.

As it does every year, the annual update incorporates new clinical information that has become available since the last guideline, with occasional revisions during the year as needed. “Standards of Medical Care in Diabetes – 2021,” was published online as a supplement to Diabetes Care.

The new standards advise that patients be assessed for food and housing insecurity, social support, and “cost-related medication nonadherence,” and those found to have difficulty referred to appropriate community resources.

“Clinicians need to be sensitive to the fact that patients may have very good reasons for not taking their medication, [as in] if they can’t afford it,” ADA chief science & medical officer Robert A. Gabbay, MD, PhD, said in an interview.

Dr. Gabbay noted that “a heightened awareness” of social determinants of health is weaved throughout the 2021 standards because of the pandemic, with information on the topic derived from a July 2020 joint consensus statement in Diabetes Care, endorsed by a number of other societies, as well as a November publication also in Diabetes Care.

“We made several recommendations that speak to social determinants of health, placing an emphasis on engaging in conversations around this subject and screening for related issues such as food insecurity that weren’t there previously,” he said.

“Screening tools are suggested. It helped us to have an in-depth scientific review of the literature to know the prevalence of this in people with diabetes. ... Having the science to put it in was a key step,” Dr. Gabbay noted.
 

Consider kidney, heart disease in type 2 treatment individualization

Recent data from trials such as CREDENCE and DAPA-HF, among others, have been added to inform the choice of pharmacologic treatment in patients with type 2 diabetes with comorbid diabetic kidney disease and chronic heart failure.

“ADA has been advocating individualization of treatment based on comorbidities for a while, but we’ve taken more steps in that direction. Beyond lifestyle for all individuals with type 2 diabetes, clinicians want to think early on about which comorbidities patients have and then think about the appropriate treatment based on that,” Dr. Gabbay said.

And for the third year in a row, the section on cardiovascular disease and risk management has been endorsed by the American College of Cardiology.

“All the things in that section are very much aligned with ACC and that’s been a great partnership,” Dr. Gabbay said.

Now, ADA is in discussions with other professional societies representing relevant specialties to create further such unified messages.

“What we all want to avoid is having multiple different guidelines. We want to speak with one voice and find common ground as much as possible. … It makes it much easier for clinicians to know what to do. That’s the goal of all this,” he noted.
 

Diabetes technology: The rise of CGM during pandemic and beyond

New information about continuous glucose monitoring (CGM) has been added to the diabetes technology section. Use of CGM is now recommended for anyone with diabetes who takes multiple daily injections or uses an insulin pump, regardless of age or diabetes type. The document provides expanded advice on use of time in range data for glycemic monitoring, particularly during the COVID-19 pandemic when remote monitoring is preferable.

Insurers are increasingly covering CGM for patients on insulin, but it’s far from universal. While the ultimate goal is to ensure access to CGM for everyone with diabetes, those treated with multiple daily insulin doses are the priority for now.

“Our hope is that as there’s greater evidence there will be more movement towards coverage. There are still so many people for whom it’s quite clear they would benefit because they’re on insulin but don’t have access to it. That’s an important area that ADA is advocating for, and it’s reflected in the standards of care,” Dr. Gabbay said.

In another technology-related revision, the term “blinded” CGM has been replaced with “professional CGM,” because clinic-based use of the devices can be “blinded” to the patient or monitored in real-time by both the patient and clinician. Also, a new recommendation has been added to address skin reactions associated with diabetes technology use.

Information about use of CGM in hospital settings during the COVID-19 pandemic has also been added in the technology section.

The COVID-19 pandemic comes up again in the section on vaccines.

“We mention that people with diabetes should be considered high priority [for COVID-19 vaccines], and that’s something that ADA is strongly advocating for because 40% of COVID-19 deaths have been in people with diabetes,” Dr. Gabbay said.

Dr. Gabbay reported being on the advisory boards of Onduo, Health Reveal, Vida Health, Lark, and Form Health.

A version of this article originally appeared on Medscape.com.

For 2021, the American Diabetes Association offers new guidance on assessing patients’ financial and social barriers to care, especially given the COVID-19 pandemic, individualizing treatment of patients with type 2 diabetes, and use of diabetes technology.

As it does every year, the annual update incorporates new clinical information that has become available since the last guideline, with occasional revisions during the year as needed. “Standards of Medical Care in Diabetes – 2021,” was published online as a supplement to Diabetes Care.

The new standards advise that patients be assessed for food and housing insecurity, social support, and “cost-related medication nonadherence,” and those found to have difficulty referred to appropriate community resources.

“Clinicians need to be sensitive to the fact that patients may have very good reasons for not taking their medication, [as in] if they can’t afford it,” ADA chief science & medical officer Robert A. Gabbay, MD, PhD, said in an interview.

Dr. Gabbay noted that “a heightened awareness” of social determinants of health is weaved throughout the 2021 standards because of the pandemic, with information on the topic derived from a July 2020 joint consensus statement in Diabetes Care, endorsed by a number of other societies, as well as a November publication also in Diabetes Care.

“We made several recommendations that speak to social determinants of health, placing an emphasis on engaging in conversations around this subject and screening for related issues such as food insecurity that weren’t there previously,” he said.

“Screening tools are suggested. It helped us to have an in-depth scientific review of the literature to know the prevalence of this in people with diabetes. ... Having the science to put it in was a key step,” Dr. Gabbay noted.
 

Consider kidney, heart disease in type 2 treatment individualization

Recent data from trials such as CREDENCE and DAPA-HF, among others, have been added to inform the choice of pharmacologic treatment in patients with type 2 diabetes with comorbid diabetic kidney disease and chronic heart failure.

“ADA has been advocating individualization of treatment based on comorbidities for a while, but we’ve taken more steps in that direction. Beyond lifestyle for all individuals with type 2 diabetes, clinicians want to think early on about which comorbidities patients have and then think about the appropriate treatment based on that,” Dr. Gabbay said.

And for the third year in a row, the section on cardiovascular disease and risk management has been endorsed by the American College of Cardiology.

“All the things in that section are very much aligned with ACC and that’s been a great partnership,” Dr. Gabbay said.

Now, ADA is in discussions with other professional societies representing relevant specialties to create further such unified messages.

“What we all want to avoid is having multiple different guidelines. We want to speak with one voice and find common ground as much as possible. … It makes it much easier for clinicians to know what to do. That’s the goal of all this,” he noted.
 

Diabetes technology: The rise of CGM during pandemic and beyond

New information about continuous glucose monitoring (CGM) has been added to the diabetes technology section. Use of CGM is now recommended for anyone with diabetes who takes multiple daily injections or uses an insulin pump, regardless of age or diabetes type. The document provides expanded advice on use of time in range data for glycemic monitoring, particularly during the COVID-19 pandemic when remote monitoring is preferable.

Insurers are increasingly covering CGM for patients on insulin, but it’s far from universal. While the ultimate goal is to ensure access to CGM for everyone with diabetes, those treated with multiple daily insulin doses are the priority for now.

“Our hope is that as there’s greater evidence there will be more movement towards coverage. There are still so many people for whom it’s quite clear they would benefit because they’re on insulin but don’t have access to it. That’s an important area that ADA is advocating for, and it’s reflected in the standards of care,” Dr. Gabbay said.

In another technology-related revision, the term “blinded” CGM has been replaced with “professional CGM,” because clinic-based use of the devices can be “blinded” to the patient or monitored in real-time by both the patient and clinician. Also, a new recommendation has been added to address skin reactions associated with diabetes technology use.

Information about use of CGM in hospital settings during the COVID-19 pandemic has also been added in the technology section.

The COVID-19 pandemic comes up again in the section on vaccines.

“We mention that people with diabetes should be considered high priority [for COVID-19 vaccines], and that’s something that ADA is strongly advocating for because 40% of COVID-19 deaths have been in people with diabetes,” Dr. Gabbay said.

Dr. Gabbay reported being on the advisory boards of Onduo, Health Reveal, Vida Health, Lark, and Form Health.

A version of this article originally appeared on Medscape.com.

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; [email protected]

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; [email protected]

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; [email protected]

A 67-year-old man with stage 3 chronic kidney disease (CKD) develops abdominal pain over 24 hours. He has had low grade fevers and nausea. He has a history of colon cancer and had a resection four years ago. Abdominal exam reveals tenderness to palpation, including rebound tenderness in his right lower quadrant. Labs: hemoglobin: 13; hematocrit: 39; white blood cells: 18,000; platelets: 333; blood urea nitrogen: 28; creatinine: 1.8 (estimated glomerular filtration rate: 37); sodium: 136; potassium: 3.9; bicarbonate: 24; chlorine: 105; and lipase: 10.

What testing would you recommend?

A) Ultrasound

B) Non contrast computed tomography (CT)

C) Contrast CT

D) MRI without gadolinium

The correct answer here is to get a contrast CT scan, as it will give you the most appropriate diagnostic information.

For years, we have hesitated to order contrast studies in our patients with CKD, for fear of causing contrast-induced nephrotoxicity. We might choose less helpful studies that avoid contrast, or might not obtain imaging that is needed. Over the years I have especially seen this in the case of avoiding computed tomography angiography (CTA) for evaluation of pulmonary embolus and choosing the much less useful ventilation/perfusion scan. The problem arises with the fact that patients with CKD are more likely to develop worsening renal function when they get sick.

The assumption had been that when kidney injury occurred after contrast that it was due to the contrast. Many recent studies refute this assumption. Lee and colleagues performed an analysis of six retrospective studies involving a total of 55,963 participants. They found that patients with CKD receiving contrast material did not have an increased risk of deteriorating renal function compared with those without CKD (odds ratio, 1.07; 95% confidence interval, 0.98-1.17).¹

The early studies reporting contrast-induced renal disease were in patients who received high osmolality contrast agents.² Most patients now receive low osmolality agents, with less nephrotoxicity.³
 

Key points of guidelines

This year, the American College of Radiology and the National Kidney Foundation put out joint guidelines that helped clarify why there is a diminished concern for contrast-induced kidney disease in the modern era.⁴ Below are some of the key points of these guidelines:

• The risk of contrast-induced acute kidney injury (AKI) from intravenous iodinated contrast media is lower than previously thought.
• Necessary contrast material–enhanced CT without a suitable alternative should not be avoided solely on the basis of contrast-induced chronic kidney insufficiency risk.
• Contrast-induced AKI risk should be determined primarily by using CKD stage and AKI.
• Patients at high risk for contrast-induced kidney injury include those with recent AKI and those with estimated glomerular filtration rate (eGFR) less than 30 mL/min per 1.73 m².

Data supporting guidelines

The data from several studies used to support these recommendations were impressive, showing just how low the risk for contrast-induced AKI is in most patients. In these studies, the risk of contrast-induced AKI has been estimated to be near 0% for patients with an eGFR greater than or equal to 45 and 0%-2% for patients with an eGFR of 30-44.^5-7 This information and recommendations make imaging much easier. In most of our patients, we can get contrast studies when we need them. The group to be concerned about are patients with eGFRs less than 30. The guidelines single out this group as the patients where risk/benefit needs to be calculated before proceeding with the study, and to use prophylactic saline hydration in patients not undergoing dialysis.

Myth: Contrast-induced renal disease is common.
 

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Lee YC et al. Contrast-induced acute kidney injury among patients with chronic kidney disease undergoing imaging studies: A meta-analysis. Am J Roentgenol. 2019 Oct;213(4):728-35.

2. Luk L et al. Intravenous contrast-induced nephropathy: The rise and fall of a threatening idea. Adv Chronic Kidney Dis. 2017 May;24(3):169-75.

3. Goldfarb S et al. Low-osmolality contrast media and the risk of contrast-associated nephrotoxicity. Invest Radiol. 1993;28(Suppl 5):7-10.

4. Davenport MS, et al. Use of intravenous iodinated contrast media in patients with kidney disease: Consensus statements from the American College of Radiology and the National Kidney Foundation. Kidney Med. 2020 Jan 22;2(1):85-93.

5. Davenport MS et al. Contrast material–induced nephrotoxicity and intravenous low-osmolality iodinated contrast material. Radiology. 2013;267(1):94-105.

6. McDonald RJ et al. Intravenous contrast material–induced nephropathy: Causal or coincident phenomenon? Radiology. 2013;267(1):106-18.

7. McDonald JS et al. Risk of intravenous contrast material–mediated acute kidney injury: A propensity scorematched study stratified by baseline-estimated glomerular filtration rate. Radiology. 2014;271(1):65-73.

A 67-year-old man with stage 3 chronic kidney disease (CKD) develops abdominal pain over 24 hours. He has had low grade fevers and nausea. He has a history of colon cancer and had a resection four years ago. Abdominal exam reveals tenderness to palpation, including rebound tenderness in his right lower quadrant. Labs: hemoglobin: 13; hematocrit: 39; white blood cells: 18,000; platelets: 333; blood urea nitrogen: 28; creatinine: 1.8 (estimated glomerular filtration rate: 37); sodium: 136; potassium: 3.9; bicarbonate: 24; chlorine: 105; and lipase: 10.

What testing would you recommend?

A) Ultrasound

B) Non contrast computed tomography (CT)

C) Contrast CT

D) MRI without gadolinium

The correct answer here is to get a contrast CT scan, as it will give you the most appropriate diagnostic information.

For years, we have hesitated to order contrast studies in our patients with CKD, for fear of causing contrast-induced nephrotoxicity. We might choose less helpful studies that avoid contrast, or might not obtain imaging that is needed. Over the years I have especially seen this in the case of avoiding computed tomography angiography (CTA) for evaluation of pulmonary embolus and choosing the much less useful ventilation/perfusion scan. The problem arises with the fact that patients with CKD are more likely to develop worsening renal function when they get sick.

The assumption had been that when kidney injury occurred after contrast that it was due to the contrast. Many recent studies refute this assumption. Lee and colleagues performed an analysis of six retrospective studies involving a total of 55,963 participants. They found that patients with CKD receiving contrast material did not have an increased risk of deteriorating renal function compared with those without CKD (odds ratio, 1.07; 95% confidence interval, 0.98-1.17).¹

The early studies reporting contrast-induced renal disease were in patients who received high osmolality contrast agents.² Most patients now receive low osmolality agents, with less nephrotoxicity.³
 

Key points of guidelines

This year, the American College of Radiology and the National Kidney Foundation put out joint guidelines that helped clarify why there is a diminished concern for contrast-induced kidney disease in the modern era.⁴ Below are some of the key points of these guidelines:

• The risk of contrast-induced acute kidney injury (AKI) from intravenous iodinated contrast media is lower than previously thought.
• Necessary contrast material–enhanced CT without a suitable alternative should not be avoided solely on the basis of contrast-induced chronic kidney insufficiency risk.
• Contrast-induced AKI risk should be determined primarily by using CKD stage and AKI.
• Patients at high risk for contrast-induced kidney injury include those with recent AKI and those with estimated glomerular filtration rate (eGFR) less than 30 mL/min per 1.73 m².

Data supporting guidelines

The data from several studies used to support these recommendations were impressive, showing just how low the risk for contrast-induced AKI is in most patients. In these studies, the risk of contrast-induced AKI has been estimated to be near 0% for patients with an eGFR greater than or equal to 45 and 0%-2% for patients with an eGFR of 30-44.^5-7 This information and recommendations make imaging much easier. In most of our patients, we can get contrast studies when we need them. The group to be concerned about are patients with eGFRs less than 30. The guidelines single out this group as the patients where risk/benefit needs to be calculated before proceeding with the study, and to use prophylactic saline hydration in patients not undergoing dialysis.

Myth: Contrast-induced renal disease is common.
 

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Lee YC et al. Contrast-induced acute kidney injury among patients with chronic kidney disease undergoing imaging studies: A meta-analysis. Am J Roentgenol. 2019 Oct;213(4):728-35.

2. Luk L et al. Intravenous contrast-induced nephropathy: The rise and fall of a threatening idea. Adv Chronic Kidney Dis. 2017 May;24(3):169-75.

3. Goldfarb S et al. Low-osmolality contrast media and the risk of contrast-associated nephrotoxicity. Invest Radiol. 1993;28(Suppl 5):7-10.

4. Davenport MS, et al. Use of intravenous iodinated contrast media in patients with kidney disease: Consensus statements from the American College of Radiology and the National Kidney Foundation. Kidney Med. 2020 Jan 22;2(1):85-93.

5. Davenport MS et al. Contrast material–induced nephrotoxicity and intravenous low-osmolality iodinated contrast material. Radiology. 2013;267(1):94-105.

6. McDonald RJ et al. Intravenous contrast material–induced nephropathy: Causal or coincident phenomenon? Radiology. 2013;267(1):106-18.

7. McDonald JS et al. Risk of intravenous contrast material–mediated acute kidney injury: A propensity scorematched study stratified by baseline-estimated glomerular filtration rate. Radiology. 2014;271(1):65-73.

A 67-year-old man with stage 3 chronic kidney disease (CKD) develops abdominal pain over 24 hours. He has had low grade fevers and nausea. He has a history of colon cancer and had a resection four years ago. Abdominal exam reveals tenderness to palpation, including rebound tenderness in his right lower quadrant. Labs: hemoglobin: 13; hematocrit: 39; white blood cells: 18,000; platelets: 333; blood urea nitrogen: 28; creatinine: 1.8 (estimated glomerular filtration rate: 37); sodium: 136; potassium: 3.9; bicarbonate: 24; chlorine: 105; and lipase: 10.

What testing would you recommend?

A) Ultrasound

B) Non contrast computed tomography (CT)

C) Contrast CT

D) MRI without gadolinium

The correct answer here is to get a contrast CT scan, as it will give you the most appropriate diagnostic information.

For years, we have hesitated to order contrast studies in our patients with CKD, for fear of causing contrast-induced nephrotoxicity. We might choose less helpful studies that avoid contrast, or might not obtain imaging that is needed. Over the years I have especially seen this in the case of avoiding computed tomography angiography (CTA) for evaluation of pulmonary embolus and choosing the much less useful ventilation/perfusion scan. The problem arises with the fact that patients with CKD are more likely to develop worsening renal function when they get sick.

The assumption had been that when kidney injury occurred after contrast that it was due to the contrast. Many recent studies refute this assumption. Lee and colleagues performed an analysis of six retrospective studies involving a total of 55,963 participants. They found that patients with CKD receiving contrast material did not have an increased risk of deteriorating renal function compared with those without CKD (odds ratio, 1.07; 95% confidence interval, 0.98-1.17).¹

The early studies reporting contrast-induced renal disease were in patients who received high osmolality contrast agents.² Most patients now receive low osmolality agents, with less nephrotoxicity.³
 

Key points of guidelines

This year, the American College of Radiology and the National Kidney Foundation put out joint guidelines that helped clarify why there is a diminished concern for contrast-induced kidney disease in the modern era.⁴ Below are some of the key points of these guidelines:

• The risk of contrast-induced acute kidney injury (AKI) from intravenous iodinated contrast media is lower than previously thought.
• Necessary contrast material–enhanced CT without a suitable alternative should not be avoided solely on the basis of contrast-induced chronic kidney insufficiency risk.
• Contrast-induced AKI risk should be determined primarily by using CKD stage and AKI.
• Patients at high risk for contrast-induced kidney injury include those with recent AKI and those with estimated glomerular filtration rate (eGFR) less than 30 mL/min per 1.73 m².

Data supporting guidelines

The data from several studies used to support these recommendations were impressive, showing just how low the risk for contrast-induced AKI is in most patients. In these studies, the risk of contrast-induced AKI has been estimated to be near 0% for patients with an eGFR greater than or equal to 45 and 0%-2% for patients with an eGFR of 30-44.^5-7 This information and recommendations make imaging much easier. In most of our patients, we can get contrast studies when we need them. The group to be concerned about are patients with eGFRs less than 30. The guidelines single out this group as the patients where risk/benefit needs to be calculated before proceeding with the study, and to use prophylactic saline hydration in patients not undergoing dialysis.

Myth: Contrast-induced renal disease is common.
 

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Lee YC et al. Contrast-induced acute kidney injury among patients with chronic kidney disease undergoing imaging studies: A meta-analysis. Am J Roentgenol. 2019 Oct;213(4):728-35.

2. Luk L et al. Intravenous contrast-induced nephropathy: The rise and fall of a threatening idea. Adv Chronic Kidney Dis. 2017 May;24(3):169-75.

3. Goldfarb S et al. Low-osmolality contrast media and the risk of contrast-associated nephrotoxicity. Invest Radiol. 1993;28(Suppl 5):7-10.

4. Davenport MS, et al. Use of intravenous iodinated contrast media in patients with kidney disease: Consensus statements from the American College of Radiology and the National Kidney Foundation. Kidney Med. 2020 Jan 22;2(1):85-93.

5. Davenport MS et al. Contrast material–induced nephrotoxicity and intravenous low-osmolality iodinated contrast material. Radiology. 2013;267(1):94-105.

6. McDonald RJ et al. Intravenous contrast material–induced nephropathy: Causal or coincident phenomenon? Radiology. 2013;267(1):106-18.

7. McDonald JS et al. Risk of intravenous contrast material–mediated acute kidney injury: A propensity scorematched study stratified by baseline-estimated glomerular filtration rate. Radiology. 2014;271(1):65-73.

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.

“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.

In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.

Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
 

CVD history produced heterogeneity for the primary endpoint

In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.

In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.

“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.

Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”

Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”

In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.

Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.

Finerenone looks better for safety

Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.

[email protected]

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.

“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.

In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.

Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
 

CVD history produced heterogeneity for the primary endpoint

In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.

In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.

“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.

Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”

Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”

In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.

Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.

Finerenone looks better for safety

Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.

[email protected]

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.

“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.

In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.

Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
 

CVD history produced heterogeneity for the primary endpoint

In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.

In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.

“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.

Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”

Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”

In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.

Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.

Finerenone looks better for safety

Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.

[email protected]