Attacking Complications to Kidney Problems in Diabetes: Atrial Fibrillation and Resistant Hypertension

Glycemic control in diabetes mellitus has been shown in landmark studies to keep circulatory, renal, and ophthalmologic complications at bay. However, once these patients with diabetes mellitus show signs of kidney dysfunction, clinicians must be vigilant for a host of other potential problems.

According to the latest National Health and Nutrition Examination Surveys (NHANES), 40% of patients with diabetes had self-reported chronic signs, kidney disease (CKD), with a 3.5-fold increased likelihood of CKD compared with the general population (Figure 1).¹ At the recent 2013 annual meeting of the American Heart Association, investigators took a closer look at addressing 2 of the more troubling problems associated with diabetes and renal disease. The microvascular abnormalities seen in patients with diabetes, which involve the kidneys and the retina, are thought to be linked through microalbuminuria (or moderately increased albumin levels). The presence of microalbuminuria is considered a sign of early diabetes-related CKD, but it is also associated with cardiovascular disease in both patients with diabetes and those without.² Microalbuminuria seen in these diabetes-related microvascular abnormalities may be connected with coronary bed microvascular irregularities, which can result in dysrhythmia.²

Therefore, the possible relationship of retinopathy, coupled with microalbuminur, ia, as well as retinal vascular were studied by researchers from the United States and Singapore.³ By studying the general population over a 14-year span, researchers sought to determine the frequency of atrial fibrillation (AF) and microalbuminuria in those with retinopathy.

At baseline, 7.1% of the 10,009 study population had retinopathy (retinal microaneurysms, 4%; retinal hemorrhage, 3%), while microalbuminuria was seen in 7.2% of the cohort. After a mean follow-up of 13.6 years, the researchers found that AF had occurred in 11.0% (1100 individuals).

The AF incidence rates were highest for patients with retinopathy and microalbuminuria and lowest for those without either potential risk factor (Table). When the investigators analyzed the cumulative incidence of AF by albumin to creatinine ratio (either <30 or ≥30), as well as retinal vascular they found that the incidence of AF increased rapidly after year 3 only in patients with both microalbuminuria and retinopathy. After adjusting for age, race, and sex, they calculated a hazard ratio for AF (with 95% confidence intervals) of 1.86 (1.54—2.24) when subjects with retinopathy were compared with those without. When they adjusted for cardiovascular risk factors, such as diabetes, high blood pressure, and prevalent heart disease, the hazard ratio for AF was 1.37 (1.12–1.67).

Even though a nonlinear connection was revealed between AF and a narrowing of retinal venous circulation, the researchers could not find a correlation with other retinal microvascular signs, such as retinal arterial circulatory narrowing or focal-generalized narrowing. Independent and interactive indications of microvessel disease in kidneys and retina, concluded the investigators,

can cause a greater risk of AF. They speculated that systems such as endothelial dysfunction, atrial fibrosis, cardiac remodeling, and autonomic dysfunction may play a role in this association. However, further study will be needed to elucidate this relationship.

New Treatment for Patients With CKD and Resistant Hypertension

The link between the renal and circulatory systems is well-known, as the renin-angiotensin-aldosterone hormonal axis regulates the balance between blood pressure and fluid in the body. The kidney plays a critical role, as it can actively remove water from the circulation, reducing blood pressure. When the system is overactive, hypertension is the result.⁴

Patients with diabetes mellitus are at risk for both CKD and hypertension, and often the renin-angiotensin—aldosterone system is the culprit.⁴ Antihypertensive agents have long been dominated by drugs that influence this hormonal axis, including diuretics, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers. However, few new antihypertensive modalities have been introduced in recent years, and patients with refractory hypertension could benefit from new treatment approaches.⁵ This is especially true for patients who are taking several blood pressure medications and still are not attaining adequate control. Experts believe that perhaps one-fifth of all patients with hypertension fall into that resistant-to-treatment category.⁶

One promising approach may not be pharmacologic in nature. Catheter-based renal denervation (Figure 2) may offer several benefits, including improved glucose metabolism.⁷ German researchers performed a pilot study using renal denervation as a novel antihypertensive therapy for individuals with treatment-resistant hypertension.⁸ They also examined whether renal denervation in these patients with CKD slowed the decline in renal function. The 15 patients in the study group, with a mean age of 66 years, were taking at least 3 antihypertensive medications, with the mean 5.8 agents. However, they had not reached a blood pressure of < 140/90 mm Hg). The study subjects all had stage 3 or 4 CKD. Eleven patients also had concomitant type 2 diabetes mellitus (T2DM).

Each patient underwent catheter-based renal denervation. After 1 year, significant reductions were achieved in blood pressure: Mean systolic blood pressure decreased from 167 ± 22 mm Hg at baseline to 141 ± 11 mm Hg (P = .004). Diastolic pressure fell as well, although this decrease did not attain statistical significance (78 ± 13 at baseline vs. 73 ± 9 mm Hg after 1 year [P = .079]). Significant reductions were also observed in average systolic 24-hour ambulatory blood pressure (13 mm Hg decrease, P = .028) and average aortic systolic blood pressure (24 mm Hg decrease, P = .001).

The mean estimated glomerular filtration rate (eGFR) decline before the renal denervation was —5.6 mL/min/173 m²/yr. After the therapy, eGFR was steady or increased (baseline: 47.0 ± 11 vs. 1 yr: 49.2 ± 14 mL/min/1.73 m²). A significant difference was seen in eGFR before and after renal denervation (–5.6 ± 4.4 vs 2.2 ± 8.0 mL/min/173 m²/yr; P = .021).

The researchers reported that none of the 15 study participants needed dialysis after the procedure or experienced a doubling of their serum creatinine levels during the 1-year follow-up.

This pilot study demonstrated that patients with resistant hypertension may benefit from interventional treatment using renal denervation, according to the researchers. They emphasize that this procedure shows the potential to mitigate the deterioration in renal function in these patients with CKD as well as treatment-resistant hypertension.

References

1. 2013 Atlas of CKD and ESRD. US Renal Data System 2013 (http://www.usrds.org/atlas.aspx). Accessed January 6, 2014.

2. McCollough DK, Bakris GL. Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus. Up to Date. http://www.uptodate.com/contents/moderately-increasedalbuminuria-microalbuminuria-in-type-2-diabetesmellitus. Updated November 2013. Accessed January 5, 2013.

3. Agarwal S, Shah T, Lopez F, et al. Retinal microvascular abnormalities, albuminuria, and atrial fibrillation incidence: The ARIC Study. Presented at the 2013 Scientific Sessions of the American Heart Association. November 16-20, 2013; Dallas, TX.

4. Lim HS, MacFadyen RJ, Lip GY. Diabetes mellitus, the renin-angiotensin-aldosterone system, and the heart. Arch Intern Med. 2004;164(16):1737-1748.

5. Monge M, Lorthioir A, Bobrie G, Azizi M. New drug therapies interfering with the reninangiotensin-aldosterone system for resistant hypertension. J Renin Angiotensin Aldosterone Syst. 2013;14(4):285-289.

6. Krum H, Granger CB. Catheter-based renal denervation: Current status and future applications. Medscape Cardiology. http://www.medscape.org/viewarticle/742356_transcript. Published June 10, 2011. Accessed January 6, 2014.

7. Mahfoud F, Schlaich M, Kindermann I, et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation. 2011;123(18)

:1940-1946.

8. Schmieder REE, Mahfoud F, Schmid A, et al. Does renal denervation stop renal function decline in treatment-resistant hypertension? Results of a pilot study. Presented at the 2013 Scientific Sessions of the American Heart Association. November 16-20, 2013; Dallas, TX.