Does this patient have diabetes-related hypertension?
Presentation of hypertension in diabetic nephropathy
A 58-year-old man presents with elevated blood pressure (BP) confirmed on two occasions by his primary care physician. At his first visit, his BP was 162/88 mmHg, and he was advised to lose weight, exercise, and limit sodium consumption. He currently feels well. His past medical history includes type 2 diabetes mellitus for 8 years, dyslipidemia treated with glyburide 5 mg daily, and atorvastatin 20 mg.
On physical exam: BP 158/92 mm Hg, pulse 68 beats/min and regular, and a body mass index of 33. Jugular venous distension is not visible. Cardiac auscultation reveals a clear S1 and S2, and no S3 or S4. Lungs are clear to auscultation and there is trace peripheral edema at his ankles. Laboratory testing performed 4 months earlier revealed a serum creatinine of 1.6 mg/dl, estimated glomerular filtration rate (eGFR) 44 ml/min/1.73m2, potassium 3.6 mEq/l, HDL 31 mg/dl, LDL 120 mg/dl, glucose 210 mg/dl, and urinary albumin-creatinine ratio 450 mg/g. The remainder of his work-up for anemia and mineral and bone disorder is unremarkable.
What tests to perform?
This patient has chronic kidney disease (CKD) Stage 3b nephropathy with severely increased proteinuria, as well as low serum potassium. These need to be confirmed, so a repeat chemistry panel for electrolytes and blood urea nitrogen/creatinine (BUN/Cr) should be performed. In addition, a repeat lipid profile and urine albumin:creatinine ratio should be obtained to assess changes that may have occurred over the preceding months. Doppler renal ultrasound should also be performed to evaluate kidney size and renal artery blood flow
Given this history, renal biopsy is generally not needed unless there is evidence of rapid decline in kidney function or nephrotic range (i.e., albuminura >3 grams/day).
His repeat labs demonstrate that serum creatinine is 1.7 with an eGFR of 40 ml/min, potassium is 3.6 mEq/L, calcium/PO4 of 9.4 mg/dl and 3.7 mg/dl, as well as a Hb of 12.5 g/L. Magnesium is also normal. Ultrasound exhibited good flow bilaterally with kidneys that are 11 cm each. No further testing is required as there is no evidence of secondary causes of hypertension.
How should patients with hypertension and chronic kidney disease be managed?
The optimal therapeutic approach for treatment of diabetic nephropathy involves combined intensive therapy targeting blood pressure control, as well as weight, hyperglycemia, and dyslipidemia (non-hypertension therapies discussed in the chapter, “Diabetic Kidney Disease: General Management”). This is best exemplified by the results of a 13.3 year follow-up study in Denmark, the Steno study. This trial evaluated the efficacy of intensive combined therapy of 160 patients with type 2 diabetes mellitus and moderately increased albuminuria. Intensive therapy reduced both microvascular and macrovascular disease. The main issues for optimal management of diabetic nephropathy are listed in Table I.
The American Diabetes Association, the National Kidney Foundation, and 2014 Expert Panel of the National Institutes of Health, as well as the American and International Societies of Hypertension updated position papers indicate that treatment goals for blood pressure in patients with diabetes and hypertension should be <140/90 mmHg. However, it is reasonable to consider a BP goal of 130/80 mmHg if a patient has very high levels of albuminuria (>300 mg/day), although this is based on limited evidence.
For BP attainment and optimal reductions in very high albuminuria, a low protein (0.6 – 0.8 grams/kg/day) and low sodium diet (2.4 grams/day) are the primary nutritional interventions. Decreases in albuminuria and BP reduction with angiotensin-converting enzyme (ACE) inhibitors or other renin-angiotensin system (RAS) inhibitors are maximized in the presence of a low sodium/low protein diet. Several randomized trials have demonstrated improvements in BP with dietary sodium restriction, with associated reductions in cardiovascular disease end points. Patients with CKD are generally less able to excrete a sodium load, making the potential benefit even greater, although there is little data available.
Approach to attain blood pressure goal
Current society and national guidelines, including the American and International Societies of Hypertension, the National Kidney Foundation, the American Diabetes Association and the 2014 Expert Panel of the National Institutes of Health state that patients with diabetes should be treated to a goal BP of <140/90 mmHg. This is a change from prior guidelines that suggested lower, more aggressive, BP goals. Importantly, the prior recommendations were not based on a large body of randomized-control trial evidence. Following recent publication of these guidelines, a monumental meta-analysis of outcome trials involving anti-hypertensive therapy in patients with type 2 diabetes was published. The analysis involved 40 trials and >100,000 patients. It confirmed that reducing systolic BP in type 2 diabetes is associated with a decrease in all-cause mortality and cardiovascular events when started at >140/90 mmHg, and treatment is targeted to a systolic BP between 130 and 140 mmHg. The only benefit of lower systolic BP is a reduction in stroke incidence below <130 mmHg. This new analysis supports that it is reasonable, in younger patients with prior ischemic stroke or early microvascular complications, to target a systolic BP <130 mmHg, if lower BPs are well tolerated with minimal side effects.
Interestingly, this meta-analysis also assessed CKD progression end points and changes in albuminuria. Consistent with current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, lowering systolic BP by 10 mmHg had no effect on CKD end points (dialysis, transplantation, or death from kidney disease.) However, the new development of albuminuria, or worsening of already present albuminuria, was reduced with a 10-mmHg decrease in systolic BP. The difference between these two end points (i.e., the lack of CKD outcome benefit with BP lowering, despite reducing albuminuria) is likely due to the short-term nature of the studies analyzed.
Since hypertension places patients with diabetes at high risk for cardiovascular morbidity and mortality, all patients with diabetes and persistent BP above 140/90 mmHg should be started on antihypertensive drug therapy (Table II). Successful implementation of concurrent non-pharmacologic therapy may permit later reduction in the dose or number of antihypertensive agents.
There is no optimal (“one size fits all”) approach to attain BP control goals, as each approach needs to be tailored to the patient phenotype and genotype. However, certain objectives and strategies are clear.
In almost all cases of advanced CKD, a minimum of two medications will be needed initially. The most recent 2014/15 guidelines and position statements recommend starting with an inhibitor of the RAS. Prior guidelines have suggested that the second medication added for BP control should be a calcium channel blocker (CCB), based on outcomes of the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial.
However, more recent data suggests that addition of a diuretic or CCB as a second agent is appropriate. Properly dosed diuretics are mandatory earlier in the treatment regimen when the patient has evidence of edema or is non-adherent with a low sodium diet.
However, achieving the BP goal within 3 – 4 months is more important than the regimen used to achieve this goal. The diuretic chosen should be appropriate for level of eGFR, i.e., loop diuretics, preferably a long-acting agent such as torsemide for those with eGFR <40 ml/min and chlorthalidone for those with higher eGFR. A general evidence-based approach put forth by an international consensus panel to treat blood pressure in CKD with severely increased proteinuria, and further updated in a position paper by the American Society of Hypertension is shown in Figure 1. It should be remembered that starting with a fixed dose combination in patients whose blood pressure is 20/10 mmHg above the guideline goal results in not only achieving goal blood pressure more quickly, but also reduces the likelihood of an adverse cardiovascular event.
The evidence for earlier forms of CKD with low levels of albuminuria or normoalbuminuria should focus on blood pressure control as there is no class of antihypertensive agent that is superior to any other for achieving this goal. However, per recent guidelines, ACE inhibitors or angiotensin receptor blockers (ARB) are the best-tolerated single agents. Current evidence indicates that in type 1 diabetes, ACE inhibitors are recommended as part of a therapeutic regimen to achieve BP goals; similar observations are seen in type 2 diabetes with both classes of RAS inhibitors.
When using RAS inhibitors in patients with CKD and years of poor blood pressure control, it is not uncommon to see a rise in serum creatinine of as much as 35% from the initial value when the medication was started and blood pressure control is achieved. Long-term follow-up studies indicate that serum creatinine elevation in this setting actually correlates with slower progression of kidney disease when followed over seven or more years. This has been observed by multiple investigators and is in the National Kidney Foundation guidelines for treatment of people with advanced kidney disease.
Importance of albuminuria reduction
Combination therapy is ultimately required in almost all patients with advanced CKD, as the algorithm in Figure 2 suggests. In patients with severely increased albuminuria and hypertension, the clinician’s focus should be on treating both. These two events are not necessarily related. Among patients with advanced proteinuric CKD, current evidence does not support the use of combined blockade of the renin-angiotensin system with both an ACE inhibitor and an angiotensin receptor blocker (ARB). This is based on multiple trials, including the VA-NEPHRON D trial, that demonstrated that combination therapy with both ACE inhibitor and ARB (or a direct renin inhibitor) do not provide superior BP control compared to ACE inhibitor monotherapy, and produced significantly more adverse events.
Use of aldosterone blockade in advanced proteinuric CKD is particularly useful as it lowers BP more than the other RAS agents in obese patients, either alone or in combination, and provides greater anti-proteinuric effects. This reduction is not solely related to further blood pressure reduction.
Clinicians are limited by hyperkalemia when treating CKD patients with a RAS inhibitor. However, recent prospective randomized trials demonstrate excellent safety and efficacy of new oral non-absorbed potassium. Patiromer is an example of one such drug and is expected to be more widely available to clinicians in late 2015 / early 2016.
If albuminuria remains severely increased, the addition of non-dihydropyridine calcium channel blockers (CCBs: verapamil, diltiazem) provides an additional blood pressure reduction along with further albuminuria reduction of 25 – 35%. Dihydropyridine CCBs do not have the same magnitude of proteinuria reduction unless used in the presence of an RAS inhibitor, and fail to protect against kidney disease progression in advanced CKD when not used with an ACE inhibitor or ARB. Moreover, guidelines state that dihydropyridine CCBs should not be used as monotherapy in CKD patients with severely increased albuminuria, but always in combination with an RAS inhibitor.
Once triple therapy with an RAS inhibitor, CCB, and appropriately dosed diuretic has been tried and the patient is still not reaching their BP goal, other options include referral to a board certified hypertension specialist (http://www.ushtndirectory.org/specialists03/UserMain.asp) or one could add a fourth agent; these include an alpha beta blocker such as carvedilol. Findings from the GEMINI trial demonstrate benefits in glycemic control and albuminuria reduction compared to metoprolol.
The antihypertensive effects of conventional beta-blockers, as well as their capability to reduce cardiovascular mortality in high-risk patients are well established, but there is no direct evidence that these agents provide additional renoprotective effects. Moreover, the addition of beta-blockers to further lower BP in the setting of advanced CKD with fully dosed RAS blockers is weak, as noted in the COSMOS study, where only a 3-mmHg additional BP reduction was noted on 24-hour ambulatory monitoring when maximal dose carvedilol was added to maximal dose lisinopril.
Newer beta-blockers with vasodilating properties, such as carvedilol and nebivolol, may reduce mortality in patients on dialysis as noted in cross-sectional studies. Moreover, recent findings demonstrate the majority of negative effects of beta-blockers are relegated to atenolol and not others in the class. These findings suggest that vasodilator beta-blockers could be used in patients with CKD.
Additional agents such as clonidine, guanfacine, minoxidil, nitrates, and hydralazine, may be used, but clonidine is not well tolerated and does not have additive BP lowering effects when used with beta-blockers, while the other agents are very sodium retaining and can actually increase BP if not used appropriately with other medications. Lastly, certain combinations of CCBs, such as diltiazem with long-acting nifedipine or amlodipine, have additive BP-lowering effects and are useful as further or fifth-line agents.
What happens to patients with diabetic nephropathy?
Once patients have established diabetic nephropathy, i.e., >300 mg/day albuminuria that persists and hypertension with an eGFR <60 ml/min, most are destined for dialysis if they do not die from cardiovascular causes before dialysis initiation. The risk of adverse cardiovascular events in this group of patients is significantly higher than age-matched controls without CKD. As well, if aggressive management of BP and other risk factors does not occur early, disease progression will proceed more rapidly.
As kidney function declines, higher doses and more antihypertensive medications will be needed to control BP, such that when eGFR is <20 ml/min, four to five drugs are commonly required to achieve BP goals.
How to utilize team care?
Nephrologists should be consulted on all patients when the eGFR is 30ml/min or less. Additionally, a board certified clinical hypertension specialist (see above) should also be consulted at any level of eGFR if BP cannot be lowered to <140/90 mmHg in any patient with CKD.
There is no specific role for nurses in such a setting except for diabetes nurse educators, who are critical for helping the patient understand and manage their blood sugars and who can reinforce the physician’s message about achieving other related goals, such as BP reduction.
These professionals are useful to ensure adherence with medication and should work with the clinician to communicate a unified message to the patient.
These are perhaps the most underutilized and most important members of the team. They can ensure that the patient understands the importance of low protein and low sodium intake as well as help reinforce their impact on outcomes.
Therapists (physical, occupational, speech, other)
Some patients suffer from depression and a therapist can help with coping of this disease and its consequences.
Are there clinical practice guidelines to inform decision-making?
Guidelines from the American Diabetes Association, the American and International Societies of Hypertension, the 2014 Expert Panel of the National Institutes of Health, and the National Kidney Foundation exist. Approaches to glucose and blood pressure management are summarized in this paper.
There are many unanswered questions such as the following:
1. What is the role of BP level on progression of nephropathy in diabetes?
2. Why doesn’t everyone with diabetes develop nephropathy, instead of only about 25 – 30%? What are the genetics of the kidney disease?
ICD-9 codes – 249.4, 250.4, 401, 997.91
What is the evidence?
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- Does this patient have diabetes-related hypertension?
- What tests to perform?
- How should patients with hypertension and chronic kidney disease be managed?
- What happens to patients with diabetic nephropathy?
- How to utilize team care?
- Are there clinical practice guidelines to inform decision-making?
- Other considerations
- What is the evidence?