Open Journal Systems

REVIEW ARTICLES

Received: 15/10/2015

Accepted: 23/11/2015

Treatment of hypertension in chronic kidney disease

Silvia Palomo-Piñón,^a Martín Rosas-Peralta,^b José Ramón Paniagua-Sierra^a

^aDivisión de Desarrollo de la Investigación, Coordinación de Investigación en Salud

^bDivisión de Investigación en Salud, Hospital de Cardiología, Centro Médico Nacional Siglo XXI

Instituto Mexicano del Seguro Social, Ciudad de México, México

Communication with: Silvia Palomo-Piñón

Email: silvia.palomo@imss.gob.mx

Systemic arterial hypertension (SAH) is a progressive cardiovascular syndrome caused by complex and interrelated causes. The early markers of this syndrome are often present even before the blood pressure (BP) elevation; therefore, SAH cannot only be classified by the BP elevation threshold, which sometimes is discreet. Its progression is strongly associated with structural and functional cardiovascular abnormalities, which lead to end-organ damage (heart, kidney, brain, blood vessels and other organs), and cause premature morbidity and death. In this sense, the BP is only a biomarker of this cardiovascular syndrome, which is why it is more useful to consider individual BP patterns of the ill patient rather than a single BP threshold. The study and treatment of hypertension in chronic kidney disease (CKD) has made some progresses, especially in patients requiring dialysis. The use of non-invasive technology to register the BP has reconfigured health care of patients in regards to the diagnosis, circadian pattern, clinical surveillance, pharmacological prescription, prognosis, and risk of cardiovascular events (as well as mortality). The opportunity in the diagnosis and treatment means a delay in the onset of complications and, also, of dialysis. The blockade of the renin-aldotensin-aldosterone system (RAAS), a regular monitoring of the dry weight of the population in dialysis, and non-pharmacological interventions to modify lifestyle are the maneuvers with greater impact on the morbidity and mortality of patients.

Key words: Hypertension; Chronic renal disease; Treatment

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Chronic kidney disease (CKD) and hypertension (HT) have a close two-way cause-effect relationship. Decreased renal function is associated with increased blood pressure (BP), and the sustained elevation of BP is a key to accelerate the decline in glomerular filtration factor in all kidney diseases. It is estimated that 50 to 75% of patients with diabetic and non-diabetic CKD have a systolic and diastolic BP > 140/90 mm Hg, respectively. Medication treatment is aimed at reducing cardiovascular risk and slowing the speed with which CKD progresses to terminal stages. This harmful positive feedback between BP and renal function has been proven through various experimental studies and human clinical trials.¹

In clinical practice, the doctor has enough information to identify the importance of this cause-effect relationship between hypertension and CKD. Although there are still several unanswered questions, recommendations have been issued based on levels of evidence regarding the screening, diagnosis, and treatment of HT in patients with CKD. The aim of this manuscript is to conduct a systematic review of the study and treatment of hypertension in the CKD population, which unlike the population without CKD presents risk inherent factors from nephropathy, which add to the traditional risk factors for cardiovascular disease and provide a higher cardiovascular risk.

Clinical evaluation of the patient

The definition of HT is a valuable component in clinical practice describing the importance of assessing the patient systematically. In 2005, Giles et al. proposed the following:

It is a progressive cardiovascular syndrome caused by complex and interrelated etiologies. Early markers of the syndrome are often present before BP rises; therefore, hypertension cannot be classified only by the threshold elevation of BP, which is sometimes discreet. Its progression is strongly associated with structural and functional abnormalities of cardiac and vascular function that damage the heart, kidney, brain, blood vessels, and other organs, and causes morbidity and premature death. In this regard, BP is only a biomarker of this cardiovascular syndrome, so it is more useful to consider the individual patient’s BP patterns instead of a single threshold BP, which often has no significant elevations.^2,3

Under this concept, patients with diabetic or non-diabetic nephropathy are considered a high-risk population to develop and perpetuate elevated BP in the course of the five stages in which CKD is classified. The definition highlights the importance of reviewing individual patterns of BP, which in daily practice is usually seldom done. Note that the diagnosis of hypertension is an activity included in all stages of kidney disease; the procedure for doing so is no different from that used in the population without CKD, and it has the same common problems, mostly related to the technique with which BP is recorded. This means that screening for diagnosis is not thorough, and mistakes are made. The fact is emphasized that the personnel recording BP must know how to do it and must do it with certified equipment recalibrated according to the manufacturer's recommendations.

Technological development has allowed the doctors rely on tools that provide useful information for the individualized study and treatment of patients. In the case of patients with CKD, ambulatory blood pressure monitoring (ABPM) has become important, because it is the most accurate method to confirm the diagnosis of hypertension, and its use has reduced the unnecessary treatment of people who do not have true HT. Also, it has been shown that ABPM is superior to other methods of multiple BP measurement to predict clinical events related to elevated BP. Although its use has been increasing in this population, it is still limited, since the equipment is not available in nephrology medical units. The procedure for obtaining a home blood pressure measurement (HBPM) instead of ABPM is also underused, particularly in the population that has not started dialysis because the patient needs training; however, home measurements have proved useful, particularly in patients on peritoneal dialysis (PD) whose treatment technique requires them learning and monitoring their BP number. Therefore, the usual tool to register BP in most nephrology medical units remains the mercury or sometimes the electronic sphygmomanometer, accompanied by a solid standardized procedure to register BP, which is not always monitored, nor it is updated in all such medical units.

Once hypertension is diagnosed in the subject with renal disease, it is essential to know the impact this has on renal function, proteinuria, and vascular organs. The doctor needs these clinical tests as soon as the diagnosis of hypertension is made, to look for possible secondary causes, as some of these have corrective treatment. In addition, the doctor must decide what pharmacological treatment is appropriate for the patient. The basic tests do not differ from those for subjects without CKD. They are: glucose, electrolytes, creatinine (SCr), glomerular filtration rate (GFR), total cholesterol, and high-density cholesterol (HDL) in serum. Proteinuria should be quantified and hematuria looked for in the course of CKD. Examination of the fundus, 12-lead ECG, and transthoracic echocardiography are also critical to find if retinopathy and hypertensive heart disease are there; finally, a bilateral renal Doppler ultrasound must be done in cases with hypertension of suspected renovascular origin. With these results, the doctor may complement the patient’s tests in order to rule out secondary causes of hypertension.

The choice of treatment not only aims to reduce the BP number to the recommended values, but also to preserve kidney function even if the patient is on dialysis (residual renal function), and to reduce the magnitude of proteinuria. Identifying cardiovascular risk factors is also important. In addition to traditional cardiovascular risk factors such as smoking, physical inactivity, overweight or obesity, and high salt intake, the patient with renal disease presents other disorders increasing their risk: anemia, inflammation, calcium/phosphorus metabolic disorders, hyperhomocysteinemia, alterations in oxidative stress, and albuminuria itself.

Importance of proper blood pressure recording

As with many other activities in medicine, the health care professionals who perform this activity require initial training and periodic review of the technique used. As mentioned above, the equipment used must be validated, periodically maintained, and recalibrated according to the manufacturer's instructions. At no time should any steps in the procedure to properly record blood pressure (BP) be skipped, for example, feeling the brachial or radial pulse before measurement to make sure it is regular; maintaining a relaxed atmosphere and a standard temperature; seating the person with the arm correctly supported; making sure that the cuff covers the entire forearm; instructing the patient to refrain from ingesting drugs and substances that modify BP (e.g., antihistamines, hormones, caffeine, and tobacco). These widely known recommendations come to be ignored in daily practice, and the BP number registered depends on this.

With office measurement, HT is usually suspected when the doctor first finds any of the following clinical situations:⁴

• Difference between arms > 20 mm Hg.
• BP number ≥ 140/90 mm Hg.

But there are other non-invasive procedures to register BP that have helped the doctor to make an accurate diagnosis: ABPM and HBPM. The procedure to do these, and the BP values considered diagnoses of hypertension, are described in the NICE guidelines.4 These tools to register BP have one or more of the following objectives: to establish the diagnosis, estimate the risk of adverse events, identify the pattern of circadian rhythm, improve drug prescribing, and monitor the BP number during treatment. Although the 2013 NICE guidelines do not specifically discuss the issue of BP in people with CKD, the criteria for diagnosing hypertension with ABPM or HBPM has been extrapolated from data in the general population, and the equivalences established with office measurement have been useful for patient monitoring.  

For patients on hemodialysis (HD), the registration of BP requires special consideration. Dynamic changes in intravascular volume before, during, and after HD give significantly different BP readings from each other. There is still controversy to define what is the BP figure to be used to assess risks and establish the prognosis of subjects in HD. Agarwal et al. have shown that recordings obtained by ABPM and HBPM are better correlated with markers of target organ damage and adverse clinical events in this population, but do not correlate with mortality. Taking BP frequently during the HD session only serves to give treatment with the least possible risk for the patient; in most cases the systolic and diastolic pressure before and after dialysis is approximately 10 mm Hg higher and lower, respectively, than that found during the procedure. In the case of patients in PD, HBPM has greater prognostic significance in detecting left ventricular hypertrophy and cardiovascular events compared with the figure recorded in the office. Because the patient in PD knows the importance of recording BP before, during, and after treatment, the possibility that they have their own equipment and have been trained to do by themselves is high, compared to the population without dialysis. In fact, it is difficult to provide an effective treatment for hypertension if they do not have home BP measurements with the auscultation method of this population.⁵

These are the reasons that nephrologists must consider, since they must start to reason that the registration of BP outside the dialysis unit is the most useful for risk assessment and prognosis, especially when they want to evaluate hypertension treatment in this population.^6,7 While the tools exist in the market, and evidence accumulates daily scientifically supporting the usefulness of ABPM and HBPM in people with kidney disease, this equipment is not available in nephrology medical units.

Finally, the development of noninvasive equipment to study the structure and function of blood vessels has also opened up the possibility of estimating the risk of cardiovascular events with other methods more accurately than can be done with BP recording alone. The arterial stiffness determined by the pulse wave velocity in the aorta, and measurements of pulse reflection have had an interesting development in the CKD population with and without dialysis. We note that the vascular evaluation methods described are not discussed because they are not the subject of the present review.^8,9

Epidemiology of hypertension in CKD

A prevalence of up to 90% of hypertension in the population with CKD not on dialysis has been reported, regardless of the presence of diabetes.^10,11 Like the general population, more than 50% of patients do not achieve the recommended figures indicating good control. Factors associated with lower BP control in these patients include: increased urinary protein excretion, greater deterioration of the glomerular filtration rate (GFR), and older age, which in daily practice results in the need for drugs at higher doses and of different kinds; in the case of the presence or absence of diabetes as a factor associated with uncontrolled BP, a difference was found just in the study by Fraser et al.¹² Patients with higher cardiovascular risk (older age, diabetes or albuminuria) and those with progression factors for KD (diabetes and albuminuria) are the population in which it is harder to obtain a figure BP recommended.  

In the case of patients on renal function replacement therapy with either PD or HD, high BP levels are directly related to cardiovascular morbidity and mortality. Due to the phenomenon of "reverse epidemiology" in the which^13,14 higher or lower systolic or diastolic BP numbers in the patient receiving dialysis are directly related to their general deterioration, numerous recommendations have been issued on the BP number suitable for this population. The reported prevalence of hypertension in dialysis was up to 86%, of which approximately 58% of patients are uncontrolled; of these, 12% were classified as refractory hypertension. Do not forget that hypertension in any renal function replacement modality reflects inadequate volume control despite the replacement therapy. That is, for subjects on dialysis, dry weight monitoring is mandatory.

Alterations in the circadian rhythm of BP in chronic nephropathy

In any individual, BP is not constant but is subject to change during day and night. Acute diurnal variations, brought by stress and exercise, are offset by multiple physiological mechanisms that allow the individual to remain free of impact on their functioning. It is known that healthy individuals have BP reduced between 10 and 20% during sleep, relative to their BP during the day. This decline has no functional impact. When subjects develop hypertension, this nighttime reduction may or may not remain. The lack of an adequate nighttime decline in BP has prognostic value because patients whose BP does not descend properly or whose pressure increases during the night have a higher prevalence of left ventricular hypertrophy, stroke, and CKD, this last usually manifested by microalbuminuria. These alterations have been described most often in people with diabetes, dysautonomia, secondary hypertension, sleep apnea, and patients with renal transplantation. Generally speaking, if the patient with hypertension retains the nighttime BP decrease between 10 and 20% compared to the daytime decrease, they are said to have a dipper circadian rhythm pattern. If the decline is greater than 20%, they are categorized as extreme dipper. When the drop is less than 10%, the pattern is of a non-dipper, and when there is no decrease they are considered a nocturnal riser.^15,16

Although the relationship between ambulatory BP, nighttime BP, circadian variation, and adverse outcomes (all-cause mortality, cardiovascular mortality, and cerebral events) is well established, it is not known with certainty whether ambulatory BP is associated with CKD and renal outcomes, because the information available is contradictory. However, a considerable number of studies have suggested that ambulatory BP and particularly nocturnal BP factors are significant and independent predictors of renal function. Lurbe et al.¹⁷ evaluated ambulatory BP of 75 patients with type 1 diabetes without hypertension or microalbuminuria for two years. Patients who developed microalbuminuria after follow-up were characterized by elevated diastolic BP during day and night, and elevated systolic BP only at night. In this work, the risk of microalbuminuria was 70% lower in subjects with a dipper pattern, compared with non-dippers (ratio of day/night BP ≤ 0.90). On the other hand, Syrseloudis¹⁸ and Oliveras¹⁹ confirmed the relationship between proteinuria and nighttime BP in patients with resistant hypertension. In connection with the GF, an elevated SCr and decreased GFR are associated with elevated nocturnal BP (riser) and the absence of nocturnal dipping (non-dipper). Agarwal and Light²⁰ studied the relationship between GFR, proteinuria, and ABP, finding that any amount of proteinuria or decreased GFR was associated with a decrease in circadian variation; only subjects with normal GFR and proteinuria showed no normal circadian variations in systolic BP. These results demonstrate a strong relationship between nighttime BP and CKD. In another study published by Agarwal and Andersen²¹ in a cohort of 277 patients with CKD, the non-dipper pattern was not a significant predictor of CKD after adjusting for 24-hour BP. In the same study, nocturnal BP was found to be a predictor of overall mortality, but not of CKD, after adjusting for daytime BP. Argawal in another study²² focused on circadian variations of BP, found that the non-dipper pattern was marginally associated with an increased risk for CKD after adjustments (RR [risk ratio] 1.95, 95% CI 0.97- 3.95, p = 0.063). Although these and other studies showed that changes in nocturnal BP were significant predictors for CKD, the tendency is to believe that renal side effects are encouraged in the presence of increased nighttime BP.^23,24

The studies mentioned are just a few of the many that have reported the possible patterns of BP in patients on replacement therapy. The systolic and diastolic BP number moves the patient‘s pattern from one category to another, making it difficult to treat hypertension that is not caused by volume overload, especially in patients in HD. The KDOQI guidelines recommend taking into account only two patterns: those obtained before dialysis, and home measurements to be obtained in the absence of intradialytic hypotension. Lacking home BP measurements, patients with persistent hypertension (figures ≥ 160 mm Hg) before, during, and after HD sessions have a high suspicion of sustained hypertension and require thorough clinical testing to identify possible factors that initiate and perpetuate hypertension in those who should consider initiating medication therapy.⁵

BP target figures in the CKD population

Because hypertension is associated with an increased risk of cardiovascular events, it is of great interest to keep in mind a figure with which this risk decreases. It is important to note that the recommendations published by the JNC-8 are supported solely by the data obtained from long-term randomized clinical trials with strong outcomes. In these recommendations, there is not enough evidence to prompt the doctor to get a BP number < 140/90 mm Hg in patients with kidney disease or diabetes.25 With the inclusion of other studies, such as meta-analyses, systematic reviews, and controlled clinical trials that exclusively explore the effects of BP number on the progression of CKD, work published by the Kidney Disease Improving Global Outcomes group, the recommendation of a figure < 130/80 mm Hg is supported, for subjects with moderate CKD and severe albuminuria (albumin rate/urinary creatinine ≥ 30 mg/g) with and without diabetes, because benefits have been observed. However, the level of this recommendation is "expert opinion",²⁶ which is the lowest level. Therefore, taking into account only controlled clinical trials with hard outcomes, a BP number < 140/90 mm Hg is recommended for the CKD population. There is insufficient data to make exclusive recommendations in the dialysis population, and recommendations are extrapolated from general studies.  

If the BP number obtained in the office is used as a recording method, then a figure < 140/90 mm Hg defines good control. This equates to an average BP 130/80 mmHg if ABPM or HBPM is used, with an average daytime BP < 135/85 mm Hg and 120/70 mmHg overnight. Significantly, the literature suggests that the 24-hour record is needed in the CKD population, since it is the only tool to rule out masked hypertension. This type of hypertension, defined as office BP with a figure < 140/90 mm Hg, but that in 24-hour record with ABPM is > 130/80 mm Hg, or HBPM > 135/85 mm Hg, has a prevalence between 40 and 70% of the population with CKD; its importance is that it is directly related to the deterioration in GFR and the magnitude of proteinuria.^5,27 This gives the patient a higher risk of cardiovascular events and earlier initiation of dialysis. In the study of Minutolo et al.²⁸ 489 with consecutive patients with CKD, the group with masked hypertension had a tripled risk of presenting a fatal or non-fatal cardiovascular event, and a quadrupled risk of initiating renal function replacement therapy after 5.2 years of follow-up.

Whether on dialysis or not, the physician should consider that the BP number is just one of the elements of the cardiovascular syndrome of hypertension, so the primary goal of treatment is to prevent and, where appropriate, address the broad spectrum complications that it represents.

Factors related to hypertension in CKD

Sodium and water

Too much sodium and water are possibly the most significant factors that hinder hypertension treatment in subjects in advanced stages of CKD and dialysis. Too much sodium and water may be the result of various factors related to the patient, such as lack of compliance with the restrictive diet, factors associated with high sodium concentration in dialysis solutions, the recurrent use of ultrafiltration models based on sodium, and restriction to three sessions per week in HD centers. The study published by the Frequent Hemodialysis Network, a clinical trial, and Dry-Weight Reduction in Hypertensive Hemodialysis Patients (DRIP), have demonstrated the importance of constantly evaluating the dry weight of the patient and thereby avoiding elevated BP. An 18% reduction in dry weight decreased systolic BP by 10 mm Hg and systolic and diastolic BP by 6.6/3.3 mm Hg, respectively.^29,30

This clinical evaluation, routine in dialysis units, is the main cause of hypertension in this population. The concept refers to the weight in which the patient remains normotensive without antihypertensive drugs until the next dialysis session,³¹ or has also been defined as the weight below which the patient presents hypotension after the completion of dialysis.³² In clinical practice, the BP graph is the most used tool for monitoring weight. It is usually done on a monthly and data are obtained from making BP before and after each HD session. The PD patient usually has a home sphygmomanometer and takes measurements on their own. The reliability of the record is limited in most cases, but it has its clinical significance. Dry weight can also be evaluated with biochemical markers, bioimpedance analysis, bioimpedance with spectroscopy, and measurement of the diameter of the inferior vena cava during inspiration. This latest study is done by ultrasound, and of the four methods mentioned, it is the most accessible for most nephrology services in the country. The relative plasma volume monitoring (RVP) during HD has also been mentioned as an alternative tool to infer volume overload. During ultrafiltration, overloaded patients show flat slopes given by the continuous filling of the intravascular space at the expense of the interstitial space and the maintenance of plasma volume, while subjects without volume overload show steep slopes from the absence of intravascular filling of the interstitial space. Because the study results have been questioned, the usefulness of RVP to determine volume overload in dialysis subjects is not clear.⁵

Lack of compliance with pharmacological and nonpharmacological indications also contributes to maintaining high levels of BP. It has been reported that subjects in replacement therapy may take more than 25 pills a day. Discontinuous intake of drugs such as beta-blockers and clonidine can cause rebound hypertension. Sleep apnea is common in subjects in HD and is associated with hypertension; treatment with positive airway pressure (CPAP) can reduce the BP number and can also have beneficial effects on the left ventricle ejection fraction. Other secondary causes of hypertension such as primary aldosteronism, Cushing’s syndrome, and pheochromocytoma should be considered in patients with uncontrolled BP at different stages of CKD.

Other conditions associated with CKD that may impair salt excretion are the reduction of functional renal mass, sympathetic nervous system activation, renin-angiotensin system imbalance, sodium chloride alteration in the distal nephron, endothelial dysfunction, and some combinations of these. The high-sodium diet not only exacerbates hypertension in patients with renal impairment, but also has the potential to cause direct damage to the kidney and decrease its function.

Variability in blood pressure

Variability in blood pressure is considered a risk factor for adverse events in hypertensive subjects. The dialysis population is particularly susceptible to upward variations due to changes in vascular elasticity and volume changes related to dialysis. It has been reported that only an increase in the standard deviation given by the increase in systolic BP before dialysis is associated with an 18% higher risk of presenting all causes of cardiovascular mortality. Most ultrafiltration during dialysis was associated with less BP variability.³³

Hypertension during dialysis

This can occur with some frequency and is often not recognized because it is not associated with immediate complications, such as hypotension. However, there are studies that even with short-term follow-ups (six months)³⁴ have documented that an increase equal to or greater than 10 mm Hg in systolic BP during the HD session is associated with a doubled risk for hospitalization or death. On the other hand there is an interesting fact in the pathogenesis of hypertension during dialysis, which is related to the mechanisms involved with the phenomenon of intradialytic hypotension: it is known that volume overload is favored by lower ultrafiltration during dialysis, and individuals with volume overload have a higher risk of intradialytic hypotension due to endothelial dysfunction and an overactive sympathetic nervous system. The interesting thing is that these same mechanisms have also been recognized as one of the causes of high BP during dialysis, which is why keeping the patient without fluid overload is essential to prevent these events.

Treatment recommendations

Renin-angiotensin-aldosterone system blocking

The previously mentioned aspects are crucial to choosing the right treatment for the patient, which depends on the cause, especially in the case of secondary hypertension and volume overload of subjects on dialysis. In the case of subjects without dialysis, drug treatment seeks not only to achieve the recommended BP value, but to reduce proteinuria, slow the progression of CKD, and reduce cardiovascular risk. There is sufficient clinical and experimental evidence, accumulated over three decades documenting the deleterious effects of increased vascular and tissue RAAS activity, especially in the kidney. An excess of Angiotensin II increases the intraglomerular pressure primarily by the constriction of efferent arterioles, causing glomerular hypertension and protein leaks through the glomerular basement membrane. The presence of angiotensin II simultaneously stimulates aldosterone production and triggers the activation of a cascade of profibrotic cytokines whose activation causes sclerosis of glomerular cells and tubulointerstitial fibrosis. Given the above premises, the pharmacological blockade of RAAS is to date the unanimous recommendation of choice for the treatment of hypertension not only on the subject with already established CKD, but in hypertensive patients in general, as numerous studies have confirmed that this blockage decreases the magnitude of proteinuria and grants nephroprotection even above the systemic hemodynamic changes affecting BP. The well-established role of RAAS to begin and maintain renal damage, in both clinical and experimental studies, has given researchers the initiative to test multiple hypotheses related to a deeper inhibition of the system, the use of multiple concurrent agents, or higher doses of a single agent, with the goal of exploring additional benefits. The results of clinical studies such as COOPERATE,³⁵ ONTARGET,³⁶ AVOID,³⁷ ALTITUDE,³⁸ VA NEPHRON-D,³⁹ among others, have made the present recommendations for the use of these drugs on subjects with CKD the following: Do not use in combination with other drugs in the same family as this has not been shown any benefit; do not use in high doses, only the recommended doses; and these can be combined with different drug classes, preferably calcium channel blockers and thiazide diuretics. At all times, the prescription of these and all antihypertensive drugs must be accompanied by recommendations to modify lifestyle, dietary changes (mainly decreasing sodium and phosphorus intake), and the treatment of patient comorbidities, like hyperglycemia, hyperuricemia, and dyslipidemia.⁴⁰ There are three types of drugs on the market that block the RAAS: angiotensin II -converting-enzyme inhibitor (ACEI), type 1 angiotensin II receptor antagonists (ARB II), and pro-renin receptor blockers (PRB); not all of them are included in the basic drugs in public health institutions. The doctor should know the general and specific benefits of different families of drugs and should use combinations that give the patient the greatest benefits.

Diuretics

Generally speaking, the type of diuretic that is prescribed in the early stages of CKD to treat hypertension is the thiazide diuretic, especially chlorthalidone. But as CKD progresses and volume overload becomes manifest, loop diuretics are chosen, whose doses are usually higher to achieve natriuresis. This difficulty reaching natriuresis is further exacerbated if the patient presents decreased serum albumin concentration; over time, the effectiveness of these drugs to achieve optimal BP control decreases. There are proposed clinical studies combining a thiazide diuretic with a loop diuretic in cases of advanced CKD (GFR < 30 mL/min/1.73m² sc), in which it has traditionally been considered that thiazides have no effect.^41.43 These studies obtained average BP reduction, but the combination has proved more effective in patients with fluid retention, which occurs in the course of CKD sometimes without being notable for the clinician. Given this fact, and with the aim of documenting volume overload early, Verdalles et al.⁴⁴ have suggested that the body composition of patients without dialysis can be assessed by bioimpedance spectroscopy and can serve as a guide for prescribing diuretics in the treatment of hypertension. The study describes 30 subjects without dialysis and with extracellular volume expansion, and 20 patients without expansion who were receiving antihypertensive drug prescriptions without success. After six months of treatment with diuretics, systolic BP decreased by 21 mm Hg in subjects with volume expansion, and 9 mm Hg in those without expansion (p < 0.01). Of the 30 subjects with volume expansion, nine obtained a figure < 140/90 mm Hg at follow-up. This novel proposal to rationalize the prescription of diuretics in patients with hypertension in CKD requires studies with large cohorts of patients before considering it for widespread use.

Salt restriction

There are several reasons why restricting salt intake is an important recommendation for the optimal control of BP in all populations: patients with nephropathy have salt-sensitive hypertension,⁴⁵ modest reductions in salt intake improve the antihypertensive effect of drugs such as RAAS inhibitors,⁴⁶ and significant reductions in salt intake improve the antiproteinuric effect of diuretics.⁴⁷ However, in daily practice it is difficult to answer the question: how much restriction should be proposed? There is no quantitative information published in the Mexican population, so a benchmark for patients can be the salt intake report from the United States Institute of Medicine. This group of experts did an analysis of all scientific studies related to "health outcomes" and "sodium intake in the diet"; they found great variability in the methodological quality of the studies, so a conclusion could not be issued. This group of experts could only recommend an intake of no more than 2.3 g per day. Although for many experts the recommendation is not ideal for people with HT and CKD in whom salt sensitivity is highly prevalent, the parameter is a reference to educate the population to try to limit salt consumption below that value.⁴⁸

Mineralocorticoid antagonists

These antagonists are limited in patients with advanced CKD use, as its main undesirable effects are hyperkalemia and increased serum SCr. However, they are efficient at reducing the BP of individuals receiving three or more antihypertensive drugs, so are fourth-line drugs, especially in the treatment of resistant hypertension. Caution is advised in subjects whose serum potassium figure is above 4.6 mEq/L, as they may have average increases of 0.4 mEq/L with these drugs. Spironolactone is contraindicated in acute renal failure and when GFR is less than 10 mL/min/1.73 m² sc. For its part, eplerenone is contraindicated when GFR falls below 30 mL/min/1.73 m² sc.²³ Those are the only two drugs available in Mexico.

Chronotherapy

Because of the risk of nocturnal hypertension in CKD, recent studies have examined the effect on the circadian rhythm of BP of administering antihypertensive drugs at night rather than during the day. The first study was reported by Hermida et al.,⁴⁹ and since then a lot of studies have been published that support the benefits of this simple maneuver on cardiovascular risk, BP control, and the effects on GF.^23,50 Future recommendations may include an evening dose of antihypertensive drugs in patients with CKD.

Lifestyle changes aimed at weight loss

For over a decade it has been known that about 13% of patients starting dialysis are obese (BMI > 35 mg/m2), and 60% of transplant patients are overweight or obese.⁵⁰ Obesity is an independent risk factor for hypertension, CKD, and kidney failure. The data on weight loss and its effect on BP and renal function in subjects with CKD are limited. McLaughlin et al.⁵¹ even used drug treatment in addition to a program of diet, exercise, and high motivation for study subjects to lose weight over 12 months. The results showed that the average weight loss was 4%, and about 22% of patients lost 22% of baseline weight and kept it off for 24 months. There were significant reductions in systolic BP at 24 months only in those patients who did not gain weight (-4 mm Hg [95% CI -3 to -11] and -8 mm Hg [95% CI -2 -14]). It is not recommended to use drugs to lose weight in the CKD population even though they are FDA approved, especially if the GFR is below 60 mL/min/1.73m2sc. It is important to motivate the patient to lose weight during the doctors’ visit, especially because studies in obese individuals with diabetes who do not yet have evidence of CKD report benefits over the intense lifestyle changes to prevent the clinical onset of nephropathy.⁵²

Conclusions

Individuals with CKD have a high prevalence of hypertension and thus a higher risk for cardiovascular events than the general population. The study and treatment of hypertension in CKD has made progress, especially in the dialysis population. Using non-invasive technology to record BP has made it possible to reform health care for patients in terms of diagnosis, circadian pattern, clinical monitoring, drug prescription, prognosis, and risk of cardiovascular events and mortality. The timeliness of diagnosis and treatment assumes a delay in the onset of complications and the initiation of dialysis. RAAS blockage, regular dry weight monitoring in the dialysis population, and non-pharmacological interventions aimed at changing the lifestyle are the maneuvers with the greatest impact on patient morbidity and mortality.

References

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