Interface Between Renal Disease and Cardiovascular Illness

Additional content is available online at Elsevier eBooks for Practicing Clinicians

The Cardiorenal Intersection

The heart and kidney are inextricably linked in terms of hemodynamic and regulatory functions. In a normal 70-kg human, each kidney weighs about 130 to 170 g and receives blood flow of 400 mL/min per 100 g, which is approximately 20% to 25% of the cardiac output, allowing the needed flow to maintain glomerular filtration by approximately 1 million nephrons ( Fig. 101.1 ). This flow is several times greater per unit weight than most other organs due to lower vascular resistance. Although the oxygen extraction is low, the kidneys account for about 8% of the total oxygen consumption of the body. The kidney has a central role in electrolyte balance, protein metabolism, and blood pressure regulation. Communication between these two organs occurs at multiple levels, including the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), vasopressin, endothelin, and the natriuretic peptides.

The obesity pandemic is spawning secondary epidemics of type 2 diabetes mellitus (DM) and HTN often leading to CKD and CVD. Among those with DM for 25 years or more, the prevalence of diabetic nephropathy as a result of microvascular disease in type 1 and type 2 DM is about 50%. Approximately half of all cases of end-stage renal disease (ESRD) result from diabetic nephropathy. All forms of kidney disease have a more rapid progression when there are maladaptive mutations in apoprotein L1 (bound to high-density lipoprotein particles and expressed in the podocytes, proximal tubules, and vascular endothelium). Mutant apoprotein L1 protects against African trypanosomiasis but is associated with both kidney and coronary heart disease ( Fig. 101.2 ). With the aging of the general population and cardiovascular care shifting toward the elderly, age-related decreased renal function comprises a major adverse prognostic factor after CVD events. CKD accelerates the progression of atherosclerosis, myocardial disease, valvular disease, and promotes an array of cardiac arrhythmias leading to sudden death.

Chronic Kidney Disease and Cardiovascular Risk

A range of estimated glomerular filtration rate (eGFR) values derived from equations defines CKD. A common definition for CKD stipulates an eGFR of less than 60 mL/min/1.73 m ² or the presence of kidney damage. With aging (age 20 to 80), the eGFR declines from about 130 to 60 mL/min/1.73 m ² , and a variety of pathobiological processes emerge when the eGFR drops below 60 mL/min/1.73 m ² or stage 3 CKD (approximately a serum creatinine [Cr] of 1.2 mg/dL in a woman and 1.5 mg/dL in a man). Because Cr is a crude indicator of renal function and often underestimates renal dysfunction in women and the elderly, eGFR or creatinine clearance (CrCl) calculated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) and Cockcroft-Gault equation, improve the assessment of renal function. CrCl is used most often for drug dosing since it incorporates body weight. For classification of disease, and prognosis, the CKD-EPI equation is preferred because it does not rely on body weight and associates best with adverse outcomes including death. The equation is: eGFR = 141 × min (Cr/κ, 1)α × max(Cr/κ, 1) − 1.209 × 0.993 × age (yr) × 1.018 [if female] × 1.159 [if Black]; where: Cr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum of Cr/κ or 1, and max indicates the maximum of Cr/κ or 1.

Another approved blood test reflecting renal filtration function and used in eGFR equations is Cystatin-C. Cystatin C is a 13 kDa protein produced by all nucleated cells. Its low molecular mass and its high isoelectric point allow it to be freely filtered by the glomerulus and 100% reabsorbed by the proximal tubule. The serum concentration of cystatin C correlates with eGFR and, in combination with a stable production rate, provides a sensitive marker of renal filtration function. Serum levels of cystatin C do not depend on weight and height, muscle mass, age or sex, making it less variable than Cr. Furthermore, measurements can be made and interpreted from a single random sample with reference intervals in women and men being 0.54 to 1.21 mg/L (median 0.85 mg/L, range 0.42 to 1.39 mg/L).

In addition, microalbuminuria at any level of eGFR indicates CKD and occurs as the result of endothelial dysfunction or damage in glomerular capillaries secondary to the metabolic syndrome, DM, and HTN. The most widely accepted definition of microalbuminuria is a random urine albumin/Cr ratio (ACR) of 30 to 300 mg/g. An ACR greater than 300 mg/g is considered gross proteinuria. The random, spot ACR is the office test for microalbuminuria recommended as part of the cardiovascular and renal risk assessment done by cardiologists and other specialists. Microalbuminuria independently predicts CVD risk for those with and without DM. The amount of albumin and protein in the urine is the most important prognostic factor for the rapid progression of CKD to ESRD. In addition both the eGFR and degree of albuminuria contribute independently to the risks of future acute kidney injury (AKI), myocardial infarction (MI), stroke, HF, and death ( Fig. 101.3 ).

Implications of Anemia Due to Chronic Kidney Disease

Blood hemoglobin (Hb) concentration is associated with CKD, and CVD. The World Health Organization defines anemia as a Hb level less than 13 g/dL in men and less than 12 g/dL in women: approximately 9% of the general adult population meets this definition. Some 20% of patients with stable coronary disease and 30% to 60% of patients with HF have anemia due to CKD. Hence, anemia is a common and easily identifiable potential cause of constitutional symptoms as well as a potential diagnostic and therapeutic target, particularly in the setting of iron deficiency or reduced availability of vitamin B ₁₂ or folic acid.

Anemia is associated with multiple adverse outcomes, and decreases tissue oxygen delivery and utilization. The cause of anemia in patients with CKD can be multifactorial due to impairment in iron transport and a relative deficiency of erythropoietin-α (EPO), an erythrocyte stimulating protein (ESP), which is normally produced by renal parenchymal cells in response to blood partial pressure of oxygen under the control of gene regulator hypoxia-inducible factor (HIF). Patients with CKD and HF resist the effects of EPO. In addition, increased circulating levels of hepcidin-25, an inhibitor of the ferroportin receptor, impair iron absorption and utilization throughout the body including the bone marrow. As Hb drops over the course of CKD, HF hospitalizations and death increase. Conversely, those patients who have had a spontaneous rise in Hb whether it be due to improved nutrition, reduced neurohormonal factors, or other unknown reasons, enjoy a significant reduction in endpoints over the next several years. This improvement is associated with a significant reduction in left ventricular mass index, suggesting a favorable change in left ventricular remodeling.

Treatment of anemia with exogenous ESPs (EPO and darbepoetin-α) increasing the Hb level from below 10 g/dL to 12 g/dL has been linked to favorable changes in left ventricular remodeling, improved ejection fraction, improved functional classification, and higher levels of peak oxygen consumption with exercise testing. However, treatment with EPO and supplemental iron which is needed in approximately 70% of cases of ESRD, is associated with three problems: (1) increased platelet activity, thrombin generation, and resultant increased risk of thrombosis; (2) elevated endothelin and asymmetric dimethylarginine which theoretically reduces nitric oxide availability, and can raise blood pressure; and (3) worsened measures of oxidative stress. Randomized trials of ESAs targeting higher levels of Hb in CKD have shown higher rates of CVD events and no improvement in mortality, progression of CKD, or health-related quality of life. The Reduction of Events With Darbepoetin Alfa in Heart Failure Trial Failure (RED-HF) randomized, 2278 patients with systolic HF and mild-to-moderate anemia (Hb = 9.0 to 12.0 g/dL) to receive darbepoetin alfa approximately 60 to 600 μg SQ q 2 to 4 weeks (target Hb = 13 g/dL) or placebo and found no reductions in HF hospitalizations or death, but a 35% excess risk of thromboembolic complications with the ESA. When the dose exposure of ESA is taken into account, it appears that cardiovascular drug toxicity and not the Hb accounts for the adverse outcomes reported in ESA trials. As a result of these trials, the current strategy is to use ESA sparingly to maintain a Hb concentration to avoid symptoms and the need for transfusion.

High-dose oral or intravenous iron may overcome the iron-reutilization defect in CKD anemia. In a meta-analysis of 64 trials (including five studies of HF patients) comprising 9004 patients, iron associated with elevations in Hb and reductions in the need for transfusion. Analysis of the five trials of HF patients with iron deficiency (509 patients received iron therapy and 342 controls) showed that intravenous iron is associated with reductions in HF hospitalizations and cardiovascular death (OR 0.39, 95% CI 0.24 to 0.63, P = 0.0001) and improvements in multiple measures of functional status. While these results need confirmation in large-scale clinical trials, they support consideration of iron repletion in patients with CKD, anemia, and HF when there is evidence of iron deficiency (iron saturation <20% and ferritin <200 ng/mL).

HIF is short-lived due to a prolylhydroxylase that breaks down this regulator of EPO expression. There are oral HIF prolyl hydroxylase inhibitors that stabilize HIF and allow greater endogenous production of EPO, improved iron transport, and elevated Hb concentrations. Phase III trials have demonstrated efficacy in maintaining Hb along with cardiovascular safety in pre-dialysis CKD and ESRD. ^,

Contrast-Induced Acute Kidney Injury (see also Chapter 21 and Fig. 21.2 )

Iodinated contrast-induced acute kidney injury (CI-AKI) is most commonly defined by the Kidney Disease International Global Outcomes criteria of a ≥0.3 (mg/dL) rise in serum Cr from baseline within 48 hours of intravascular administration or a ≥50% elevation from baseline over the course of hospitalization. The National Cardiovascular Data Registry Cath-PCI ( n = 985,737 who underwent elective and urgent percutaneous coronary intervention [PCI]) reported 69,658 (7.1%) cases of CI-AKI (Cr rise ≥0.3 mg/dL) and 3005 (0.3%) cases of AKI requiring dialysis. Transient rises in Cr are associated with longer hospital ward and intensive care unit stays, MI, stroke, HF, rehospitalization, and death after coronary angiography, PCI, and angiography followed by cardiac surgery ( Fig. 101.4 ).

Post angiography-AKI has three potential pathophysiologic mechanisms: (1) direct toxicity of iodinated contrast material to nephrons, (2) microshowers of atheroemboli to the kidneys (due to catheter and wire exchanges above the renal arteries), and (3) contrast material- and atheroemboli-induced intrarenal vasoconstriction. Direct toxicity to nephrons with iodinated contrast media appears related to the ionicity and osmolality of the contrast media given in the milieu of CKD. Microshowers of cholesterol emboli may occur in about 50% of percutaneous interventions using an aortic approach; most episodes are clinically silent. However, in approximately 1% of high-risk cases, an acute cholesterol emboli syndrome can develop, manifested by acute renal failure, mesenteric ischemia, decreased microcirculation to the extremities, and, in some cases, embolic stroke. Because there is less trans-aortic movement of wires and catheters, trans-radial coronary intervention is associated with approximately 22% to 50% lower rates of CI-AKI. , Intrarenal vasoconstriction as a pathological vascular response to contrast media in CKD and perhaps as an organ reaction to superimposed cholesterol microemboli also injure the kidney. Hypoxia triggers activation of the renal SNS and further reduces renal blood flow ( Fig. 101.5 ). The most important predictor of CI-AKI is eGFR less than 60 mL/min/1.73 m ² , a proxy for a reduced number of functioning nephrons that must take on the filtration load with increased oxygen demands in the face of reduced delivery, and hence a greater susceptibility to cytotoxic, ischemic, and oxidative injury.

Prevention of Contrast-Induced Acute Kidney Injury

Patients with preexisting CKD (baseline eGFR <60 mL/min/1.73 m ² ), and in particular, those with CKD and DM merit a mitigation strategy for CI-AKI. The presence of CKD, DM, and other risk factors including hemodynamic instability, use of intra-aortic balloon counterpulsation, HF, older age, and anemia in the same patient entail a risk of CI-AKI over 50%. The informed consent process of a high-risk patient before the use of intravascular iodinated contrast should include discussion of CI-AKI. CI-AKI prevention involves consideration of four issues: (1) intravascular volume expansion, (2) choice and quantity of contrast material, (3) trans-radial or femoral approach, and (4) postprocedural monitoring and expectant care.

Because iodinated contrast is water soluble, it is amenable to prevention strategies that expand intravascular volume, increase renal filtration and tubular flow of urine into collecting ducts, and then into the ureters and bladder. CI-AKI responds to intravascular administration of isotonic crystalloid solutions to enhance renal elimination of contrast via the urine. Numerous randomized trials have compared isotonic bicarbonate solutions to intravenous saline. The largest and highest quality trials have shown no differences in the rates of renal outcomes. ^, Patient factors should guide the use of either isotonic crystalloid solution. The POSEIDON (Prevention of Contrast Renal Injury with Different Hydration Strategies) trial randomized 396 patients with eGFR less than 60 mL/min/1.73 m ² and one additional risk factor to a strategy of measurement of left ventricular end-diastolic pressure (LVEDP) and expanding plasma volume versus usual care. Each group had standard of care of normal saline 3 mL/kg for 1 hour before cardiac catheterization. The LVEDP guided approach with more intensive fluid administration during and after the procedure resulted in a 69% relative risk reduction in CI-AKI, p = 0.005. Thus, it is reasonable to consider a 250 mL intravenous administration of normal saline before the procedure and achieve a urine output of approximately 150 mL/hr throughout and after the procedure.

Randomized trials of iodinated contrast agents have demonstrated the lowest rates of CI-AKI with nonionic, iso-osmolar iodixanol. A meta-analysis restricted to 25 head-to-head, prospective, double-blind, randomized, controlled trials that compared iodixanol with low-osmolar contrast media (LOCM) in adult patients undergoing angiographic examinations with serum Cr values at baseline and following CM administration. The relative risk of CI-AKI (Cr rise ≥0.5 mg/dL) occurring for iodixanol was 0.46, p= 0.004, compared to LOCM as summarized in Figure 101.6 . These data indicate that iodixanol (290 mOsm/kg) is less nephrotoxic than LOCM agents with osmolalities ranging from 600 to 800 mOsm/kg when given intra-arterially. However, there appears to be no significant difference in rates of CI-AKI between iodixanol and LOCM when contrast is administered in lower-risk patients or intravenously.

Although it is desirable to limit contrast to the smallest volume possible in any setting, there is disagreement about a “safe” contrast limit. The lower the eGFR, the less contrast material may cause CI-AKI. In general, it is desirable to limit the contrast medium to less than 30 mL for a diagnostic procedure and less than 100 mL for an interventional procedure. If staged procedures are planned, it is advantageous to have more than 10 days between the first and second contrast exposures if CI-AKI has occurred with the first procedure. As mentioned above, the trans-radial approach is associated with significantly lower risk of CI-AKI when controlling for all other factors.

Most trials of preventive strategies for CI-AKI have been small, underpowered, and inconclusive. After many small, suggestive studies, a large ( n = 2308) randomized trial of N-acetylcysteine 1200 mg p.o. bid the day before and after the procedure showed no differences in the rates of CI-AKI (12.7% for both groups), ESRD, or other outcomes. This result received support from a larger trial ( n = 5177) of diagnostic angiography and PCI demonstrating no impact of N-acetylcysteine or sodium bicarbonate. As a result, neither N-acetylcysteine nor any other drug or intravenous solution is approved for the prevention of CI-AKI.

A suggested algorithm for risk stratification and prevention of CI-AKI is shown in Figure 101.7 . An eGFR less than 60 mL/min/1.73 m ² mandates preprocedural volume expansion, use of trans-radial access if possible, iodixanol or LOCM as the contrast agent, and minimization of contrast volume. Postprocedural monitoring is critical in the current era of short stays and outpatient procedures. In general, high-risk patients in the hospital should have hydration started 1 to 3 hours before the procedure and continued at least 3 hours afterward. Serum Cr should be measured 24 hours after the procedure. Outpatients, particularly those with eGFR less than 60 mL/min/1.73 m ² , should have either an overnight stay or discharge to home with 48-hour follow-up and serum Cr measurement. If severe CI-AKI is going to develop, patients usually have a rise of Cr greater than 0.5 mg/dL in the first 24 hours after the procedure. Thus, for those who do not have this degree of serum Cr elevation and are otherwise uncomplicated, discharge to home may be considered. Those patients with eGFR less than 30 mL/min/1.73 m ² , should have a discussion of the possibility of dialysis and nephrology consultation for possible pre- and post-procedure hemofiltration and dialysis management.

Cardiac Surgery Associated Acute Kidney Injury

AKI occurs in approximately 15% of patients after forms of cardiac surgery with or without use of cardiopulmonary bypass. Rates of AKI are higher when coronary angiography is done on the same day or less than 5 days between the angiogram and the surgery. Cardiac surgery exposes patients to many factors including endogenous/exogenous toxins (free heme, catalytic iron), metabolic factors, ischemia and reperfusion, neurohormonal activation, inflammation, and oxidative stress, all of which may contribute to renal tubular injury heralded by reduced urine output and a rise in serum Cr after cardiac surgery. KDIGO (Kidney Disease Global Outcomes) criteria can be used to identify AKI in this patient group ( Fig. 101.8 ). Various blood and urine markers may predict post-operative AKI. Off-pump cardiac surgery does not seem to lower rates of AKI. Trials of natriuretic peptides, corticosteroids, alpha melanocytic stimulating hormone agonists, complement inhibitors, and remote ischemic preconditioning have failed to prevent AKI. Thus, there are no accepted forms of prophylaxis or treatment for cardiac surgery associated with AKI at this time.

Acceleration of Vascular Calcification

When the eGFR falls below 60 mL/min/1.73 m ² , filtration and elimination of phosphorus falls. In addition, a lower production of 1,25 dihydroxyvitamin D leads to a relative hypocalcemia. Thus, subtle degrees of hyperphosphatemia and hypocalcemia trigger increased release of parathyroid hormone (PTH) causing liberation of calcium and phosphorus from bone. The bone, in turn, produces greater amounts of fibroblast growth factor-23, which directs the kidneys to increase the clearance of phosphorus but also promotes left ventricular hypertrophy (LVH). As a result of this abnormal bone and mineral metabolism, patients with ESRD have markedly increased absolute values and rates of accumulation of arterial calcification as well as LVH. A variety of in vitro stimuli can induce vascular smooth muscle cells to assume osteoblast-like functions, including handling of phosphorus, oxidized low-density lipoprotein cholesterol (LDL-C), vascular calcification factor, PTH, and PTH-related peptide.

No specific strategy to manipulate calcium-phosphorus balance or to treat secondary hyperparathyroidism changes the annual rate of increase in coronary artery calcium score or cardiovascular events.

Renal Disease and Hypertension (See Also Chapter 26 )

The kidney is a central regulator of blood pressure and controls intraglomerular pressure through autoregulation. Sodium retention stimulates increases in systemic and renal arteriolar pressure in an attempt to force greater degrees of filtration in the glomerulus. Glomerular injury activates a variety of pathways that further increase systemic blood pressure. This effect sets up a vicious circle of more glomerular and tubulointerstitial injury and worsened HTN. A cornerstone of management of combined CKD and CVD is strict blood pressure control. In most patients with CKD and proteinuria, three or more antihypertensive agents are needed to achieve a goal blood pressure of less than 130/80 mm Hg. The Systolic Blood Pressure Intervention Trial (SPRINT) randomized 9361 patients without DM having a mean eGFR of 71 mL/min/1.72 m ² and found that a systolic blood pressure target of 120 mm Hg is associated with reduced rates of first occurrence of MI, acute coronary syndrome (ACS), stroke, HF, or death from cardiovascular causes. However, there were no differences in the rates of progression to CKD, ESRD, or any other renal outcome. When a significant (≥20%) reduction in eGFR was seen within the first 6 months of intensive combination antihypertensive therapy, there was a 33% reduction in cardiovascular events and no difference in mortality suggesting the blood pressure reduction should not be compromised for excess concern over Cr. The key lifestyle issues for management of CKD and HTN include dietary changes with sodium restriction, weight reduction of ≥15% to a target body mass index less than 25 kg/m ² , and exercise for 60 min/day most days of the week. Pharmacological therapy aims for strict blood pressure control with an agent that antagonizes the RAAS often in combined action with a thiazide-type diuretic. Dihydropyridine calcium channel blockers alone because of relative afferent arteriolar dilation increase intraglomerular pressure and worsen glomerular injury, and thus should be avoided as singular agents for blood pressure control. Combinations of multiple RAAS-blocking drugs (angiotensin converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARB], direct renin inhibitor) provide no additional benefit but cause more complications. Clinical clues such as poorly controlled blood pressure on more than three agents, abdominal bruits, smoking history, peripheral arterial disease, and a marked change in serum Cr with administration of ACEI/ARB should raise the possibility of bilateral renal artery stenosis. Although renal artery stenosis accounts for less than 3% of ESRD cases, it represents a potentially treatable condition (see Chapter 26, Chapter 44 ). Catheter-based renal sympathetic denervation improves blood pressure in patients with resistant HTN, and additional trials are addressing lesser degrees of HTN and clinical outcomes including major cardiovascular events including HF.

Diagnosis of Acute Coronary Syndromes in Patients with Chronic Kidney Disease (See Also Chapter 38 , Chapter 39 )

Patients with CKD have higher rates of silent ischemia, which cluster with serious arrhythmias, HF, and other cardiac events. About half of stable outpatients with CKD will have a high-sensitivity cardiac troponin I (cTnI) or cTnT above the 99th percentile of normal. The degree of elevation of cTn is associated with left ventricular mass, coronary disease, severity of renal disease, and all-cause mortality. Thus with the use of high-sensitivity assays, in general, cTnI is more advantageous in the diagnostic evaluation of CKD or ESRD patients with acute chest discomfort, while chronic elevations of cTnT are more common and more prognostic in stable patients. The diagnosis of MI in patients with CKD or ESRD can be confirmed with serial troponin measurements demonstrating approximately fivefold rise above the first value since so many are above the 99th percentile of normal at baseline. The skeletal myopathy of CKD can elevate creatine kinase, myoglobin, and some older generation cTnI/cTnT assays, making these tests less desirable.