Cross-Talk between the Kidney and the Cardiovascular System
Kerstin Amann*,
Christoph Wanner and
Eberhard Ritz
* Department Pathology, Friedrich-Alexander University Erlangen, Erlangen, Department of Internal Medicine, Julius-Maximilian University Würzburg, Würzburg, and Department of Internal Medicine, Ruperto-Carola University, Heidelberg, Germany
Address correspondence to: Prof. Eberhard Ritz, Department Internal Medicine, Nierenzentrum, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany. Phone: +49-6221-601705; Fax: +49-6221-603302; E-mail prof.e.ritz{at}t-online.de
In recent years, increasing evidence has been provided thateven minor renal dysfunction is a powerful cardiovascular riskfactor that induces typical cardiovascular alterations and thuspredisposes to coronary heart disease as well as to noncoronarycardiovascular problems. This first had been noted in patientswith diabetes but now has been confirmed amply in patients withoutdiabetes as well. Numerous heterogeneous abnormalities havebeen described in patients with early renal dysfunction (e.g.,microalbuminuria, reduced estimated GFR). One final common pathwayseems to be endothelial cell dysfunction. The link between albuminuriaand generalized endothelial cell dysfunction (as indicated bydiminished flow-mediated vasodilation, markers of endothelialcell dysfunction, sloughed off endothelial cells, and high transcapillaryalbumin escape rate) is unclear. In patients with early renaldysfunction, a long list of classical and nonclassical cardiovascularrisk factors have been identified: Elevated asymmetric dimethyl-L-arginineconcentrations, markers of microinflammation, oxidative stress,features of metabolic syndrome, abnormal adipokine concentrations,dyslipidemia, inappropriate activation of the renin-angiotensinsystem, and sympathetic overactivity. The mechanisms that linkdysfunction of the kidney and the cardiovascular system arebeing sought. The most interesting unifying concept, however,is deranged fetal programming linking nephron underdosing tothe increased cardiovascular risk.
Although the high risk for cardiovascular death, particularlyfrom coronary heart disease (CHD), had been recognized earlyafter introduction of maintenance hemodialysis (1), it is onlyrelatively recently that the high cardiovascular risk in patientswith minor renal dysfunction has been appreciated fully (2).This link first had been noted in patients with diabetes. Thisobservation prompted Deckert et al. (3) to propose the conceptthat albuminuria was a marker for and linked to a generalizedendothelial cell defect as documented by an increased transcapillaryalbumin escape rate (4,5). Only much later was it recognizedthat albuminuria and proteinuria (6,7) are cardiovascular riskfactors in patients without diabetes as well. This by now hasbeen well documented by several large population-based studies(8–10) and by controlled intervention trials. The latteralso suggested that the prediction of cardiovascular eventsby albuminuria extends into the range of albumin values thatconventionally have been considered to be within the normalrange (11,12) as had been found previously also in diabetes(13). The observation that changes in albuminuria during treatmenttranslate into changes of cardiovascular events is suggestivefor but not definite proof of a causal role of albuminuria (14).
In parallel, after the unexpected observation in the HypertensionDetection and Follow-up Program (HDFP) study (15), it by nowalso has been confirmed amply that even minor elevations ofserum creatinine or reductions in estimated GFR—even moresensitive, increases of cystatin C (16)—predict cardiovascularevents and cardiovascular death in the general population (17,18)and particularly in patients who undergo cardiac interventions(19) or ischemic events (20).
Types of Cardiovascular Events Observed in Patients with Minor Renal Dysfunction
In the seminal paper of Lindner et al. (1), it had been postulatedthat in dialyzed patients, cardiac ischemia from CHD was themajor cause of death, pointing to accelerated atherogenesis.Although coronary atherosclerosis undoubtedly is more frequentin patients with renal disease than in the background population,it has emerged that myocardial infarction is only the thirdmost common cause of cardiovascular death, at least in dialyzedpatients; sudden death and heart failure are more frequent causes.According to the statistics of US Renal Data System (USRDS),CHD accounted for 6% of all deaths in dialyzed patients comparedwith 8.2% in the 4D study. In contrast, other cardiac causesaccounted for 33% in USRDS and 35% in 4D, and stroke accountedfor 10% in USRDS and 6% in 4D. It is obvious that despite undoubtedexperimental (21–23) and clinical (24) evidence of acceleratedatherogenesis in renal failure, there is more to cardiac deathin renal patients than CHD. What is remarkable in the contextof cardiovascular risk in patients with minor renal dysfunctionis our observation that in the experimental model of the apoE–/–mouse, atherogenesis is accelerated by as little reduction ofrenal function as uninephrectomy (21).
For patients with early stages of renal dysfunction, there islittle information on the exact breakdown of the types of cardiovasculardeath. It has been well documented that the frequency of atheroscleroticdisease and congestive heart failure is increased in patientswith minor reduction of GFR (25). Furthermore, an excess ofcoronary events and death according to CHD criteria has beennoted even in microalbuminuric patients (26). Many aspects ofthis relation have not been clarified, and this issue will continueto be an important task for future epidemiologic work. Thatcardiac abnormalities are seen with minor renal dysfunctionalso is illustrated by our past experimental studies: Even relativelymodest resection of renal parenchyma caused striking left ventricularhypertrophy (LVH), cardiac fibrosis, microvessel disease witha selective capillary deficit, and wall thickening of intramyocardialarterioles in the hypertrophied heart (Figure 1) (27,28).
Figure 1. Typical changes of the myocardium in a subtotally nephrectomized rat with moderate experimental renal failure (A) compared with a sham-operated control animal (B). Semithin sections show methylene blue and basic fuchsin stain. Marked thickening of the wall of an intramyocardial arteriole with hypertrophy and hyperplasia of vascular smooth muscle cells, activation and expansion of the perivascular interstitial tissue with increased amounts of collagen fibers and interstitial fibroblasts, and a lower number of capillary profiles per area of myocardium are demonstrable in renal failure (A) compared with the normal morphology in a sham-operated control rat (B).
Because in renal patients sympathetic overactivity is seen (29)and may occur even before GFR decreases, at least in hypertensivepatients with autosomal dominant polycystic kidney disease (30),we suspect that sudden death makes a major contribution evenat this early stage. This caveat of the heterogeneity of factorsis appropriate to prevent overly simplifying paradigms to explainthe elevated cardiovascular risk.
As indicated in the previous section, it would be naïveto assume that one single mechanism accounts for all that thereis to cardiovascular dysfunction in renal disease. Nevertheless,one mechanism that seems to be central in the genesis of manydifferent aspects of cardiovascular dysfunction in renal patientsstands out as one potential final common pathway, namely endothelialcell dysfunction. Endothelial cell dysfunction has been documenteddirectly by measuring indices such as flow-mediated vasodilation(31,32) and indirectly by measuring circulating markers of endothelialcell dysfunction (33,34) and markers of processes that are knownto interfere with endothelial cell function, e.g., oxidativestress (32,35,36), microinflammation (35,37–40), adipokineabnormalities such as low serum adiponectin levels (41), andothers. More direct evidence for endothelial damage also isprovided by the observation of circulating endothelial cell–derivedmicroparticles’ adversely affecting endothelial cell function(42) and of circulating endothelial cells that had been sloughedoff the endothelial cell layer (43,44). Furthermore, it is increasinglyrecognized that atherosclerosis is the combined result of damageto the resident cells and repair by circulating bone marrow–derivedendothelial precursor cells (45). Against this background, itis of interest that the number and the function of such precursorcells are diminished in renal patients (46,47) for reasons thathave not been clarified fully.
Numerous factors that have an adverse impact on endothelialcell function are demonstrable in patients with primary renaldisease even when whole-kidney GFR still is normal. An incompletelist comprises apolipoprotein abnormalities (48,49), elevatedconcentrations of asymmetric dimethyl-l-arginine (ADMA) (50),and elevated concentrations of homocysteine (51), the role ofwhich as a cardiovascular risk factor is dubious, however (52).Furthermore insulin resistance, a powerful predictor of cardiovascularevents, is seen even when whole-kidney GFR still is normal (53).This finding is of note because insulin resistance also is afeature of microalbuminuria (54) and a predictor of microalbuminuriain patients with type 2 diabetes (55). Damaged endothelial cellspresumably are more sensitive to the injurious effects of furtherinsults, e.g., elevated BP, analogous to the increased susceptibilityof glomeruli to higher BP in diabetes (56).
It is widely known that in patients with renal dysfunction,cerebrovascular events are more frequent (57), and malfunctionas well as remodeling of central arteries occur (58). Becauseof limitations of space, we focus here on the heart.
A number of potential pathogenetic factors that cause cardiacmalfunction in renal disease have been identified in experimentalstudies using the renal ablation model. Among others, a potentialpathogenetic role of parathyroid hormone on LVH, interstitialfibrosis, and thickening of intramyocardial arterioles has beenfound (59). This observation is consistent with several clinicalstudies showing that parathyroid hormone concentrations correlatewith cardiac morbidity and cardiac death in dialysis patients(60).
Apart from increased afterload (elevated BP, aortic stiffening)and preload (hypervolemia, anemia), the cardiac abnormalitiesare amplified by the activation of local systems such as therenin-angiotensin system (RAS) and the endothelin (ET) system.Using PCR, in situ hybridization, and immunohistochemistry,increased mRNA and protein expression of ET-1 were found inthe heart of subtotally nephrectomized rats compared with controls(61). This is of particular interest because high ET-1 serumlevels together with increased protein expression of ET-1 alsowere found in the heart of uremic patients (62). In addition,LVH was found to correlate closely with serum ET-1 concentrations(63).
Intervention studies using experimental models of renal failurewere of interest because they identified some potential pathogeneticprinciples in renal–cardiac interaction. Persistence ofLVH was noted in rats with moderate renal failure despite correctionof anemia by blood transfusion and hypertension by sympatholyticagents (64). In contrast, in recent studies, LVH was amelioratedbut not abrogated by administration of angiotensin-convertingenzyme (ACE) inhibitors, sympatholytic agents, ET receptor blockers,and recombinant human erythropoietin (rhEPO) (65–67).An experimental study using the bradykinin receptor blockerHoe140 documented that in uremic animals, the beneficial effectof ACE inhibition on LVH is mediated via bradykinin (67).
In the same experimental model, treatment with ACE inhibitors,ET receptor blockers, and calcium channel blockers also preventedwall thickening of intramyocardial arteries after subtotal nephrectomy(65) (Figure 1). In this case, the effect of ACE inhibitorscould be dissociated from accumulation of bradykinin. In contrast,nonspecific antihypertensive treatment (dihydralazine and furosemide),sympatholytic agents, or correction of anemia with rhEPO didnot prevent intramyocardial microarteriopathy (68).
In addition to arteriolar changes, reduction of capillary densityis another factor that interferes with oxygen delivery. In subtotallynephrectomized rats with moderate renal failure of short (65)and long duration (69), cardiac capillary length density, i.e.,the total length of all capillaries contained within a unitvolume of myocardium, was reduced approximately 25% (Figure 1).Capillary rarefaction occurs not only in the hypertrophied heartof patients or rats with renal failure but also in other typesof hypertension or LVH, respectively. The decrease in capillarydensity is significantly more pronounced in uremia, however,and leads to an increase in intercapillary distance, potentiallycompromising blood and oxygen supply of cardiomyocyte underconditions of increased demand. These conditions render themyocardium more susceptible to ischemic injury and may particularlyincrease the cardiac risk in uremic patients (70). The findingof lower capillary supply suggests that in the LVH of uremicpatients, capillary growth does not keep pace with cardiomyocytegrowth, apparently because the expression of angiogenic signals(vascular endothelial growth factor) is diminished or becauseinhibitors of capillary angiogenesis are present. Clarificationof these points requires further experiments.
Intervention trials also gave some hints as to the pathomechanismsunderlying the decrease in cardiac capillary supply: It wasprevented by the central sympatholytic agent moxonidine (65)by selective and nonselective ET receptor blockers (66,71) andin recent studies also by the blocker metoprolol (72). In contrast,treatment with the calcium channel blocker nifedipine or theACE inhibitor ramipril or correction of anemia with rhEPO didnot affect myocardial capillary density. It is interesting thatadministration of the bradykinin receptor antagonist Hoe140resulted in a further decrease of myocardial capillary supply(67). The sensitivity of the cardiac vasculature to bradykininpresumably is explained by the fact that uremia is a state ofdecreased bioavailability of nitric oxide (NO) (73).
The relation between kidney malfunction and heart malfunctionis a two-way process. Renal malfunction causes cardiac problems,and, conversely, in both experimental studies (74) and clinicalobservations (75), cardiac malfunction causes progressive renalmalfunction. The study of van Dokkum et al. (74) examined theeffects of myocardial infarction on the loss of renal functionin unilaterally nephrectomized rats. The degree of focal segmentalsclerosis and of proteinuria was more pronounced in the animalswith myocardial infarction, and a significant correlation wasfound between left ventricular pressure and proteinuria. Thedata suggest that cardiac damage aggravates mild renal dysfunction,possibly via neurohumoral signals. This mutual interaction justifiesthe concept of a "cardiorenal syndrome" (76).
It presumably is easy to convince the reader that renal dysfunctionis bad for cardiovascular outcome. It is much more difficultto explain why there is a link between kidney and the cardiovascularsystem. For instance, why do endothelial cells, say, of a coronaryartery, "know" that the glomerulus leaks protein. It is easyto envisage that in the glomerulus, endothelial cells are affectedby altered function of podocytes, the main controller of glomerularpermselectivity. There is overwhelming evidence of intense cross-talkbetween podocytes and glomerular endothelial cells that is mediatedprimarily by vascular endothelial growth factor (77,78). Theinteraction between leaking glomeruli and endothelial cellsin the systemic circulation, however, remains enigmatic. Littleevidence has come forward for the original hypothesis of a commonabnormality of charge or composition of the basal membrane ofglomeruli and extrarenal vessels, respectively (3). Althoughthe role of podocytes in controlling glomerular permselectivityis paramount, one little discussed possibility is that the endothelialglycocalyx, which is heavily involved in the genesis of vascularpathology (79,80), also controls vascular permeability (81).Possibly, this also is the case in the glomerulus, as suggested,for instance, by the observation that injection of proteasesthat digest the glycocalyx causes almost instantaneous massiveproteinuria without changes in podocyte morphology (82). Thepossibility of a common glycocalyx defect in the glomerulusand in the systemic circulation is worth considering in futurestudies.
Several pathways through which reduced glomerular filtrationtheoretically may influence endothelial function are conceivable.These possibilities are not mutually exclusive: (1) Accumulationof substances that normally are excreted via the kidney; (2)failure of the kidney to produce active substances such as therecently described renalase (83); (3) reduced metabolic functionof the kidney as illustrated by the example of ADMA: In patientswith mild to moderate renal failure, the concentration of ADMAis correlated to surrogate markers of cardiovascular risk (84)and also is a powerful predictor of progression of renal dysfunctionand of cardiovascular events (85,86). Although the plasma concentrationin renal patients are not dramatically elevated, at these concentrationsas found in renal patients, ADMA modifies gene expression patternsin endothelial cells (87). ADMA acts as an inhibitor of NO synthase,reducing the bioavailability of NO (88,89); it is well establishedthat diminished production of NO is a feature of renal failure(73,90). Although both asymmetric ADMA and its isomer symmetricSDMA are excreted via the kidney, we had noted that SDMA concentrationswent in parallel with creatinine, whereas ADMA concentrationsdid not (91). We had postulated that ADMA metabolism by dimethylargininedimethylaminohydrolase, an enzyme whose activity is high inthe kidney, was diminished in renal disease (91). This hypothesisis supported by recent genetic experiments (92).
Unknown are the exact mechanisms by which sympathetic activityis dramatically increased in patients with renal disease evenwhen whole-kidney GFR still is normal (30). Increased afferentsignals that emanate from the damaged kidney raise the activityof hypothalamic centers, but the triggering intrarenal signalshave not been identified (93). Sympathetic overactivity is ofcourse particularly deleterious in patients with cardiovasculardisease and may contribute to the excessive frequency of suddendeath and high case fatality rate of ischemic events in renalpatients.
A further unresolved issue that is relevant in this contextis whether in renal disease there is inappropriate activationof local RAS of cardiovascular structures, as suggested by theobservation of increased angiotensin II formation in the isolatedperfused hind limb of uremic rats (94) and increased expressionof components of the RAS in the heart of subtotally nephrectomizedrats (28). As a further possibility, it was suggested recentlythat the LVH and LV fibrosis in uremia are caused by increasedconcentrations of the cardiotonic steroid marinobufagenin (95)and possibly also telocinobufagin (96), which not only inhibitthe Na+,K+,ATPase but also generate oxidative stress.
The metabolic syndrome is a widely known factor that predisposesnot only to cardiovascular events but also to chronic kidneydisease (97). An attractive hypothesis that suggests a linkbetween the predisposition to renal disease and to the metabolicsyndrome is the hypothesis of "nephron underdosing" proposedby Brenner et al. (98). They postulated that aberrant fetalprogramming by genetic factors or malnutrition and other insultsto the pregnant mother leads to the formation of fewer glomeruli.The hypothesis of a relation between fewer nephrons and hypertensionhas been proved (99), at least in white individuals (100). Suggestive,although not definitive, evidence points also to a link betweenmalnutrition during the fetal period and albuminuria (101).A link between preexisting predisposition to hypertension anddevelopment of renal disease is suggested by the observationthat diabetic (102) and nondiabetic (103) renal disease is seenmore frequently in families with hypertension and that in patientswith normal urinary findings at baseline, the risk for futureESRD is predicted by BP at baseline (104). Finally, numerousexperimental observations support the concept of a link betweennephron number and susceptibility to glomerular damage (105,106).Conversely, Barker et al. (107) originally proposed the hypothesisthat he recently confirmed in a retrospective study that impairedintrauterine development predisposes also to increased cardiovascularrisk and cardiovascular events in adult life. Whether fetalprogramming can cause adverse cardiovascular effects by directlyaffecting the intrauterine development of cardiovascular structuresis a possibility that has not been explored so far.
In the past, in view of the devastating cardiovascular prognosisof patients who are on dialysis, the main emphasis of researchwas on ESRD. Patients who reach ESRD constitute only a minoritywho have survived; indeed, the risk for death, mainly from cardiovascularcauses, has been reported to be much higher than the risk forstarting dialysis (25). It is obvious from the evidence herethat the cumulative cardiovascular risk builds up progressivelythroughout the earlier stages of chronic kidney disease, andthis must be the focus of future research and intervention.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Top
Abstract
Introduction
blocker metoprolol (72). In contrast, treatment with the calcium channel blocker nifedipine or the ACE inhibitor ramipril or correction of anemia with rhEPO did not affect myocardial capillary density. It is interesting that administration of the bradykinin receptor antagonist Hoe140 resulted in a further decrease of myocardial capillary supply (67). The sensitivity of the cardiac vasculature to bradykinin presumably is explained by the fact that uremia is a state of decreased bioavailability of nitric oxide (NO) (73). 
