European Journal of Cardiovascular Medicine

Biomarkers are indicators of clinical end points and suggest initiation, susceptibility and progression of a disorder. Biomarkers provide appropriate stratification and targeting of therapies so that cost-effective and clinically efficient treatment could be provided to patients.[1] Biomarkers in chronic kidney disease have not only indicated on progression of the disease but cardiac involvement as well. Apart from cystatin C which is of recent consideration as an essential biomarker, it needs complex processes for estimation.

Creatinine, Uric acid, Parathyroid hormone have all been consistently associated with cardio renal syndrome. Cardiovascular dysfunction has been the major cause of mortality in end stage renal disease. Right ventricle involvement indicates a prolonged and severe cardiac dysfunction than the left ventricle, though left ventricular involvement is early.

A biomarker intended to be substituted for a clinical endpoint is called a surrogate endpoint. In this study serum creatinine, uric acid and parathyroid hormone levels have been examined if they could reflect right ventricular functions as indicated as right ventricular systolic pressures (RVSP) and tricuspid annular plane systolic excursion (TAPSE) in ESRD.

Aims & Objectives

1. To evaluate serum levels of Parathormone, uric acid and creatinine as markers of right ventricular dysfunction in ESRD.
2. To predict the severity of disorder by correlating the markers with RVSP, TAPSE and hemoglobin.

Study Type

Retrospective analysis.

Study Population

All patients with ESRD who presented for preanaesthetic check for renal transplantation.

Study Period

December 24 to March 25.

Study Place

DSMCH, Siruvachur, Perambalur.

Study Sample

30

A total of 30 patients who underwent successful renal transplantation in the above study period were examined for the aforesaid parameters.

Most of them were in the age group of 35–40 years of age. The haemoglobin of males ranged from 7 to 9.5 g/dl and in females from 8.2 to 8.4 g/dl.

The right ventricular systolic pressure was inversely proportional to the haemoglobin levels. The lowest hemoglobin of 6.4 g/dl had an RVSP of 58 mm Hg. From the scatter plot diagram below, we may appreciate more number of patients’ hemoglobin between 7.0 g/dl and 9.0 g/dl had RVSP between 30 to 50 mm Hg which is mild to moderate pulmonary hypertension (p = 0.185).

TAPSE, which is more sensitive of right ventricular dysfunction, showed p of 0.123 with hemoglobin levels. Parathormone levels were more sensitive and statistically significant indicator of RVSP (right ventricular systolic pressure) (p = 0.132) than uric acid (p = 0.63) or creatinine (p = 0.53). Serum creatinine showed significant probability variation with TAPSE (0.177).

In early stages of chronic kidney disease the risk of incident heart failure is increased. The synergistic failure of both organs namely heart and kidney is termed cardio renal syndrome.^[2]

There are 5 types of cardio renal syndromes.

Types 1 and 2 are primarily heart failure leading on to renal failure.^[3,4]

Type 3 is acute kidney injury leading to acute cardiac event.

Type 4 is chronic kidney disease causing cardiac injury, and Type 5 is systemic renal cardiac syndrome.

The pathophysiology of cardiac and renal dysfunction involves shared risk factors such as hypertension, diabetes, peripheral artery disease, and obesity.

These increase the risk of acute events and accelerate the progression to end-organ damage, namely renal failure apart from cardiac dysfunction.

Renal perfusion is around 25% of cardiac output. Hence, with a fall in cardiac output, there is low intra-renal pressure, low renal blood flow state but filtration fraction of glomeruli are preserved by renal autoregulation in early phases of the disorder.

In patients on RAAS (Renin Angiotensin Aldosterone System) inhibition drugs for hypotension, if there is mild reduction in renal blood flow. Efferent arteriolar constriction may improve GFR. In later phases, afferent arteriolar constriction also occurs and there is loss of glomeruli and fall in filtration fraction. Cardio renal connectors are systemic modulators which include endothelial dysfunction, inflammation, sympathetic nervous system (SNS) activation, RAAS and ROS activation. These modulators indirectly affect the estimated GFR. Oxidative stress has negative influence on heart. SNS (sympathetic nervous system) activation can modify ultrafiltration co-efficient and lead to salt and water retention.^[5] Patients in End Stage Renal Disease are on haemodialysis, usually through vascular access on arteriovenous fistula. High pulmonary blood flow, a direct result of AV fistula, may cause pulmonary hypertension.^[6] The right ventricle fails when there is pressure or volume overload or myocardial disease such as RV infarction or cardiomyopathy. The commonest cause of RV failure is pulmonary hypertension. Epidemiologically, the commonest, the first and most frequent pathology for development of pulmonary hypertension is left ventricular failure. Echocardiogram is important in the diagnosis and to quantify RASP, IVC diameter, collapsibility index & TAPSE have been particularly indicated.^[7] Though right ventricle is treated as a younger brother of left ventricle in the contractile apparatus, it gains importance when right ventricle has to work hard against a pressure or volume overload to the lungs. Interdependency and orchestration between the two ventricles is observed in cardiac disorders. In end stage renal disease, the two ventricles seem to function in a divergent manner. A poor ejection fraction (stroke volume) and a high systolic pressure (peripheral vascular), high diastolic blood pressure (peripheral vascular resistance) due to the overactive Renin Angiotensin Aldosterone system in renal failure.

Anatomy and Mechanisms of Right Ventricular Function

Right ventricle is triangular in side section and crescent-like in cross section. It is made up of Superficial, circular and deeper longitudinal fibres.

The superficial fibres encircle the heart and are continuous with the subepicardial fibres of LV. The deep longitudinal fibres run from apex to base of heart. RV contracts in 3 ways:

1. Inward motion of RV free wall.
2. Via shortening of longitudinal fibres pulling apex to base of heart.
3. Through traction by LV contraction.

The contraction of the longitudinal fibres contribute most to the systolic function of RV while the LV traction component contributes about 20–40% of RV cardiac output. The right ventricle ejects the same stroke volume as LV but against a much lower resistance of the pulmonary vasculature. This results in the RV stroke work being almost one-fourth that of LV, hence the thinner RV wall. Because of the low resistance presented by the pulmonary circulation, RV continues to eject through the early phase of systole. As such, there is no isovolumic relaxation phase on right side. The interventricular septum is shared by both ventricles. RV infarction or significant pulmonary embolism shifts the septum to left. This shift impairs LV.

Diastolic filling and its contractility, RV cannot handle a pressure overload in the same way as a gradually increasing volume overload. Acute rise in pulmonary pressure manifests as hypotension and cardiogenic shock. When the PAP rises more gradually, RV dilates to preserve flow output. Eventually RV fails, becomes more spherical and tricuspid regurgitation ensues causing right heart failure. Development of pulmonary hypertension in left ventricular failure increases afterload against which RV has to pump. Severe left ventricular failure may result in reduced coronary perfusion for the right ventricle. LV dilatation which is early to occur in end stage renal disease impairs RV diastolic function. Thus RV failure behaves as common final pathway.^[8]

The causes of right heart failure can be classified into three categories:

1. Secondary to pulmonary hypertension.
2. RV and Tricuspid valve pathology.
3. Disease of pericardium.

Pulmonary hypertension is the most Common causes of right heart failure

WHO classified pulmonary hypertension into 5 types, all of which are pre-capillary, except Type 2 which is post-capillary. The pre-capillary types have a normal or low wedge pressure.

Chronic renal disease leading to RHF belongs to Type 5.

Technical Clues to Diagnosis by Echocardiogram will be: TAPSE and RVSP

TAPSE is tricuspid annular plane systolic excursion. It is a rapid and reproducible parameter as it is a surrogate of the longitudinal fibers’ function. Because of the RV’s geometry and the complex 3D shape, measurement of RV function is a challenge.

TAPSE measures the tucking effect of the apex on the tricuspid annulus. It is not affected by loading condition. It is angle dependent. Longitudinal displacement of 17mm or less is indicative of poor RV function and poor prognosis.^[9] The TAPSE score is an important parameter that determines cardiac index and right ventricular function. It is measured using M-mode echocardiography in the apical four chamber view to generate an image that illustrates systolic longitudinal displacement of lateral tricuspid annulus towards the apex. As the septal attachment of tricuspid annulus is relatively fixed, the major component of longitudinal systolic motion occurs at this point.

TAPSE closely correlates with right ventricular ejection fraction measured by radionuclide angiography.

Role of Biomarkers

The prominent role of biomarkers is early detection of Acute Kidney Injury or chronic kidney disease. As far as CKD is concerned, predicting the progression of CKD, whether slow or rapid, outcomes of CKD and predicting the cardiovascular disease due to the renal disorders, are all indicated by various parameters.

Biomarkers are such parameters described in relation to the site of injury of nephron.

Glomerular injury is detected by serum creatinine, BUN, serum cystatin C, plasma neutrophil gelatinase associated lipocalin (NGAL) and proenkephalin.^[10] Various urinary tubular injury markers also have been described.

Direct and indirect risk factors linking chronic kidney disease and cardiovascular disease have been studied elaborately. Lipid profile, parathyroid hormone, hemoglobin, homocysteine and uric acid have been found to be associated with coronary artery disease due to renal failure which is a major cause of mortality in patients with CKD on dialysis.

Normal values of parathyroid hormone are 15–60 pg/dl. There is a 3 picomol/litre rise in parathyroid hormone for every 10 ml/min fall in eGFR for 1.73 m² body surface area. Hemoglobin falls by 0.2–0.5 g/dl for every 10 ml/min fall of eGFR while 10–15 µmol/L of uric acid increases for every fall in GFR.^[11] Parathyroid hormone and hemoglobin have been recognised as direct risk factors for development of congestive heart failure along with systolic blood pressure and phosphate levels.

Anaemia in CKD is caused by a combination of various factors including erythropoietin deficiency, functional iron deficiency and chronic inflammation. For every 0.5 g/dl fall in hemoglobin, an associated 30% increase in frequency of left ventricular mass was noted. Similarly, in another study, every 1 gm/dl decrease in hemoglobin was associated with 50% increased risk of left ventricular dilatation and 25% increased risk of cardiac failure. Ammonia enhances the risk of rise in pulmonary pressures due to vascular changes such as endothelial dysfunction and increased vascular resistance.

Parathyroid hormone concentrations rise as a direct result of declining GFR early in progression of CKD. Secondary hyperparathyroidism can be found in 20% of patients with CKD stages one and two. Parathormone increases as a consequence of lack of negative feedback from declining 1, 25 hydroxy vitamin D and calcium concentration and rising concentration of serum phosphate. Parathyroid hormone has been implicated in atherogenesis, calcification of atherosclerotic lesions and also in modifying cardiac fibrosis. Impaired myocardial metabolism and structure occurred after parathyroidectomy, suggesting that high concentrations of PTH may damage the heart.^[12] A meta-analysis of 12 studies has shown that the risk of cardiovascular disease is 50% higher among patients in groups with highest PTH concentrations compared with those of the lowest.^[13] Uric acid is cleared by the kidney (almost amounting to 70%), and its concentration increases as GFR falls, so that each 10 ml/min per 1.73 m² lower estimated GFR is associated with 10–15 μmol/L increase in uric acid concentration. Positive associations between uric acid concentration and a risk of coronary heart disease of 10% has been reported.^[14] In our study, the serum parathormone levels ranged between 250–1750 pg/dl, normal being 15–65 pg/dl. All these patients had significant cardiac dysfunction, especially a raised right ventricular systolic pressure (P = 0.132). As already explained, left ventricular involvement is early and a right ventricular dysfunction in the form of pulmonary hypertension or severe tricuspid regurgitation suggests progressive disease. An anaemic patient with poor hemoglobin was more likely to have high RVSP (P = 0.185). Rise in creatinine showed a fall in TAPSE (P = 0.177).

Cardiovascular dysfunction has been the major cause of morbidity and mortality in CKD and ESRD patients. Hence, predictors of the cardiac involvement become essential to be evaluated to prognosticate patients in ESRD. Serum cystatin C and neutrophil gelatinase-associated lipocalin have proved promising but need complex processes for detection. Simple and familiar biomarkers have also been evaluated and found to be clinically useful to predict progression and outcome of chronic kidney disease.

Rise in uric acid and parathyroid hormone levels have been consistently associated with poor ejection, raised right ventricular systolic pressure, and fall in TAPSE measurements by echocardiogram.

However, further larger studies are needed to substantiate our findings. All our patients had improved cardiac function following renal transplantation.

1.       Libby P, Ridker PM. Biomarkers and use in precision medicine. Chap. 10. In: Braunwald Editor Heart Disease. Elsevier 2022: p. 102.

2.       Damman K, McMurray JJV. Cardiorenal syndromes. Chap. 40. In: Skorecki K, ed. Brenner & Rector the Kidney. 10th edn, Vol. 1. Philadelphia, PA, USA: Elsevier 2020: p. 1800.

3.       Jentzer EA, Muller G, Damman K, et al. Pathophysiology of cardiorenal syndromes (CRS) in acute heart failure. Curr Heart Fail Rep 2018;15:99–111.

4.       Cruz DN, Schmidt-Ott KM, Vescovo G, et al. Pathophysiology of cardiorenal syndrome type 2 in stable chronic heart failure: workgroup statements from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contributions to Nephrology 2013;182:117-36.

5.       McCullough PA, Kellum JA. Pathophysiology of acute cardiorenal syndromes (AKI). Contrib Neph 2013;182:82–98.

6.       Frishberg Y, Dorit Rinat et al. Renal Replacement Therapy (Dialysis and Transplantation) in ESRD. Chap. 71. In: Yu ASL, Chertow GM, Luyckx V, et al, eds. Brenner and Rector the Kidney. 11th edn. Elsevier 2020.

7.       Ibrahim BS. Right ventricular failure. EJ Cardiol Pract 2016;14(32):12.

8.       Voelkel NF, Quaife RA, Leinwand LA, et al. National heart, lung and blood institute working group on cellular and molecular mechanisms of right heart failure. Circulation 2006;114(17):1883–91.

9.       Forfia PR, Fisher MR, Mathai S, et al. Tricuspid annulus displacement predicts mortality in pulmonary hypertension. Am J Respir Crit Care Med 2006;174(9):1034–41.

10.    Koyner JL, Parikh CR. Clinical Utility of Biomarkers of AKI in cardiac surgery and critical illness. Clin J Am Soc Nephol 2013;8:1034-42.

11.    Haynes R, Wheeler DC. Cardiovascular aspects of kidney disease. Chap. 54. In: Brenner & Rector the Kidney. 1st edn. Elsevier 2020: p. 1888.

12.    Palmer SC, Hayen A, Macaskill P, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risk of cardiovascular disease in individuals with chronic kidney disease. JAMA 2011;305:1119-27.

13.    Van Ballegooijen AJ, Reinders I, Visser M, et al. Parathyroid hormone and cardiovascular disease events: a systematic review and meta-analysis of prospective studies. Am Heart J 2013;165:655-64.e5.

14.    White J, Sofat R, Hemani G, et al. Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrin 2016;4:327-36.