Pulmonary hypertension and renal dysfunction: a narrative review

Introduction

Chronic kidney disease (CKD) is a major global health burden, progressively leading to end-stage renal disease (ESRD) and necessitating renal replacement therapies (1). Cardiovascular disease remains the leading cause of morbidity and mortality in this population (2). Among the spectrum of cardiovascular complications, pulmonary hypertension (PH) has emerged as a highly prevalent and severe complication in patients with CKD (3, 4).

The pulmonary circulation and the kidneys exhibit a constant, complex and bidirectional interaction. While some patients develop PH secondary to established left heart or respiratory comorbidities, a significant proportion develop PH driven directly by the uraemic milieu, severe endothelial dysfunction, volume overload and the haemodynamic burden of arteriovenous fistulas (AVFs) used for haemodialysis (3, 4). Reflecting this complex aetiology, current PH guidelines classify CKD-PH within group 5—PH with unclear and/or multifactorial mechanisms (5–7).

The development of PH in patients with CKD is independently associated with poorer outcomes, including a higher risk of death. Similarly, renal dysfunction in patients with PH and specifically with pulmonary arterial hypertension (PAH) is an independent predictor of mortality (3). Given the growing recognition of this cardiopulmonary–renal axis, this narrative review aims to summarise the current literature regarding the definition, epidemiology and intricate pathophysiological mechanisms linking PH and CKD. Furthermore, we outline the diagnostic, clinical and therapeutic implications of this dual burden, highlighting the critical need for multidisciplinary collaboration between pulmonologists, nephrologists and cardiologists to optimise patient outcomes.

Definition and classification of PH

PH is defined as a mean pulmonary artery pressure (mPAP) >20 mmHg, measured using right heart catheterisation (RHC) (5–7). PH can be subdivided into three subtypes depending on other haemodynamic variables: pre-capillary PH, isolated post-capillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH). Pre-capillary PH is present when pulmonary artery wedge pressure (PAWP) is ≤15 mmHg and pulmonary vascular resistance (PVR) is >2 Wood units (WU). IpcPH is defined as PH with PAWP >15 mmHg and PVR ≤2 WU. In CpcPH, both PAWP and PVR are elevated (5–7). Although RHC is the gold standard for PH diagnosis, echocardiography is widely used for non-invasive assessment of right heart morphology and function, as well as estimating systolic pulmonary artery pressure (sPAP) (5, 6). Doppler echocardiography can be used to measure the peak tricuspid regurgitation velocity (TRV) and derive the tricuspid regurgitation pressure gradient (TRPG). Other echocardiographic variables such as inferior vena cava (IVC) diameter and collapsibility can be used to estimate right atrial pressure (RAP). The sum of TRPG and RAP is the estimated sPAP (5, 6). RAP approximation on echocardiography can be inaccurate when compared with directly measured RAP on invasive RHC (8), while TRPG is an indirectly derived value. For these reasons, echocardiographic estimates of sPAP correlate only moderately with direct measurements on RHC (9).

Current PH guidelines recommend that modern echocardiographic screening assigns a low, intermediate or high probability of PH based primarily on TRV rather than estimated sPAP (5, 6). Specifically, a TRV >2.8 m/s, particularly when accompanied by other indirect echocardiographic signs of right ventricular (RV) pressure overload (such as right ventricle dilation or flattened interventricular septum), indicates an intermediate or high probability of PH (5, 6). Despite these recommendations, estimated sPAP has been widely used in older clinical studies to define PH, especially in cohorts without strict indications for RHC, such as CKD or ESRD patients (10). Most of these studies used estimated sPAP >35 mmHg as a cut-off for PH, as this value was shown to correlate with elevated mPAP on RHC (11).

PH is classified into five groups, based on pathophysiological mechanisms, clinical features and haemodynamic profile: PAH (group 1), PH associated with left heart disease (group 2), PH associated with chronic lung disease or hypoxia (group 3), PH associated with pulmonary artery obstruction (group 4) and PH with unclear and/or multifactorial mechanisms (group 5) (5–7). Group 5 includes several disorders that can lead to PH through various mechanisms, including CKD with or without haemodialysis. Patients with PH can present with features of more than one group; in those cases, clinicians are encouraged to classify them based on the dominant pathophysiological mechanism (7).

Definition and classification of CKD

CKD is defined as a clinically relevant abnormality in the structure or function of the kidneys, which is persistent for at least 3 months (1). These abnormalities include changes in urine sediment, haematuria, albuminuria, electrolyte imbalances due to tubular dysfunction and structural anomalies detected by imaging or histological examination (1).

CKD is classified using the “cause”, “glomerular filtration rate” and “albuminuria” (CGA) system, which includes cause, glomerular filtration rate (GFR) category (G1-G5) and albuminuria category (A1-A3) (1).

Epidemiology of PH in CKD

PH is frequent in CKD patients and is associated with poorer outcomes, with decreased survival and a higher risk of cardiovascular events (3). Most studies on CKD cohorts have used echocardiography to define PH (10), but there are several reports that confirm the same results in RHC-confirmed PH (Table 1). The prevalence of PH is higher in more advanced stages of CKD, with the highest prevalence in patients with ESRD undergoing renal replacement therapy (RRT) (4, 10, 12, 13). Among RRT modalities, haemodialysis is consistently associated with a higher risk of PH compared with peritoneal dialysis (10, 14–16). In a large retrospective study of 2351 CKD patients, the prevalence values for PH in CKD stages G1, G2, G3a, G3b, G4 and G5 were 2.2%, 6.7%, 9.4%, 6.6%, 15.2% and 20%, respectively (17). In this same study, haemodialysis patients had a PH prevalence of 37.5% (17).

This observation was first reported in 2003, in a study of 58 haemodialysis patients which showed a PH prevalence of 39.7% (16). PH was associated with poorer survival (16). Notably, patients with potential causes of PH, such as cardiac or pulmonary disease, were excluded from this cohort, suggesting an effect of either CKD or dialysis on the pulmonary vasculature (16). Based on these findings, the fourth World Symposium on PH from 2008 included ‘chronic renal failure on dialysis’ among the causes of PH with unclear and/or multifactorial mechanisms (group 5 of the PH classification) (27).

Mechanisms of PH in CKD

Comorbidities

Some cases of PH in CKD may be explained by other causes (Figure 1). There is epidemiological overlap between CKD and several known aetiologies of PH (4). Connective tissue diseases which cause PAH (group 1 PH), such as systemic sclerosis and systemic lupus erythematosus, frequently involve the kidneys as well (28, 29). Cardiovascular comorbidities such as heart failure, atrial fibrillation and ischaemic heart disease, which cause group 2 PH, are frequent in CKD (2, 30). In particular, heart failure with preserved ejection fraction is exceptionally common in this cohort due to CKD-induced systemic inflammation, arterial stiffness and left ventricular hypertrophy, making it a primary driver of post-capillary PH (group 2), which is the most common type of PH in CKD (11, 29). Chronic obstructive pulmonary disease is one of the causes of group 3 PH and it is an important comorbidity in CKD (31). Obesity, which is linked to hypoventilation syndromes—another cause of group 3 PH—is also frequent in CKD (32, 33). Venous thromboembolism, which can cause group 4 PH, has a higher prevalence in patients with reduced estimated glomerular filtration rate (eGFR), especially in ESRD (34–36). However, not all associations between CKD and PH can be explained by comorbidities. Some CKD patients have ‘unexplained PH’, a term first introduced by Yigla et al. (37) in 2000. It is also plausible that in some patients who do have an identified cause of PH, renal impairment or dialysis may contribute to the pathophysiology of PH.

Figure 1.

PH and kidney transplantation

Kidney transplantation (KT) is the definitive treatment of ESRD as it restores normal glomerular filtration, reverses uraemia-induced endothelial dysfunction, normalises volume status and mitigates bone-mineral metabolism dysregulation (77). In addition, after successful KT, AVFs can be ligated, as haemodialysis is no longer necessary. KT thus resolves many of the mechanisms of PH in CKD. Indeed, patients with CKD and PH who undergo KT survive longer than those who remain on dialysis (77). A significant proportion of patients with PH who undergo KT experience normalisation of PAP after KT (16, 78, 79). The resolution of PH post-KT is associated with improved survival, similar to that of patients without PH before KT (79).

Clinical implications of PH in patients with CKD

The presence of PH in patients with CKD poses significant diagnostic and therapeutic challenges that require multidisciplinary collaboration. From a diagnostic perspective, echocardiography remains the primary non-invasive screening tool, but its timing is critical in patients undergoing haemodialysis. Because volume fluctuations between dialysis sessions affect haemodynamics, echocardiography should ideally be performed post-dialysis, when the patient has achieved their dry weight, in order to avoid overestimation of sPAP (39). If the clinical probability of PH is high and its confirmation would alter management, RHC is needed to accurately differentiate between pre-capillary and postcapillary phenotypes (20, 39).

Pulmonary vasodilators used in the treatment of PAH are not approved in group 5 CKD-associated PH (5, 6). Given the significant contribution of volume overload and left heart disease in CKD-PH, the off-label use of pulmonary vasodilators in these patients may cause harm and should be reserved strictly for patients who have an overlapping group 1 PAH diagnosis or, occasionally, as an off-label ’bridge to transplant’ in carefully selected candidates with severe pre-capillary haemodynamics (5, 6, 39). When prescribing PAH drugs in severe CKD, rigorous monitoring is mandatory, as many of these agents or their active metabolites require dose adjustments in the setting of reduced eGFR to avoid systemic toxicity (39).

The management of CKD-PH relies primarily on addressing underlying conditions and modifiable mechanisms (3, 39). Strict volume control by optimising dialysis and ensuring adequate ultrafiltration can lead to marked reductions in pulmonary artery pressures (20, 39). Furthermore, clinicians must proactively screen for and treat comorbid left heart disease (PH group 2) and chronic lung disease (PH group 3), which are highly prevalent in CKD patients (4). For patients with high flow AVFs, surgical flow reduction should be considered to offload the right ventricle (76). If alternative therapies like peritoneal dialysis or KT are feasible, complete AVF ligation is also a viable option.

PH should be taken into consideration when establishing the indication and timing of KT. Current guidelines do not take PH into account and severe PH is sometimes considered a contraindication for KT due to increased peri-operative mortality (3, 79). However, evidence suggests that KT may improve or resolve PH in a substantial number of patients, an effect which is associated with improved survival (79).

Renal dysfunction in PH

Just as PH is frequently identified in CKD patients, renal dysfunction is also frequent in patients with PH (3). The prevalence of renal dysfunction, typically defined as eGFR <60 mL/min/1.73 m², ranges between 13.5% and 36% depending on study population, PH aetiology and diagnostic criteria for PH. In a cohort of 1088 patients with all-cause PH, the prevalence of eGFR <60 mL/min/1.73 m² was over 30% (13). In a cohort of 2386 PAH patients from the American Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), the prevalence was 28.3% (23). Even when eGFR is normal, 20% of PAH patients exhibit elevated urinary albumin-to-creatinine ratios (24). In a meta-analysis of 6694 participants from 18 phase 3 clinical trials for PAH and CTEPH, the prevalence was only 13.5%, but this was likely due to the fact that renal dysfunction was an exclusion criterion in half of the trials included in the meta-analysis (26). At any rate, the prevalence of renal dysfunction in PH is higher than the estimated 9.1% prevalence in the general population (3).

Across multiple large cohorts, worsening renal function is consistently associated with higher PH disease severity. Patients with lower eGFR have a worse haemodynamic profile on RHC, in particular higher mPAP, RAP and PVR and lower CO (19, 26). They have a more severe World Health Organization (WHO) dyspnoea functional class (19, 23) and walk shorter distances at the 6-min walk test (19, 23, 26). They also have higher levels of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NTproBNP) (18, 23, 26). NTproBNP is particularly elevated in renal dysfunction because it is primarily cleared by the kidneys (18).

Renal dysfunction is independently associated with poorer outcomes in PH (3). Lower eGFR at baseline predicts shorter survival across all groups of PH and the risk of death increases progressively with worsening kidney function (13, 23). In PAH and CTEPH, a 10 mL/min/1.73 m² decrease in baseline eGFR is associated with a 16% increased risk of mortality or clinical worsening (26). Beyond baseline renal function, a longitudinal decline in eGFR of ≥10% also predicts mortality and all-cause hospitalisation (23).

Mechanisms of renal dysfunction in PH: the right-heart cardio–renal syndrome

The mechanisms of renal dysfunction in patients with PH include impaired renal arterial perfusion, increased renal venous congestion and neurohumoral dysregulation stemming from RV failure (3). The interplay of these mechanisms has been described as the ‘right-heart cardio-renal syndrome’ (3). Patients with PH have increased PVR, which leads to RV dysfunction and decreased CO. This can be exacerbated by the bowing of the interventricular septum, which impairs left ventricular filling (3, 26). This state of low CO underfills the renal arterial system and lowers renal perfusion pressure. The kidneys respond to this perceived volume depletion by overactivating the RAAS and the sympathetic nervous system (3, 23). This neurohumoral activation causes afferent arteriolar vasoconstriction, salt and fluid retention (hypervolemia), and reduced eGFR (3).

Right heart failure directly elevates RAP and central venous pressure, causing blood stasis in the systemic and renal veins (23, 26). Because the kidneys are enclosed in a rigid capsule, this venous congestion significantly increases intraparenchymal pressure, leading to parenchymal oedema, tubular compression and collapse, intracapsular tamponade and tissue hypoxia (3, 26). The combination of elevated venous pressure and decreased arterial perfusion severely impairs the trans-glomerular pressure gradient, driving a sharp decline in the GFR (3). Venous congestion triggers an abnormal tubulo–glomerular feedback loop where the release of adenosine causes the afferent arteriole to constrict and the efferent arteriole to dilate, further reducing GFR (3). Additionally, right-heart failure and systemic congestion trigger the release of various inflammatory cytokines (such as interleukin-6 and tumor necrosis factor) and vasoactive substances (such as ET-1, arginine-vasopressin and prostaglandins), which directly promote kidney tissue alterations and vascular injury (3, 22).

Clinical implications of renal dysfunction in PH

The high prevalence and prognostic impact of renal dysfunction in PH have important clinical implications. Renal function should be routinely assessed and integrated into the management of patients with PH, as even mild reductions in eGFR are associated with higher mortality (23). Albuminuria may also be a useful biomarker in PH, as it is associated with poorer prognosis (24). Other biomarkers such as NT-proBNP require careful interpretation in patients with significant renal dysfunction, as levels may be falsely elevated due to inadequate clearance through the kidneys (18).

Therapeutic management of right-heart cardio-renal syndrome requires a delicate balance. Loop diuretics are the mainstay of treatment to relieve systemic venous congestion and reduce renal intraparenchymal pressure. However, overly aggressive diuresis can further reduce CO and impair renal arterial perfusion, potentially worsening eGFR (3). Therefore, diuretic therapy must be carefully titrated with close monitoring of serum creatinine and electrolytes.

Renal dysfunction should not preclude patients from receiving disease-modifying PAH therapies. By lowering PVR, increasing CO and decreasing RAP, targeted PAH therapies directly counteract the haemodynamic drivers of the right-heart cardio-renal syndrome (26). PAH-specific therapies induce a modest but statistically significant improvement in eGFR, suggesting reversibility of the cardio-renal interaction once RV function is optimised (26). Nevertheless, dose adjustments and rigorous monitoring for drug toxicity remain essential, particularly for agents cleared by the kidneys (39).

Conclusions

PH and CKD frequently occur together, and the combination carries a poorer prognosis than either disease in isolation. In patients with PAH, renal dysfunction is independently associated with worse outcomes and should be taken into consideration when stratifying risk. CKD-associated PH is a complex, multifactorial disorder driven by a combination of volume overload, uraemic endothelial dysfunction and high CO induced by AVFs. Its management requires a nuanced, pathophysiologically targeted approach, focusing on optimising fluid balance and correcting underlying comorbidities. Echocardiography and RHC should be performed after haemodialysis to minimise the effect of volume overload. PH should be taken into consideration when evaluating patients for KT, since transplanted patients frequently exhibit improved pulmonary haemodynamics and better survival. Ultimately, improving outcomes in patients with concurrent PH and CKD relies heavily on close multidisciplinary collaboration between nephrologists, pulmonologists and cardiologists.