Pulmonary hypertension (PH) is a complex, heterogeneous disease of great importance to the field of kidney transplantation (KT). Patients with end-stage renal disease (ESRD) have comorbid cardiovascular and pulmonary disease and often suffer from volume overload. Not surprisingly, they are frequently diagnosed with PH, with an overall reported incidence around 20%–45% in dialysis patients.1 The usual criterion for diagnosing PH is a mean pulmonary artery (PA) pressure ≥ 25 mm Hg, corresponding to a right ventricular systolic pressure (RVSP) ≥35–40 mm Hg as measured by echocardiography. Simply diagnosing elevated PA pressures in patients awaiting KT is insufficient; it is also crucial to distinguish the etiology and hemodynamic phenotypes of PH (Figure 1).2 Due to a high incidence of hypertensive heart disease and diastolic dysfunction, many ESRD patients have World Health Organization (WHO) Group 2 PH, also termed “postcapillary” or PH secondary to left heart disease.3 A minority have WHO Group 1 PH, also known as “precapillary” or pulmonary arterial hypertension (PAH), due to remodeling and narrowing of pulmonary arterioles. Finally, PH due to ESRD itself, in the absence of other clear etiologies, is categorized as WHO Group 5. Proposed mechanisms of Group 5 PH include high cardiac output from arteriovenous fistulae, neurohumoral changes of uremia, and hyperparathyroidism. In many cases, it is challenging or impossible to tease out a single cause of PH in an individual ESRD patient. Mixed, overlapping etiologies may exist (Figure 1). The implications of various PH categories for pretransplant and posttransplant outcomes and prognosis, and the optimal treatment strategies for each, are incompletely known.
The article by Caughey et al in this issue of Transplantation addresses several of these topics.4 The authors utilize the University of North Carolina Cardiorenal Registry, a large (n = 788) single-center, prospectively collected cohort of ESRD patients evaluated for KT. All patients were screened for PH by transthoracic echocardiography (TTE), performed on an interdialytic day, and read by a single cardiologist. Tricuspid regurgitant jet velocity ≥2.9 m/s, representing an RVSP of approximately 40 mm Hg, was considered diagnostic of PH. Doppler measurements of left heart diastology were also performed to assess for elevated left atrial pressure (eLAP). The implication is that patients with PH and eLAP have a postcapillary (WHO Group 2 or 5) contribution to PH—largely expected for a heavily dialyzed population (73% of patients in the study). Surprisingly, over half of the patients in Caughey et al with PH lacked Doppler evidence of eLAP—suggesting a precapillary etiology. In a survival analysis (median follow-up of 4.4 y), the subgroup of PH without eLAP was at the highest risk for mortality within 5 years of evaluation for KT, with a hazard ratio (HR) of 2.96 compared to the reference group lacking both PH and eLAP. Patients with eLAP, regardless of PH status, had a modestly increased risk of death (HR ~ 1.6).
The reliance on a single echocardiogram in Caughey et al to both diagnose and categorize PH has several potential problems. First, the gold standard for diagnosis of PH is right heart catheterization (RHC), which allows precise measurement of pulmonary hemodynamics. The agreement between TTE and RHC for diagnosing PH is imperfect, with a reported sensitivity of 83% and specificity of 72%.5 The accuracy of eLAP determination by TTE may be particularly problematic considering that intravascular volume depends on timing relative to dialysis. PA pressures and pulmonary capillary wedge pressure are reduced after dialysis, and in 1 small study, it was only possible to diagnose precapillary PH by RHC after dialysis with patients close to their dry weight.6 In Caughey et al, all patients underwent TTE on the day before dialysis; in this setting, it is surprising that only 45% of patients with PH also had eLAP (compared to the 80%–100% reported in comparable studies using RHC).6,7 This discrepancy may be due to the relatively strict TTE criteria (Grade 2 diastolic dysfunction) employed by Caughey et al to diagnose eLAP.
Diagnostic dilemmas aside, how should providers caring for patients awaiting KT utilize this information? The poorer outcome in patients with predominantly precapillary PH begs the question of whether more aggressive identification and management of these can improve outcomes. While it is impractical to screen all candidates with RHC, patients with moderate or severely elevated RVSP (≥45 mm Hg) on TTE, corresponding to about 10%–15% of the UNC Cardiorenal cohort, are more likely to have PH physiology beyond simple volume overload.3 Referring such patients for RHC will clarify the etiology as precapillary, postcapillary, or mixed. For those with predominantly precapillary PH, nephrologists should consider consultation with a PH specialist for advanced management (Figure 1). Specialists may initiate and titrate modern pulmonary vasodilator therapies such as endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins.3 Whether these will improve waitlist survival is unknown—management was not captured in the Caughey et al study. Optimistically, it may be possible to improve posttransplant outcomes with targeted therapy. Several studies suggest worse allograft function and survival in PH patients after KT,8,9 possibly due to reduced cardiac output and impaired graft perfusion.10 The findings in Caughey et al present both the following challenges and opportunities: to better characterize and appropriately manage PH in KT candidates, define the influence of PH on outcomes, and hopefully improve pretransplant and posttransplant survival in this population.
1. Tang M, Batty JA, Lin C, et al. Pulmonary hypertension, mortality, and cardiovascular disease in CKD and ESRD patients: A systematic review and meta-analysis. Am J Kidney Dis. 2018; 72175–83
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10. Zlotnick DM, Axelrod DA, Chobanian MC, et al. Non-invasive detection of pulmonary hypertension prior to renal transplantation is a predictor of increased risk for early graft dysfunction. Nephrol Dial Transplant. 2010; 2593090–3096