Chronic kidney disease following left ventricular assist device implantation: contemporary insights and future perspectives

Abstract

In the last decade, an increasing number of left ventricular assist devices (LVADs) have been implanted to treat patients with end-stage heart failure. Although LVAD therapy improves hemodynamics and survival, it is also associated with potentially life-threatening complications. A common and significant complication following LVAD implantation is chronic kidney disease (CKD), which is associated with high morbidity and mortality. Despite improvements in kidney function early after LVAD implantation, creatinine levels return to pre-implantation levels or higher in the long term. With the increasing number of LVAD implantations in the last decades, it is essential to focus on LVAD-associated CKD in order to improve the outcomes of LVAD therapy. In addition, identifying potential markers for early diagnosis may optimize perioperative management and prevent disease progression, which may now be the only realistic therapeutic option. This review describes the definition, diagnosis, incidence, pathophysiology, and risk factors for CKD after LVAD implantation. Additionally, future perspectives on the prevention and management of CKD in LVAD patients are discussed.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10741-025-10571-6.

Introduction

Worldwide, chronic heart failure (HF) represents a significant public health burden, contributing to high healthcare costs and increased mortality, affecting millions of patients. Despite remarkable advances in treatment strategies over the past three decades, the 5-year mortality rate remains high at 75% [1]. Heart transplantation is the ultimate therapeutic intervention for patients with end-stage HF [2]. However, resources remain limited due to the extreme shortage of donor hearts. Over the past two decades, implantable left ventricular assist devices (LVADs) have emerged as a bridge to heart transplantation, profoundly changing the natural course of the disease. According to the Intermacs Registry Report, more than 25,000 LVADs have been implanted since 2006, with a 5-year survival rate of 61% [3].

Kidney dysfunction is a common complication in patients with end-stage HF. This dysfunction often manifests as cardiorenal syndrome, representing a maladaptive interaction between the kidney and the heart. In fact, 91% of patients hospitalized for acute cardiac decompensation exhibit some degree of kidney dysfunction, which initiates a cascade of mechanisms leading to kidney injury [4]. The impact of cardiac dysfunction on the kidneys can be acute or chronic, both of which are associated with increased hospital admissions and length of stay. Furthermore, even with appropriate treatment, kidney dysfunction persists and leads to 1.5–9.5 times higher long-term mortality rates compared to patients with normal kidney function [5, 6].

Early after LVAD implantation, the kidneys often show functional improvement due to recovery of renal venous congestion and an increase in renal blood flow. Post-LVAD eGFR improves by 50% compared to pre-LVAD baseline in as much as 40% of patients. Several studies have demonstrated that kidney function is preserved in the subsequent months following the implementation of LVAD [2, 5]. However, in a subset of patients, kidney function may regress to pre-LVAD levels or even decline further and become chronic (Fig. 1) [3]. The underpinning mechanisms of chronic kidney disease (CKD) in the long-term of LVAD implantation remain poorly understood [2]. This state-of-the-art review summarizes current evidence, provides contemporary insights, and outlines future perspectives on CKD in patients with long-term LVAD support.

Fig. 1.

Advanced mixed modeling illustrating the evolution of eGFR over 2 years of follow-up, stratified by preoperative CKD stage [3]. CKD chronic kidney disease, eGFR estimated glomerular filtration rate

Definition of chronic kidney disease

CKD is characterized by structural or functional abnormalities of the kidneys, persisting for a minimum duration of three months. The stages of CKD are defined based on the underlying cause, glomerular filtration rate (GFR), and level of albuminuria [7]. However, the current serum creatinine-based system presents challenges in accurately estimating kidney function due to the inherent limitations of its calculation. Firstly, kidney injury may be present before a discernible elevation in creatinine levels. Secondly, various factors, including weight, nutritional status, muscle mass, volume overload, gender, age, and diuretic usage, all influence creatinine concentrations [6]. It is important to note that post-LVAD, recovery of volume status and increased muscle mass can increase serum creatinine levels without a true kidney injury being present. The term “worsening kidney function” has been introduced to delineate these scenarios and avoid considering them as true kidney injury [7].

Prevalence of CKD in LVAD patients

The prevalence of post-LVAD CKD varies considerably across different studies, depending on the included populations, study design, and criteria used to diagnose CKD. According to a report by Kirklin et al., the prevalence of pre-LVAD CKD is approximately 64% and 30% if mild (Stage 1–2-3) and moderate (Stage 4–5) alterations in kidney function are considered, respectively. However, CKD’s prevalence decreases significantly to 6% if severe kidney function alterations are noted (Need for renal replacement therapy) [8].

The severity of post-LVAD CKD is correlated with higher mortality. Hospital mortality rates reach 50% and heart transplantation does not reverse this risk of complications, underscoring the persistent risk of complications in post-LVAD CKD patients [2, 9]. Furthermore, end-stage kidney disease and subsequent dialysis are associated with an increased risk of complications, including prolonged hospital stays due to increased infection risk (32%), hypervolemia (14%), and stroke (11%) [10, 11].

Pathophysiology of CKD in LVAD patients

The pathophysiology of prolonged post-LVAD CKD is multifactorial, marked by the intricate interplay of various factors influencing kidney function and microvascular anatomy. Three overarching headings could be used to characterize the underlying etiological factors: (i) Patient-related factors (pre-implant factors), (ii) Factors related to the surgical procedure and the LVAD’s direct effects on kidney function (peri-implant), and (iii) The factors related to the long-term effects of LVAD support (post-implant). Figure 2 visually represents these three pivotal categories and their interconnected dynamics in the context of long-term post-LVAD CKD.

Fig. 2.

Pathophysiology of CKD in LVAD patients. Three major categories englobe the causes of kidney dysfunction in LVAD patients. (i) Patient-related factors (pre-implant factors), (ii) Factors related to the surgical procedure and the LVAD’s direct effects on kidney function (peri-implant), and (iii) Factors related to long-term effects of LVAD support (post-implant)

Pre-LVAD implantation factors

Patient characteristics and kidney reserve

Preoperative kidney function is a critical determinant of both early and long-term kidney outcomes following LVAD implantation. Baseline eGFR is strongly associated with the trajectory of renal function after surgery, with lower preoperative eGFR predicting a higher risk of persistent or progressive CKD [11]. Other important predictors of renal outcomes include patient age, diabetes, hypertension, and chronic right-sided heart dysfunction [12]. Elevated central venous pressure often reflects chronic right-sided heart failure (RHF) and is linked to impaired renal perfusion and structural kidney changes even before LVAD surgery. Additionally, the duration and severity of pre-LVAD heart failure, as indicated by high INTERMACS profiles and elevated filling pressures, are associated with more severe renal venous congestion and reduced kidney reserve [13, 14]. Identifying and optimizing these preoperative characteristics is crucial for risk stratification, perioperative planning, and predicting long-term renal prognosis in LVAD recipients.

Kidney dysfunction in patients with end-stage HF

The kidneys and the heart interact closely, and functional deterioration of one affects the other. This crosstalk is known as cardiorenal syndrome. Kidney dysfunction might appear during acute HF or coexist with chronic HF. Acute kidney injury (AKI) is prevalent and reported in more than half of patients hospitalized with acute decompensated HF. On the other hand, CKD is documented in around one-quarter of patients with chronic HF. However, in advanced HF, its prevalence increases to 50% and reaches 70% in patients with cardiogenic shock [15].

The assessment of pre-LVAD kidney function provides valuable prognostic insights. Pre-LVAD eGFR values below 60 ml/min are correlated with an elevated risk of RHF, stroke, and HF, particularly in patients who do not experience an improvement in kidney function during the post-LVAD period. Despite an initial improvement in kidney function within the first-month post-LVAD implantation, the trajectory of kidney function exhibits a variable pattern [16]. A study by Bujo et al. demonstrated that the initial rise in eGFR often reverts to baseline levels, followed by a gradual decline over long-term LVAD support [2]. Walthers outlines five phenotypic trajectories of kidney function in patients following device implantation. While most patients included in groups I and II exhibited behavior consistent with that observed in previous studies, a small cohort comprising young patients with recent-onset HF demonstrated more pronounced and sustained improvement in kidney function [17].

Additionally, patients should be optimized preoperatively for conditions that could potentially impair kidney function, such as diabetes, hypertension, and the use of nephrotoxic drugs. Hemodynamic optimization, especially in the setting of preoperative congestive heart failure, of the right filling pressures is crucial for the prevention of perioperative right heart failure and acute kidney injury failure [18].

Peri-LVAD implantation factors

Perioperative acute kidney injury

AKI is defined by the KDIGO criteria as an acute rise in serum creatinine and is staged into three levels of severity (Stage 1: creatinine ≥ 0.3 mg/dL within 48 h or ≥ 1.5 times baseline within 7 days or reduced urine output < 0.5 mL/kg/h for >6 h; Stage 2: creatinine 2.0–2.9.0.9 times baseline or reduced urine output < 0.5 mL/kg/h for ≥ 12 h; Stage 3: creatinine 3.0 times baseline or increase in serum creatinine ≥ 4 mg/dl or initiation renal replacement therapy (RRT) or reduced urine output < 0.3 mL/kg/h for ≥ 24 h or anuria ≥ 12 h) [6]. This standardized definition and staging system are essential for accurate diagnosis AKI and prognostication in patients with advanced heart failure and those supported by LVADs.

Major heart surgery is an independent risk factor for the development of postoperative AKI. This risk extends to surgeries involving LVADs and is accompanied by a substantial early decline in kidney function post-LVAD implantation. Muslem et al. reported a notable incidence of postoperative AKI of 70%, with 45% in AKI Stage I, 16% in AKI Stage II, and 9% in AKI Stage III. Those with more severe AKI exhibited a more significant decrease in eGFR per year compared to those with AKI I-II and non-AKI groups [19].

Perioperative kidney injury is intricately linked to various factors, including alterations in kidney perfusion, oxygenation, and systemic activation of the inflammatory cascade. Furthermore, complications such as low cardiac output syndrome and vasoplegia post-surgery may exacerbate kidney dysfunction by causing prolonged hypoperfusion [20]. Finally, AKI may be associated with the administration of nephrotoxic medications, such as vancomycin, attributable to vasoconstriction, allergic interstitial nephritis, and tubular toxicity [21]. On the other hand, interventions aimed to reduce the duration of extracorporeal circulation time, maintain blood pressure for optimal organ perfusion, minimize blood loss, and prevent reoperations have demonstrated efficacy in reducing the risk of AKI [3, 22].

In the postoperative period, managing RHF, maintaining hemodynamic stability, and avoiding fluid overload play a critical role in preventing AKI [3, 23]. Monitoring and optimizing hemodynamic status (i.e., Central venous pressure (CVP), pulmonary artery pressures, and cardiac output) is paramount in preventing AKI or mitigating its severity. Acute RHF constitutes a relatively frequent complication following LVAD surgery, which may develop immediately (early-term RHF) post-LVAD implantation or long-term (late RHF) [24, 25]. The development of acute RHF should be prevented and optimally treated, as it may lead to AKI and subsequently cause chronic impairment of kidney function in the long term [26]. AKI and CKD should not be viewed as separate entities, but rather as interconnected conditions. The relationship is cyclical. AKI can lead to CKD and CKD increases the risk of AKI. AKI on top of CKD worsens both conditions [26].

Nephrotoxic drugs should be stopped or changed to less harmful alternatives. In the event of a progressive deterioration of kidney function, RRT, including intermittent hemodialysis or continuous veno-venous hemofiltration, may become necessary to manage metabolic disorders and maintain optimal volume status [23]. In theory, initiating RRT at an early stage to reduce postoperative congestion can preserve kidney function and prevent the development of chronic kidney disease in the long term [23, 27]. However, conclusive evidence regarding the optimal timing for initiating RRT necessitates comprehensive future research.

Device type and flow

LVADs are classified into three generations based on their flow characteristics, specifically pulsatile or continuous flow. Continuous flow LVADs, characterized by a steady flow, mitigate endothelial shear stress and reduce energy loss [28]. The transition from physiologically pulsatile to non-pulsatile continuous flow may contribute to the development of kidney dysfunction [29]. Although using the latest generation continuous flow LVAD devices has been demonstrated to improve survival rates and time free from major adverse events, such as gastrointestinal bleeding, neurovascular events, and arrhythmias, this beneficial effect has not been demonstrated in terms of kidney dysfunction [10].

The HeartMate 3 LVAD (Abbott, Chicago, IL, USA) uses a magnetic levitation motor and generates artificial pulsatility, thereby reducing shear stress and the risk of hemolysis and thrombus formation. This becomes particularly significant as the risk of renal tubular toxicity escalates with the accumulation of free hemoglobin in the kidneys [30]. In this context, reperfusion may activate inflammatory pathways, releasing nitric oxide and free radicals, contributing to kidney injury [10, 31].

Post-LVAD implantation

Cardiac output is dependent on the pump’s speed in continuous-flow LVAD patients. The pulsatility index, indicative of flow pulse magnitude through the pump, is influenced by volume and contractility, with higher assistance correlating with a lower pulsatility index [32]. Improved left ventricular function prompts increased venous return, leading to elevated diastolic pressure. This alteration in pressure can induce morphological changes in the right ventricle, particularly in patients with residual right ventricular failure or exacerbated tricuspid regurgitation, resulting in renal congestion and diminished renal perfusion [23, 33].

Blood pressure in continuous flow systems shows the interaction between the LVAD and the cardiovascular system [34]. The HeartMate 3 generates an artificial asynchronous pulsation, resulting in blood flow by the native heart with cyclic systolic and diastolic phases. Two components dependent on the device are observed: LVAD-diastolic blood pressure and LVAD systolic blood pressure [35].

Under normal circumstances, vessels respond to elevated pressure through shear-stress cycles of the vessel wall, inducing nitric oxide production by endothelial cells, leading to increased flow. The extent of this increase in flow depends on the type of pump flow in LVAD patients. Animal models have demonstrated that nitric oxide production decreases in cardiac bypass. However, systemic vascular resistance increases in continuous flow compared to pulsatile flow, indicating diminished endothelial shear stress and lower endothelial nitric oxide production [36].

A comparison of different LVAD flows revealed that pulsatile LVAD support results in decreased changes in the muscular layer of the renal artery and inflammation by regulating Angiotensin-1 receptors and angiotensin-converting enzyme [37]. Furthermore, a mechanical cardiac support system has been shown to reduce plasma renin and aldosterone activity to levels similar to those observed in normal individuals, with the maximum effect observed at 21 days. Nevertheless, the long-term sustainability of this approach remains uncertain [36]. The decline in renin-angiotensin-aldosterone system (RAS) activity reduces systemic blood pressure, as LVAD flow is more sensitive to pressure fluctuations than the normal heart. An increase in afterload secondary to elevated blood pressure reduces LVAD flow and alters the renin-angiotensin system activity [33]. Continuous flow is also associated with increased sympathetic system activity and a lack of baroreceptor responsiveness to low pulsatility, which results in alterations in the regulation of organ perfusion [37].

Furthermore, continuous flow-LVADs negatively affect peripheral vascular endothelial cells and heart muscle anatomy. The continuous flow increases vascular reactivity and reduces flow-mediated dilation at the peripheral vascular level. The medial layer thickens at the level of the myocardial arterioles [38]. Additionally, the continuous flow is related to a marked increase in the transcription of several antioxidant genes compared to pulsatile flow. Consequently, patients subjected to continuous flow are at a high risk of ongoing oxidative stress in endothelial cells [39]. Taken together, it appears that continuous flow may have disadvantages compared to pulsatile flow from a kidney perspective, but this hypothesis remains to be elucidated. On the other hand, there is a significant body of literature regarding myocardial reverse remodeling at cellular and molecular levels with continuous-flow LVADs that favorably impact myocardial structure and function [40].

Chronic hemolysis and risk of CKD

Hemolysis is defined as a plasma-free hemoglobin concentration >40 mg/dl, irrespective of manifesting clinical symptoms. Unfortunately, chronic hemolysis is a complication of all kinds of mechanical circulatory support devices, with an incidence ranging from 5 to 18% [41]. Device hemocompatibility, activation of the immune system and coagulation cascade by flow dynamics, and shear stress are the main causes of intravascular hemolysis [41]. The release of substances derived from hemoglobin precipitates the production of nitric oxide and free radicals, thereby exacerbating vascular reactivity, which contributes to tubular necrosis [30].

The reaction between the heme group and iron results in the depletion of nitric oxide, which is necessary for regulating vasoreactivity, renal blood flow, and glomerular hemodynamics. These reactions also activate redox reactions that produce free hydroxyl radicals, leading to lipid peroxidation and mitochondrial dysfunction, resulting in tubular necrosis [30]. In the absence of hemolysis, these substances are scavenged, and their consequences are limited by haptoglobin and hemopexin. However, hemolysis events become evident, increasing the risk of complications. These include thrombosis, device malfunction, stroke, and mortality [42]. Luckily, while different kinds of LVADs cause hemolysis at varying rates, currently used HM3 devices induce much less hemolysis [43]. Further research is needed to demonstrate a concrete link between post-LVAD hemolysis, hemosiderosis, and CKD.

Late right-sided heart failure

Late-onset RHF is noted in up to 19% of LVAD patients with a median duration of 1.3 years post-implantation. However, there is a discernible reduction in the incidence of RHF to 5% within the first month following LVAD implantation [44, 45]. The lack of a definitive distinction between early and late-onset RHF adds complexity to the understanding of this phenomenon [44]. Comprehensive insights into these distinctions, including definitions and severity categorizations, are presented in Table 1.

Table 1.

Key points regarding the onset of CKD following LVAD implantation

	Key points
1	LVAD implantation transiently improves kidney function, but in the long term, the effect is not sustained, leading to a high incidence of CKD.
2	The LVAD heart-kidney relationship is a complex phenomenon influenced by several, including those occurring before, during, and after surgery.
3	CKD following LVAD implantation has a deleterious impact on survival, with patients requiring RRT exhibiting a 46% higher mortality rate than patients who do not require RRT.
4	The management of CKD in LVAD patients remains a significant challenge. To effectively slow the progression of the disease, it is essential to improve the diagnosis, closely monitor risk factors (such as hypertension, diabetes, RV dysfunction), and implement targeted treatments to control them.
5	The prevention of RHF is of paramount importance in the prevention of CKD. Hemodynamic parameters can guide the avoidance of overload and afterload increase.
6	ACE-I/ARB but not MRA improves kidney function.
7	The prevention of CKD and RRT begins with the rigorous screening of LVAD candidates, particularly in individuals with low eGFR, proteinuria, and microalbuminuria before implantation.
8	The response of kidney to LVAD is influenced by several factors, including changes in flow, activation of shear stress forces, neurohormonal activation, and hemolysis. The control of these factors may be key to preventing the progression of CKD.
9	The creatinine measurement is not the most accurate method for diagnosing kidney injury. Alternative approaches, such as using biomarkers and biochemistry, are being investigated to provide a more timely and accurate diagnosis of kidney injury.
10	Identifying phenotypes associated with right ventricular dysfunction is a crucial step in developing precision medicine, which can potentially reduce the impact on kidney and complications associated with this condition.

RRT  renal replacement therapy, CKD chronic kidney disease, LVAD left ventricular assist device, MRA mineralocorticoid receptor antagonists, RHF right heart failure

Chronic RHF appears to be associated with the progression of vasculopathy, arrhythmias, and aortic insufficiency [25]. RHF also precipitates arrhythmias, resulting in elevated left ventricular end-diastolic pressure, impaired aortic valve opening, and worsening congestion [46]. Pre-LVAD tricuspid regurgitation, low cardiac index, and right ventricular stroke work index have been identified as risk factors for RHF. Patients with RHF, particularly those with elevated right atrial pressure (RAP) and a low PAPi (< 2), have an increased risk of AKI. Nevertheless, the long-term consequences of early-term hemodynamic alterations remain uncertain in the context of evolving into CKD [47]. High RAP/PCWP is associated with the development of late-onset RHF, subsequently leading to late kidney dysfunction, adverse outcomes, and heightened mortality rates (7.1% in mild cases and 17.9% in severe cases at six months) [2, 16]. Biochemical markers, including low hemoglobin and platelet levels, elevated leukocyte count, bilirubin, and C-reactive protein, have been demonstrated to be associated with an increased risk of RHF within the first year post-LVAD implantation [48].

Hypertension in continuous-flow LVAD patients

Centrifugal pumps have an increased afterload and preload sensitivity relative to their predecessor pulsatile flow pumps and the normal heart. Centrifugal continuous-flow LVADs increase diastolic blood pressure and flow, particularly at higher pump speeds [32]. Moreover, human research indicates that mean and diastolic systemic blood pressures increase while the systolic systemic blood pressure remains constant following LVAD implantation [49].

Hypertension is a well-known independent risk factor for CKD, especially in patients with pre-existing kidney injury [50]. Besides, over a quarter of HF patients concurrently contend with CKD as a comorbid condition [50, 51]. Typically, kidney microvasculature is shielded from elevated systemic blood pressure and fluctuations through autoregulatory vasoconstriction of the preglomerular vasculature, thereby maintaining a relatively constant renal blood flow. However, patients with CKD exhibit an increased vulnerability to kidney injury even at moderate blood pressure elevations [50, 52]. Therefore, it is essential to reduce systemic blood pressure to the normotensive range to prevent the development of CKD and the progression of kidney injury in patients with pre-existing CKD.

The challenges in the reliable assessment of blood pressure due to the lack of a discernible pulse in LVAD recipients complicate the effective management of hypertension and systemic blood pressure in this population. The accurate measurement of mean arterial pressure necessitates the utilization of Doppler or oscillometric cuffs. Regrettably, prevailing guidelines for hypertension management post-LVAD implantation primarily rely on expert consensus and clinical experiences, lacking a robust foundation in high-level evidence-based research [53].

Derangement of neurohormonal imbalance/RAS

The RAS is a complex neurohormonal network that plays a role in cardiac and vascular remodeling through the ACE/Angiotensin II/AT1R pathway. A counter-regulatory pathway, ACE2/Angiotensin 1–7/MasR, also serves as a control pathway. In HF patients, there is a downregulation of AT1R and AT2R receptors and an upregulation of ACE2 compared to the healthy population [54]. However, following LVAD implantation, both angiotensin II receptors and ACE2 are downregulated, contingent upon the duration of device support and the severity of the underlying disease. Pre-LVAD, cardiac renin levels are elevated, accompanied by angiotensin depletion. Following LVAD implantation, despite an elevation in angiotensin and angiotensin II levels, the release of renin diminishes due to reduced stimulus associated with normalized blood pressure [55].

The pharmacological intervention also has a remarkable influence on the RAS response. Notably, patients prescribed angiotensin-converting enzyme inhibitors (ACE-I) exhibit distinct patterns compared to those not receiving such treatment. ACE-I reduces angiotensin II levels, triggering negative feedback that upregulates renin, thereby sustaining elevated levels even in the presence of normalized blood pressure. In addition to its blood pressure regulatory role, ACE-I plays a pivotal role in cardiac remodeling, a critical aspect of HF. Despite improvements in systemic pressure with LVAD support, studies indicate that cardiac remodeling persists; however, concomitant use of LVAD and ACE-I has been associated with reductions in collagen deposition and cardiac stiffness [55].

Notable findings from Brinkley’s series involving 11,493 LVAD patients indicate a reduction in mortality with ACE-I/ARB use, whereas similar benefits were not observed with mineralocorticoid receptor antagonists (MRAs). The impact on kidney function manifested as a decrease in creatinine levels, although with a limited follow-up of 12 months. Strikingly, patients receiving ACE-I/ARB therapy exhibited a higher incidence of hemolysis, but a causal relationship with kidney dysfunction has not been established [56]. However, it should be noted that most data on neurohormonal blockade are still limited and need further investigation.

Other risk factors

Animal investigations have demonstrated that continuous-flow LVADs induce arterial smooth muscle hyperplasia, periarterial inflammatory infiltration, and interstitial nephritis in afferent arterioles. Additionally, these devices stimulate the secretion of an anti-proliferating cell nuclear antigen-antibody. The change in vascular smooth muscle produces desensitization of α-receptors, which leads the baroreceptors to respond inadequately to the blood pressure alterations. This phenomenon partially explains the observed progressive deterioration in kidney function over time [57].

A critical yet underestimated situation is muscle mass recovery and cachexia improvement secondary to HF. The increase in functional reserve and physical capacity can raise creatinine without implying a worsening of kidney function. Using creatinine-based formulas that underestimate eGFR and post-implantation mass gain may denote an unreal decrease in eGFR. However, other mechanisms for measuring kidney function have not been validated in patients with LVAD [57].

In response to ischemia, healthy vessels produce vasodilatation downstream of resistance. The vascular reactivity index becomes >1 after 90–150 s of ischemia release. In advanced HF and LVAD patients, this capacity is reported to be limited, which could impair the response of kidney vessels to flow changes [9]. The vascular reactivity index < 1 and loss of reactivity are associated with poor endothelial function, leading to impaired kidney function and adverse cardio-cerebrovascular events [58].

Potential role of biomarkers in the diagnosis and follow-up of CKD

AKI biomarkers have a particular role in the diagnosis. However, their performance in predicting CKD is not firmly established. For instance, kidney injury molecule-1, a biomarker indicative of tubular injury, is increased in patients with stage 3 CKD. Similar observations have been reported with L-type or liver-type fatty acid-binding proteins [7]. Regrettably, no substantive evidence supports their utility in predicting or diagnosing CKD. However, the measurement of changes in low molecular weight metabolites in fluids and tissues (metabolomics), such as 5-methoxy tryptophan (5-MTP) and asymmetric dimethylarginine (ADMA), represents a promising avenue for future research. The reduction of 5-MTP (5-MTP) appears to correlate with renal functional deterioration. ADMA, which is related to atherosclerosis, exhibits inhibitory effects on nitric oxide synthesis, thereby impairing endothelial function associated with glomerular hypertension. ADMA is a potentially compelling biomarker in patients with LVADs; however, further research is imperative to establish its clinical utility [59].

The role of kidney biopsy in the diagnosis of AKI and CKD

A kidney biopsy is the definitive method for diagnosing kidney injury and understanding underlying processes, but it is rarely performed in advanced heart failure patients due to associated risks of the procedure and underlying cause is already anticipated. To date, no large-scale studies on kidney biopsies in this population are available. Case series suggests that kidney injury in these patients is linked to chronic venous congestion, ischemic tubular injury, and progressive interstitial fibrosis, with lesser contributions from focal segmental glomerulosclerosis or arteriolosclerosis. Additionally, kidney biopsies are not favored for diagnosing CKD after LVAD implantation due to the patient’s vulnerability and the need for ongoing anticoagulation therapy [60, 61].

Clinical impact of CKD

CKD and the need for RRT have been demonstrated to increase mortality in LVAD patients. Of note, the patients requiring RRT exhibit a five-year survival rate of 46%, markedly lower than their counterparts who do not need it (Fig. 2) [62].

Another critical complication is the increased risk of bleeding, particularly from the gastrointestinal tract. Patients with continuous flow-LVADs are prone to degrade von Willebrand factor multimers. Furthermore, the use of anticoagulants increases the risk of bleeding [63].

Stroke emerges as another prominent complication following LVAD implantation. Independent of LVAD implantation, CKD itself is associated with a higher risk of stroke; however, this risk increases more in LVAD patients with accompanying CKD. Specifically, patients with continuous-flow LVADs have an increased risk of ischemic and hemorrhagic stroke, with a prevalence ranging between 12% and 21%, leading to mortality rates of 25%. Additionally, CKD is associated with a twofold increase in the risk of device-related infections [64].

Prevention and management of CKD in LVAD patients

The utility of biomarkers in the timely diagnosis of CKD is currently limited. However, future advancements in biomarker research and metabolomics may yield more precise and earlier detection of CKD patients [65]. Given the multifactorial influence on creatinine concentration for estimating kidney function, factors such as sarcopenia, nutritional status, and edema removal must be considered to discern the clinical relevance of alterations in creatinine levels.

The prevention of LVAD-associated CKD is based on the control of established risk factors. The preservation of kidney function following LVAD implantation is of paramount importance. The mitigation of volume overload and the modulation of the autonomic nervous and renin-angiotensin systems represent pivotal interventions in avoiding kidney injury [49].

Several observational cohorts have shown that ACE-Is and ARBs but not mineralocorticoid receptor antagonists (MRAs) have been shown to improve outcomes of LVAD patients. However, data were obtained from nonrandomized studies and specifically linking ACE-Is and ARBs to preservation of kidney function are limited and heterogenous. MRAs may predispose to hyperkalemia, which is associated with higher mortality during LVAD support; thus, monitoring potassium levels and renal function is essential [56, 66]. Given the lack of randomized post-LVAD data, we caution against over-interpreting outcome associations. Recent studies of LVAD recipients indicate that there may be improvements in congestion and hemodynamics with sodium-glucose co-transporter 2 (SGLT2) inhibitor use, the outcomes for the kidneys and definitive endpoints remain uncertain and vary across reports [67, 68]. In the absence of randomized trials, we suggest individualized use of these medications in LVAD recipients. Monitoring blood pressure and vascular responsiveness, coupled with adjusting medications based on individual patient responses, is essential to mitigate the influence of hemodynamic instabilities on kidney function [69].

A recent study has demonstrated that continuous flow LVADs are associated with increased subclinical hemolysis, resulting in elevated levels of circulating plasma-free hemoglobin (pfHgb). Furthermore, plasma-free hemoglobin (pfHgb) levels have been found to inhibit the activity of ADAMTS-13, which is a critical factor in preventing the accumulation of von Willebrand factor multimers and thereby avoiding the formation of microthrombi [70]. A prospective study by Bartoli and colleagues underscored a significant association between high levels of pfHgb and lactate dehydrogenase and increased device thrombosis in LVAD patients. Consequently, thrombosis at renal tubules represents a potential avenue for investigating the etiology of kidney dysfunction in these patients [70].

Two options for chronic dialysis can be applied to LVAD patients: hemodialysis and peritoneal dialysis. For hemodialysis, dialysis can be performed via a catheter or fistula. Theoretically, the absence of pulsatile flow and the frequent hospitalizations of patients, which often lead to repeated vascular interventions, can make hemodialysis through a fistula challenging. Central catheters, on the other hand, are associated with a higher risk of infection. While tunneled catheters have a lower risk of infection than temporary venous dialysis catheters, they carry a higher risk of bleeding complications during placement. In addition, most of the LVAD patients elicit relatively low blood pressures, making hemodialysis cumbersome. Therefore, in LVAD patients, peritoneal dialysis may be preferred due to its lower infection risk and less impact on hemodynamics during dialysis [71]. However, there is no study demonstrating the superiority of one chronic dialysis modality over the other.

Future perspectives

The primary target in the long-term management of LVAD patients is the early identification of those at high risk for kidney dysfunction. The inability to adequately control the pertinent confounders and the failure of existing biomarkers to create contemporary risk prediction models fall short of accurately predicting long-term kidney outcomes [19, 24, 62]. Noteworthy, investigating clinical phenotypes and defining phenotypes containing both patient characteristics and hemodynamic profiles represent significant advances in understanding the heterogeneity of LVAD-related kidney dysfunction. Future research will facilitate the development of risk scores and the implementation of prevention measures in high-risk patients.

Patients with venous congestion, low cardiac index, and impaired diuresis, as measured by urinary net sodium concentration, are more likely to exhibit RHF, necessitating early and sustained inotropic support [24, 72, 73]. Remote PA pressure monitoring in LVAD patients may reduce CKD incidence. Interventions that improve renal functional reserve and renal perfusion have been shown to significantly reduce the risk of AKI after cardiopulmonary bypass, as noted after amino acid infusion. Investigating the effects of these interventions in patients undergoing LVAD surgery and the long-term impact of early positive outcomes would be beneficial [74].

Exploring the reversal of renin-angiotensin-aldosterone function to baseline levels in the post-LVAD period would be beneficial. In particular, the long-term continuance of ACE-I and ARBs could favor kidney function [73]. In future directions, ARNIs and SGLT2 inhibitors and their potential impact on LVAD patients with CKD should be investigated. Finerenone has an effect on slowing the progression of CKD and reducing albuminuria, and it may also have a positive effect on the long term renal outcome in the LVAD patient group [75]. The relationship between endothelial reactivity loss and kidney dysfunction risk has not been studied. Understanding this relationship could be pivotal in defining the renal response to the flow changes induced by these devices.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

LVAD

Left ventricular assist device

CKD

Chronic kidney disease

HF

Heart failure

AKI

Acute kidney injury

eGFR

Estimated glomerular filtration rate

AR1

Angiotensin 1 receptors

ACE

Angiotensin-converting enzyme

RAS

Renin-angiotensin system

RHF

Right heart failure

RRT

Renal replacement therapy

Author contributions

Concept – IA, GG, OS, KC; Design - IA, GG, OS, KC; Supervision – ER, IR, OS, KC; Resources - IA, GG, PJ, DAH, ER, IR, CI, OS, KC; Materials - NA; Data Collection and/or Processing - NA; Analysis and/or Interpretation - NA; Literature Search - IA, GG, PJ, DAH, ER, IR, CI, OS, KC; Writing Manuscript - IA, GG, PJ, OS, KC; Critical Review – ER, IR, OS, KC.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics committee approval

NA.

Informed consent

NA.

Financial disclosure

None.

Competing interests

The authors declare no competing interests.