In our study, we found a correlation between LVMI and renal function in a homogenous immunocomplex-mediated CKD population of IgAN patients. The baseline renal function was an independent predictor of LVMI. In the case of higher LVMI, CV and renal composite endpoints were higher.
It is well known that hypertension is a major factor in the development of LVH in chronic hemodialyzed patients . However, in the early stages of CKD, when blood pressure elevation is not so significant, the mechanism of the relationship between CKD and LVH is not fully characterized.
Echocardiography and ECG have been used to measure LVH in patients with CKD for many years. In patients with advanced renal disease (CKD 3–4), echocardiography may overestimate LVMI due to its dependence on the intravascular volume  while ECG, even with definitive criteria, is generally a less reliable method . In recent years, magnetic resonance imaging (CMRI) of the heart has become the gold standard method for measuring left ventricular size as well as the degree of myocardial fibrosis in patients with CKD . However the availability of CMRI is still limited, echocardiography, which is widely used in the daily clinical routine to monitor and follow many patients, is more practical at considerably lower cost, and is a more easily accessible method. Thus the value of the echocardiography examination should be important in CKD.
Previous studies have shown that LVH is more common in patients with CKD than in the general population, affecting 40–78% of patients . In addition, there is a gradual increase in LVMI with the progression of CKD [24–25]. CKD and CVD share risk factors such as hypertension, vascular stiffness, and endothelial dysfunction [26–27]. The pathomechanism of increasing LVMI during CKD is unknown, although we also observed here an inverse relationship between LVMI and renal function. Thus it seems important to follow up on the changes in LVMI.
Known CV risk factors such as baseline eGFR, proteinuria, and hypertension are also risk factors for CKD progression, contributing to the acceleration of renal function loss and progression to ESKD. However, the progression of CKD, which is a complex process, cannot be explained in all cases by these traditional risk factors.
In our study, we analyzed the associated factors of LVMI and the predictive effect of LVMI for CV and renal endpoints. Based on the correlation between LVMI and GFR in IgAN, elevated LVMI may predict the progression of renal disease and CV events, especially in men, before reaching ESKD. In our IgAN patients, we found that the increased LVMI had a significant effect on both combined and renal and CV outcomes in males. This can be partly explained by the increased incidence of male CV events in general. Male IgAN patients had worse progression for CKD, in part due to more severe CV complications as known from an earlier study published by Deng et al. .
Paoletti et al. observed similar results in non-homogeneous chronic kidney patients with higher LVMI than non-diabetic CKD patients in stages 3–4. In patients with stage 1 CKD, it was proved that LVMI is a good prognostic indicator of mortality . A similar finding was obtained by Huang et al. showing that patients with higher LVMI had a higher risk of impaired renal function regardless of the degree of renal impairment .
By contrast, Tripepi et al. measured the risk of death and heart failure in CKD (CRIC study) and found that LVMI alone did not provide a clear prognostic value. The discrepancy between the studies may be explained by the fact that the patients of the CRIC study were not a homogeneous CKD population and included CKD patients with different etiologies, follow-up time was shorter and the endpoints were different (only death and de novo heart failure). In our study, we examined a homogeneous patient population with IgA nephropathy , and with longer follow-up, and, despite a lower number of cases, we were able to strengthen the prognostic role of LVH.
Eckardt et al. examined the type of LVH in CKD. They found that the prognosis was the worst in those with eccentric LVH and intermediate in those with concentric LVH . Paleotti et al. found that LVH is a strong predictor of the risk of poor CV and renal outcomes independent from LV geometry in patients with CKD . In contrast to these studies, we found that the presence of concentric hypertrophy in IgAN patients was the worst prognostic LV geometry in both sexes. Other studies found concentric hypertrophy the most common LV geometry alteration and the worst in terms of progression in general, in the case of hypertension, obesity, sleep apnea syndrome, and CV disease [34–35]. Our data suggest that, like in other diseases, concentric hypertrophy is the worst prognosis in IgAN (and possibly in other CKDs).
We suggest that an increased LVMI and a decreased eGFR may synergistically have an impact on the poor prognosis. Worsening renal function, higher incidence of LVH, and CV complications resulting in a worse prognosis and impaired left ventricular geometry (higher LVMI). As a result of this, LVH and impaired renal function seem to be enhancing processes for each other. But the connection between the deterioration of kidney function and LVH is not elucidated.
Animal and human studies showed that elevated FGF23 levels in CKD can induce the development of LVH. It has also been confirmed that activation of local RAAS via the FGF23-mediated process promotes myocardial hypertrophy and fibrosis . So, these non-specific alterations in CKD may play a role in IgAN as well. Recent biomarker studies have consistently highlighted the importance of LVH in the progression of CKD. In addition to echocardiography, the measurement of these biomarkers may provide additional data for screening high-risk patients to initiate early treatment. In the MESA study , cardiac MR-defined “malignant” LVH, which refers to the co-existence of LVH and elevated soluble cardiac biomarkers (such as troponin T for myocardial damage, NT-proBNP for myocardial hemodynamic stress) and LVH, may predict asymptomatic left ventricular dysfunction, the development of heart failure (particularly the HFrEF), and CV mortality in the general population. It also draws the attention to the need for more aggressive treatment of these patients with “malignant” LVH. Among patients with CKD, a novel biomarker, so-called growth differentiation factor 15 (GDF-15) was associated with abnormal left ventricular structure and early changes in left ventricular function measured by echocardiography .
Some studies examined different biomarkers in the pathomechanism of LVH in CKD. Kim et al.  in CKD patients demonstrated that serum Klotho is an independent biomarker of LVMI but it was not that of arterial vessel wall stiffness. Protein-bound uremic toxins (such as indoxyl sulfate (IXS) and p-cresol sulfate (PCS), which have been described in recent years, may also have a pathogenic role in the development of LVH, and asymptomatic cardiac dysfunction due to their cardiotoxic effects , although these effects are not specific for IgAN, but rather for CKD. Further examinations are needed to find the most important biomarkers in the pathomechanism of LVH in CKD.
Increased RAAS activity and hypertension in CKD also increase the incidence of vascular events thus RAAS blockade is the standard treatment (recommended in all guidelines) in these patients in general and also for the patients who have IgAN [41–47]. Based on our former results, and others, we thought that RAAS also plays a key role in the development of arterial stiffness and LVH in renal disease as in IgAN [42–44]. In our study, 76% of the IgAN patients were hypertensive, similarly to those in the study by Wanga et al. (71% hypertensive of IgAN patients . Hypertension is a very common complication in IgAN [41, 42] affecting 50–70% of patients, and this was confirmed by our data. However, there are no data on whether ACEI and/or ARB treatment could promote LVMI-lowering effects in patients with IgAN. In our study, at the start more than 75% of the patients received ACEI and/or ARB therapy, therefore, we were not able to analyze users and non-users of RAAS inhibitor treatment. By the end of the observation, almost all patients received RAAS blockers.
In our study, there was no significant difference in the use of a RAAS inhibitor between LVH and non-LVH patients. Based on this observation, RAAS may not be so important in the evaluation of LVH. However, it should be noted that the blood pressure of the study population was well treated. Patients with IgAN exhibiting higher LVMI had a deteriorated renal function, and increased incidence of ESKD and CV complications in both sexes, compared to those with lower myocardial mass. However, this may be particularly important, since further progression of CKD may be accelerated in older age and with impaired renal function. More complications may develop with worse CV status in these patients, which may also worsen the prognosis by creating a “vicious circle”.
Nohara et al. described that in early CKD (stages 1–3) patients, LVMI, urinary protein, and Hb levels were independently associated with factors for progression to dialysis . Similarly in our cohort, there was also an independent association between LVMI and Hb, but not with urinary protein. These also highlight the need to treat hypertension and anemia to prevent LV remodeling not only during the dialysis stage but also from early CKD stages . In CKD patients, there is a better survival rate among those treated with EPO up to a hemoglobin level of 10–12 g/dl, whereas normalization of hemoglobin levels were not beneficial . In our study, there was no significant difference between the lower and higher LVMI group in Hb level and ESA was used in neither group.
In the latest meta-analysis by Maki et al., it was shown that LVM change may be useful as a surrogate marker for benefits of interventions intended to reduce mortality risk in CKD .
Limitations of the study:
Our results indicated that LVMI the value obtained from echocardiography has prognostic significance, however, difficulties may occur during echocardiographic measurement. In some subpopulations, specifically in the elderly, a lack of cooperation can be a problem. Renal function was determined by estimating GFR, which is widely accepted in the literature. The extent and change of proteinuria were not examined in the present study. The evaluation of the results may also be weakened by the low number of cases and especially low number of female patients. To exclude interindividual differences, in the echocardiography exam two investigators examined all patients. We did not examine the histological abnormalities underlying progression, such as microvascular damage (TMA/MA = thrombotic microangiopathy/microangiopathy) in the kidney biopsy specimens. We did not focus on the changes in the LVMI in our cohort, although it would also have been an important parameter for prognosis.
Despite these limitations, the results of this study highlight that the onset of target organ damage in CKD is predicted by increased LVH.