Abstract
This observational cohort study aimed to identify factors influencing long-term renal outcomes in 170 patients with biopsy-proven malignant hypertension (MHT)–associated renal thrombotic microangiopathy (TMA) who were dialysis-independent at baseline, recruited between 2008 and 2023. Over a median follow-up of 23.5 months, 52 patients (30.6%) progressed to end-stage renal disease (ESRD). Those developing ESRD exhibited significantly higher total cholesterol levels, heavier proteinuria, a greater proportion of global glomerulosclerosis, more advanced interstitial fibrosis/tubular atrophy, and lower baseline eGFR, along with lower use of renin-angiotensin-aldosterone system (RAAS) inhibitors. In Cox regression analysis, elevated total cholesterol (HR = 1.48 per 1 mmol/L change; 95% CI: 1.24–1.77, p < 0.001) and a higher percentage of glomerulosclerosis (HR = 1.24, 95% CI: 1.15–1.33, p < 0.001; per 5% increase of glomerulosclerosis) were independent risk factors for ESRD, while RAAS inhibitor use was associated with a significantly reduced risk (HR = 0.45, 95% CI: 0.25–0.82, p = 0.009). These findings underscore the prognostic value of lipid profiles and histologic injury severity in MHT-associated TMA and support the protective role of RAAS blockade in preserving renal function, which may guide risk stratification and therapeutic decisions in this high-risk population.
Keywords: MHT, thrombotic microangiopathy, renin-angiotensin system inhibitors, renal function
Introduction
MHT-associated renal thrombotic microangiopathy (TMA) is a severe complication of MHT [1,2], characterized by acute renal crisis, rapid deterioration of renal function, and distinctive renal vascular lesions. These lesions typically involve thickening of fibrous intimal tissue in small arterioles, endothelial cell proliferation and swelling, leading to luminal narrowing [3,4]. The pathological features of kidney lesions in MHT-associated renal TMA closely resemble those observed in other forms of TMA [5].
The incidence of MHT has remained constant over the past four decades, with an estimated annual occurrence of 1–2 individuals per 100,000 people [6,7]. Although renal prognosis in patients with MHT-associated renal TMA has improved since the 1970s with advancements in antihypertensive therapy, recent studies have reported 5-year renal survival and patient survival rates of only 50% and 75%, respectively [8]. The introduction of calcium channel blockers (CCBs) and renin-angiotensin system (RAAS) blockers after 1980 further improved outcome, with 5-year renal and overall survival rates reaching 81% and 90%, respectively [9,10]. However, a considerable proportion (approximately 14%) of patients continue to exhibit a decline in renal function [11], with 16% to 28% progressing to end-stage renal disease (ESRD) within 5–10 years [12].
Previous research has associated long-term renal prognosis of MHT-related kidney injury with baseline creatinine, proteinuria during follow-up, and blood pressure control [12–14]. However, many of these studies lacked support from renal biopsy pathology results, leaving the relationship between renal pathological features and long-term renal prognosis unclear. Thus, it is imperative to conduct further studies to investigate the long-term renal prognosis and its influencing factors in patients with biopsy-proven MHT-associated renal TMA, with a relatively large sample size.
In the present study, we aimed to address this knowledge gap by analyzing a well-characterized cohort of MHT patients with renal TMA over the past 15 years (2008–2023). The objective was to explore the long-term renal prognosis of these patients and identify relevant prognostic factors to guide clinical practice and improve patient quality of life. We hypothesized that specific clinical and pathological features would be associated with progression to ESRD, and that early identification of these factors could inform more targeted treatment strategies.
Methods
Study design and population
This single-center observational cohort study was conducted at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China, from January 2008 to June 2023. Patients diagnosed with biopsy-proven MHT-associated renal TMA were enrolled. Inclusion criteria for the study were: (1) age ≥ 18 years; (2) diagnosed with MHT; (3) renal biopsy-proven with TMA; (4) without missing important baseline data. Exclusion criteria included (1) TMA caused by lupus nephritis, Shiga toxin-induced HUS, preeclampsia, infection, drug toxicity, and renal transplantation; (2) presence of malignant tumors; (3) baseline-dependent dialysis; (4) any follow-up period less than 1 month. The study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki. Approval for the study was granted by the ethics committee at the First Affiliated Hospital of Sun Yat-sen University (No. IEC [2022]710). All patients were provided with the requisite information and gave their consent in the form of their signature on the informed consent document.
MHT is characterized by extreme BP elevations (typically defined as systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥120 mmHg) and acute microvascular damage affecting various organs, in particular the retina, brain, and kidney. Hypertensive retinopathy grade III or IV is characterized by bilateral retinal flame-shaped hemorrhages and/or exudates or cotton wool spots with or without papilledema [2,13,15]. Renal TMA was mainly diagnosed by pathological characteristics, including the presence of arteriolar and/or glomerular intracapillary thrombosis and fibrinoid necrosis, often accompanied by the accumulation of fragmented erythrocytes within capillary lumens; glomerular capillary endothelial cells proliferation and swelling; the subendothelial space widening; marked intimal elastic fiber hyperplasia (i.e. onion-skinning), and severe luminal stenosis or even occlusion [16]. Acute heart failure (AHF) clinical manifestations include dyspnea, fatigue, pulmonary rales, peripheral edema, and distended jugular veins at physical examination [17]. Hypertension-related cardiac involvement include: marked left ventricular hypertrophy (LVH), abnormalities of repolarization on electrocardiogram (ECG), and increased troponin [13].
Data collection and renal histopathology
The demographic data, including age, sex, smoking and drinking habits, history of diabetes, and acute left heart failure at baseline, were recorded. The clinical data comprised measurements of body mass index (BMI) and blood pressure. The baseline laboratory data included hemoglobin, serum albumin, total cholesterol, estimated glomerular filtration rate (eGFR), and 24-h urinary protein. Anemia (hemoglobin <100 g/L, elevated lactate dehydrogenase (LDH) (LDH >240 U/L), thrombocytopenia (platelets < 150 × 109/L). The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EIP) [18]. The echocardiographic imaging data provided information regarding the thickness of interventricular septum, left ventricular posterior wall, and left ventricular ejection fraction. The following medication data were also extracted: agents containing RAAS inhibitors [including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and angiotensin receptor-neprilysin inhibitor (ARNI)], α-blockers, β-blockers, CCB and statins.
The core needle biopsies were processed in accordance with standard protocols and subsequently allocated for light and electron microscopy. Two pathologists and one nephropathologist conducted a comprehensive assessment of all patients, evaluating the following parameters: clinical presentation and laboratory tests, global glomerulosclerosis, segmental glomerulosclerosis, IF/TA, and vascular parameters (including vascular hyalinosis, fibrinoid necrosis, and onion skin lesions) under light microscopy. Endothelial changes were assessed under electron microscopy.
Primary study endpoint
The primary endpoint was ESRD development during the follow-up, which was defined as the requirement for chronic dialysis or kidney transplantation at the end of follow up.
Statistical analysis
Normally distributed continuous data are displayed as the mean ± standard deviation (SD), while non-normally distributed continuous data is expressed as the median (interquartile range). Group comparisons were conducted using either the t-test or the Mann–Whitney U test. The frequency or percentage is used to represent categorical data, and the chi-squared test was used for intergroup comparisons. The Kaplan-Meier method was conducted to plot survival curves and evaluate renal survival rates in patients. Univariate and multivariate Cox proportional hazards models were employed to identify factors associated with renal prognosis. All statistical tests employed were two-tailed, and the predetermined significance threshold was set at p < 0.05. All analyses were performed using the statistical software packages R 3.3.2 (https://www.r-project.org, The R Foundation) and Free Statistics Software version 1.8.
Results
Demographic and clinical characteristics
From 1 January 2008 to 30 June 2023, a total of 310 patients were diagnosed with MHT-associated renal TMA at the First Affiliated Hospital of Sun Yat-sen University. After excluding 96 patients who received dialysis at baseline (65 undergoing hemodialysis and 31 undergoing peritoneal dialysis), 42 patients lacking follow-up data, and two patients with a follow-up duration of less than 1 month, a total of 170 patients were included in the final analysis (Figure 1). As shown in Table 1, the median age was 35.0 years, with 146 male patients, accounting for 85.9% of the total. A family history of hypertension was present in 84 patients, accounting for 49.4% of the total. Additionally, 63 patients had concomitant kidney diseases, including 42 with IgA nephropathy, 6 with focal segmental glomerulosclerosis (FSGS), 5 with chronic interstitial nephritis, 4 with benign nephrosclerosis, 2 with diabetic nephropathy, and 4 with other causes.
Figure 1.
Flow chart of patient screening. Abbreviations: MH-TMA, MHT-associated renal thrombotic microangiopathy; HD, hemodialysis; PD, peritoneal dialysis.
Table 1.
Baseline characteristics of 170 patients with MHT associated renal TMA.
| Variable | Total (n = 170) | Non-ESRD (n = 118) | ESRD (n = 52) | p value |
|---|---|---|---|---|
| Clinical data | ||||
| Male [n (%)] | 146 (85.9) | 103 (87.3) | 43 (82.7) | 0.428 |
| Age (years) | 35.0 (30.0, 41.0) | 35.0 (30.0, 41.0) | 34.0 (28.0, 41.2) | 0.485 |
| BMI (kg/m2) | 24.5 (22.3, 27.6) | 24.4 (22.5, 27.4) | 25.9 (21.9, 28.0) | 0.683 |
| Smoking [n (%)] | 80 (47.1) | 60 (50.8) | 20 (38.5) | 0.136 |
| Alcohol [n (%)] | 54 (31.8) | 39 (33.1) | 15 (28.8) | 0.587 |
| Diabetes [n (%)] | 8 (4.7) | 4 (3.4) | 4 (7.7) | 0.250 |
| AHF at baseline [n (%)] | 42 (24.7) | 28 (23.7) | 14 (26.9) | 0.656 |
| Comorbid with other kidney diseases [n (%)] | 63 (37.1) | 41 (34.7) | 22 (42.3) | 0.347 |
| Hypertension family history [n (%)] | 84 (49.4) | 60 (50.8) | 24 (46.2) | 0.573 |
| Hypertensive retinopathy [n (%)] | 0.219 | |||
| I | 1 (0.6) | 1 (0.9) | 0 (0) | |
| II | 8 (5.0) | 8 (7) | 0 (0) | |
| III | 104 (65.0) | 74 (64.9) | 30 (65.2) | |
| IV | 47 (29.4) | 31 (27.2) | 16 (34.8) | |
| Laboratory and imaging data | ||||
| Hemoglobin (g/L) | 113.0 (97.0, 128.0) | 116.5 (97.5, 129.8) | 109.5 (92.8, 119.0) | 0.053 |
| Platelets (×109/L) | 264.5 (209.0, 331.8) | 277.5 (219.8, 341.8) | 233.0 (191.8,273.8) | 0.004 |
| Schistocytes [n (%)] | 12/52 (23.08) | 10/42 (23.81) | 2/10 (20.0) | 1.000 |
| Platelets < 150 × 109/L [n (%)] | 9 (5.3) | 4 (3.4) | 5 (9.6) | 0.134 |
| Albumin (g/L) | 37.9 (34.3, 40.8) | 38.0 (35.0, 41.0) | 37.9 (33.0, 40.2) | 0.216 |
| LDH (U/L) | 226.0 (172.0, 300.8) | 219.0 (170.0, 288.0) | 252.0 (199.5, 328.5) | 0.092 |
| Elevated LDH [n (%)] | 56/126 (44.44) | 37/92 (40.22) | 19/34 (55.88) | 0.157 |
| Total cholesterol (mmol/L) | 4.8 (4.0, 5.7) | 4.6 (4.0, 5.4) | 5.3 (4.2, 6.1) | 0.003 |
| LDL-c (mmol/L) | 3.0 (2.4, 3.6) | 2.9 (2.4, 3.5) | 3.3 (2.4, 3.7) | 0.192 |
| Serum potassium (mmol/L) | 3.9 (3.6, 4.3) | 3.9 (3.6, 4.3) | 4.0 (3.6, 4.4) | 0.48 |
| eGFR (mL/min/1.73 m2) | 14.7 (9.4, 23.7) | 17.8 (11.3, 25.8) | 10.4 (8.3, 13.9) | < 0.001 |
| Proteinuria (g/24 h) | 1.4 (0.8, 2.3) | 1.2 (0.7, 1.9) | 2.2 (1.5, 3.0) | < 0.001 |
| ITS (mm) | 14.0 (12.5, 16.0) | 14.0 (12.5, 16.0) | 13.0 (12.0, 15.0) | 0.093 |
| Hypertension-related cardiac involvement [n (%)] | 123 (72.4) | 87 (73.7) | 36 (69.2) | 0.546 |
| Pathological data | ||||
| Global glomerulosclerosis (%) | 28.4 (17.4, 50.0) | 25.9 (15.7, 41.0) | 46.9 (23.5, 67.0) | < 0.001 |
| Segmental glomerulosclerosis (%) | 2.3 (0.0, 5.6) | 2.0 (0.0, 5.0) | 3.0 (0.0, 7.0) | 0.263 |
| IF/TA [n (%)] | 0.026 | |||
| ≤50% | 84 (49.4) | 65 (55.1) | 19 (36.5) | |
| >50% | 86 (50.6) | 53 (44.9) | 33 (63.5) | |
| Arteriolar hyalinosis [n (%)] | 92 (54.1) | 68 (57.6) | 24 (46.2) | 0.167 |
| Fibrous necrosis [n (%)] | 48 (28.2) | 28 (23.7) | 20 (38.5) | 0.049 |
| Onion dermatoid [n (%)] | 107 (62.9) | 78 (66.1) | 29 (55.8) | 0.199 |
| Thrombosis in vascular lumens [n(%)] | 28 (16.5) | 16 (13.6) | 12 (23.1) | 0.177 |
| Red blood cell fragments in vessels [n (%)] | 12 (7.1) | 8 (6.8) | 4 (7.7) | 1.000 |
| Medication | ||||
| ACEI/ARB/ARNI [n (%)] | 125 (73.5) | 100 (84.7) | 25 (48.1) | < 0.001 |
| β-blocker [n (%)] | 144 (84.7) | 100 (84.7) | 44 (84.6) | 0.983 |
| α-blocker [n (%)] | 104 (61.2) | 67 (56.8) | 37 (71.2) | 0.076 |
| CCB [n (%)] | 162 (95.3) | 110 (93.2) | 52 (100) | 0.108 |
| Statins [n (%)] | 88 (51.8) | 65 (55.1) | 23 (44.2) | 0.192 |
| Plasma/eculizumab therapy | 0 | 0 | 0 | -* |
Data are median (25th, 75th percentiles), mean ± SD, or n (%). Where not specified, the available n is the same as the total number of cases in the top row.
None of the patients received eculizumab/plasma therapy.
Abbreviations: AHF, acute heart failure; LDH, lactate dehydrogenase; LDL-c, low density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; ITS, interventricular septum thickness; IF/TA, interstitial fibrosis/tubular atrophy; CCB, Calcium channel blockers.
Renal biopsy and histopathological characteristics
All patients with MHT-associated renal TMA underwent percutaneous renal biopsy. The various histopathologic features of the MHT patients with renal TMA under light microscopy and electron microscopy are shown in Supplemental Figure 1. Light microscopic analysis revealed typical series of pathological changes in TMA, including diffuse capillary loop wrinkling (Supplementary Figure 1A), marked intimal thickening of renal arterioles (Supplementary Figure 1B), fibrinoid necrosis of arteriolar walls (Supplementary Figure 1C), and vessel wall thickening with ‘onion-skinning’ appearance and luminal occlusion (Supplementary Figure 1D). In addition, electron microscopy analysis revealed swelling of endothelial cells, prominent subendothelial widening with flocculent deposits underneath and new base membrane formation, leading to narrowing of capillary lumen (Supplementary Figure 1E-1F). The renal biopsy results revealed that global glomerulosclerosis was 28.4% (17.4, 50), hyaline arteriolar changes in 92 (54.1%), onion skin changes in 107 (62.9%), fibrinoid necrosis in 48 (28.2%), intravascular thrombosis in 28 (16.5%), intravascular red blood cell fragments in 12 (7.1%) and tubular atrophy/interstitial fibrosis >50% in 86 (50.6%) (Table 1).
Baseline data and survival prognosis
A total of 104 patients (65%) exhibited grade III hypertensive retinopathy, 47 patients (29.4%) displayed grade IV hypertensive retinopathy, and 123 patients (72.4%) exhibited cardiac involvement. The baseline maximum serum creatinine was 390.5 (273.0, 582.2) µmol/L, and the median eGFR was 14.7 (9.4, 23.7) mL/min/1.73 m2. The 24-h urinary protein concentration was 1.4 (0.8, 2.3) g/24 h, and the interventricular septum thickness was 14 (12, 16) mm (Table 1). Patients who progressed to ESRD exhibited higher proteinuria (2.2 vs. 1.2 g/24 h, p < 0.001), higher baseline cholesterol (5.3 vs. 4.6 mmol/L, p = 0.003), and a greater prevalence of global glomerulosclerosis (46.9% vs 25.9%, p < 0.001). They exhibited lower eGFR (10.4 vs 17.8 mL/min/1.73 m2, p < 0.001), platelet count (233 vs 277.5 × 109/L, p = 0.004), and received less likely to receive RAAS inhibitor treatment (ACEI/ARB/ARNI) (48.1% vs 84.7%, p < 0.001). None of the patients received eculizumab/plasma therapy (Table 1).
The median follow-up period was 23.5 (9.9, 47.0) months, during which 52 patients (30.6%) progressed to the point of requiring renal replacement therapy, including 28 who underwent hemodialysis, 21 who underwent peritoneal dialysis, and 3 who underwent kidney transplantation. The cumulative renal survival rates for all patients at the 1st, 3rd, 5th, 7th, and 9th years of follow-up were 91.8%, 73.1%, 53.3%, 41.4%, and 31.0%, respectively (Figure 2).
Figure 2.
Kaplan–Meier curves of renal survival rates in all patients.
Factors influencing the long-term prognosis of patients with MHT-associated renal TMA
The univariate Cox regression analysis demonstrates that total cholesterol, 24-h urinary protein, baseline eGFR, proportion of global glomerulosclerosis, tubulointerstitial fibrosis, and the use of RAAS inhibitors (ACEI/ARB/ARNI) were associated with the long-term prognosis of patients with MHT-associated renal TMA (p < 0.05). Considering that 24-h urinary protein is collinear with eGFR, it was not included in the multivariate model. The multivariate Cox regression analysis, which incorporated the remaining five indicators, indicated that baseline cholesterol [HR = 1.48 (95% CI: 1.24–1.77), p < 0.001] and the proportion of global glomerulosclerosis [HR = 1.24 (95% CI: 1.15–1.33), p < 0.001] were independent risk factors for progression to ESRD. The use of agents with RAAS inhibitors (ACEI/ARB/ARNI) [HR = 0.45 (95% CI: 0.25–0.82), p = 0.009] was identified as a protective factor (Table 2).
Table 2.
Cox regression analyses of factors associated with renal survival.
| Univariate analysis |
Multivariate analysis |
|||||
|---|---|---|---|---|---|---|
| Variables | HR | 95% CI | p value | Adjusted HR | 95% CI | p value |
| Age (per years) | 0.97 | 0.94–1.01 | 0.127 | |||
| Sex (male vs. female) | 1.57 | 0.76–3.25 | 0.228 | |||
| Comorbid with other kidney diseases (yes vs. no) | 2.03 | 1.14–3.6 | 0.016 | 1.41 | 0.71–2.82 | 0.331 |
| Statins (yes vs. no) | 1.04 | 0.6–1.82 | 0.879 | |||
| Platelets (per 100 × 109/L) | 0.77 | 0.55–1.08 | 0.13 | |||
| Total cholesterol (per 1 mmol/L) | 1.35 | 1.13–1.61 | 0.001 | 1.48 | 1.24–1.77 | <0.001 |
| Proteinuria (per 1 g/24 h) | 1.43 | 1.26–1.62 | < 0.001 | |||
| eGFR (per 10 mL/min/1.73 m2) | 0.43 | 0.28–0.66 | <0.001 | 0.63 | 0.40–1.00 | 0.05 |
| Global glomerulosclerosis (per 5% change) | 1.26 | 1.18–1.33 | <0.001 | 1.24 | 1.15–1.33 | <0.001 |
| IF/TA (>50% vs. ≤50%) | 2.89 | 1.63–5.11 | <0.001 | 1.30 | 0.66–2.54 | 0.445 |
| Fibrinoid necrosis (yes vs. no) | 0.96 | 0.55–1.69 | 0.897 | |||
| ACEI/ARB/ARNI (yes vs. no) | 0.36 | 0.21–0.63 | <0.001 | 0.45 | 0.25–0.82 | 0.009 |
Abbreviations: HR, hazard ratio; CI, confidence interval; eGFR, estimated glomerular filtration rate; TAIF, tubular interstitial fibrosis.
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor.
Survival analysis
Kaplan-Meier survival curves indicated that patients who received treatment with RAAS inhibitors exhibited a markedly elevated cumulative renal survival rate in comparison to those who were not treated with RAAS inhibitors (p < 0.001) (Figure 3).
Figure 3.
Kaplan–Meier curves of renal survival in patients with or without ACEI/ARB/ARNI treatment.
Discussion
The incidence of MHT remains a significant health concern despite lifestyle interventions. Reported incidences of renal TMA in MHT vary widely, from 5% [19–21] to 44% [22], likely due to the varying TMA definitions. In this study, we defined MHT-associated renal TMA by the presence of TMA lesions on renal biopsy in patients with a history of MHT. However, in clinical practice, most patients who present with MHT and renal failure do not undergo renal biopsy. Therefore, the diagnosis of TMA is dependent on laboratory data (such as a low platelet count accompanied by elevated lactate dehydrogenase or fragmented red blood cells) rather than histopathological changes. This may result in a significant underestimation of the incidence of MHT-associated renal TMA. This discrepancy can be attributed to the fact that renal TMA in patients with MHT may not exhibit the hematological signs of systemic TMA [23]. In a single study, only 24% of patients who had undergone renal biopsy and been confirmed as having hypertension-associated renal TMA exhibited thrombocytopenia (platelet count <150 × 109/L) [24]. In the study conducted by Zhang et al. a decrease in platelet count was observed in only 16% of patients [25]. In our study, only 9 patients (5.3%) experienced a decrease in platelet count. The relatively low incidence of thrombocytopenia in our cohort is primarily due to the fact that severe thrombocytopenia is a relative contraindication for renal biopsy. Since our study focuses on biopsy-confirmed renal TMA, patients with significant platelet reduction were not included at the baseline stage.
Despite improvements in prognosis with new antihypertensive drugs, a significant proportion of MHT-associated renal TMA patients still progress to ESRD. Our study observed that 30.6% of patients progressed to ESRD, and a cumulative renal survival rate of 31.0% at 9 years, higher than previously reported rates of 16% to 28% [12]. While the baseline eGFR is typically considered an independent risk factor for progression to ESRD [19,26], our study did not confirm this association. These differences may be attributed to the poorer baseline renal function in our patients population. The median eGFR in this cohort was 14.7 mL/min/1.73m2, indicating advanced renal failure, which to some extent determines the long-term renal prognosis of the patients. Additionally, the limited sample size may have contributed to this finding, the associations of eGFR with ESRD might reach statistical significance with a larger sample size.
Long-term renal prognosis in MHT is closely associated with blood pressure control during follow-up [11,13,19,27]. Our study revealed that initiating treatment with RAAS inhibitors (ACEIs/ARBs/ARNIs) at baseline decreased the risk of progression to ESRD. This protective effect of ACEIs/ARBs/ARNIs was consistent across different comorbidity subgroups, reflecting the central role of RAAS inhibitors in the pathogenesis of MHT-associated renal TMA [28–30]. Additionally, the pro-inflammatory effect of angiotensin II serves to exacerbate renal fibrosis [31], highlighting the importance of RAAS inhibition. ARNIs represent a novel class of pharmaceutical agents with a dual-channel, multitarget mechanism of action that includes vasodilation, enhanced sodium excretion, and the inhibition of both the RAAS and the sympathetic nervous system [32]. These actions are instrumental in protecting target organs, reduce the incidence of cardiovascular events, and improve the prognosis of patients with comorbid heart and kidney diseases [33–35]. While we included patients treated with ARNIs, the relatively small number limited directly efficacy comparison with other ACEIs/ARBs in patients with MHT-induced renal TMA-related kidney injury, warranting further research.
Additionally, the proteinuria level during the follow-up period has been correlated with the renal prognosis of patients with MHT [12]. The extent of change in 24-h proteinuria throughout follow-up is also a significant factor linked to renal prognosis in MHT. Although we did not follow up our patients with 24-h urinary protein quantification, the administration of medications containing RAAS inhibitors components (ACEI/ARB/ARNI) largely reduced proteinuria in our patients, which may also be associated with a diminished risk of ESRD progression [36,37].
The higher reported prevalence of cardiac involvement in our study might reflect differences in case ascertainment and outcome definitions. First, our cohort comprises exclusively renal biopsy–proven malignant hypertension–related TMA, whereas prior series often included broader or differently defined populations [38]. Second, we adopted a composite cardiac endpoint encompassing marked LVH, ECG repolarization abnormalities, and/or elevated troponin, rather than using LVEF ≤50% to define severe cardiac involvement [39]. Third, consistent with the prior reports, our patients exhibited normal or only mild thrombocytopenia at baseline, this profile may be associated with a more indolent yet aggressive disease course and delayed diagnosis, resulting in greater cumulative target-organ (cardiac and renal) damage before enrollment [23,39].
Our study identified elevated baseline total cholesterol level as an independent risk factor for ESRD in patients with MHT-associated renal TMA, a relationship previously unexplored. Our findings suggested that higher baseline cholesterol was an independent risk factor for ESRD in patients with mHTN-associated renal TMA [40]. This association may be explained by the following potential mechanisms. On the one hand, elevated serum cholesterol levels are associated with compromised vascular endothelial function, promoting arterial intimal thickening and luminal narrowing. In the context of mHTN, this vascular vulnerability may predispose patients to arteriolar fibrinoid necrosis and exacerbation of renal TMA, accelerating kidney injury progression [3,15]. On the other hand, recent studies have identified cholesterol oxidation products as biomarkers of oxidative stress [41]. Increased serum cholesterol may reflect heightened oxidative stress, which can impair mitochondrial function in endothelial cells and further contribute to microvascular damage in renal TMA. Finally, elevated cholesterol levels may reflect the cumulative burden of proteinuria, with higher cholesterol levels indicating more severe proteinuria, which exacerbates glomerulosclerosis and tubulointerstitial fibrosis [12].
Our study also identified the proportion of global glomerulosclerosis as an independent risk factor for the progression to ESRD, aligning with the findings previous findings [27]. However, unlike earlier studies, we did not find an association between tubulointerstitial fibrosis and prognosis. There are two primary reasons for this lack of association: firstly, the degree of TA/IF in our study population was higher, with 94.7% of patients exhibiting more than 25% fibrosis. Secondly, TA/IF ≥50% was significantly associated with poor prognosis in the univariate model, but did not reach significance in the multivariate analysis. This may be attributed to the relatively small sample size, and these associations might achieve statistical significance with a larger sample size.
Additionally, although our study did not find that sex affects prognosis, the proportion of males with malignant hypertension in our research was as high as 85.9%, while the incidence of malignant hypertension in females was relatively low, mainly for the following reasons: firstly, estrogen can improve vascular endothelial function. Secondly, estrogen may counteract the hypertensive effects of the RAS by increasing NO production. Additionally, differences in lifestyle factors contribute, as women generally have lower smoking rates.
Our study has a retrospective design, which means we cannot exclude the influence of confounding, unidentified factors on the long-term outcomes of our cohort. Secondly, since our study is single-center and includes only Asian patients, our results may not be applicable to patients with MHT-related renal TMA from other ethnic backgrounds. Thirdly, due to the extended time span of the patients included in this study, some laboratory data, such as LDH, haptoglobin, coombs test, ADAMTS-13 cleaving protease, and schistocyte are incomplete. Additionally, genetic testing was not regularly performed, which prevents us from completely ruling out the potential for atypical hemolytic uremic syndrome (aHUS), constituting a limitation of this study. However, our study benefits from consistent patient follow-up and parameter tracking throughout the disease course. To the best of our knowledge, our study represented the largest sample size of malignant hypertension-associated renal TMA confirmed by renal biopsy. Additionally, this cohort had the longest follow-up duration to date.
In conclusion, the renal survival rates for patients with MHT-associated renal TMA at 1 and 5 years were 91.8% and 53.3%, respectively. Elevated baseline total cholesterol and a higher proportion of glomerulosclerosis are independent risk factors for progression to ESRD, whereas the use of RAAS inhibitor drugs (ACEI/ARB/ARNI) at baseline is associated with a reduced risk of disease progression. These findings underscore the importance of early and effective management of blood pressure and cholesterol levels in improving renal outcomes for patients with MHT-associated renal TMA.
Supplementary Material
Acknowledgments
We gratefully thank the pathologists affiliated with the First Affiliated Hospital of Sun Yat-sen University for the instruction of kidney biopsy results. Wei Chen, and Qinghua Liu participated in the development of research ideas and the design of the study, and revised the manuscript; Jianbo Li and Youqi Li performed the analysis and interpretation of data, and drafted the manuscript. Zhong Zhong, Zefang Dai, Naya Huang, Xuwen Shen, Shicong Yang and Jianwen Yu collected and analyzed the clinical data, and helped to draft the manuscript. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work.
Funding Statement
This work was supported by grants from the National Natural Science Foundation of China (Nos.82470811, 82170737, 82370707); Basic and Applied Basic Research Foundation of Guangdong Province (No.2025A1515010689, 2023A1515012477, 2022A1515012532); Guangzhou Municipal Programme of Science and Technology (No.2024B03J1337); Guangzhou science and technology planning project (No.2023A04J2183);Guangzhou Science and Technology Project (No.202206080010) and Key Laboratory of National Health Commission, Key Laboratory of Nephrology, Guangdong Province, Guangzhou, China.
Declarations
The authors declare that all data supporting the findings of this study are available within the paper. The results presented in this paper have not been published previously in whole or part, except in abstract format.
Disclosure statement
No potential conflict of interest was reported by the authors.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to their containing information that could compromise the privacy of research participants.
References
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Associated Data
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Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to their containing information that could compromise the privacy of research participants.