Abstract
Hypertension (HTN) is increasing among young people. Notably, younger individuals are more susceptible to malignant hypertension (MHT). The occurrence and renal prognosis in MHT patients with thrombotic microangiopathy (TMA) across different age groups remains undetermined. This prospective cohort study evaluated 292 MHT patients with TMA in China from 2008 to 2023. We examined the clinical and pathological characteristics according to median age categories (≤35 years and >35 years). The associations of age with renal outcomes were examined in Cox regression models. The primary outcome was long-term renal replacement therapy (RRT). The secondary outcome was an increase of at least 15% in estimated glomerular filtration rate (eGFR). Among 292 patients, individuals younger than 35 years had significantly higher proteinuria, proportion of patients with immunoglobulin A nephropathy (IgAN), and global sclerosis ratio compared to those older than 35 years. Age ≤35 years was associated with a worse outcome of long-term RRT outcome (Hazard ratios [HRs]: 1.60 [95% confidence interval [CI]: 1.06–2.40]) and better improvement of ≥15% increase in eGFR (HRs: 1.93 [95% CI: 1.20–3.11]). Serum creatinine >565 μmol/L and proteinuria >1.41 g/d were associated with a higher risk of long-term RRT, while serum albumin >35 g/L was correlated with a lower risk of it. Tubular atrophy/interstitial fibrosis >50% was an unfavorable factor for ≥15% increase in eGFR. In conclusion, young age contributed to a better renal improvement of ≥15% increase in eGFR, especially within 6 years. However, a worse outcome of long-term RRT also occurred in the younger MHT patients with TMA.
Keywords: Malignant hypertension, thrombotic microangiopathy, age, renal pathology, nephrosclerosis
Introduction
Malignant hypertension (MHT) is a type of hypertensive emergency characterized by acute elevation of blood pressure (BP) and is usually associated with retinopathy and renal damage [1]. The annual number of hospitalizations with a primary discharge diagnosis of MHT was stable before 2007, but increased significantly thereafter [2]. Furthermore, González et al. showed that renal damage in MHT at presentation was common, affecting 63% of patients [3]. Thrombotic microangiopathy (TMA) is an important complication of MHT. The pathological events of TMA may result from direct damage to the vascular endothelium caused by extreme increases in BP, especially in the kidney [4]. It has been reported that TMA is associated with a significantly worse renal outcome and nephrosclerosis [5].
The median age of patients with MHT is approximately 40 years [6]. A retrospective observational cohort study in Japan found that the median age of MHT was 47 years, and the patients with MHT were markedly younger than other acute hypertensive events [7]. In addition, Bureau et al. showed that among 114 young patients under 40 years of age with MHT, 52% of cases were diagnosed with isolated severe nephrosclerosis and 20% with TMA. Moreover, the creatinine level on admission and the presence of fibrosis >30% on biopsy were associated with an increased risk of dialysis at 6 months in young patients [6]. However, the incidence and renal prognosis in patients with MHT accompanied by TMA across different age groups have not been adequately reported.
In this study, we analyzed a well-characterized cohort of MHT patients with TMA over the past 15 years (2008–2023). We investigated the association between age and nephrosclerosis in MHT, including clinical characteristics, histopathological features, and risk of renal progression and improvement.
Methods
Study design and population
This observational, single-center, cohort study consecutively enrolled mHTN patients with renal biopsy-proven TMA diagnosed at the First Affiliated Hospital of Sun Yat-sen University from January 2008 to June 2023. Without exclusion, a total of 292 patients aged from 16 to 76 were included in this study and classified into two groups according to age at diagnosis: age ≤35 years and age >35 years. The age cutoff of 35 years was selected based on the median age of the entire cohort (35 years, IQR 30–41), which allowed for balanced group sizes and minimized arbitrary categorization. The eligibility criteria for the cohort study were: (1) patients meeting the diagnostic criteria for mHTN; (2) renal biopsy-proven TMA; (3) all patients were screened for secondary causes of TMA, such as autoimmune diseases, infections, pregnancy, and medications. All patients underwent biopsy within two weeks of admission. In addition, the exclusion criteria for atypical hemolytic uremic syndrome (aHUS) patients with hypertension (HTN) in our cohort include: (1) patients with benign HTN accompanied by aHUS were excluded; (2) patients with secondary TMA caused by other underlying diseases, including infectious diseases, malignancies, pregnancy-related disorders, rheumatic autoimmune diseases, kidney transplantation, and adverse drug reactions, were also excluded. The study was conducted in accordance with the Declaration of Helsinki. Ethics committee approval was provided at the First Affiliated Hospital of Sun Yat-sen University. All patients provided written informed consent.
The diagnosis of MHT was based on the detection of a sharp and sudden increase in BP (particularly diastolic [DBP] BP > 130 mmHg), often accompanied by hypertensive retinopathy grade 3 or 4 (bilateral retinal flame-shaped hemorrhages and/or exudates or cotton wool spots with or without papilledema) and with progressive target organ dysfunction [8,9]. TMA was mainly diagnosed by pathological characteristics, including arteriolar and/or glomerular intracapillary thrombosis, often with accumulation of fragmented erythrocytes within capillary lumens, and focally ischemic or congested glomerular tufts [10]. The patients with TMA caused by hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, pregnancy, tumor, drug toxicity, and renal transplantation were excluded from the study.
Data collection and renal histopathology
The baseline was established at the time of MHT diagnosis. Data of the following parameters were collected: demographic characteristics including gender, smoking, drinking, and body mass index (BMI). Clinical and laboratory data included BP at admission and discharge, hemoglobin, platelet count, serum albumin, total cholesterol, total triglyceride, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), blood urea nitrogen, serum creatinine, estimated glomerular filtration rate (eGFR), C3 and 24-h proteinuria. Medication data were also extracted: angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), sacubitril/valsartan, α blockers, β blockers, sulodexide soft capsule, statin, and beraprost sodium. The eGFR was calculated using the chronic kidney disease (CKD) Epidemiology Collaboration equation [11]. Mean arterial pressure (MAP) was defined as one-third of systolic BP (SBP) plus two-thirds of DBP. All the data were collected and restructured from medical records and computer files at the First Affiliated Hospital of Sun Yat-sen University.
The core needle biopsies underwent standard processing techniques and were divided for light and electron microscopy. Two pathologists and one nephropathologist evaluated all cases for the following parameters. Light microscopic parameters included diagnosis of immunoglobulin A nephropathy (IgAN), global sclerosis, and segmental sclerosis. Tubulointerstitial parameters included tubular atrophy/interstitial fibrosis (IFTA) and tubular epithelial cell exfoliation. Moreover, vascular parameters, including vascular hyalinosis, fibrinoid necrosis, onion skin lesions, intravascular thrombosis, and intravascular red blood cell (RBC) fragments were collected. Electron microscopy examination included the endothelial change.
Outcomes
Outcomes included kidney progression and kidney improvement. The primary outcome of the analysis was long-term renal replacement therapy (RRT), defined as a need for chronic dialysis or kidney transplantation at the end of follow-up. The secondary endpoint was renal function improvement defined by an increase of at least 15% in eGFR at the end of follow-up compared with eGFR at the diagnosis of MHT. Between January 2008 and June 2023, we defined 9 years as the end of the follow-up for renal outcomes, due to the long follow-up of some patients. During 2008 and 2023, 45 patients (15% of the total cohort) were lost to follow-up. The reasons for drop-out were categorized as follows: relocation or inability to contact, voluntary withdrawal and noncompliance with follow-up visits.
Statistical analysis
Quantitative data are shown as median with interquartile range (IQR). Qualitative variables are presented as numbers and percentages. Categorical variables were compared using the Chi-square test, whereas Student’s t test or Mann–Whitney U test was applied for continuous variables. The cumulative survival and recovery probability of renal outcomes according to age groups was calculated using Kaplan–Meier (K–M) curves, and a log–rank test was performed to analyze differences. Hazard ratio (HR) and respective 95% confidence intervals (CIs) for long-term RRT and a ≥ 15% increase in eGFR in the ≤35 years group compared with the >35 years group were calculated using multivariable Cox proportional hazards regression analyses. We investigated the association between age and long-term RRT or a ≥ 15% increase in eGFR, with and without adjustment for the selected confounders. The model included some variables with p < 0.2 in the univariable Cox proportional hazards regression analyses. All statistical tests were two-tailed and the significance level was set at p < 0.05. K–M curves were carried out with R version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria). Other statistical analyses were performed using SPSS version 25.0 (IBM Co., Armonk, NY).
Results
Baseline characteristics of the study population
Among 292 MHT patients with TMA, the median age at diagnosis was 35 years old. Thus, 152 (52.05%) patients in the ≤35 years group and 140 (47.95%) in the >35 years group were analyzed in this study, and the study flow chart is shown in Figure S1. The baseline characteristics of the patients are presented in Table 1. The majority of patients in the overall study population were male (89%). Patients in the ≤35 years group had a lower prevalence of alcohol consumption and lower SBP at discharge (median 134 mm Hg vs. 138 mm Hg, p = 0.009) compared to the older age group. Median admission SBP and DBP were 159 mmHg (IQR 138–181) and 110 mmHg (IQR 87–114), respectively, with no differences between groups. In medical treatment, the younger age group had a lower proportion of ARB and beraprost sodium treatment. However, there is no significant difference in the use of ACEI and Sacubitril/valsartan between younger and older patients. On the contrary, patients aged ≤35 years had higher proteinuria (median 1.58 g/d vs. 1.32 g/d, p = 0.048) compared to the older patients.
Table 1.
Baseline characteristics in different age groups.
| Characteristics | Total (n = 292) | Age |
p Value | |
|---|---|---|---|---|
| ≤35 (n = 152) | >35 (n = 140) | |||
| Demographics | ||||
| Sex, male, n (%) | 260 (89.0) | 135 (88.8) | 125 (89.3) | 0.898 |
| Smoking, n (%) | 129 (44.2) | 62 (40.8) | 67 (47.9) | 0.224 |
| Drinking, n (%) | 84 (28.8) | 34 (22.4) | 50 (35.7) | 0.012 |
| BMI, kg/m2, median (IQR) | 24.1 (22.1, 27.0) | 23.7 (21.7, 27.1) | 24.4 (22.5, 26.7) | 0.429 |
| BP, mmHg, median (IQR) | ||||
| SBP on admission | 159 (138, 181) | 156 (141, 175) | 160 (136, 189) | 0.227 |
| DBP on admission | 100 (87, 114) | 101 (88, 114) | 98 (86, 114) | 0.913 |
| MAP on admission | 117 (105, 136) | 117 (106, 133) | 118 (103, 140) | 0.638 |
| SBP on discharge | 136 (127, 144) | 134 (127, 140) | 138 (128, 147) | 0.009 |
| DBP on discharge | 82 (77, 90) | 82 (77, 89) | 84 (77, 90) | 0.526 |
| MAP on discharge | 101 (93, 107) | 100 (92, 106) | 101 (94, 109) | 0.157 |
| Comorbidities, median (IQR) | ||||
| Diabetes, n (%) | 16 (5.5) | 6 (3.9) | 10 (7.1) | 0.231 |
| History of primary hypertension, n (%) | 218 (74.7) | 105 (69.1) | 113 (80.7) | 0.022 |
| Family history of hypertension, n (%) | 120 (41.1) | 58 (38.2) | 62 (44.3) | 0.288 |
| Acute left heart failure, n (%) | 98 (33.6) | 49 (32.3) | 49 (35.0) | 0.617 |
| Laboratory variables, median (IQR) | ||||
| Hemoglobin, g/L | 106 (89, 123) | 104 (89, 123) | 106 (89, 123) | 0.858 |
| Platelet count, × 10⁹/L | 252 (201, 320) | 253 (206, 316) | 250 (188, 327) | 0.613 |
| Serum albumin, g/L | 37.3 (33.3, 40.5) | 36.9 (33.2, 40.1) | 37.8 (33.3, 41.0) | 0.085 |
| Total cholesterol, mmol/L | 4.7 (4.0, 5.7) | 4.6 (4.1, 5.9) | 4.8 (4.0, 5.6) | 0.766 |
| Triglyceride, mmol/L | 1.77 (1.30, 2.34) | 1.83 (1.36, 2.43) | 1.65 (1.27, 2.15) | 0.058 |
| HDL-c, mmol/L | 0.99 (0.83, 1.19) | 0.99 (0.83, 1.19) | 1.00 (0.85,1.19) | 0.749 |
| LDL-c, mmol/L | 2.98 (2.40, 3.62) | 2.92 (2.37, 3.60) | 3.04 (2.40, 3.63) | 0.479 |
| Urea nitrogen, mmol/L | 15.0 (10.8, 19.9) | 15.0 (10.8, 19.5) | 15.3 (11.1, 20.2) | 0.649 |
| Scr, μmol/L | 566 (325, 847) | 585 (341, 880) | 526 (300, 824) | 0.203 |
| Urea acid, μmol/L | 474 (387, 567) | 486 (393, 567) | 468 (374, 566) | 0.644 |
| eGFR, ml/min per 1.73 m2 | 10.3 (6.2, 19.8) | 10.3 (6.2, 19.2) | 10.4 (6.2, 20.9) | 0.762 |
| C3, g/L | 0.97 (0.85, 1.15) | 0.97 (0.83, 1.19) | 0.98 (0.85, 1.12) | 0.927 |
| 24-h proteinuria, g/d | 1.41 (0.83, 2.56) | 1.58 (0.87, 2.78) | 1.32 (0.70, 2.09) | 0.048 |
| Medications, n (%) | ||||
| ACEI | 61 (20.9) | 32 (21.1) | 29 (20.7) | 0.943 |
| ARB | 147 (50.3) | 68 (44.7) | 79 (56.4) | 0.046 |
| Sacubitril/valsartan | 66 (22.6) | 40 (26.3) | 26 (18.6) | 0.114 |
| α blockers | 181 (62.0) | 90 (59.2) | 91 (65.0) | 0.309 |
| β blockers | 251 (86.0) | 131 (86.2) | 120 (85.7) | 0.908 |
| Sulodexide soft capsule | 149 (51.0) | 72 (47.4) | 77 (55.0) | 0.192 |
| Statin | 133 (45.5) | 73 (48.0) | 60 (42.9) | 0.376 |
| Beraprost sodium | 75 (25.8) | 28 (18.5) | 47 (33.6) | 0.003 |
BMI: body mass index; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure; HDL-c: high density lipoprotein cholesterol; LDL-c: low density lipoprotein cholesterol; Scr: serum creatinine; eGFR: estimated glomerular filtration rate; C3: complement 3; ACEI: angiotensin converting enzyme inhibitors; ARB: angiotensin II receptor blocker.
Renal biopsy and histopathological characteristics
Representative histopathological findings of renal biopsies from MHT patients with TMA are shown in Figure 1. Under light microscopy, glomerular capillary wrinkling, luminal narrowing of arterioles and fibrinoid necrosis of the arteriolar wall can be seen in the glomerular area (Figure 1(A)). In addition, arteriolar endothelial cell swelling and proliferation, medial thickening of arteries, and onion-skin lesions were found (Figure 1(B,C)). Electronic micrograph showed diffuse winkling of the capillary loop (Figure 1(D)).
Figure 1.
Representative renal biopsy findings of MHT patients with TMA. (A) Light microscopy image showed glomerular capillary loop wrinkling, luminal occlusion of arterioles and fibrinoid necrosis of the arteriolar wall (red arrowheads) (PASM), 400X. (B) Arteriolar endothelial cell swelling and proliferation with onion skin lesions and luminal narrowing (PAS), 400X. (C) Arterial atherosclerosis with medial thickening and intimal fibrosis. Wall thickening and luminal narrowing of arteries and arterioles. Onion-skin lesions of interstitial arteries (red arrowhead) (PAS), 400X. (D) Electronic micrograph showed diffuse winkling of the capillary loop, 5000X. PASM: periodic acid–silver methenamine; PAS: periodic acid-Schiff.
Renal histopathological characteristics are shown in Table 2. In our population, 29.5% of the patients were diagnosed with IgA nephropathy, and it is about two times higher in younger patients compared to those in the >35 years group (39.5% vs. 18.6%, p = < 0.001). In addition, a total of 55% of the patients in the ≤35 years group had global sclerosis ratio >33%, while only 45% of patients in the >35 years group. Moreover, the majority of patients (76.7%) had tubular atrophy and IFTA affecting >50% of the renal biopsy surface area. Either arteriolar hyalinosis or onion-skin lesions were common (52.4 and 59.9%, respectively). However, fibrinoid necrosis and intravascular thrombosis were occasionally observed, occurring in 97 (33.2%) and 52 (17.8%) patients, respectively. There was no significant difference in these tubular and vascular pathological lesions between the two age groups.
Table 2.
Histopathological findings of patients.
| Characteristics | Total (n = 292) | Age |
p Value | |
|---|---|---|---|---|
| ≤35 (n = 152) | >35 (n = 140) | |||
| With IgAN, n (%) | 86 (29.5) | 60 (39.5) | 26 (18.6) | <0.001 |
| Global lesions, n (%) | ||||
| Global sclerosis, number, median (IQR) | 8 (4, 13) | 8 (4, 15) | 7 (4, 11) | 0.133 |
| Global sclerosis ratio, n (%) | 0.048 | |||
| ≤33 | 143 (49.0) | 66 (43.4) | 86 (56.6) | |
| >33 | 149 (51.0) | 77 (55.0) | 63 (45.0) | |
| Segmental sclerosis, number, median (IQR) | 0.5 (0.0, 2.0) | 0.5 (0.0, 2.0) | 0.5 (0.0, 1.0) | 0.629 |
| Segmental sclerosis, n (%) | 0.01 (0.00, 6.25) | 0.03 (0.00, 7.11) | 0.01 (0.00, 6.25) | 0.793 |
| Tubular lesions, n (%) | ||||
| IFTA | 0.457 | |||
| ≤50 | 67 (23.3) | 32 (21.5) | 35 (25.2) | |
| >50 | 221 (76.7) | 117 (78.5) | 104 (74.8) | |
| Tubular epithelial cell exfoliation | 99 (33.9) | 45 (29.6) | 54 (38.6) | 0.106 |
| Vascular lesions, n (%) | ||||
| Arteriolar hyalinosis | 153 (52.4) | 74 (48.7) | 79 (56.4) | 0.186 |
| Fibrinoid necrosis | 97 (33.2) | 51 (33.6) | 46 (32.9) | 0.900 |
| Onion skin lesions | 175 (59.9) | 86 (56.6) | 89 (63.6) | 0.223 |
| Intravascular thrombosis | 52 (17.8) | 27 (17.8) | 25 (17.9) | 0.983 |
| Intravascular RBC fragments | 29 (9.9) | 18 (11.8) | 11 (13.9) | 0.255 |
IgAN: IgA nephropathy; RBC: red blood cell; IFTA: tubular atrophy/interstitial fibrosis.
Risk of age on primary outcome of long-term renal replacement therapy
During the follow-up from 2008 to 2023, 115 (46.9%) patients progressed to long-term RRT. Patients younger than 35 years had worse outcomes, with 58.3% (67/115) progressing to long-term RRT at a median time of 11.3 months (IQR 1.1–31.9 months) after diagnosis (Figure 2). With regard to risk factors for long-term RRT, age, hemoglobin, serum albumin, serum creatinine, proteinuria, renin-angiotensin system blockers treatment, and IgAN were adjusted for the Cox proportional regression model in multivariate analysis. The model also confirmed a poor outcome associated with age ≤35 years compared to age >35 years in both unadjusted (HR 1.57, 95% CI 1.08–2.30, p = 0.019) and adjusted analyses (adjusted HR 1.60, 95% CI 1.06–2.40, p = 0.024). Additionally, serum creatinine >565 μmol/L (adjusted HR 5.08; 95% CI 3.12–8.26; p < 0.001), and proteinuria >1.41 g/d (adjusted HR 2.33; 95% CI 1.48–3.68; p < 0.001) were associated with a higher risk of long-term RRT, whereas serum albumin >35 g/L was associated with a 43% lower risk of the primary outcome (Table 3).
Figure 2.
Kaplan–Meier survival curves of time to long term renal replacement therapy based on age.
Table 3.
Cox regression analysis for long-term renal replacement therapy according to age.
| Variables | Long-term renal replacement therapy |
|||||
|---|---|---|---|---|---|---|
| Univariate analysis |
Multivariate analysis |
|||||
| HR | 95% CI | p Value | adjusted HR | 95% CI | p Value | |
| Age (per, years) | ||||||
| >35 | 1 (ref) | 1 (ref) | ||||
| ≤35 | 1.57 | 1.08–2.30 | 0.019 | 1.60 | 1.06–2.40 | 0.024 |
| Sex, male | 0.83 | 0.48-1.44 | 0.514 | -- | -- | |
| SBP on discharge, mmHg | ||||||
| ≤130 | 1 (ref) | -- | -- | |||
| >130 | 0.93 | 0.63-1.39 | 0.736 | -- | -- | |
| History of primary hypertension | ||||||
| No | 1 (ref) | -- | -- | |||
| Yes | 0.54 | 0.36-0.81 | 0.003 | -- | -- | |
| Hemoglobin, g/L | ||||||
| ≤105 | 1 (ref) | 1 (ref) | ||||
| >105 | 0.52 | 0.36-0.76 | 0.001 | 0.87 | 0.57-1.34 | 0.521 |
| Serum albumin, g/L | ||||||
| ≤35 | 1 (ref) | 1 (ref) | ||||
| >35 | 0.46 | 0.31-0.68 | <0.001 | 0.57 | 0.36-0.88 | 0.012 |
| Scr, μmol/L | ||||||
| ≤565 | 1 (ref) | 1 (ref) | ||||
| >565 | 4.99 | 3.24-7.68 | <0.001 | 5.08 | 3.12–8.26 | <0.001 |
| 24-h proteinuria, g/day | ||||||
| ≤1.41 | 1 (ref) | 1 (ref) | ||||
| >1.41 | 2.68 | 1.75-4.11 | <0.001 | 2.33 | 1.48–3.68 | <0.001 |
| RAAS blockers | ||||||
| No | 1 (ref) | 1 (ref) | ||||
| Yes | 0.68 | 0.46-0.998 | 0.049 | 0.80 | 0.53-1.21 | 0.291 |
| With IgAN | ||||||
| No | 1 (ref) | -- | -- | |||
| Yes | 2.64 | 1.79-3.88 | <0.001 | -- | -- | |
| Global sclerosis ratio, % | ||||||
| ≤33 | 1 (ref) | -- | -- | |||
| >33 | 4.01 | 2.64-6.09 | <0.001 | -- | -- | |
HR: hazard ratio; CI: confidence interval; SBP: systolic blood pressure; Scr; serum creatinine; RAAS blockers: renin-angiotensin system blockers; IgAN: IgA nephropathy; IFTA: tubular atrophy/interstitial fibrosis.
Risk of age on secondary outcome of eGFR increase ≥15%
For the secondary outcome of a ≥ 15% increase in eGFR, the ≤35-year-old group showed better renal improvement, with 51.9% (40/77) achieving this endpoint at a median time of 6.9 months (IQR 2.1–15.1 months). K–M analysis further demonstrated a sustained advantage in eGFR recovery for younger patients compared to the >35-year-old group, particularly within the first 6 years of follow-up (Figure 3). Cox regression models were further analyzed. The univariate and multivariate analysis of risk factors according to different age groups are shown in Table 4. In the multivariate analysis of the Cox regression model, age, SBP on discharge, history of primary HTN, serum creatinine, RAAS blockers treatment, and IFTA were included for adjustment. Similarly, the age ≤35 years group appeared to have a 93% higher improvement in the secondary endpoint (≥15% increase in eGFR) and showed a better outcome compared to the age >35 years group (adjusted HR 1.94; 95% CI 1.20–3.15; p = 0.007) (Table 4). Meanwhile, the presence of IFTA >50% on renal biopsy was a negative factor for renal improvement (adjusted HR 0.60; 95% CI 0.37–0.98; p = 0.039).
Figure 3.
Kaplan–Meier survival curves of time to renal improvement based on age.
Table 4.
Cox regression analysis for ≥15% increase in eGFR according to age.
| Variables | ≥15% increase in eGFR |
|||||
|---|---|---|---|---|---|---|
| Univariate analysis |
Multivariate analysis |
|||||
| HR | 95% CI | p Value | adjusted HR | 95% CI | p Value | |
| Age (per, years) | ||||||
| >35 | 1 (ref) | 1 (ref) | ||||
| ≤35 | 1.99 | 1.25-3.16 | 0.004 | 1.94 | 1.20–3.15 | 0.007 |
| Sex, male (vs. female) | 0.671 | 0.35-1.28 | 0.225 | -- | -- | |
| SBP on discharge, mmHg | ||||||
| >130 | 1 (ref) | 1 (ref) | ||||
| ≤130 | 1.61 | 1.01-2.59 | 0.048 | 1.24 | 0.74-2.07 | 0.414 |
| History of primary hypertension | ||||||
| No | 1 (ref) | 1 (ref) | ||||
| Yes | 0.942 | 0.52-1.72 | 0.845 | 0.90 | 0.47-1.71 | 0.746 |
| Hemoglobin, g/L | ||||||
| ≤105 | 1 (ref) | -- | -- | |||
| >105 | 1.15 | 0.73-1.82 | 0.550 | -- | -- | |
| Scr, μmol/L | ||||||
| ≤565 | 1 (ref) | 1(ref) | ||||
| >565 | 0.63 | 0.37-1.07 | 0.088 | 0.77 | 0.44-1.36 | 0.362 |
| 24-h proteinuria, g/24 h | ||||||
| ≤1.41 | 1 (ref) | -- | -- | |||
| >1.41 | 1.19 | 0.73-1.95 | 0.488 | -- | -- | |
| RAAS blockers | ||||||
| No | 1 (ref) | -- | -- | |||
| Yes | 0.66 | 0.39-1.11 | 0.115 | 0.59 | 0.34-1.04 | 0.068 |
| With IgAN, n (%) | 1.32 | 0.72-2.42 | 0.373 | -- | -- | |
| Ratio of sclerotic glomeruli, % | ||||||
| ≤33 | 1 (ref) | -- | -- | |||
| >33 | 1.05 | 0.63-1.75 | 0.855 | -- | -- | |
| IFTA, % | ||||||
| ≤50 | 1 (ref) | 1 (ref) | ||||
| >50 | 0.55 | 0.34-0.87 | 0.011 | 0.60 | 0.37–0.98 | 0.039 |
eGFR: estimated glomerular filtration rate; HR: hazard ratio; CI: confidence interval; SBP: systolic blood pressure; Scr: serum creatinine; RAAS blockers: renin-angiotensin system blockers; IgAN: IgA nephropathy; IFTA: tubular atrophy/interstitial fibrosis.
Discussion
In this study, our data showed that patients with MHT younger than 35 years had significantly higher proteinuria, proportion of patients with IgAN, global sclerosis ratio, and lower SBP on admission compared to patients older than 35 years. Furthermore, age ≤35 years was associated with a higher risk of long-term RRT (HRs: 1.60 [95% CI: 1.06–2.40]) and better improvement of ≥15% increase in eGFR (HRs: 1.93 [95% CI: 1.20–3.11]) after adjustment for confounding variables. We also identified serum creatinine >565 μmol/L, proteinuria >1.41 g/day as risks for long-term RRT, and IFTA > 50% as an adverse factor for ≥15% increase in eGFR. Serum albumin levels above 35 g/L have been shown to be protective against long-term RRT.
In China, HTN increases with age. The prevalence of HTN was >55% among citizens ≥65 years of age and 11% among 35–44 years between 2012 and 2015 [12,13]. In patients with MHT, Bayer et al. found a median age of 40 years (IQR 32–46) in a cohort of French TMA [14]. In this study, MHT patients with TMA ranged in age from 16 to 76 years, with only 2 patients aged ≥60 years. The median age was 35 years, in agreement with several previous studies, and even younger in some cases [7,15]. In a recent retrospective study of young patients with MHT, it was found that 31% of patients required dialysis at 6 months and only 7% of patients had normal renal function [6]. However, the renal prognosis between young and older MHT patients remains unknown. Thus, we investigated the clinical features and renal prognosis based on age groups divided by the median age of 35.
Among the patients of MHT with TMA in our study, we surprisingly observed that the younger group showed a worse outcome of long-term RRT over 9 years of follow-up, but also a better outcome of ≥15% increase in eGFR especially in 6 years compared to the older group. Given better vascular function and structure in the young [16], it seems to be reasonable that the age ≤35 years group performed a better renal improvement in a relatively short time. In addition, our study revealed a 2-fold increase in the prevalence of IgAN diagnosis in the younger age group, compared to those aged over 35. IgAN is the most common CKD in China and is mainly diagnosed between 20 and 40 years of life [17–19]. Pitcher et al. reported that 50% of IgAN patients reached kidney failure or died in the study period and almost all patients were at risk of progression to kidney failure within their expected lifetime in a large IgA nephropathy cohort [20]. Furthermore, patients with IgAN and MHT exhibited significantly more advanced renal insufficiency and lower eGFR levels, compared to those with less severe HTN [21]. Therefore, the higher prevalence of IgAN in the ≤35 years group may partly explain the poor outcome of long-term RRT in younger patients. Moreover, HTN in the young population was a major risk factor for renal and cardiovascular events [22,23]. MHT with TMA may be associated with worse kidney function for a long period [5]. Further research is needed to explore the underlying reasons and mechanisms in young patients.
The pathophysiological interplay between MHT and IgA nephropathy may explain the paradoxical findings of a worse long-term outcome, but a better eGFR improvement in the shorter term for the younger group [24]. For younger MHT patients, the combination of immune-mediated glomerular injury (driven by mesangial IgA deposition) and inherent vascular hyperreactivity creates an environment with a high risk of MHT. For example, RAAS overactivation in IgAN-induced glomerular ischemia promotes the release of excessive amounts of renin, which increases angiotensin II-mediated vasoconstriction. Additionally, endothelial dysfunction involving IgA complexes reduces nitric oxide (NO) synthesis and amplifies oxidative stress, impairing vascular autoregulation. Based on this, early aggressive intensive BP management (e.g., RAAS inhibitors + CCBs) reverses MHT-driven organ damage in younger patients [25]. RAAS blockade alleviates efferent arteriolar constriction, resolving glomerular ischemia and reducing podocyte stress. Improved peritubular capillary flow reactivates tubular epithelial function (e.g., creatinine secretion, electrolyte reabsorption), driving relatively rapid eGFR recovery.
As mentioned above, IgAN was more prevalent in our younger cohort (39.5% vs. 18.6%, p < 0.001), as was the global sclerosis ratio (55% vs. 45%, p = 0.048). However, no significant difference was observed in the incidence of fibrinoid necrosis between the groups (33.6% vs. 32.9%, p = 0.900). The global sclerosis ratio in these patients primarily reflects chronic histological damage [26,27], while fibrinoid necrosis in MHT is predominantly driven by angiotensin-mediated vascular wall necrosis and leakage, typically indicating acute vascular injury [28,29]. IgAN is associated with chronic glomerulosclerosis, and fibrinoid necrosis is relatively rare in IgAN [30]. The lack of significant differences in fibrinoid necrosis between the groups may be attributed to the higher prevalence of IgAN in the younger cohort. Furthermore, younger patients may have superior vascular elasticity, which could delay the progression of fibrinoid necrosis [31,32]. In contrast, older patients often have comorbidities such as atherosclerosis or diabetes that exacerbate vascular damage through alternative mechanisms, rather than fibrinoid necrosis alone [33,34].
In this study, overt serum creatinine and proteinuria were risk factors for long-term RRT in patients with MHT. Supporting our notion, Guerin et al. have concluded serum creatinine levels increase independently and significantly the risk of death in patients with MHT and renal failure [35]. Additionally, data from a retrospective study in Spain found that proteinuria maintained its significance as a risk factor associated with an unfavorable renal prognosis in people with MHT [3]. The crucial role of proteinuria among our patients is in agreement with the important prognostic influence that proteinuria has been shown to play in CKDs [36]. However, several studies have shown that the absence of proteinuria or low levels of proteinuria in IgAN and diabetic kidney disease also carry a high risk of CKD progression and kidney failure, suggesting a similar situation in MHT with TMA that we should focus on [20,37]. Furthermore, our study found that serum albumin >35 g/L was associated with a 43% lower risk of long-term RRT, consistent with the patients of diabetes on dialysis in a North Carolina study [38].
IFTA, one of the major histological changes of nephrosclerosis, was considered to be the best predictor of CKD progression [39]. In diabetic nephropathy and IgA nephropathy, IFTA was identified as the pathological determinant for renal events (requirement of dialysis or a 50% decline in eGFR from baseline) and all-cause mortality [40,41]. We confirmed IFTA> 50% is an unfavorable factor for ≥15% increase in eGFR of MHT with TMA. Few studies evaluate the correlation between IFTA and renal outcomes in MHT with TMA. However, El Karoui et al. concluded that MHT biopsies disclosed greater IFTA than biopsies of hypertensive patients without MHT in IgAN [21]. In this study, IFTA was found to be an independent predictor of renal function outcome. Moreover, IFTA may impact the renal improvement of a ≥ 15% increase in eGFR in young patients, which may further explain the worse outcome of long-term RRT.
Our study has several limitations. First, the study population comprised Asian, mostly Chinese patients, and our findings may not apply to populations from different geographic origins. Second, the influence of confounding, non-identified factors on the long-term outcome of our cohort cannot be ruled out. Third, there was likely an influence of bias through the limitation of subjects to patients with renal biopsy. Fourth, only baseline clinical and laboratory data were assessed and the progression or improvement of MHT with follow-up was not available in this study, and the inability to account for the duration of preexisting HTN is a limitation in this study. In addition, the presence of other distinct glomerular diseases and the lack of immunosuppression data in our study might affect the primary outcome for some of the patients with glomerulonephritis and contribute to renal prognosis and outcomes in MHT, which requires to be further investigation. Finally, the small sample sizes in eGFR improvement for each group constrain more comprehensive analyses.
Conclusion
In conclusion, the occurrence of MHT is common in young patients. This is the first prospective study to demonstrate that young age was correlated with better renal improvement (≥15% increase in eGFR), especially within 6 years. Nevertheless, a worse outcome of long-term RRT also occurred in the younger MHT patients with TMA. Our results highlight the need for more attention to the clinical care in young patients and further research to better understand the pathogenesis of MHT in younger individuals.
Supplementary Material
Acknowledgments
We gratefully thank the pathologists affiliated with First Affiliated Hospital of Sun Yat-sen University for the instruction of kidney biopsy results. Wei Chen, Feng He and Qinghua Liu participated in research ideas and study design; Jianbo Li and Jianwen Yu participated in data acquisition. Zhaocai Zhou, Zhong Zhong, and Naya Huang participated in statistical analysis and writing. Yiqin Wang, Zhengmei Lin and Zhi Song participated in supervision and mentorship. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work. The datasets generated and/or analyzed during this study are not publicly available due to privacy and ethical restrictions but are available from the corresponding author on reasonable request.
Funding Statement
This study was supported by grants from the National Natural Science Foundation of China (Nos. 82470748, 82170737, 82370707), National Key Research and Development Project of China (No. 2021YFC2501302), Guangdong Natural Science Foundation (Grant nos. 2022B1515020106, 2023A1515012477), Key Laboratory of National Health Commission, and Key Laboratory of Nephrology, Guangdong Province, Guangzhou, China (Nos. 2002B60118 and 2020B1212060028), the Guangdong Provincial Department of Science and Technology (Grant no. 202201020273), and Guangzhou Municipal Programme of Science and Technology (2024B03J1337).
Disclosure statement
We declare that the results presented in this paper have not been published previously in whole or part, except in abstract format. The authors report no conflicts.
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