Significant proteinuria as a predictor of renal prognosis in malignant hypertension patients with thrombotic microangiopathy: a prospective cohort study

Abstract

Background

Malignant hypertension (mHTN) is the most severe form of hypertension. Thrombotic microangiopathy (TMA) serves as both a complication of mHTN and a contributor to its progression by exacerbating renal damage. Proteinuria is a common manifestation of mHTN. However, the impact of proteinuria on renal prognosis in mHTN patients with TMA is unclear.

Methods

This observational cohort study included 276 mHTN-associated TMA patients based on renal biopsy from 2008 to 2023. Demographic characteristics, laboratory results, and histopathological findings were recorded and compared between the mild (< 1 g / 24 h) and significant (≥ 1 g / 24 h) proteinuria groups. Propensity score matching (PSM) was used to adjust for baseline differences. Cox regression model was employed to evaluate risk factors associated with renal prognosis.

Results

Among the 276 patients included in the study, 185 (67.0%) had significant proteinuria, while 91 (33.0%) had mild proteinuria at baseline. After PSM, 83 pairs of patients with mHTN-associated TMA were matched. Patients with significant proteinuria exhibited lower serum albumin, and higher ratio of global sclerosis compared to patients with mild proteinuria. Moreover, mHTN-associated TMA with significant proteinuria was independently associated with receiving renal replacement therapy (RRT) (adjusted hazard ratio (aHR), 1.30; 95% confidence interval (CI), 1.16–1.46; P < 0.001) compared with mild proteinuria. This association remained significant after PSM (aHR, 1.29; 95% CI, 1.13–1.47; P < 0.001). Furthermore, mHTN-associated TMA patients with significant proteinuria had a lower incidence of renal function recovery with a reduction in creatinine levels than in patients with mild proteinuria in the absence of intensive blood pressure control.

Conclusion

In mHTN-associated TMA patients, the presence of significant proteinuria serves as a strong predictor of poor renal outcome.

Clinical trial number

Not applicable.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12882-025-04407-6.

Introduction

Malignant hypertension (mHTN) is the most severe form of hypertension, defined by very high blood pressure (BP) accompanied by retinal hemorrhages, exudates, and papilledema (grade Ⅲ/Ⅳ hypertensive retinopathy) on funduscopic examination [1]. A study from Birmingham revealed that the overall incidence rate of mHTN is 6 new cases per 100,000 individuals per year. In addition, the five-year survival rate for patients with mHTN is 90%. Among them, 10–35% of patients require dialysis okidney transplantation [2, 3]. Renal damage represents a common event in the course of mHTN [4]. Although the use of medications has further improved the prognosis, the number of patients on hemodialysis for mHTN has also increased in hemodialysis registries in the Netherlands and elsewhere in Europe [5]. Thrombotic microangiopathy (TMA), a condition characterized by endothelial injury or dysfunction, stands as one of the most classic and severe complications of mHTN [6]. The intricate relationship between mHTN and TMA highlights that they can exacerbate each other. Severe hypertension can induce endothelial damage and microangiopathic changes. Meanwhile, TMA can further intensify hypertension through mechanisms such as renal ischemia and activation of the Renin-Angiotensin-Aldosterone System (RAAS) [7]. Previous studies have confirmed that mHTN with pathological manifestations such as TMA is associated with significantly poor renal outcome and nephrosclerosis [8, 9]. However, the risk factors for renal prognosis in mHTN-associated TMA patients have rarely been comprehensively investigated.

Proteinuria has been identified as the most widely recognized and well-studied risk factor for progression to end-stage renal disease (ESRD) in various kidney diseases [10–13]. An early study has highlighted the relationship between proteinuria and renal function in mHTN [14]. A retrospective study also showed that proteinuria may be an independent predictor of poor outcomes, including death or dialysis, in patients with mHTN [15]. However, not all patients in these studies underwent renal pathological examination, and reports on the relationship between proteinuria and mHTN-associated TMA are limited.

The aim of this study was to describe the clinical and pathological characteristics of patients with mHTN-associated TMA and to identify risk factors for worse renal outcomes. The study highlighted the prognostic value of proteinuria for renal outcomes and provided insight into optimal blood pressure management in mHTN-associated TMA patients.

Methods

Study population and cohort

In this prospective cohort study, 276 hospitalized patients with renal damage related to mHTN-associated TMA were enrolled at the First Affiliated Hospital of Sun Yat-sen University from 2008 to 2023. All patients underwent screening to exclude secondary causes of TMA, including infections, autoimmune diseases, transplant-associated TMA, malignancy, pregnancy, and drug-induced causes. A diagnosis of mHTN-associated TMA was established when patients had a clinical diagnosis of mHTN combined with clinicopathological evidence of TMA, after ruling out these secondary factors. Patients with less than three months of follow-up were excluded from the study. mHTN-associated TMA patients were categorized according to the proteinuria level and divided into two different groups, including mild proteinuria group (n = 91) and significant proteinuria group (n = 185). To ensure comparability and minimize selection bias, we applied propensity-score matching (PSM) to adjust for baseline differences between the mild proteinuria and significant proteinuria groups. This study was conducted in accordance with the ethical standards of the Declaration of Helsinki. It was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (No. IEC [2022] 710). Written informed consent was obtained from all patients. No financial compensation was provided.

Definitions

mHTN was diagnosed based on the detection of a marked elevation of systolic blood pressure (SBP) levels of 180 mmHg or greater and/or diastolic BP (DBP) levels of 120 mmHg or greater, accompanied by grade III or IV hypertensive retinopathy according to the Keith-Wagener-Barker classification and/or evidence of imminent or progressive target organ dysfunction secondary to hypertension [16, 17]. The diagnosis of mHTN-associated TMA was confirmed based on renal pathological features, including various pathological changes such as capillary loop wrinkling, capsule thickening, significant renal artery intimal thickening, vessel wall “onion skin” appearance thickening, fibrinoid necrosis, intravascular thrombosis, ischemic glomerular changes, and tubular necrosis [6, 17, 18]. In this study, severe cardiac involvement was defined as a left ventricular ejection fraction ≤ 50% [19]. According to relevant studies and guidelines, proteinuria in mHTN patients was defined as mild proteinuria (< 1 g / 24 h) and significant proteinuria (≥ 1 g / 24 h) [15, 20–23]. In our study, systolic blood pressure (SBP) was controlled to ≤ 130 mmHg as the criterion for intensive blood pressure management, based on consultation with both international and national clinical guidelines [23, 24].

Data collection and renal histopathology

Blood and urine samples were obtained within the first 24 h of patient admission. All patients underwent comprehensive diagnostic evaluations, including chest radiography, renal ultrasound, and echocardiography. Baseline clinical and demographic data were systematically collected, including age, sex, body mass index (BMI), blood pressure readings, 24-hour proteinuria levels, platelet counts, hemoglobin levels, albumin concentrations, cholesterol levels, triglycerides, low-density lipoprotein cholesterol (LDL-c), serum creatinine, uric acid, and serum complement C3 and C4 levels. Mean arterial pressure (MAP) was defined as one-third of the SBP plus two-thirds of the diastolic blood pressure (DBP). Prescription data included statins, sulodexide, febuxostat, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs), sacubitril/valsartan (ARNI), and various antihypertensive medications, including α-blockers, β-blockers, and calcium channel blockers.

Percutaneous renal biopsy specimens were routinely processed according to established protocols. Renal biopsies were processed for standard light microscopy, electron microscopy, and direct immunofluorescence. Immunofluorescence was performed using fluorescein isothiocyanate-conjugated antibodies specific for human immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), complement component 1q (C1q), complement component 3 (C3), and both kappa (κ) and lambda (λ) light chains. All biopsies were reviewed by two senior pathologists. In case of disagreement, discussions were held until consensus was reached. Light microscopic data including the number of glomeruli, the percentage of global sclerosis, segmental sclerosis and tubular atrophy/interstitial fibrosis. Additionally, vascular parameters, including hyaline degeneration, fibrinoid necrosis, “onion skin” appearance, intravascular thrombosis, and intravascular erythrocyte (RBC) fragments were also documented. Electron microscopic evaluation included identification of subepithelial, subendothelial, or mesangial deposits and assessment of the degree of endothelial cell swelling.

Study outcomes

The primary outcome of the study was renal replacement therapy (RRT), which was defined as the need for hemodialysis, peritoneal dialysis, or kidney transplantation during follow-up. All patients were followed up by nephrologists and trained nurses through office visits or telephone interviews, and the last follow-up date was June 30, 2023.

Statistical analysis

Continuous variables were presented as mean ± standard deviation (SD) or the median (interquartile range, 25th, 75th percentile) depending on their distribution. Continuous variables were compared using the Mann-Whitney U test for non-normally distributed variables and the Student’s t-test for normally distributed variables. Categorical variables were expressed as frequencies (percentages), and analyzed with the chi-squared test or the Fisher exact test. Time to reach study outcomes was estimated using the Kaplan-Meier model, with survival comparisons between the mild proteinuria group and the significant proteinuria groups based on the log-rank test. Crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using univariate and multivariate Cox proportional hazards regression models. Variables that were statistically significant in the univariate analysis or considered clinically relevant to kidney outcomes were included in the multivariate analysis [25]. To adjust for the baseline differences and to minimize potential selection bias, PSM was applied between the mild proteinuria group and the significant proteinuria group. Supplementary Table 1 lists the variables included in the PSM for adjustment. A 1:1 match was performed using the greedy-matching algorithm with a caliper of 0.02 [26, 27]. A Survival analysis was used to assess the prognosis before and after PSM. All statistical analyses were performed using SPSS (version 25.0; IBM, Armonk, NY, USA), with P < 0.05 indicating a statistically significant result.

Results

Baseline demographics and characteristics

Between 2008 and 2023, a total of 276 patients underwent clinical renal biopsy and were pathologically diagnosed with mHTN-associated TMA. These patients were included in this study. A flow chart illustrating this process is shown in Supplementary Fig. 1. 91 (33.0%) patients were in the mild proteinuria group and 185 (67.0%) patients were in the significant proteinuria group. The baseline characteristics of the patients before and after PSM are shown in Table 1. Patients with significant proteinuria had lower serum albumin levels (mean ± standard deviation: 36.1 ± 5.0 vs. 38.5 ± 4.3 g/L; P < 0.001) and higher serum creatinine levels (median (interquartile range): 484.0 (296.0, 694.5) vs. 337.0 (199.0, 700.0) µmol/L; P = 0.005) than those with mild proteinuria.

Table 1.

Baseline clinical and pathological characteristics before and after propensity score matching

Characteristic		Entire cohort			Propensity score-matched cohort
	Total (n = 276)	Mild proteinuria (n = 91)	Significant proteinuria (n = 185)	P-value	Mild proteinuria (n = 83)	Significant proteinuria (n = 83)	P-value
Clinical characteristics
Age, years	35.8 ± 8.8	35.7 ± 8.6	35.8 ± 8.9	0.889	35.8 ± 8.2	35.2 ± 8.2	0.649
Male, n (%)	247 (89.5)	84 (92.3)	163 (88.1)	0.285	76 (91.6)	76 (91.6)	>0.999
BMI, kg/m2	24.8 ± 4.0	24.5 ± 4.1	24.9 ± 4.0	0.369	24.5 ± 4.0	24.5 ± 3.7	0.954
Smoking, n (%)	125 (45.3)	40 (44.0)	85 (45.9)	0.755	38 (45.8)	38 (45.8)	>0.999
Drinking, n (%)	81 (29.3)	25 (27.5)	56 (30.3)	0.631	25 (30.1)	28 (33.7)	0.617
SBP, mmHg	217.8 ± 24.9	216.9 ± 22.7	218.2 ± 25.9	0.678	216.2 ± 22.7	219.9 ± 26.7	0.335
DBP, mmHg	136.8 ± 20.6	133.7 ± 19.7	138.3 ± 30.0	0.082	134.8 ± 19.3	137.0 ± 19.0	0.455
MAP, mmHg	163.9 ± 19.2	161.4 ± 17.1	165.1 ± 20.1	0.137	161.9 ± 17.4	164.6 ± 18.9	0.33
Laboratory values
Platelet count, 10^9/L	261.5 ± 85.6	255.2 ± 78.7	264.6 ± 88.8	0.392	277.7 ± 96.2	273.8 ± 87.1	0.782
Hemoglobin, g/L	107.4 ± 23.0	110.3 ± 24.3	106.0 ± 22.3	0.145	108.6 ± 23.8	108.9 ± 23.5	0.937
Serum albumin, g/L	36.9 ± 4.9	38.5 ± 4.3	36.1 ± 5.0	<0.001	38.5 ± 4.3	36.4 ± 4.8	0.004
Total cholesterol, mmol/L	4.7 (4.0, 5.6)	4.8 (4.0, 5.7)	4.7 (4.0, 5.6)	0.887	4.7 (4.0, 5.6)	4.5 (3.7, 6.0)	0.736
Triglycerides, mmol/L	1.8 (1.3, 2.3)	1.6 (1.3, 1.6)	1.8 (1.3. 2.5)	0.05	1.6 (1.3, 2.1)	1.8 (1.3, 2.4)	0.149
LDL-C, mmol/L	3.0 (2.4, 3.6)	3.0 (2.4, 3.7)	2.9 (2.3, 3.6)	0.952	3.0 (2.3, 3.5)	2.9 (2.2, 3.7)	0.961
Serum creatinine, mmol/L	447.5 (263.0, 696.8)	337.0 (199.0, 700.0)	484.0 (296.0, 694.5)	0.005	363.0 (203.0, 703.0)	427.0 (294.0, 620.0)	0.17
eGFR, mL/min/1.73m2	10.6 (6.5, 21.1)	15.4 (6.4, 27.2)	10.2 (6.6, 17.2)	0.013	13.3 (6.4, 25.8)	11.2 (7.0, 17.8)	0.304
Uric acid, mmol/L	479.5 ± 132.0	464.9 ± 123.7	486.8 ± 135.7	0.197	471.8 ± 124.5	473.2 ± 140.7	0.944
C3, g/L	1.0 (0.8, 1.2)	1.0 (0.8, 1.1)	1.0 (0.8, 1.2)	0.717	1.0 (0.9, 1.2)	1.0 (0.8, 1.8)	0.197
C4, g/L	0.3 (0.2, 0.4)	0.3 (0.2, 0.4)	0.3 (0.2, 0.4)	0.635	0.3 (0.2, 0.4)	0.3 (0.2, 0.3)	0.15
Hypocomplementemia C3 (%)	23 (8.3)	6 (6.6)	17 (9.2)	0.465	6 (7.2)	9 (10.8)	0.42
Ejection fraction	60.6 ± 9.7	61.8 ± 9.5	60.1 ± 9.8	0.203	62.1 ± (9.8)	62.0 ± (9.3)	0.309
Severe cardiac involvement (%)	36 (13.0)	10 (11.0)	26 (14.1)	0.478	11 (13.3)	12 (14.5)	0.822
Medications, n (%)
Statin	128 (46.4)	38 (41.8)	90 (48.6)	0.28	34 (41.0)	37 (44.6)	0.638
Sulodexide	142 (51.4)	49 (53.9)	93 (50.3)	0.576	45 (54.2)	39 (47.0)	0.352
Febuxostat	58 (21.0)	15 (16.5)	43 (23.2)	0.195	14 (16.0)	17 (20.5)	0.55
ACEI	59 (21.4)	17 (18.7)	42 (22.7)	0.444	17 (20.5)	18 (21.7)	0.849
ARB/ARNI	180 (65.2)	63 (69.2)	117 (63.2)	0.326	57 (68.7)	54 (65.1)	0.621
α−βλοχκερ	168 (60.9)	55 (60.4)	113 (61.1)	0.918	49 (59.0)	49 (59.0)	>0.999
β−βλοχκερ	236 (85.5)	77 (84.6)	159 (85.9)	0.768	70 (84.3)	72 (86.7)	0.659
CCB	266 (96.4)	87 (95.6)	179 (96.8)	0.734	79 (95.2)	81 (97.6)	0.682

Data are median (25th, 75th percentile), mean ± standard deviation and percentage unless otherwise indicated. BMI, body mass index. SBP, systolic blood pressure. DBP, diastolic blood pressure. MAP, mean arterial pressure. LDL-C, low density lipoprotein cholesterol. eGFR, estimated glomerular filtration rate. C3, complement 3. C4, complement 4. ACEI, angiotensin-converting enzyme inhibitor. ARB, angiotensin Ⅱ receptor blocker. ARNI, sacubitril-valsartan. CCB, calcium channel blocker. Hypocomplementemia C3 was defined as a serum complement 3 concentrations below 0.75 g/L. Severe cardiac involvement was defined as a left ventricular ejection fraction less than or equal to 50%

After PSM, 83 patients with significant proteinuria were matched with 83 patients with mild proteinuria (Supplementary Fig. 1). A reassessment of the baseline characteristics after PSM showed that a satisfactory balance had been achieved between the two groups. Patients with significant proteinuria had lower serum albumin levels compared to patients with mild proteinuria (36.4 ± 4.8 vs. 38.5 ± 4.3, P = 0.004) (Table 1). No significant differences were observed between the two groups with regard to other laboratory data or drug treatment.

Renal histopathological characteristics

All patients with mHTN-associated TMA underwent percutaneous renal biopsy (Fig. 1). Light microscopic analysis revealed a typical set of pathological changes in mHTN-associated renal TMA, including vessel wall thickening exhibiting an “onion skin” appearance (Fig. 1a), characteristic intimal thickening, and mucus degeneration within the renal artery (Fig. 1b). Additionally, there was diffuse wrinkling of the capillary loops accompanied by capsular thickening (Fig. 1c). The electron micrograph demonstrated endothelial cell swelling and significant subendothelial widening with the presence of flocculent material beneath (Fig. 1d).

Fig. 1.

Representative light, electron microscopic, and immunofluorescence findings in mHTN patients with TMA. (a) Periodic acid-Schiff (PAS) staining showing vessel wall thickening with an “onion skin” appearance (red arrow). (b) PAS staining showing typical intimal thickening and mucus degeneration of renal artery. (c) PAS staining showing diffuse winkling of the capillary loop and capsular thickening. a-c, scale bar: 50 μm. (d) Electron micrograph showing endothelial cell swelling, and marked subendothelial widening with flocculent material underneath. Scale bar: 2 μm

The renal histopathologic findings of the patients are shown in Table 2. Compared to patients with mild proteinuria, patients with significant proteinuria had a lower number of glomeruli (22.0 (16.0, 31.0) vs. 27.0 (19.0, 35.0), P = 0.010) and a higher prevalence of global sclerosis (37.9 (20.0, 65.5) vs. 27.3 (17.2, 45.7), P = 0.011). In addition, patients with significant proteinuria exhibited a higher prevalence of fibrinoid necrosis than in patients with mild proteinuria (51 (27.6) vs. 38 (41.8), P = 0.018). After PSM, patients with significant proteinuria also had a higher prevalence of global sclerosis (47.8 (23.1, 70.4) vs. 27.3 (17.0, 45.7), P = 0.003). No significant differences were observed in the prevalence of other pathological features between the two groups.

Table 2.

Histopathologic findings of patients before and after propensity score matching

Characteristic		Entire cohort			Propensity score-matched cohort
	Total (n = 276)	Mild proteinuria (n = 91)	Significant proteinuria (n = 185)	P-value	Mild proteinuria (n = 83)	Significant proteinuria (n = 83)	P-value
Global lesions, n (%)
Number of glomeruli, number	24.0 (18.0, 33.0)	27.0 (19.0, 35.0)	22.0 (16.0, 31.0)	0.010	28.0 (19.0, 35.0)	22.0 (16.0, 32.0)	0.054
Global sclerosis (%)	33.3 (18.9, 60.8)	27.3 (17.2, 45.7)	37.9 (20.0, 65.5)	0.011	27.3 (17.0, 45.7)	47.8 (23.1, 70.4)	0.003
Segmental sclerosis (%)	0.0 (0.0, 6.3)	0.9 (0.0, 5.0)	0.0 (0.0, 7.1)	0.446	0.0 (0.0, 5.0)	2.2 (0.0, 7.4)	0.247
Tubular atrophy/interstitial fibrosis, n (%)				0.311			0.552
<25%	10 (3.6)	6 (6.6)	4 (2.2)		5 (6.0)	1 (1.2)
25–50%	55 (19.9)	18 (19.8)	37 (20.0)		17 (20.5)	17 (20.5)
50–75%	159 (57.6)	52 (57.1)	107 (57.8)		31 (37.3)	25 (30.1)
>75%	48 (17.4)	14 (15.4)	34 (18.4)		14 (16.9)	12 (14.5)
Vascular lesions, n (%)
Hyaline degeneration	148 (53.6)	50 (54.9)	98 (53.0)	0.757	45 (54.2)	41 (49.4)	0.534
Fibrinoid necrosis	89 (32.2)	38 (41.8)	51 (27.6)	0.018	37 (44.6)	27 (32.5)	0.111
Onion skin appearance	167 (60.5)	57 (62.6)	110 (59.5)	0.611	49 (59.0)	49 (59.0)	>0.999
Intravascular thrombosis	49 (17.8)	21 (23.1)	28 (15.1)	0.105	20 (24.1)	14 (16.9)	0.249
Intravascular RBC fragments	27 (9.8)	9 (9.9)	18 (9.7)	0.966	9 (10.8)	9 (10.8)	>0.999

Data are median (25th, 75th percentile) and percentage unless otherwise indicated. RBC, red blood cell

Risk of significant proteinuria on the primary outcome of renal replacement therapy in patients with mHTN-associated TMA

After a median follow-up period of 48.8 months (95% CI, 34.6–63.1), the primary outcome occurred in 93 patients (42.9%). The cumulative effect of patients with significant proteinuria on the hazard of RRT was higher compared to patients with mild proteinuria (overall comparison, P = 0.018; propensity score-matched comparison, P = 0.011; Fig. 2). In the crude analysis, patients with significant proteinuria exhibited a higher risk of RRT compared to patients with mild proteinuria (HR, 1.40; 95% CI, 1.15–1.70; P = 0.001). This difference remained statistically significant after adjustment for both the overall comparison (adjusted HR, 1.30; 95% CI, 1.16–1.46; P < 0.001) and the propensity score-matched comparison (adjusted HR, 1.29; 95% CI, 1.13–1.47; P < 0.001) (Table 3).

Fig. 2.

Cumulative risk of renal replacement therapy in patients with mild proteinuria versus significant proteinuria: (a) overall comparison. (b) propensity score-matched comparison. The primary outcome of this study was defined as starting renal replacement therapy. RRT, Renal Replacement Therapy

Table 3.

Association between mild proteinuria group and significant proteinuria group and study outcome within the crude analysis, multivariable analysis, and propensity score matching analysis

Variable	HR (95% CI) for study outcome	P-value
The primary outcome of starting renal replacement therapy
No. of events/No. of patients at risk (%)	93/217 (42.9)	<0.001
Mild proteinuria	20/65 (30.8)
Significant proteinuria	73/152 (48.0)
Crude analysis a	1.40 (1.15–1.70)	0.001
Multivariable analysis b	1.30 (1.16–1.46)	<0.001
Propensity score matching c	1.29 (1.13–1.47)	<0.001

^a The HRs from the bivariable model in all patients from the unmatched study

^b The HRs from the multivariable stratified Cox proportional hazards regression model, with additional covariate adjustment

^c The HR from propensity score-matched sample, constructed using 1: 1 earest neighbor matching with a 0.02 caliper

The primary outcome was defined as starting renal replacement therapy

In addition, risk factors for RRT in patients with mHTN-associated TMA are presented in Supplementary Fig. 2. In the multivariable Cox regression model, we adjusted for variables that were either statistically significant (P < 0.05) in the univariable analysis or considered clinically relevant to kidney outcomes. Patients with significant proteinuria were more likely to require RRT than patients with mild proteinuria (adjusted HR, 1.30; 95% CI, 1.16–1.46; P < 0.001). Moreover, lower platelet count (adjusted HR, 0.996; 95% CI, 0.993–0.999; P = 0.010), and higher serum creatinine (adjusted HR, 1.003; 95% CI, 1.003–1.004; P < 0.001), higher prevalence of global sclerosis (adjusted HR, 1.06; 95% CI, 1.03–1.09; P < 0.001), and a higher proportion of tubular atrophy/interstitial fibrosis ≥ 50% (adjusted HR, 3.19; 95% CI, 1.36–7.50; P = 0.008) were associated with an increased risk of RRT in patients with mHTN-associated TMA.

A comparable pattern was observed in the PSM cohort (Fig. 3). After the multivariable Cox regression analysis, patients with significant proteinuria (adjusted HR, 1.29; 95% CI, 1.13–1.47; P < 0.001), higher serum creatinine levels (adjusted HR, 1.003; 95% CI, 1.002–1.004; P < 0.001), and a higher prevalence of global sclerosis (adjusted HR, 1.06; 95% CI, 1.03–1.10; P < 0.001) and segmental sclerosis (adjusted HR, 1.34; 95% CI, 1.07–1.67; P = 0.010) in a renal biopsy specimen were identified as risk factors for RRT in patients with mHTN-associated TMA. No differences in medication use were observed in the PSM cohort.

Fig. 3.

Forest plot showing the result of Cox regression analysis for the primary outcome of renal replacement therapy in the propensity score-matched cohort. (a) The univariate Cox regression analysis. (b) The multivariable Cox regression analysis. *P < 0.05. HR, hazard ratio. 95% CI, 95% confidence interval. BMI, body mass index. SBP, systolic blood pressure. DBP, diastolic blood pressure. HDL-C, high density lipoprotein cholesterol. LDL-C, low density lipoprotein cholesterol. C3, complement 3. ACEI, angiotensin-converting enzyme inhibitor. ARB, angiotensin Ⅱ receptor blocker. ARNI, sacubitril-valsartan. Hypocomplementemia C3 was defined as a serum complement 3 concentrations below 0.75 g/L. Severe cardiac involvement was defined as a left ventricular ejection fraction less than or equal to 50%

Intensive blood pressure control management

To assess the benefit of intensive blood pressure control, patients were divided into two groups based on SBP at the time of discharge. The effect of proteinuria on renal prognosis was evaluated. Table 4 showed that in the SBP>130mmHg group, patients with significant proteinuria exhibited a lower incidence of renal function recovery of a 25% decrease in creatinine compared to patients with mild proteinuria (P = 0.032). Similarly, patients with significant proteinuria were less likely than those with mild proteinuria to have a favorable renal function recovery of a 50% decrease in creatinine than those with mild proteinuria (P = 0.027). However, no significant difference was observed between the two groups for the aforementioned two endpoints of renal function recovery when SBP ≤ 130 mmHg (P > 0.05).

Table 4.

Estimated event rates among intensive blood pressure control between mild proteinuria group and significant proteinuria group

Event	SBP ≤ 130mmHg			SBP>130mmHg
	Mild proteinuria	Significant proteinuria	P-value	Mild proteinuria	Significant proteinuria	P-value
Long term RRT	7 (26.9)	26 (43.3)	0.151	13 (33.3)	47 (51.1)	0.062
Recovery 1	15 (60.0)	39 (62.9)	0.801	24 (68.6)	46 (47.4)	0.032
Recovery 2	5 (20.0)	21(33.9)	0.201	15 (45.5)	24 (25.0)	0.027
Recovery 3	0 (0.0)	6 (20.0)	0.571	6 (30.0)	12 (21.1)	0.540

RRT: renal replacement therapy

Recovery 1: A 25% decrease in creatinine, or a decrease in creatinine to normal, or renal survival free from replacements therapy for one month

Recovery 2: A 50% decrease in creatinine, or a decrease in creatinine to normal, or renal survival free from replacements therapy for one month

Recovery 3: Free from dialysis for patient dependent on dialysis at baseline

Discussion

This observational cohort study showed that mHTN-associated TMA patients with significant proteinuria had lower serum albumin levels and higher global sclerosis scores compared to patients with mild proteinuria. In addition, patients with significant proteinuria were more likely to progress to RRT compared with the mild proteinuria group (overall comparison, HR 1.30; 95% CI 1.16–1.46; P < 0.001; propensity score-matched comparison, HR 1.29; 95% CI 1.13–1.47; P < 0.001). Furthermore, multivariable regression analysis revealed that higher serum creatinine levels were associated with an increased likelihood of requiring RRT. Moreover, the pathological changes in the kidney, including the extent of global sclerosis and segmental sclerosis were identified as unfavorable factors for RRT. Finally, our study found that significant proteinuria may be a strong risk factor for poor renal function recovery in the absence of intensive blood pressure control.

In mHTN patients, kidney complications are frequently associated with a poor prognosis. These renal issues often manifest as proteinuria, hemolysis, low platelet count, and impaired kidney function. These characteristics are very similar to the key features of TMA [28]. TMA has been recognized as a complication of mHTN, with a reported prevalence ranging from 14 to 46% [29, 30]. A study conducted in Spain showed that mHTN patients with TMA exhibited a higher incidence of kidney failure than those without TMA [2]. Recent evidence indicates that aberrant activation of the complement alternative pathway (cAP) is a hallmark of TMA pathogenesis [31, 32]. Abnormal complement levels correlate with poorer renal outcomes, suggesting that complement dysregulation may contribute to the progression of mHTN-associated TMA. Nevertheless, more the underlying mechanisms and clinical implications of mHTN complicated by TMA remain to be explored.

Although the effective treatment with antihypertensive agents could improve renal function, a significant proportion of surviving patients still require long-term dialysis or transplantation [5, 33]. Our study confirmed that 42.9% (93/217) of mHTN-associated TMA patients required RRT during the follow-up period. This highlights the importance of identifying risk factors early on and intervening promptly to improve patient outcomes. In a single-center retrospective analysis, Manuel Praga and his colleagues suggested that mean proteinuria during the follow-up period is pivotal in determining the renal outcomes of patients with mHTN [34]. A study from Birmingham also confirmed that elevated serum creatinine and proteinuria levels are significant risk factors for the presence of renal dysfunction in mHTN patients [15]. These observations were consistent with our conclusions, suggesting that patients with significant proteinuria were more likely to require RRT treatment compared to those with mild proteinuria. Therefore, persistent proteinuria can be considered as a significant predictor of adverse outcomes in mHTN-associated TMA patients.

Given that RAAS activation is a key pathogenic mechanism in mHTN and that RAAS blockers have specific anti-proteinuric properties [35], the relationship between the use of RAAS blockers and adverse outcomes associated with RRT was analyzed. It was observed that the use of ARB/ARNI was associated with a decreased likelihood of requiring RRT in mHTN-associated TMA patients. However, when included in a multivariate Cox regression analysis, ARBs were not found to be a protective factor. Nevertheless, their dual mechanism of reducing blood pressure and proteinuria levels cannot be overlooked in the recovery of renal function [36]. Our previous research showed that sacubitril/valsartan treatment was associated with a potential benefit to renal function in patients with mHTN-associated TMA compared to ACEI/ARB treatment. This effect can be attributed to the mechanistic advantages of ARNI, which inhibit the degradation of endogenous natriuretic peptides. This enhances their effects on natriuresis, diuresis, and vasodilation, while also suppressing the release of excessive renin and aldosterone [25]. These findings suggest that ARNI might be a superior therapeutic strategy for the management of this serious condition in terms of renal recovery. In addition, none of the patients in our cohort with mHTN-associated TMA received plasma replacement therapy or eculizumab therapy. Some treatments include plasma replacement or exchange, alongside emerging therapies, such as the complement C5 inhibitor eculizumab [37]. Cavero et al. showed that renal and hematological responses are significantly better with eculizumab compared to plasmapheresis. Eculizumab has been shown to improve renal survival in patients with mHTN, and these benefits appear to be independent of the severity of hypertension and complement genetic abnormalities [1]. Future studies with standardized, comprehensive data are needed to clarify the roles of plasma therapy and eculizumab in mHTN-associated TMA and their effects on renal outcomes.

Serum albumin is a widely used as clinical biomarker with prognostic value for numerous health outcomes [38]. A retrospective study revealed that hypoalbuminemia was related to a poorer renal prognosis in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN). In addition, the study found that the serum albumin level had a significant inverse correlation with proteinuria and glomerular lesions [39]. This conclusion is supported by our data. In the present study, we found that low serum albumin level was a negative factor for the renal outcome of RRT in mHTN-associated TMA patients. Furthermore, our baseline data showed that patients with mHTN-associated TMA and significant proteinuria had lower albumin levels than those with mild proteinuria. This effect remains after PSM and may be attributed to the following factors. On the one hand, the extensive damage to the glomerular filtration barrier results in massive proteinuria, which often leads to albumin loss and ultimately manifests as nephrotic syndrome [40]. On the other hand, systemic inflammation, compromised nutritional status, and endothelial dysfunction further exacerbate hypoalbuminemia [41, 42]. These observations suggested that hypoalbuminemia may serve as an independent predictor of unfavorable renal outcomes in this patient population, highlighting the need for further investigation to confirm these associations and explore potential therapeutic interventions.

Glomerulosclerosis and tubular atrophy/interstitial fibrosis are chronic, irreversible changes that are often observed in a renal biopsy specimen [43, 44]. Previous studies have indicated that chronic changes are associated with worse renal outcomes [45–47]. S. kadiri et al. demonstrated that glomerulosclerosis is a prominent feature of primary mHTN and may contribute to renal dysfunction in mHTN patients. Those with global glomerulosclerosis appeared to have the highest serum creatinine levels [48]. Previous research has also emphasized the importance of segmental glomerulosclerosis as an effective factor for predicting predictor of renal prognosis [33]. Similarly, our study found that both global glomerulosclerosis and segmental glomerulosclerosis were independent risk factors for RRT in mHTN-associated TMA patients. In addition to glomerular variables, tubular atrophy/interstitial fibrosis is another valuable predictor of worse renal prognosis in kidney disease. A study conducted in Northern India by Sanjay Vikrant et al. found that patients with IgA nephropathy and mHTN who exhibited tubular atrophy/interstitial fibrosis of at least 25% were less likely to respond favorably to treatment [49]. This finding is consistent with ours that tubular atrophy/interstitial fibrosis > 50% was independently predictive of progression to RRT in mHTN-associated TMA patients. These conclusions further confirm the value of pathological features in predicting renal prognosis.

Cardiac involvement is a recognized complication in patients with mHTN and TMA. Previous studies have reported that approximately 28% of patients with concomitant TMA and mHTN exhibit cardiac involvement, with 27% classified as severe [19, 28]. In our cohort, 13% of patients had severe cardiac involvement based on a left ventricular ejection fraction ≤ 50%, which is lower than previous reports and may reflect differences in population or assessment methods. In the present study, severe cardiac involvement was not associated with long-term renal replacement therapy risk in either the overall or PSM cohorts. Future studies with larger cohorts and standardized assessments are needed to clarify the role of cardiac involvement in renal outcomes. Including cardiac variables in prognostic models may improve risk stratification and treatment guidance for patients with mHTN-associated TMA.

Determining the optimal treatment target for blood pressure in patients with kidney disease has emerged as a key area of investigation [50]. A meta-analysis showed that intensive blood pressure control significantly reduced both cardiovascular events and proteinuria. Patients with vascular and renal disease experienced the greatest absolute benefit [51]. Nevertheless, the precise target for blood pressure to prevent deterioration of renal function in patients with mHTN, especially those with TMA, remains uncertain. A study in Australia showed that intensive blood pressure reduction appeared to protect against kidney failure events in patients with chronic kidney disease [52]. Our study found that without intensive blood pressure control, the mild proteinuria group showed better renal function recovery than the significant proteinuria group. This conclusion indirectly supports the importance of proteinuria in renal prognosis. Further studies are therefore needed to evaluate the benefits of intensive blood pressure control on renal outcomes in mHTN-associated TMA patients.

Our study has several limitations. First, while all diagnoses of TMA were established through renal histopathology, our study lacked a comprehensive diagnostic classification of the various TMA etiologies. It is important to note that we identified TMA associated with mHTN after ruling out secondary causes. However, some key parameters for the clinical diagnosis of TMA, including haptoglobin, peripheral smear, reticulocyte count, lactate dehydrogenase (LDH), and a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) levels, were not collected in our study. Future studies will improve data collection. Second, due to the severity and variability of kidney impairment, proteinuria was measured within 24 h of admission. However, acute kidney injury may be influenced by other factors, such as hemodynamic changes. This could lead to overestimation, even when the primary cause is malignant hypertension. Third, the median change in creatinine varied among patients in our intensified blood pressure control cohort. Some patients showed decreases, some remained stable, and a few experienced increases. Therefore, we did not report summary statistics for changes in serum creatinine by group, which may limit the interpretability of the results. Fourth, caution is warranted when generalizing these findings to patients from different ethnic backgrounds, as our study was confined to Chinese individuals with mHTN-associated TMA. Fifth, some important confounders, such as C-reactive protein (CRP), CKD history, diabetes status, liver function, and other medications, were not included in this analysis. Their impact deserves consideration in future studies to better control for potential bias. Although PSM was employed to mitigate selection bias, the reduced sample size after matching may have decreased statistical power, increasing the risk of missing true effects. In addition, the significant differences in baseline albumin levels after PSM highlight an important limitation: PSM did not fully account for unmeasured confounders that may independently influence albumin levels. Consequently, residual confounding might still be present. Finally, the 15-year study period may have included therapy changes that affected the results. The lack of complement activation, complement gene testing and tubular injury markers limited our understanding of the mechanisms. Future studies should have a longer follow-up period and include such variables to better understand mHTN-associated TMA.

Conclusion

In conclusion, this study contributes to the accumulating evidence supporting that significant proteinuria is identified as a strong prognostic factor for predicting unfavorable renal outcomes in patients of mHTN-associated TMA. Therefore, monitoring the level of proteinuria in individuals with mHTN-related TMA may provide valuable insights into the potential trajectory of renal health, enabling healthcare professionals to make more informed decisions regarding patient management and treatment strategies.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

ADAMTS13

A disintegrin and metalloproteinase with thrombospondin motifs 13

ARB

Angiotensin receptor blocker

ACEI

Angiotensin-converting enzyme inhibitor

BP

Blood pressure

BMI

Body mass index

C1q

Complement component 1q

C3

Complement component 3

cAP

Complement alternative pathway

Cis

Confidence intervals

CRP

C-reactive protein

DBP

Diastolic blood pressure

DN

Diabetic nephropathy

ERSD

End-stage renal disease

RBC

Erythrocyte

HRs

Hazard ratios

IgA

Immunoglobulin A

IgG

Immunoglobulin G

IgM

Immunoglobulin M

LDL-c

Low-density lipoprotein cholesterol

LDH

Lactate dehydrogenase

mHTN

Malignant hypertension

MAP

Mean arterial pressure

PSM

Propensity score matching

RRT

Renal replacement therapy

SD

Standard deviation

SBP

Systolic blood pressure

T2DM

Type 2 diabetes mellitus

TMA

Thrombotic microangiopathy

Author contributions

All authors contributed to each of the following aspects of the study: Jianbo Li and Feng He designed the research study and revised the manuscript. Wanxin Shi and Xingji Lian collected the data and wrote the paper. Wenchuan Li, Rong Lian, Shengyou Yu and Zefang Dai were responsible for data acquisition. Zhong Zhong, Yiqin Wang, and Wei Chen were responsible for data analysis and statistical analysis. All authors reviewed and approved the final manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82070752, 82470748, 82170737, 82370707), National Key Research and Development Project of China (No. 2021YFC2501302, 2022YFC2705103, 2022YFC2705100, 2022YFC2705104), 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), Guangzhou Municipal Programme of Science and Technology (2024B03J1337), and the Science and Technology Projects in Guangzhou, China (No. 2023A04J0613).

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-sen University (No. IEC [2022] 710). All procedures involving human participants were performed after obtaining informed consent from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.