Introduction

Hypertensive emergency is a condition in which elevated blood pressure results in the injury of various organs, such as the cardiovascular system, central nervous system, and renal system [1–3]. Malignant hypertension with severe papilledema requires immediate management [3]. Malignant hypertension may be diagnosed incidentally without any history of hypertension, or may be preceded by a period of essential hypertension [3–5]. Significant proteinuria is an uncommon finding in patients with benign nephrosclerosis associated with essential hypertension. In contrast, malignant hypertension often causes proteinuria, which can sometimes reach the levels seen in nephrotic syndrome [4, 5]. Hypertension is one of the etiological factors of secondary focal segmental glomerulosclerosis (FSGS), which is mediated by adaptive structural–functional changes and associated initially with normal renal mass [4–7]. However, the pathology of the kidney in patients with hypertension and heavy proteinuria is still uncertain.

Here, we report a case of secondary FSGS associated with malignant hypertension in a patient with malignant hypertension, retinopathy, hemolytic anemia, and renal dysfunction with nephrotic syndrome.

Case report

A 32-year-old Japanese man presented with a 1-month history of visual disturbance, headache, and loss of appetite. He had been diagnosed with essential hypertension 10 years earlier, but did not take any medications. He had a history of moderate intake of alcohol (drinking alcohol on weekends) and no history of smoking or drug abuse. The family history included a hypertensive father who died of cerebral hemorrhage at 46 years of age. The patient visited an ophthalmologist at our hospital for persistent visual disturbance and headache. He was found to have severe hypertension (230/160 mmHg) and hypertensive retinopathy, and was referred to our department for further management.

The patient was alert on admission. His height was 172 cm and body weight was 65 kg. His blood pressure was 250/130 mmHg, pulse rate 125 beats/min, and body temperature 37.3 °C. Physical examination showed systolic heart murmur (LEVINE II/VI), and pretibial edema. Visual activity showed numerous digitorum (counting finger), and funduscopy revealed stage IV on the Keith–Wagener classification, including findings of exudates, blot hemorrhages, and papilledema. Chest X-ray showed cardiomegaly (cardiothoracic ratio = 52.2 %), and echocardiography indicated systolic cardiac dysfunction (ejection fraction = 56 %, ventricular asynergy in inferior left ventricular wall, and small pericardial effusion). The plasma level of brain natriuretic peptide was elevated (3989.5 pg/ml). These findings indicated hypertensive cardiac dysfunction. Neurological examination showed no focal signs, but head computed tomography (CT) and magnetic resonance imaging (MRI) revealed focal edema in the pons and white matter of the frontal and occipital lobes.

Serum levels of creatinine (Cr 7.07 mg/dl), blood urea nitrogen (BUN 49.9 mg/dl), and uric acid (8.4 mg/dl) were elevated. Urinalysis showed 4+ proteinuria (10.7 g/day), 3+ hematuria (50–99 erythrocytes/high-power field), no sugar, various sediments, and urinary oval fat bodies (10–19/whole field). Urinary β2-microglobulin concentration was 2291 μg/ml. Serum levels of total protein (6.2 g/dl) and serum albumin (3.1 g/dl) were slightly decreased, and total cholesterol (263 mg/dl) and LDL cholesterol (160 mg/dl) were slightly elevated. These findings indicated renal dysfunction with nephrotic syndrome-like status. Blood analysis also showed hemolytic anemia with thrombocytopenia (erythrocyte count 362 × 104/μl, hemoglobin 11.9 mg/dl, hematocrit 33.5 %, platelet count 11.6 × 104/μl, and haptoglobin 3.0 mg/dl), but ADAMTS13 activity (98 %) was within the normal range. Serological survey showed normal levels of immunoglobulins, complement, antinuclear antibody, and antineutrophil cytoplasmic antibody. Table 1 summarizes the laboratory data on admission.

Table 1 Laboratory findings on admission
Full size table

Based on these findings, he was diagnosed as malignant hypertension with multiple organ damage, including the cardiovascular system, central nervous system, and renal system. The patient was treated with intravenous nicardipine, a calcium channel blocker (Fig. 1). However, he developed anuria on day 2 after admission with elevation of serum Cr level to 9.4 mg/dl, requiring hemodialysis from days 3 to 39. From day 4, his urine volume started to recover gradually.

Fig. 1
figure 1

Clinical course. Malignant hypertension, renal dysfunction, and nephrotic syndrome were present in the early period after admission. Hemodialysis was performed between days 3 and 39. Treatment of malignant hypertension resulted in a decrease in blood pressure and gradual recovery of renal function to mild-to-moderate renal dysfunction, allowing discontinuation of hemodialysis and resolution of the nephrotic syndrome to about 2.0 g/day of proteinuria

Full size image

The cause of malignant hypertension was investigated. Plasma renin and aldosterone were high (renin activity >20 ng/ml/h, active form renin 363.8 pg/ml, aldosterone 302.9 pg/ml). Hormonal assays showed slightly elevated dopamine (54 pg/ml) and noradrenaline (625 pg/ml), but normal adrenaline (47 pg/ml). The urinary catecholamine level was within the normal range. Abdominal CT and MRI showed no atrophic changes in both kidneys. Magnetic resonance angiography showed apparently normal left and right renal arteries. Thus, blood and urinary laboratory tests and the imaging studies failed to detect any cause of hypertension. Therefore, the diagnosis was considered to be primary (essential) malignant hypertension. The laboratory data related to malignant hypertension are summarized in Table 2.

Table 2 Laboratory data concerning malignant hypertension
Full size table

Since the first day of admission, the patient was placed on antihypertensive medications, including calcium channel blocker (nifedipine 20–60 mg) and angiotensin II receptor blocker (ARB, olmesartan 10–20 mg) (Fig. 1). The blood pressure fell to 150/94 mmHg, but proteinuria remained within the nephrotic range (3.2 g/day), and serum albumin level gradually decreased to 2.1 g/dl, with an increase in the total cholesterol (263 mg/dl), indicating the development of nephrotic syndrome.

During hemodialysis under a stable blood pressure level, renal biopsy was performed 29 days after admission in order to determine the renal prognosis and the pathological changes associated with the nephrotic syndrome. Examination of the renal biopsy sample showed prominent changes in the renal arteries (Fig. 2). Marked intimal fibrosis with onion-skin lesions were noted in numerous arterioles, consistent with malignant hypertension. The biopsy material contained 19 glomeruli; 1 was obsolete and 5 tended to show glomerular collapse with wrinkled glomerular basement membrane. In addition, 3 glomeruli showed segmental glomerular hypercellularity with foam cell infiltration and hyperplasia of epithelial cells in Bowman’s space, resembling the features of FSGS, the cellular variant in the Columbia classification. The remaining glomeruli showed minor glomerular abnormalities. Tubular atrophy and interstitial fibrosis were also noted. Immunostaining for CD34, CD68, and α-smooth muscle actin (α-SMA) showed that segmental glomerular sclerotic lesions were characterized by the loss of CD34+ glomerular capillaries with CD68+ infiltrating macrophages and α-SMA+ activated mesangial cells (Fig. 3). Hyperplastic epithelial cells in Bowman’s capsule showed loss of podocyte marker (CD10) and the expression of parietal epithelial cell marker (AE1/AE3). Immunofluorescence examination showed focal segmental deposition of IgM, C3, and C1q in segmental sclerotic lesions, although no deposition of IgG, IgA, C3, or C4 was noted in glomeruli. Electron microscopic examination showed diffuse injury of glomerular capillary endothelial cells, focal effacement of podocyte foot processes, and focal detachment of podocytes from the glomerular basement membrane (Fig. 4). The final diagnosis was malignant nephrosclerosis and secondary FSGS.

Fig. 2
figure 2

Light microscopy (a, d Masson trichrome stain b, f periodic acid silver methenamine stain, c periodic acid-Schiff stain, e elastica Masson-Goldner stain; magnification: a ×200, b ×600, c–f ×800). Renal biopsy specimens showed marked thickening of the intima of the arterioles (arrow in a) and segmental sclerosis (arrowhead in a). About 60 % of the interstitium showed atrophy of the renal tubules with fibrosis. In one glomerulus, hyperplasia of epithelial cells was detected in Bowman’s space (arrowheads in b). Two glomeruli showed segmental endocapillary hypercellularity with infiltration of foam cells (arrows in c and d) and hyperplasia of epithelial cells in Bowman’s space (arrowheads in c and d). Arterioles showed marked intimal thickening without elastosis (e) but with intimal fibrosis (also known as onion-skin lesion) (f)

Full size image
Fig. 3
figure 3

Immunohistochemical examination of representative glomeruli with segmental sclerosis (a staining for CD34; b staining for CD68; c staining for α-smooth muscle actin, α-SMA; d staining for CD10; e staining for AE1/AE3; magnification: a–e ×800). The segmental sclerotic lesion was characterized by the loss of CD34+ glomerular capillaries (arrows in a) with increased deposition of glomerular extracellular matrix and presence of CD68+ macrophages (arrowheads in b) and α-SMA+ activated mesangial cells (arrowheads in c). Hyperplastic epithelial cells on segmental sclerosis were characterized by the loss of normal podocyte marker CD10 and the expression of Bowman’s epithelial cell marker cytokeratin (AE1/AE3)

Full size image
Fig. 4
figure 4

Electron microscopy (magnification: a ×8,000, b ×20,000, c, d ×7,000). Diffuse glomerular endothelial cell injury was detected, which was characterized by diffuse widening of the subendothelial space (arrowheads in a) with mesangial interposition (arrow in b), increased number of endothelial cells with swelling of the cytoplasm (arrowheads in c), and loss of fenestrae in glomerular capillaries. Segmental injury of glomerular epithelial cells was also noted, which was characterized by focal detachment of podocytes from the glomerular basement membrane (arrowheads in b), focal effacement of the foot processes, villi formation, two nuclei per podocyte (arrow in d), and vacuolar formation in the podocyte cytoplasm (arrowhead in d)

Full size image

Treatment with a calcium channel blocker (nifedipine 60 mg), ARB (olmesartan 40 mg), β-blocker (atenolol 50 mg), and renin inhibitor (aliskiren 150 mg) continued, and the patient’s renal function showed gradual recovery, allowing the discontinuation of hemodialysis (Fig. 1). The most recent measures of renal function were BUN of 36.5 mg/dl, Cr 3.14 mg/dl, and proteinuria 1.8 g/day, without hemodialysis.

Discussion

We have reported a case of malignant hypertension with nephrotic syndrome and renal dysfunction. Renal biopsy showed FSGS lesions and endothelial cell injury in addition to typical features of malignant nephrosclerosis. We consider that the nephrotic syndrome in this patient was associated with the development of secondary FSGS in malignant hypertension. Antihypertensive therapy, including ARB, rescued renal dysfunction and nephrotic syndrome. Although the characteristic pathology of hypertensive nephropathy with nephrotic-range proteinuria remains uncertain, secondary FSGS should be considered in patients with malignant hypertension and nephrotic-range proteinuria.

In malignant hypertension, many patients present with hematuria and proteinuria, and some patients show nephrotic-range heavy proteinuria [4, 5]. Since hypertension is considered to be an etiological factor of secondary FSGS [6, 7], it is conceivable that secondary FSGS develops in malignant hypertension with nephrotic syndrome. Although several experimental animal studies concerning malignant hypertension and the formation of FSGS lesions in the kidney have been reported [8–11], the clinical studies of the kidney histology in malignant hypertension have generally not emphasized the prominence of FSGS [4, 5]. Only a few clinical studies described the development of FSGS in malignant hypertension [12–14], and these studies reported that FSGS may occur in primary malignant hypertension with nephrotic-range proteinuria, and may contribute to renal dysfunction. In addition, a few cases of renal artery stenosis with malignant hypertension and nephrotic syndrome have been reported [15–20]. In such cases, histopathological examination of the contralateral kidney often shows lesions of FSGS with benign or malignant nephrosclerosis. In the present case, we did not detect conditions that could cause secondary hypertension, such as renovascular stenosis. The diagnosis of renal biopsy was, therefore, essential (primary) malignant nephrosclerosis with secondary FSGS.

Three mechanisms can be involved in the development of secondary FSGS in patients with malignant hypertension: glomerular hypertension and hyperfiltration, activation of the renin–angiotensin II–aldosterone system, and glomerular endothelial cell injury.

Hemodynamic factors are generally believed to play an important role in the development of secondary FSGS [6, 7, 21–24]. The most important causes of secondary FSGS are conditions associated with high intraglomerular filtration pressure, including uncontrolled severe hypertension. In addition, loss of functioning nephrons may contribute to the augmentation of glomerular hypertension and hyperfiltration [6, 7, 24]. Since 6 out of 19 glomeruli showed global sclerosis or glomerular collapse with glomerular ischemia in the renal biopsy samples, glomerular hyperfiltration after loss of functioning nephrons also developed in the present case. Glomerular ischemia and collapse is also known as one of the etiologies of secondary FSGS, such as arteriosclerosis and cholesterol embolism [6, 7, 25]. In our case, however, FSGS lesions developed mainly in non-collapse glomeruli. We, therefore, considered that the glomerular hypertension and hyperfiltration in malignant hypertension and secondary to nephron loss might contribute to the podocyte injury, as well as the development of secondary FSGS lesions.

Molecular pathogenesis, i.e., activation of the renin–angiotensin–aldosterone system, may play a role in the damage associated with hyperfiltration injury [26–28]. Malignant hypertension is usually accompanied by a high secretion of renin by the kidney, which is not downregulated by the rise in blood pressure. In addition, local tissue angiotensin II is also activated in renal angiotensin-converting enzyme [29]. Angiotensin II contributes to systemic hypertension by constricting the efferent arterioles, causing an increase in intraglomerular pressure and filtration fraction. In addition, angiotensin II also acts directly on the endothelial cells as well as podocyte injury to result in the development of glomerular disease [26–28]. Indeed, in a rat model, angiotensin II-dependent hypertension exhibits endothelial cells and podocyte injury as well as secondary FSGS [11]. The present case indicates that glomerular hypertension and hyperfiltration as well as activation of the renin–angiotensin system may be mediated by secondary FSGS, because the present case of malignant hypertension with nephrotic syndrome was treated successfully with antihypertensive agents, including ARB.

Glomerular endothelial cell injury could also have contributed to the secondary FSGS in the present case. Malignant nephrosclerosis is considered to be a form of thrombotic microangiopathy [4, 5]. The extremely high blood pressure in patients with malignant hypertension can cause direct injury of the endothelium, probably shear stress injury, with the activation of endothelial cells, in small arteries and glomeruli. In our case, hemolysis was present from the admission. Although hemodialysis might influence the augmentation of glomerular endothelial cell injury in renal biopsy findings, we considered that the major mechanism of endothelial cell injury in our case was associated with malignant hypertension. Electron microscopy showed diffuse and global endothelial cell injury in glomeruli. Endothelial injury may result in switching from the endothelial anticoagulant phenotype to the procoagulant phenotype, which is characterized by decreased fibrinolytic activity, including the upregulation of plasminogen activator inhibitor-1, exposure of the thrombogenic subendothelial surface, platelet activation, and cellular activation with upregulation of adhesion molecules, chemokines, cytokines, and transcription factors [30–32]. Infiltration of macrophages and foam cell differentiation with the production of several cytokines also develops in the glomeruli after endothelial cells and podocyte injury [33–36]. Combined, all these factors may contribute to podocyte damage. The exact mechanisms of how endothelial injury contributes to FSGS are not fully understood, but it is assumed that endothelial cell injury probably leads to podocyte damage through endothelial–podocyte interaction [37, 38].

In summary, the present case serves as a reminder that the development of secondary FSGS in malignant nephrosclerosis should be considered in patients with severe hypertension and nephrotic-range proteinuria. It also illustrates the importance of hemodynamic factors, including glomerular hypertension and hyperfiltration, activation of the renin–angiotensin–aldosterone system, and glomerular endothelial cell injury, in glomerular injury and podocyte damage, leading to the development of secondary FSGS in malignant hypertension. The results also emphasize the importance of both the control of blood pressure and the inhibition of the renin–angiotensin–aldosterone system in the management of nephrotic syndrome with malignant hypertension.