Hyponatremic hypertensive syndrome and posterior reversible encephalopathy secondary to unilateral renal artery stenosis - a case report

Abstract

Background

Renal artery stenosis is one of the secondary causes of hypertension in children. Hyponatremic hypertensive syndrome (HHS) is an uncommon disorder usually seen in adults with unilateral renal artery stenosis and atherosclerosis but it’s rarely reported in children.

Case presentation

A 5-year-old male child presented with generalized tonic clonic convulsions associated with severe hypertension, hyponatremia, hypokalemia, and polyuria. Laboratory tests revealed elevated plasma renin activity, and aldosterone level. The diagnosis of hyponatremic hypertensive syndrome secondary to unilateral renal artery stenosis was made. MRI of the brain was consistent with posterior reversible leukoencephalopathy syndrome (PRES). The patient responded to left renal artery stenting with control of blood pressure.

Conclusions

Findings of hyponatremia, hypokalemia, hypertension, polyuria can be attributed to unilateral renal artery stenosis with associated HHS. Early recognition is important for early management of such treatable condition to prevent irreversible renal damage.

Background

Hypertension in children requires appropriate and rapid diagnosis to identify secondary causes including coarctation of the aorta, renal parenchymal diseases, renal artery stenosis, and endocrine diseases. Renovascular hypertension accounts for up to 25% cases of severe hypertension in children [1, 2, 3, 4]. Fibromuscular dysplasia of the renal arteries predominates, representing 60% of cases [5]. The combination of hypertension and hyponatremia, hyponatremic hypertensive syndrome (HHS), can be seen in a number of disorders including acute and chronic renal failure [6], malignant hypertension [7], renin-secreting tumors [8–12] and renal ischemia. Hyponatremic hypertensive syndrome (HHS) was at first reported in adults but it is still considered a rare condition in children [1, 2].

HHS caused by renal ischemia has been reported infrequently [13]. It could result from any cause of high renin conditions. The most common etiology in children is unilateral renal artery stenosis. Without the appropriate and timely treatment, hypertensive encephalopathy, retinopathy, cardiomyopathy, and nephropathy can develop [14].

We describe a 5-year-old male child with HHS, caused by unilateral renal artery stenosis, presenting with seizures, hypertension, hyponatremia, polyuria and polydipsia, complicated by posterior reversible leukoencephalopathy syndrome (PRES).

Case Presentation

5 years-old male child of non-consanguineous marriage, who has no any systemic disease, presented with one day history of generalized tonic clonic convulsions that happened 4 times the day before being admitted. It was not associated with fever. He had one month history of headache and 2 years history of polyuria, polydipsia and failure to gain weight properly. His Physical examination revealed body weight 15 kg (3rd percentile), height 99 cm (3rd percentile), blood pressure 205/150 mmHg (there was no blood pressure discrepancy between upper and lower extremities), heart rate 140/min. There was normal neurological examination and no palpable abdominal mass. Laboratory studies revealed persistent hyponatremia, hypokalemia, metabolic alkalosis and normal blood glucose level (Table 1). Urine Na + was 48 mEq/L and Cl − was 52 mEq/L. The urine analysis was also significant for microalbuminuria (urine albumin/creatinine ratio of 277 mg/g creatinine). MRI of the brain revealed left small area of parieto-occipital demyelination consistent with PRES (Fig. 1). In addition, plasma renin level 128 (normal range 3.5–36 pg/mL), aldosterone 471 (normal range 14.2–156 pg/mL). Also investigations for vasculitis demonstrated normal C3, C4 levels, negative anti-neutrophil cytoplasmic antibody (ANCA), and weak positive anti-nuclear antibody (ANA). Fundus examination on the right side was normal. However, on the left side, it showed hypertensive retinopathy and papilledema. Left ventricular hypertrophy was evidenced by echocardiography. During admission, he had polyuria with urine output ranging from 10 ml/kg/hr in the first 2 days of admission then down to 4–5 ml/kg/hr. Abdominal ultrasound examination showed no masses, normal liver and spleen. Renal ultrasonography revealed hyperechoic right kidney (8.5 cm in length) and relatively smaller left kidney (7 cm in length). Doppler ultrasound studies indicated left renal artery stenosis. The presence of hyperreninemic hypertension, natriuresis, hyponatremia and hypokalemia makes HHS more likely. Computed tomography (CT) angiography confirmed left renal artery stenosis with relatively small sized left kidney. The left renal artery showed proximal short stenotic segment of about 6 mm in length, causing significant luminal reduction of 60–75% with lower peri-renal collateral branch from the inferior mesenteric artery (Fig. 2).

For management of this case, fluid deficit was corrected by glucose normal saline administration. His blood pressure declined from 205/150 mmHg to 160/100 mmHg. Intravenous hydralazine and oral slow-release nifedipine were initially used. The systolic blood pressure gradually decreased to 130–150 mmHg on the 4th day after adding oral methyldopa, oral carvedilol and then oral doxazosin. On the 6th day, it declined to 110–125 mmHg after escalating the doses of the previously mentioned oral medications. With control of his blood pressure, his serum Na level began to get higher than at admission and his polyuria began to improve gradually. Hypokalemia was corrected by intravenous potassium and later by oral potassium. The decision was made to proceed with renal artery stenting. Overall, electrolyte abnormalities such as hyponatremia and hypokalemia were corrected within one week after admission, and resolution of polyuria, polydipsia, proteinuria, and hypertension were achieved 3 weeks after renal artery stenting. Antihypertensive drugs were tapered. Since hospitalization, he has been free of seizures.

Discussion And Conclusions

Renovascular hypertension should be considered in children with suspected secondary hypertension, as well as in those with high plasma renin, hypokalemia, or hypertension so severe that it necessitates more than two agents to normalize the BP [15]. A number of causes of renovascular disease are shown in Table 2 [3]. Fibromuscular dysplasia is the most common cause [5]. Hypertension with hyponatremia in the setting of renovascular disease is better known as hyponatremic hypertension syndrome (HHS) [3]. There are few case reports of HHS as a presenting feature of renal artey stenosis [16, 17].

The symptoms of HHS include central nervous system (CNS) abnormalities such as headache, confusion, and seizures as in this case, along with weight loss, polydipsia, and polyuria [1, 18]. Laboratory abnormalities include hyponatremia, hyperreninemia, hypokalemia, hyperaldosteronemia, metabolic alkalosis, and high urinary sodium, and protein levels [3]

This is a case of 5-year-old male child who presented with seizures and severe hypertension. Coarctation of aorta was unlikely as we could not find higher blood pressure in the upper limb than the lower limb. Echocardiography had excluded it. The boy had no any manifestations of systemic disease or findings suggestive of renal parenchymal disease. The presentation with hypertension, hyponatremia, hypokalemia, polyuria was a guide to suspect HHS as a most likely diagnosis. The MRI of brain was suggestive of PRES secondary to hypertension.

The main pathogenesis of HHS is renal ischemia. As explained by Atkinson et al [19] (Fig. 3), the critical renal ischemia increases renin secretion, resulting in high angiotensin II levels, which raise the blood pressure by its direct vasoconstrictor effect and secondary hyperaldosteronism as well. A sudden rise in arterial pressure can cause glomerular hyperfiltration and subsequential pressure natriuresis [20] of the non-stenotic kidney, leading to volume depletion and hyponatremia that may result in further renin secretion from the ischemic kidney, and higher aldosterone response to angiotensin II [21, 22]. Hypokalemia, as a result of hyperaldosteronism, may further increase renin secretion [23], thus intensifying the vicious circle. The hyponatremia may result also from stimulation of thirst and antidiuretic hormone (ADH) release in response to the dual stimuli of high levels of angiotensin II and volume depletion [24, 25].

Metabolic alkalosis is also a consequence of the renin-angiotensin-aldosterone system activation [3]. Glomerular hyperfiltration of the contralateral healthy kidney, attributed to hyperreninemia-induced hypertension, could lead to tubulointerstitial injury by hypercalciuria and hyperuricosuria [26]. Proteinuria in cases of HHS can be due to the glomerular hyperfiltration, proteinuric effect of angiotensin II, and/or tubulointerstitial injury by hypercalciuria and hyperuricosuria [27].

Ding et al. [14] reviewed 15 reported pediatric cases of HHS secondary to unilateral renal artery stenosis with the mean age at onset was 4.03 ± 3.38 years with male predominance (11/15) which is similar to our case gender and age. The combination of hypertension, polydipsia, and polyuria were the most common presentations (14/15), followed by hyponatremic seizure (7/15).

Agarwal et al. [13] reported 32 adult patients with hyponatremic-hypertensive syndrome with the main symptoms of headache, disturbed consciousness, or confusion in 24 patients; weakness, weight loss, thirst, and/or polyuria in 15 patients. 7 patients had papilledema and/or retinal hemorrhages. Our case had similar manifestations with fundus examination showing hypertensive retinopathy in the left eye.

Posterior reversible leukoencephalopathy syndrome (PRES) has only been described in cases with the primary diagnoses of glomerulonephritis, systemic lupus erythematosus, Henoch–Schönlein purpura, hemolytic uremic syndrome, or hemato-oncologic diagnoses [28, 29, 30]. Risk factors for development of PRES can include hypertension, infection, and presence of inflammatory cytokines, collagen vascular disease, organ transplantation and immunosuppressive agents [30, 31].

The pathophysiology of PRES secondary to hypertension could be explained by reduced cerebral blood flow and capillary leak with endothelial dysfunction leading to hypoperfusion and ischemia. The posterior region of the brain is more vulnerable to ischemia due to its impaired autoregulation and decreased sympathetic innervation. Hypertension, however, is not present in 20–40% of cases and the pathophysiology of other etiologies is not well understood [31]. Early diagnosis is important for rapid initiation of treatment to prevent permanent sequelae. Clinical features include hypertension, seizures (42%), visual changes (33%), headache (17%), and disturbed conscious level (8%) [28]. PRES dagnosis is confirmed with MRI with FLAIR (fluid-attenuated inversion recovery), in which white matter lesions and edema appear bright, where bilateral white matter abnormalities in the watershed zones of posterior regions and vasogenic subcortical edema are expected to be seen [30, 31].

Other causes of hyponatremia in patients with hypertension, rather than renal artery stenosis, include thiazide diuretics [32], renin-secreting tumors [8–12], acute intermittent porphyria [33], malignant hypertension [7], acute or chronic renal failure [6]. These need to be considered, along with renal ischemia, in the differential diagnosis of the hypertensive patient with hyponatremia.

Masavkar et al [34] reported a patient with unilateral renal artery stenosis secondary to Takayasu arteritis. The patient had hyponatremia, hypokalemia, polydipsia, polyuria, weight loss, and high renin and aldosterone levels which are compatible with a diagnosis of HHS. In most adult patients with HHS, the underlying renal pathology has been atherosclerosis. However, in children, HHS has been described with renal ischemia due to fibromuscular dysplasia, Wilm’s tumor, neurofibromatosis type 1, and renal damage secondary to bladder dysfunction [16, 17, 35–37].

The main lines of treatment of renal artery stenosis associated HHS include correction of volume depletion, correction of hypokalemia, control of the hypertensive crisis along with correction of the underlying renal artery stenosis. Volume depletion needs to be corrected first to improve systemic blood flow and prevent further injury resulting from renal ischemia [38]. Control of hypertension can be done by intravenous calcium channel blocker [39]. The use of diuretics is not recommended as fluid and sodium wasting will be aggravated which could further activate the renin-angiotensin-aldosterone (RAA) system [40]. angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker should be introduced for cases with HHS, to block the over-activation of the RAA system [35]. However, ACE-inhibitors are generally contraindicated as first line antihypertensives. In cases of bilateral renal artery stenosis, or cases with solitary kidney, they can cause dilation of glomerular efferent arteriole, decreased glomerular filtration rate (GFR), and acute kidney injury [15]. Surgical correction of renal artery stenosis can be achieved by percutaneous renal angioplasty, renal artery reconstruction or unilateral nephrectomy [34]. Nephrectomy is required if an affected kidney contributes < 10% of the global renal function or if percutaneous transluminal angioplasty fails [41]. Our patient had received antihypertensive drugs including intravenous hydralazine, beta blocker and calcium channel blocker. He was later managed by renal artery stenting.

Late recognition of HHS without adequate management can cause severe kidney injury as a result of ischemia, hypoperfusion and infarction [4]. The delay in diagnosis is also responsible for other end organ damage, as left ventricular hypertrophy, risk of severe irreversible neurological damage due to the effect of the hypertensive and hyponatremic encephalopathy [4, 38]. Some patients had residual hypertension despite aggressive treatment [14]. The explanation for this residual hypertension could include restenosis of the renal artery following angioplasty as reported by a longitudinal study by Zhu et al [42], chronic kidney disease caused by prolonged tissue hypoxia and proteinuria that could lead to hypertension despite restoration of renal blood flow [43] and irreversible remodeling of vascular endothelium induced by the uncontrolled hypertension itself which results in permanent hypertension [44]. The prognosis of PRES secondary to renal disease, such as our patient, is excellent as most patients recover with minimal neurological sequelae [30].

In conclusion, HHS caused by unilateral renal artery stenosis is a potentially curable and reversible disease especially when promptly diagnosed and appropriate treatment is initiated. Hypertension, natriuresis, hyponatremia, hypokalemia are clinical clues for diagnosis. The rarity of HHS in children may be due to its under-recognition by primary care physicians and pediatricians as well. Early diagnosis and prompt treatment of HHS helps to prevent continuous renal damage and other life-threatening complications. This case highlights the importance of blood pressure measurements for early detection of hypertension at any age, especially in children presenting with unexplained polyuria and polydipsia.

Abbreviations

ANCA, Anti-neutrophil cytoplasmic antibody; ANA, Anti-nuclear antibody; ADH, antidiuretic hormone; CT, Computed tomography; FLAIR, fluid-attenuated inversion recovery; GFR; glomerular filtration rate; HHS, Hyponatremic hypertensive syndrome; PRES, posterior reversible leukoencephalopathy syndrome; RAA, renin-angiotensin-aldosterone

Declarations

Acknowledgments

Not applicable

Authors' contributions

Conceptualization, ASK and MAS; collecting patient data and writing preparation, MAS; writing review and editing, ASK, MAS; Manuscript review and final editing, MEAG, RMYA. All authors have read and agreed to the final version of the manuscript.

Funding

None

Availability of data and materials

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

Ethics approval and consent to participate

Not applicable.

Consent for publication

The patient’s parents have provided written informed consent for publication of identifying information/images in an online open-access publication.

Competing interests

The authors declare that they have no competing interests.

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