Young‐Adult Hypertension as a Presentation of Familial Renal Disease

A previously healthy 20-year-old woman presented to the hospital with a 2-day history of headache, nausea, vomiting, and a blood pressure (BP) of 240/150 mm Hg. She also described mild visual blurriness and transient numbness of the right upper extremity. Eight months before admission and prior to initiation of oral contraceptive pills (OCPs) (1 mg ethynodiol, 35 μg estradiol) for control of mild metromenorrhagia, recorded BPs were ≈120/70 mm Hg. After 2 days of treatment, BP improved to 150/100 mm Hg and the patient was discharged on metoprolol 50 mg b.i.d. A negative workup for secondary etiologies included 24-hour urine collections for vanillylmandelic acid assay, metanephrines, and catecholamines, a postcaptopril renal scan, and an abdominal magnetic resonance imaging scan. A brain magnetic resonance imaging scan was normal. Laboratory testing revealed blood urea nitrogen 25, creatinine 1.6, and urinalysis with 1+ protein. OCPs were discontinued, and she was referred to the hypertension clinic. Physical examination revealed an obese white female with body mass index 38, BP 164/96 mm Hg. There was no edema or striae, peripheral pulses were intact without bruits, and there was no retinopathy. Family history was significant; the patient's maternal grandmother had hypertension without known renal disease. Her mother was several years post renal transplant for end-stage renal disease (ESRD) secondary to biopsy-proven focal segmental glomerulosclerosis (FSGS). Her mother had renal disease with proteinuria and azotemia without hypertension and was not obese. Her father and 15-year-old sister were normal. Illicit drug use was denied. Additional workup proceeded with a normal renal artery magnetic resonance angiography study, antinuclear antibody negative, human immunodeficiency virus negative, sedimentation rate of 36, negative hepatitis serology, a normal 24-hour urine free cortisol collection, and normal renal ultrasonography. Six months following OCP cessation, ongoing treatment with hydrochlorothiazide, metoprolol, and lisinopril resulted in blood pressure of 140/100 mm Hg. Serum creatinine levels were consistently 1.8–2.0 mg/dL with a creatinine clearance of 73 cc/min, and a 24-hour urine protein collection was 2.5 g. The patient was referred for renal biopsy. Light microscopy and electron microscopy findings were consistent with focal segmental glomerulosclerosis (Figure 1 and Figure 2). Light microscopy of renal biopsy revealing a dark crescent-shaped area of segmental sclerosis partially occluding the right side of the glomerulus consistent with focal segmental glomerulosclerosis (Jones methenamine silver stain) Electron microscopy of renal biopsy showing effacement of podocyte foot processes. Portions of red blood cells are seen in the intravascular space to the left of the broad basement membrane running diagonally from top to bottom and left to right. The darker gray lumpiness attached to the right of the basement membrane represents foot process fusion (characteristic of focal segmental glomerulosclerosis) Initial suspicion was that this patient's hypertension was related to OCPs because of the documented onset on antimetromenorrhagia therapy. Most often OCP-related BP elevations are between 4 and 9 mm Hg systolic although diastolic elevations can be seen.1 Severe elevation in previously normotensive persons is a rare observation.2 BP elevations on OCPs most often return to pretreatment levels following 3–6 months of cessation1 but remained elevated for this patient. Malignant hypertension on OCPs can occur2 in association with nephrotic-range proteinuria and azotemia. However, the family history of FSGS in the context of proteinuria and azotemia raised the prospect of underlying familial renal disease. The persistence of renal dysfunction and near nephrotic proteinuria necessitated the renal biopsy. FSGS has become the leading cause of idiopathic nephrotic syndrome in the United States, replacing membranous glomerulopathy, and is particularly common in the adult African-American population.3 The US renal disease systems database demonstrates both the rising prevalence of ESRD caused by FSGS (Figure 3) and also the disparate ethnic distribution predisposing African Americans for unknown reasons (Figure 4).3 Almost two thirds of African-American adults with nephrotic syndrome demonstrate the FSGS lesion on renal biopsy.4 FSGS is frequently resistant to medical intervention, which usually consists of at least 4 months of high-dose steroids. Fifty percent of patients progress to ESRD in 3–8 years.5 The major risk factors for progression are a creatinine level >1.3 mg/dL, and nephrotic-range proteinuria (>3 g/24 hours) at the time of presentation.6 US renal disease systems database demonstrating the rising prevalence of end-stage renal disease (ESRD) caused by focal segmental glomerulosclerosis (FSGS) according to ethnic group for the years shown US renal disease systems database showing the annual incidence rates of end-stage renal disease (ESRD) caused by focal segmental glomerulosclerosis in cases/million from 1995 to 1999 by ethnic group, and the disproportionately high rate in the African-American group compared with the general US population (US pop) Familial FSGS has been associated with both dominant and recessive Mendelian inheritance.7 Recessive FSGS has been characterized by early childhood onset, rapidly progressive renal disease, and has been mapped to chromosome 1q 25–31. This particular case discussion more likely involves autosomally dominant FSGS. Autosomally dominant FSGS typically has a later more gradual onset than recessive FSGS, and has been associated with mutations in the ACTN 4 gene, which encodes α-actinin-4.7, 8 Interestingly, this FSGS case presented with a hypertensive emergency, but her mother with FSGS had a more typical presentation with nephrotic syndrome without hypertension. Genetic and acquired influences were probably involved: a maternal grandmother had hypertension without kidney disease (genetic effect); this patient was obese compared with her lean mother and was also taking OCPs (acquired or environmental effects). Hypertension may be a consequence of low-dose estrogen-containing OCPs (30 μg estrogen), and together with a family history of hypertension, obesity, and underlying renal disease may increase the risk of severe hypertension when taking these agents.9 FSGS associated with obesity, reduced nephron mass (i.e., solitary kidney), reflux nephropathy, human immunodeficiency virus infection, heroin, or sickle cell disease usually occurs with glomerulomegaly and less extensive foot process fusion than in patients with primary or familial FSGS.10 However, there could not be any commentary with regard to this possible distinction based on the few glomeruli available for microscopic examination in the current case. Although nephrotic syndrome is the most common presenting feature of FSGS, Korbet5 observed that nonnephrotic presentations including hypertension (45%), microscopic hematuria (45%), and renal insufficiency (30%) are quite frequent. Whereas a 4-week course of high-dose steroids followed by intermittent dosaging commonly leads to complete remission in children with nephrotic syndrome due to minimal change disease, <30% with FSGS will respond to short-course steroids. A few series have reported 44% complete response rates in children with nephrotic syndrome secondary to FSGS treated with high-dose steroids of at least 4–6 months' duration.11, 12 Adults may be somewhat less responsive, in the 20%–30% range.4 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers have been shown to reduce proteinuria and renal disease progression in nondiabetic renal disease, including primary glomerulopathies.10 Greatest benefit appears to occur with nephrotic-range proteinuria. A few small studies of ACE inhibitors in patients with primary focal segmental glomerulosclerosis have shown reduction in proteinuria without slowing the progression of renal decline.13, 17 One retrospective study of 48 patients with biopsy-proven FSGS showed no additional antiproteinuric effect of adding steroids to an ACE inhibitor alone.15 ACE inhibition in FSGS secondary to obesity, reflux nephropathy, reduced nephron mass, and sickle cell disease have shown 50% reductions in proteinuria with stabilization of renal function.13 However, secondary FSGS in general has a better prognosis with regard to ESRD than primary FSGS. The spectrum of obesity-related glomerulopathy, including FSGS, has become more prevalent with an increasingly obese population but is associated with a lower incidence of nephrotic-range proteinuria and a more indolent clinical course than primary FSGS.18 Both ACE inhibition and significant weight loss (approximately a 10% reduction in body mass index), can significantly reduce proteinuria in obesity-related FSGS.18, 19 One retrospective study of 40 African-American patients with FSGS did not demonstrate any renoprotective benefit with either ACE inhibitors or steroids,14 and African Americans with primary FSGS are generally believed to be less responsive to therapy.20, 21 Counseling sessions with this patient led to a strategy of maximizing ACE inhibition to achieve a goal BP <130/80 mm Hg, and reducing weight. The lower likelihood of benefit with prolonged high-dose steroids and her obesity led to a decision against such a trial. For nephrotic FSGS patients with relative contraindications to prolonged high-dose steroids such as obesity, diabetes, or psychiatric problems, other agents such as cytoxan, azathioprine, and chlorambucil have been used for 6–8 months attaining 30%–40% remission rates, but none have been subjected to a large, randomized trial.20 This patient refused the option of prolonged alternative immunosuppression. Her presentation with renal insufficiency and near-nephrotic proteinuria along with her mother's history of ESRD give her a less-favorable prognosis for avoiding ESRD within the next decade. Fortunately, although primary FSGS can recur in as many as 30% of renal transplants20 and is an occasional cause for allograft rejection, this has not yet been the case for the patient's mother.