NDT Advance Access originally published online on November 25, 2005
Nephrology Dialysis Transplantation 2006 21(2):522-525; doi:10.1093/ndt/gfi288
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A 14-year-old girl with renal abnormalities after brief intrauterine exposure to enalapril during late gestation
1 Department of Nephrology, Institute of Internal Medicine, 2 Department of Pathology, Institute of Laboratory Medicine, 3 Department of Pediatrics, Institute for the Health of Women and Children and 4 Department of Clinical Physiology, The Cardiovascular Institute, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden
Correspondence and offprint requests to: Gregor Guron, MD, PhD, Department of Nephrology, Institute of Internal Medicine, The Sahlgrenska Academy at Göteborg University, Box 432, 405 30 Göteborg, Sweden. Email: gregor.guron{at}kidney.med.gu.se
Keywords: albuminuria; angiotensin-converting enzyme inhibitors; kidney development; renin–angiotensin system; urine-concentrating ability
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Introduction |
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In addition to its important role in the regulation of extracellular fluid homeostasis, an intact renin–angiotensin system (RAS) is essential for normal kidney development [1]. Several case reports have described fatal acute renal failure and renal tubular dysplasia in fetuses and newborns exposed to angiotensin-converting enzyme (ACE) inhibitors [2] or angiotensin II type-1 (AT1) receptor antagonists [3] during the second or third trimester. Notably, nephrogenesis is completed at about gestational week 36 in humans. Experimental studies have shown that interruption of the RAS during ongoing nephrogenesis, either pharmacologically or by gene knockout techniques, produces abnormalities in renal morphology and function that bear similarities to those described in case reports, and that normal kidney development is mainly mediated through the AT1 receptor [1,4,5]. Renal morphological abnormalities in these animals are characterized by papillary atrophy, wall thickening of pre-glomerular arterioles, and tubular atrophy and dilatation [1,4,5]. Functional defects are mainly characterized by a marked impairment in urinary concentrating ability [1]. Recent studies have demonstrated important roles for the AT1 receptor in tubular growth [6], branching morphogenesis [5] and the establishment of normal tubular cell–cell and cell–matrix interactions [7] in the developing kidney. In addition, angiotensin II is important for normal development of the renal pelvis and ureter [4].
Although maternal use of drugs that block the RAS during the second and third trimester sometimes induces fatal acute renal failure and renal tubular dysplasia in newborns, it is not known what the long-term consequences are on the kidney in survivors. We here describe a patient who was exposed to the ACE inhibitor enalapril during gestational weeks 28–36 and who at 14 years of age presented with a marked impairment in urinary concentrating ability, proteinuria and a reduction in glomerular filtration rate (GFR). This renal phenotype resembles that described in laboratory animals exposed to ACE inhibitors during a corresponding interval of kidney development.
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Case |
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A 14-year-old Caucasian girl was evaluated in the paediatric nephrology clinic because of persistent proteinuria. Proteinuria (1+ to 2+ on dipstick) had been detected 7 years earlier during an episode of cystitis. However, isolated proteinuria persisted after resolution of the infection. At 14 years of age, urinary protein excretion ranged from 1.8 to 2.7 g/24 h and the serum creatinine level was 108 µmol/l. On physical examination, the patient's weight was 60 kg, height 159 cm, blood pressure (BP) 120/60 mmHg, and she appeared normal.
The patient's mother had end-stage renal disease and had been diagnosed with nephrosclerosis after a kidney biopsy at 24 years of age. She had had hypertension since her teens, and at the time of the biopsy she had a GFR of 38 ml/min per 1.73 m2, but no proteinuria. At 27 years of age, she became pregnant with the now 14-year-old girl, and was treated with a combination of labetalol (400 mg twice a day), amiloride (5 mg/day) and hydrochlorothiazide (50 mg/day) from the start of pregnancy, with the addition of prazosin (2 mg twice a day) in the second trimester. Due to poor BP control, enalapril at a dose of 5 mg/day was added in gestational week 28, and in gestational week 32 the daily dose of enalapril was increased to 10 mg. In gestational week 36, cardiotocographic abnormalities were observed and labour was induced. The delivery was uneventful although there was modest oligohydramnios. The newborn baby girl weighed 2140 g, Apgar scores were 8 at 1 and 5 min, and she appeared normal on physical examination. In the neonatal care unit, she developed transient acute renal failure and anuria with a peak serum creatinine of 890 µmol/l on postnatal day 8. A BP of 60/40 mmHg was recorded on postnatal day 4. Urine analyses, and renal ultrasonography, were normal. There was a spontaneous recovery without need for dialysis, and 8 weeks after birth creatinine levels were 69 µmol/l. Her medical history was then uneventful until the detection of proteinuria 7 years later.
The main results from examinations at 14 years of age are summarized in Table 1. Urinary protein electrophoresis showed a distinct pattern of selective glomerular proteinuria and no Bence-Jones proteins. The GFR, measured by [51Cr]EDTA clearance, was moderately reduced, and there was a marked impairment in urinary concentrating ability of renal origin (Table 1). Venous blood gases and urine analyses during baseline conditions revealed a normokalaemic (3.9 mmol/l), normal plasma anion gap (15 mmol/l) metabolic acidosis, with an inappropriately high urinary pH and a positive urine anion gap (Table 1). Urinary electrolytes were: Na, 83 mmol/l; K, 37 mmol/l; and Cl, 92 mmol/l. Similar acid–base data were obtained on two separate occasions, and results were compatible with type 1 (distal) renal tubular acidosis (RTA). The calculated transtubular potassium gradient (TTKG) was 7.7 and within the normal range [8]. Ultrasonography showed normal-sized kidneys with mild, diffuse, bilateral, hyperechogenicity, but no other pathology. Kidney dimercapto-succinic acid (DMSA) scintigraphy was normal. In addition, complete blood counts, serum protein electrophoresis, erythrocyte sedimentation rate, and plasma levels of glucose, electrolytes, phosphate, C-reactive protein, complement and antinuclear antibodies were normal.
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A percutaneous renal biopsy was performed and light microscopy revealed enlarged glomeruli without sclerosis or cell proliferation, and focal tubular dilatation (Figure 1). Of a total of 10 glomeruli, six showed a maximal glomerular diameter exceeding 300 µm (range 240–390 µm). Immunofluorescence analyses were negative. Arteries, arterioles, tubular epithelial cells and the interstitium appeared normal. There was no interstitial fibrosis or inflammation. Electron microscopy revealed that glomerular basement membranes were somewhat thin although within the normal range (Figure 2). There was modest fusion of podocyte foot processes but no depositions (Figure 2).
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Discussion |
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Intrauterine exposure to ACE inhibitors, or AT1 receptor antagonists, gives rise to acute renal failure in the neonatal period which presumably is caused mainly by hypotension and a reduction in glomerular capillary pressure secondary to an ongoing lack of AT1 receptor activation. In addition to the direct haemodynamic effects of these drugs, we now know from experimental studies in different species that an intact RAS is essential for normal structural development of the kidney [1,4]. Thus, it is feasible to hypothesize that exposure to drugs that block the RAS during a period of ongoing nephrogenesis in humans may give rise to permanent renal abnormalities, as has been demonstrated in animals. The patient described in the present report showed renal morphological and functional alterations at 14 years of age after exposure to enalapril during the final 8 weeks of nephrogenesis (i.e. from gestational weeks 28 to 36). To our knowledge, this is the first report presenting such a long-term follow-up of a patient exposed in utero to drugs that block the RAS.
The major renal dysfunctions in the 14-year-old girl were a marked impairment in urinary concentrating ability of renal origin, a modest reduction in GFR, type 1 RTA and proteinuria. In general, these findings are in good agreement with our observations in adult rats treated with enalapril briefly during the latter stages of nephrogenesis. In these rats, we have repeatedly found that the GFR, measured by [51Cr]EDTA clearance, is reduced by 10–30% [1], a reduction similar to the one in this 14-year-old girl. In addition, Bos-Thompson et al. [3] reported a comparable reduction in GFR (plasma creatinine ranging from 97 to 124 µmol/l) in a 30-month-old child exposed to the AT1 receptor antagonist valsartan from gestational weeks 0 to 25. One possible explanation for the reduction in GFR in the 14-year-old girl could be a reduced number of functioning nephrons, as neonatal treatment with the AT1 receptor antagonist losartan in rats has been shown to decrease the number of glomeruli [9,10]. Interestingly, six out of 10 glomeruli on the biopsy from the 14-year-old girl were clearly enlarged. Presumably, the glomerular hypertrophy could be explained by this patient having a reduced number of glomeruli and a compensatory hyperfiltration of the remaining nephrons. Moreover, and in line with the hypothesis put forward by Brenner and co-workers [11], we speculate that an increase in glomerular capillary pressure of residual nephrons could have contributed to progressive glomerular structural injury and the development of proteinuria.
Interestingly, the most striking functional abnormality in the 14-year-old girl was a pronounced defect in urinary concentrating ability which was of renal origin. This finding is in agreement with earlier observations of a nephrogenic urine concentration defect in mice, rats and pigs subjected to RAS inhibition during nephrogenesis [1]. However, in the experimental studies, the urine concentration defect was accompanied by papillary atrophy. Although renal ultrasonography did not reveal any hydronephrosis or macroscopic medullary changes in the 14-year-old girl, we cannot rule out the existence of such abnormalities. In support of an altered integrity of the renal medulla, she also presented with distal RTA. As the medullary collecting duct is an important site of acid secretion, in addition to solute-free water reabsorption, an abnormality in medullary collecting duct function could presumably explain both the distal RTA and the urine-concentrating defect.
Could there be any cause for the renal abnormalities in this 14-year-old patient other than intrauterine exposure to enalapril? Considering that the mother had chronic renal failure, one might suspect a hereditary kidney disease. However, in contrast to the situation in the daughter, the mother had no proteinuria even when the GFR had reached 38 ml/min/1.73 m2, at which stage biopsy revealed nephrosclerosis. In addition, renal histological changes in the 14-year-old girl were unspecific, and could not be classified into any hereditary kidney disease. Concerning other medications taken by the mother during pregnancy, labetalol, diuretics and prazosin are unlikely to have adverse effects on the fetus [12].
In conclusion, we report the case of a girl who was exposed to enalapril from gestational weeks 28 to 36, developed transient acute renal failure in the neonatal period, and who at 14 years of age presented with a marked impairment in urinary concentrating ability of renal origin, a modest reduction in GFR, type 1 RTA and proteinuria. The renal phenotype in this 14-year-old girl demonstrated a clear resemblance to that described in animals treated with ACE inhibitors during a corresponding period in kidney development. These findings indicate that brief exposure to ACE inhibitors during late gestation may give rise to chronic renal abnormalities in humans, and suggest that exposed children should be followed-up later in life.
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Acknowledgments |
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This study was supported by the Swedish Research Council (grant no. 2002-3665), the Swedish National Heart and Lung Foundation, Jeanssons Foundation, the Göteborg Medical Society, the Swedish Medical Society, the Åke Wiberg Foundation and the Magnus Bergvall Foundation. The technical assistance of Ulla Höök is acknowledged.
Conflict of interest statement. None declared.
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References |
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Accepted in revised form: 8.11.05
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