Farahnak Assadi

Effect of Microalbuminuria Lowering on Regression of Left Ventricular Hypertrophy in Children and Adolescents with Essential Hypertension

Microalbuminuria (MA) is associated with increased cardiovascular risk in adult hypertensive patients, but no study has specifically examined the effects of MA lowering on regression of left ventricular hypertrophy (LVH) among pediatric patients with hypertension. Fifty-five patients with essential hypertension, 11–19 years old, were prospectively studied. All patients received concomitant therapy of hydrochlorothiazide and angiotensin-converting enzyme inhibitor. Five patients also required angiotensin receptor blocker to achieve the blood pressure goal. Baseline and 12-month follow-up measures of left ventricular mass index (LVMI), determined by echocardiography and urine microalbumin/creatinine ratio (MA/Cr), were collected. MA was defined as MA/Cr >30 μg/mg. LVH was defined as LVMI >38.6 g/m2.7. The primary end points were reductions in MA and LVMI of 25% or more. Weight (r = 0.83), body surface area (r = 0.85), body mass index (BMI) (r = 0.86), systolic blood pressure (SBP) (r = 0.57), diastolic blood pressure (DBF) (r = 0.49), mean arterial pressure (r = 0.53) and MA (r= 0.87) were all univariate correlates of LVMI. In a multiple regression analysis, MA, BMI and SBP were significant correlates of LVMI. MA alone explained 76% of the variance of LVMI, whereas BMI and SBP explained only 1.6 and 0.4% of the variance, respectively. MA was the most significant correlate of follow-up LVMI after BMI and SBP were included in the overall multiple regression models. Thus, MA is a strong predictor of LVH in hypertensive children and adolescents. MA lowering halts the progression of LVH or induces its regression.

Efficacy, Safety, and Pharmacokinetics of Candesartan Cilexetil in Hypertensive Children Aged 6 to 17 Years

This 4‐week randomized, double blind, placebo‐controlled study (N=240), 1‐year open label trial (N=233), and single‐dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy‐one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8–11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P<.01 compared to placebo for SBP and for the mid and high doses for DBP; placebo‐corrected 4.9/3.0–7.5/6.2 mm Hg). The slopes for dose were not, however, different from zero (P>.05). The response rate (SBP and DBP <95th percentile) after 1 year was 53%. The pharmacokinetic profiles in 6‐ to 12‐ and 12‐ to 17‐year‐olds were similar and were comparable to adults. Eight candesartan patients discontinued treatment because of an adverse event. Candesartan is an effective, well‐tolerated antihypertensive agent for children aged 6 to 17 years and has a pharmacokinetic profile that is similar to that in adults.

The epidemic of pediatric chronic kidney disease: the danger of skepticism

Chronic kidney disease (CKD) is a serious, common and costly public health problem and its incidence is on the rise across the globe (1-3). Globally, the prevalence of CKD stage 2 or lower reported to be approximately 18.5 and 58.3 per million children (3). CKD is also a risk factor for cardiovascular disease (CVD), stroke, and heat failure (4). Children with CKD mainly die of cardiovascular cases and infections rather than that from renal failure. Pediatric CKD imposes a large burden on society that is increasing despite ongoing efforts to control the disease. The burden is unevenly distributed by race and economic status. Whereas evidence suggests that preventive strategies could substantially reduce the burden. There are indications that such strategies are not yet in place. The disease largely contributing to the CKD populations are type 2 diabetes, hypertension and focal segmental glomerulonephritis (FSGS) (2,5). Children at risk of CKD include those from congenital anomalies of the kidney and urinary tract (CAKUT), hereditary disorders such as polycystic kidney disease and medullary cystic disease, premature and low birth weights or family history of CKD (3,6). Early detection and treatment are cost effective and neglecting these problems can be very expensive. We do have treatment regimens that are safe, relatively simple, and if not perfect, quite effective. Unfortunately, CKD is usually asymptomatic early in the course of disease until kidney function is severely compromised. Therefore, it seems that the best approach to the problem of the under-diagnosis of CKD is to ensure that all health care professionals, both generalists and specialists, understand the importance of the early detection of kidney disease. In our opinion, nephrologists can play significant role in the education of health professionals, particularly primary care providers. This will help to call attention to CKD, a pathology whose impact on public health is enormous and is rapidly rising. Primary care physicians are at the forefront of detection and management of early CKD. The primary care physicians should be made especially aware that every patient at increased risk of CKD should be systematically screened for the presence of CKD. The primary care physician is responsible for coordinating care with the various specialists (nephrologists, cardiologists and diabetologists) involved in managing CKD. Awareness and communications between the health professionals and nephrologists may be the single most effective step in achieving better outcome in CKD. Increased patient awareness and understanding of CKD would also improve compliance with CKD management and avoidance of medications that can further affect renal function. The primary care interventions that can slow the progression of CKD include treating hypertension to normal blood pressure levels using ACE inhibitors and ARB in both diabetics and non-diabetic patients, maintaining careful glycemic control in those with diabetes, following a low-protein diet, and monitoring patients for the development of microalbuminuria. Treating dyslipidemia, losing weight, stop smoking, and managing anemia also help delay progression of early CKD (7-10). In a recent study, Amin AP and his colleagues reported that among adult patients with established CKD, the risk for progression to end-stage renal disease begins to rise with systolic blood pressure above 140 mmHg (11). Only patients who had a systolic blood pressure of 150 mmHg or greater remained at a statistically significantly higher risk for CKD compared with those who had a systolic blood pressure lower than 130 mmHg. These data suggest that systolic blood pressure reduction below the target goal could increase the risk for heart attack or stroke. In addition, guidelines recommending that blood pressure should be measured in both arms. A difference in systolic blood pressure of 10-15 mmHg or more between arms could identify patients at high risk of symptomatic peripheral vascular disease and mortality who might benefit from further assessment (12,13). Many patients with CKD still receive suboptimal care. The problem is both lack of diagnosis and inadequate treatment. Screening with urinary microalbumin measurement has not been widely used in high risk population for CKD (14). Estimation of the glomerular filtration rate (eGFR) is not properly utilized. More distressing are the data that patients who have had these tests are often not prescribed the cardinal components of the accepted therapeutic regimen. Most widely used eGFR based on serum creatinine are the Modification of Diet in Renal Disease (MDRD) study for adults (15) and the Schwartz equation for children (16). These equations can be calculated at the bedside or issued by the laboratory provide accurate GFR estimates from 20 to 60 mL/min/1.73 m2 with good accuracy but poor bias and precision as well as the lack of calibration material. Furthermore, the Schwartz equation currently overestimates GFR due to a change in the methods used to measure creatinine (17). Lately cystatin C was introduced as a GFR estimate superior to creatinine that can detect mild GFR reduction between 60-90 mL/min/1.73m2. However, no reference method and no uniform calibration material exist for cystatin C either. Further, limitations are the effect of thyroid dysfunction, use of glulcocorticoids and potentially the presence of CVD on cystatin C levels. In a more recent study Schwartz GJ and his associates proposed new equations to estimate GFR in children with CKD, which is based not only on height, gender, and patients’ age and anthropomorphic characteristics, but also on serum creatinin, cystatin C, and blood urea nitrogen (18). These equations are useful in the range of GFR between 15 to 75 ml/min/1.73 m2. Further study of children with higher GFR values will improve the use of these equations for children with CKD. Therefore, supplementing GFR estimates with urinary microalbumin screening seems to be necessary for early detection of CKD.

Quantitation of microalbuminuria using random urine samples

Abstract Microalbuminuria is a harbinger of progressive renal disease and cardiovascular complications in patients with diabetes mellitus. The method most commonly used to measure microalbuminuria relies on a timed urine collection, either a 24-h or overnight specimen, which is time-consuming, cumbersome, and often inaccurate. We compared microalbumin-creatinine ratio (UMA/UCr) in a random urine sample obtained after the first voided morning specimen with the quantity of microalbumin in a 24-h collection to determine whether the UMA/UCr correlates with the microalbumin content of 24-h urine collection. In a study of 124 urine samples from 97 pediatric patients with type I diabetes, daily microalbumin excretion varied from 7 to 108 mg/24-h with a mean of 55.7±18.2 mg and UMA/UCr ranged from 5 to 59 µg/mg with a mean of 39.4±11.3. An excellent correlation was found between the microalbumin excretion measured in 24-h urine collections and the random urine UMA/UCr specimens (r=0.89, P<0.001). All patients who excreted more than 30 mg microalbumin in the 24-h specimen also had a UMA/UCr of more than 20 µg/mg in the randomly voided sample. Microalbuminuria was unlikely if the UMA/UCr was below 20 µg/mg. The results of this study indicate that the measurement of UMA/UCr in a second voided morning specimen is a simple and reliable method for monitoring microalbuminuria in diabetic patients and may replace the need to assess quantitative microalbumin excretion on 24-h urine collections.

The Growing Epidemic of Hypertension Among Children and Adolescents: A Challenging Road Ahead

Currently, it is clear that primary hypertension begins in childhood and that it contributes to the early development of chronic kidney disease (CKD). Hypertension also increases the risk of cardiovascular morbidity and mortality, and that risk rises as blood pressure levels escalate. As among adult patients, overweight and obesity rates are on the rise among children and adolescents with primary hypertension and can develop target organ damage including left ventricular hypertrophy. An elevated level of C-reactive protein (CRP) and microalbuminuria are early manifestations of cardiovascular disease and CKD in hypertensive patients. Lifestyle interventions are recommended for all children with hypertension. Pharmacologic therapy should be added for symptomatic children, those with stage 2 hypertension, and children with prehypertension and stage 1 hypertension who exhibit an insufficient response to lifestyle modifications. Although the recommendations for choice of drugs generally are similar for children and adults, dosages for children should be lower, based on weight, and adjusted very carefully. Medications that are effective and safe for children and adolescents include thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel-blockers. Hypertension is not being detected early enough for initiation of a treatment regimen to reduce death and disability. Initiatives should be undertaken to make health care providers and the general population more aware of the seriousness of hypertension in children and adolescents. This review focuses on the principles underlying the importance of a team approach for hypertension control, especially one that incorporates increased data sharing using enhanced health information technology for early detection and intervention.

Acetazolamide for prevention of contrast-induced nephropathy: a new use for an old drug.

Reactive oxygen species play a major role in the pathogenesis of contrast-induced nephropathy (CN). Hydration with sodium bicarbonate (HCO3−) can reduce the incidence of CN in high-risk patients, suggesting a direct causal relationship between low pH of tubular fluid and enhanced activity of generated reactive oxygen species to damage renal tubular cells. Whether acetazolamide (AZ), a carbonic anhydrase inhibitor, is more effective than HCO3− unknown. Ninety-six children with stable chronic renal insufficiency were randomly assigned to receive either a 154 mEq/L infusion of sodium bicarbonate (HCO3−) (n = 46) or 0.9% sodium chloride plus oral AZ (n = 50) at a rate of 3 ml/kg/hr for 1 hour before and 1 ml/kg/hr for 6 hours after the radiographic procedure. Serum creatinine concentration (Scr) was measured before and 48 hours after the procedure. The primary endpoint was an increase in the Scr concentration of ≥25% 48 hours after the contrast administration. The baseline clinical and biochemical characteristics of the two groups were similar. The mean Scr concentration after contrast administration was significantly lower in the AZ group (p = 0.02) than in the HCO3− group (p = 0.27). The mean absolute decrease in Scr concentration at 48 hours was significantly greater in the AZ group (p < 0.01). Four of the 46 patients (8.7%) in the HCO3− group had an increase in the Scr concentration of ≥25% compared with none of the 50 patients (0%) in the AZ group (p = 0.049). Thus, compared to HCO3−, AZ plus saline hydration was more effective for the prevention CN after radiographic procedure.

Poland syndrome associated with renal agenesis

Poland syndrome is characterized by unilateral aplasia or hypoplasia of the sternocostal portion of the pectoralis major muscle and ipsilateral syndactyly. In some cases other associated anomalies, including renal malformations, dextrocardia, and vertebral abnormalities, have been reported. We report a 7-month-old girl with Poland syndrome who also presented with ipsilateral renal agenesis. This report suggests that renal structural anomaly may be an integral part of this syndrome. We recommend renal imaging studies be performed on all children with Poland syndrome.

C-reactive protein and incident left ventricular hypertrophy in essential hypertension.

Elevated C-reactive protein (CRP) levels have been associated with increased cardiovascular risk in hypertensive adults. The aim of this study was to determine whether plasma CRP level is more predictive of left ventricular hypertrophy (LVH) than is ambulatory blood pressure (BP) in hypertensive children. Baseline and 12-month follow-up measures of BP, body mass index (BMI), low-density lipoprotein/high density lipoprotein cholesterol, left ventricular mass (LVM), and CRP data collected from 48 newly diagnosed, untreated hypertensive children were analyzed. CRP was measured by a highly sensitive nephelometric method. Left ventricular mass index (LVMI) was calculated as LVM/height2.7, and LVH was defined as LVMI >38.6 g/m2.7 being the cut-point for the 95th percentile found in healthy children. Average systolic BP (SBP), diastolic BP (DBP), SBP index, and DBP index were calculated. All patients received hydrochlorothiazide therapy in combination with angiotensin converting enzyme inhibitor treatment. Five patients also had angiotensin receptor blocker therapy to reach the target BP (<95th percentile corrected for age and gender). In a multiple regression analysis, LMVI was correlated with CRP, BMI, SBP, and SBP index. CRP alone explained 77% of the variance of LVMI, whereas BMI, SBP, and SBP index explained only 1.3, 0.3, and 0.4% of the variance, respectively. CRP was also the most significant correlate of follow-up LVH. In conclusion, elevated CRP level is significantly associated with LVH in children with essential hypertension. BP reduction with renin–angiotensin system blocker and hydrochlorothiazide therapy reduces LVH while lowering CRP level.

Liddle syndrome in a newborn infant

Abstract. A 10-week-old female infant developed hypertension. The elevated blood pressure was associated with metabolic alkalosis and urinary chloride wastage. The family history was unremarkable. Her urinalysis, blood urea nitrogen (BUN), and serum creatinine concentrations were all normal. A renal ultrasound was normal. A technetium-99m diethylenetriaminopentoacetic acid (DTPA) renal scan with captopril showed normal blood flow bilaterally. The head ultrasound and echocardiogram were normal. Blood epinephrine, norepinephrine, catecholamines, thyroxine, and steroid levels were also normal. Treatment with various combinations of labetalol, hydralazine, captopril, methyldopa, nifedipine, and spironolactone, all at high doses, failed to control the elevated blood pressure. Serum aldosterone level and peripheral plasma renin activity were low. The lack of therapeutic response to spironolactone, with a good response to amiloride and recurrence of hypertension and metabolic alkalosis after amiloride cessation that was subsequently treated with amiloride, established the diagnosis of Liddle syndrome. To our knowledge, this is the youngest patient with Liddle syndrome that has been reported in the literature.

Hyponatremia: a problem-solving approach to clinical cases

Hyponatremia, defined as a serum sodium concentration of <135 mmol/L, often develops as a consequence of elevated levels of arginine vasopressin (AVP) hormone. AVP elevation can occur in a number of common clinical conditions, including syndrome of inappropriate secretion of AVP, volume depletion, postoperative states, heart failure, cirrhosis, neuroendocrine disorders and trauma. A history of concurrent illness and medication use, assessment of extracellular fluid volume as well as measurement of serum and urine osmolality and urine sodium concentration will help to establish the primary underlying causes. Presence or absence of significant neurologic signs and symptoms must guide treatment. Symptomatic hyponatremia must be treated promptly with 3% hypertonic saline to increase the serum sodium by 1-2 mmol/L per hour until symptoms abate, or a total magnitude of correction of 12 mmol/L in 24 hours or 18 mmol/L in 48 hours is achieved. Initial infusion rate (ml/kg per hour) can be estimated by body weight (kg) x desired rate of increase in sodium (mmol/L per hour). An overly rapid increase in sodium (>12 mmol/L per 24 hours) may result in serious neurologic injury. Fluid restriction and loop diuretic are frequently employed to treat volume overload. Vasopressin receptor antagonists provide prompt and effective water diuresis and increase in serum sodium concentration in both euvolemic and hypervolemic hyponatremia. In this review article, the author introduces a problem-solving approach to dissect the different clinical cases with hyponatremia and presents simple algorithms for the evaluation and management of hyponatremia that are useful at the bedside to improve quality, safety and cost-effectiveness of the patients care.