Michael Freundlich

Suppression of renin–angiotensin gene expression in the kidney by paricalcitol

The renal renin-angiotensin system plays a major role in determining the rate of chronic renal disease progression. Treatment with activators of the vitamin D receptor retards the progression of experimental chronic renal disease, and vitamin D is known to suppress the renin-angiotensin system in other organs. Here we determined if the beneficial effects of paricalcitol (19-nor 1,25-dihydroxyvitamin D(2)) were associated with suppression of renin-angiotensin gene expression in the kidney. Rats with the remnant kidney model of chronic renal failure (5/6 nephrectomy) were given two different doses of paricalcitol thrice weekly for 8 weeks. Paricalcitol was found to decrease angiotensinogen, renin, renin receptor, and vascular endothelial growth factor mRNA levels in the remnant kidney by 30-50 percent compared to untreated animals. Similarly, the protein expression of renin, renin receptor, the angiotensin type 1 receptor, and vascular endothelial growth factor were all significantly decreased. Glomerular and tubulointerstitial damage, hypertension, proteinuria, and the deterioration of renal function resulting from renal ablation were all similarly and significantly improved with both treatment doses. These studies suggest that the beneficial effects of vitamin D receptor activators in experimental chronic renal failure are due, at least in part, to down-regulation of the renal renin-angiotensin system.

Calcium and vitamin D metabolism in children with nephrotic syndrome.

Although abnormalities of calcium and vitamin D metabolism are recognized in children with nephrotic syndrome, longitudinal observations are not available in these patients during periods of relapse and remission. We report observations in 58 children (mean age 10.1 years) with nephrotic syndrome and normal glomerular filtration rate. Hypocalcemia, modest hyperparathyroidism, and strikingly low calcidiol levels were identified during episodes of relapse. Most alterations were transient, and normalized on remission. The plasma concentration of calcitriol, the most active metabolite of vitamin D, was found to be normal in both relapse and remission. In the presence of hypocalcemia and hyperparathyroidism, however, normal plasma calcitriol levels in relapse may be inappropriately low and reflect a state of relative deficiency. Concurrent glucocorticoid therapy did not modify the results. A corollary of our observations is that children with relapsing or protracted nephrotic syndrome are at risk of developing metabolic bone disease, even without impairment of glomerular filtration rate.

Vitamin D insufficiency and deficiency in children with early chronic kidney disease.

OBJECTIVE To assess the prevalence of abnormal vitamin D status in children and adolescents with chronic kidney disease (CKD). STUDY DESIGN This was an outpatient cross-sectional, retrospective study of 258 patients, mean age 12.3 +/- 5.2 years, with an average estimated glomerular filtration rate (eGFR) of 106 +/- 51 mL/min/1.73 m2 (range, 0 to 220 mL/min/1.73 m2). Serum 25-hydroxy-vitamin D [25(OH)D], calcium, phosphorus, and parathyroid hormone levels, as well as selected anthropometric variables, were analyzed. RESULTS Reduced 25(OH)D concentrations (< 30 ng/mL) were found in 60% of the patients. In 28%, the concentration was < 20 ng/mL, indicating vitamin D deficiency. Patients with more advanced CKD were more likely to have vitamin D deficiency compared with those with incipient CKD or normal GFR (42% vs 26%; P = .03) and displayed more prominent hyperparathyroidism. Suboptimal vitamin D status was similar in males and females, but was significantly more prevalent in older (P < .01), non-Caucasian (P < .01), and overweight (P = .02) patients. Patients with early-stage CKD (eGFR > 60 mL/min/1.73 m2) and with vitamin D deficiency were significantly shorter than their counterparts with 25(OH)D levels > 20 ng/mL (P = .02). CONCLUSIONS Vitamin D insufficiency and deficiency are very prevalent in pediatric patients across all stages of CKD, particularly in non-Caucasian and obese patients, and may contribute to growth deficits during the earliest stages of CKD.

Persistence of serum lipid abnormalities in children with idiopathic nephrotic syndrome

We investigated the severity and duration of hyperlipidemia in 59 nephrotic children during relapse and remission. Serum total cholesterol and triglyceride values were greater than or equal to 95th percentile for age and sex in all patients with minimal change nephrotic syndrome in relapse and in patients with non-MCNS and persistent proteinuria. Most of these patients also had a significant elevation of low- and very-low-density lipoproteins. A significant number of children with MCNS during prolonged remission had elevated serum concentrations of total cholesterol (46%), triglycerides (42%), LDL (29%), and VLDL (40%). Persistence and severity of lipid changes correlated well with duration of disease and frequency of relapses. Significantly decreased HDL and HDL/LDL were found in patients with non-MCNS and persistent proteinuria. Our results suggest that nephrotic children may have prolonged periods of hyperlipidemia even after clinical remission. In addition, some of these children with significantly decreased HDL/LDL may be at increased risk of developing premature atherosclerosis.

The Kidney in Sickle Cell Disease

Sickle cell disease (SCD) and trait (SCT) are acknowledged as existing in North America and Africa but often overlooked is the fact that they also are found in Central America and northern South America, primarily in those areas into which blacks were brought from Africa. Hemoglobin A is the normal hemoglobin which has a glutamic acid in position 6, while hemoglobin S is the characteristic hemoglobin of sickle cell disease and has a valine in position 6 (1). In an SCD or SCT patient in crisis, hemoglobin gels and leads to the formation of the classically sickled shape red blood cell (RBC); when hemoglobin S remains in its gel status, the RBC’s become irreversibly (or permanently) sickled (2).

A novel epithelial sodium channel β-subunit mutation associated with hypertensive Liddle syndrome

Low-renin hypertension responsive to amiloride-thiazide therapy in a 4-year-old Afro-Haitian girl suggested Liddle syndrome. Urine steroid profiling substantiated the diagnosis and DNA analysis of the epithelial sodium channel (ENaC) revealed a novel heterozygous βENaC mutation in the patient and in her hypertensive father. Liddle syndrome should be considered as a cause of hypertension in young children particularly with suppressed renin activity.

Less Commonly Recognized Features of Childhood Nephrotic Syndrome

This article reviews aspects in the clinical presentation of nephrotic syndrome that are not generally considered characteristics of the syndromes definition. The importance of various general clinical aspects such as hematuria, hypertension, and other laboratory or histologic findings are discussed. The clinical relevance and management of other specific aspects such as lipid alterations, coagulation abnormalities, calcium and vitamin D metabolism, and nutritional complications derived from the nephrotic syndrome also are included in this review.

Paricalcitol Downregulates Myocardial Renin–Angiotensin and Fibroblast Growth Factor Expression and Attenuates Cardiac Hypertrophy in Uremic Rats

BACKGROUND Vitamin D attenuates uremic cardiac hypertrophy, possibly by suppressing the myocardial renin-angiotensin system (RAS) and fibroblast growth factors (FGFs). We compared the suppression of cardiac hypertrophy and myocardial expression of RAS and FGF receptor genes offered by the vitamin D analog paricalcitol (Pc) or the angiotensin-converting enzyme inhibitor enalapril (E) in experimental uremia. METHODS Rats with 5/6 nephrectomy received Pc or E for 8 weeks. Renal function, systolic blood pressure, and cardiac hypertrophy were evaluated. Myocardial expression of RAS genes, brain natriuretic peptide (BNP), and FGF receptor-1 (FGFR-1) were determined using quantitative reverse-transcription (pRT)-PCR. RESULTS Blood pressure, proteinuria, and serum creatinine were significantly higher in untreated uremic animals. Hypertension was significantly reduced by E but only modestly by Pc; however, cardiac hypertrophy in the untreated group was similarly attenuated by Pc or E. Upregulation of myocardial expressions of renin, angiotensinogen, FGFR-1, and BNP in untreated uremic animals was reduced similarly by Pc and E, while the angiotensin II type 1 receptor was downregulated only by E. CONCLUSIONS Uremic cardiac hypertrophy is associated with activation of the myocardial RAS and the FGFR-1. Downregulation of these genes induced by Pc and E results in similar amelioration of left ventricular hypertrophy despite the different antihypertensive effects of these drugs.

Pediatric cardiomyopathies: causes, epidemiology, clinical course, preventive strategies and therapies

Pediatric cardiomyopathies, which are rare but serious disorders of the muscles of the heart, affect at least one in every 100,000 children in the USA. Approximately 40% of children with symptomatic cardiomyopathy undergo heart transplantation or die from cardiac complications within 2 years. However, a significant number of children suffering from cardiomyopathy are surviving into adulthood, making it an important chronic illness for both pediatric and adult clinicians to understand. The natural history, risk factors, prevalence and incidence of this pediatric condition were not fully understood before the 1990s. Questions regarding optimal diagnostic, prognostic and treatment methods remain. Children require long-term follow-up into adulthood in order to identify the factors associated with best clinical practice including diagnostic approaches, as well as optimal treatment approaches. In this article, we comprehensively review current research on various presentations of this disease, along with current knowledge about their causes, treatments and clinical outcomes.

Longitudinal FGF23 and Klotho axis characterization in children treated with chronic peritoneal dialysis

Background Fibroblast Growth Factor-23 (FGF23) and cofactor Klotho are key regulators of mineral metabolism in chronic kidney disease (CKD), but little is known about the mechanisms that regulate their production. This study evaluates longitudinal changes of FGF23 and Klotho levels and their regulatory factors in children on chronic peritoneal dialysis (PD). Methods FGF23, Klotho, 25(OH) vitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone (PTH) plasma concentrations were measured during 1 year of follow-up in PD children. Anthropometric and dialytical parameters were evaluated in addition to mineral metabolism variables. Results Thirty-one patients under chronic PD were followed for 12 months. FGF23 mean plasma levels at Month 1 were significantly increased compared with controls, 215.1 ± 303.6 versus 9.4 ± 5.7 pg/mL, respectively (P < 0.001). Baseline Klotho levels were 41% lower in patients compared with controls, 132.1 ± 58 versus 320 ± 119.4 pg/mL, respectively (P < 0.001), and did not correlate with FGF23 and phosphorus levels. At Month 12, FGF23 (195 ± 300 pg/mL) and Klotho levels (130 ± 34 pg/mL) remained similar to baseline values. Log-FGF23 correlated significantly with height/age Z score (r= −0.38) and residual renal function (r = −0.44), but no correlation was found with serum phosphorus, phosphate intake, PTH and vitamin D levels. The log-FGF23 strongly correlated with calcium levels at Months 1, 6 and 12, however, this relationship was blunted if serum phosphorus was >6 mg/dL. By multiple regression analysis, calcium was the strongest variable determining FGF23 levels. Conclusions In this longitudinal study, FGF23 levels are markedly increased, and Klotho levels are reduced in PD children compared with controls. FGF23 levels appeared to be regulated primarily by serum calcium, showing a significant correlation at each time of measurement. This relationship was lost in patients with phosphorus >6 mg/dL. These observations may have important consequences to the therapeutic management of phosphate homeostasis in CKD patients.