V. Matti Vehaskari

Low birth weight-associated adult hypertension in the rat.

Abstract Epidemiological surveys have suggested that intrauterine growth retardation is a risk factor for the development of hypertension in later life. A rat model of intrauterine growth retardation, induced by maternal low-protein diet during the second half of pregnancy, was used to study the relationship between birth weight and adult hypertension. The offspring were born at term and were allowed to nurse normally until weaned to standard chow at 4 weeks of age. They had 15% lower birth weights than control offspring, with complete catch-up growth by age 4 weeks. Both females and males developed progressively worsening hypertension beginning at 8 weeks. The 11-month survival rate was 69% versus 100% in control animals. During the early stages of the hypertension, plasma creatinine was normal, plasma sodium concentration was slightly higher than that of control animals, plasma renin activity was suppressed, and the males had mild proteinuria. Renal function remained normal throughout the 11-month observation period, but plasma renin activity gradually rose above control values. Angiotensin-converting enzyme inhibition by enalapril, begun at 8 weeks of age, was effective in completely normalizing the blood pressure, but did not totally prevent the extra mortality. Sprague- Dawley and Wistar rat strains developed equally severe hypertension after maternal protein deprivation, despite their different susceptibilities to nephrosclerosis with aging. In conclusion, maternal low-protein diet resulted in low birth weight and adult hypertension in the rat. Primary sodium retention and expanded extracellular volume may be critical factors during the development of the hypertension.

Clinical trial of focal segmental glomerulosclerosis in children and young adults

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Effect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients.

Abstract:  Tacrolimus has become an effective alternative to cyclosporine as a component of primary immunosuppression in pediatric renal transplant patients, but the information on the pharmacokinetic characteristics of tacrolimus in young patients is still limited. The primary objective of this study was to determine the effect of patient age, ethnicity, and concurrent steroid administration on tacrolimus pharmacokinetics in pediatric renal transplant patients. The study population consisted of 30 pediatric patients, age 1.5–18.6 yr, who received a kidney transplant between July 1999 and February 2004. After twice daily dosing was stabilized based on clinical judgment, at least 5 days postoperatively, tacrolimus levels were drawn prior to, and 1, 2, 4, 8, and 12 h after the morning dose. The mean dose of tacrolimus was 0.12 mg/kg/dose. Mean trough level was 11.9 ± 5.0 ng/mL. Mean area under the curve (AUC) was 192 ± 84 with a range of 78–360 h × (ng/mL). The correlation between trough level and AUC was only fair (r = 0.74); later time points correlated better with AUC, and an excellent correlation (r = 0.96) was obtained between the mean of trough and 2‐h level (C2) and AUC. There was a negative correlation between age and dose per body weight (r = −0.68). African‐American patients had marginally lower drug exposure with similar dosing. Three age groups (<5, 5–12, and >12 yr) were compared with respect to dosing and AUC. Despite similar AUC in all three groups, the mean dose per kg required to achieve the AUC was 2.7‐ and 1.9‐fold higher in the <5 and 5–12‐yr groups, respectively, compared with the >12‐yr group. Nine of the 30 patients were on a totally steroid‐free regimen. Their tacrolimus dose and trough levels were similar to those of steroid‐exposed patients, but their mean AUC was 41% higher. Our results show an inverse correlation between age and required tacrolimus dose, wide interindividual variation, and greater exposure with steroid‐free regimen despite no change in trough level.

Heritable forms of hypertension

Among the causes of secondary hypertension are a group of disorders with a Mendelian inheritance pattern. Recent advances in molecular biology have unveiled the pathogenesis of hypertension in many of these conditions. Remarkably, the mechanism in every case has proved to be upregulation of sodium (Na) reabsorption in the distal nephron, with accompanying expansion of extracellular volume. In one group, the mutations involve the Na-transport machinery in distal tubule cells themselves: the distal convoluted tubule (DCT) cell and the principal cell of the collecting duct. Examples include Liddle’s syndrome, with an activating mutation of epithelial Na channel (ENaC); two types of Gordon’s syndrome, with mutations in two regulatory kinases [with no lysine (K) serine/threonine protein kinases (WNK)1 or WNK4]; and apparent mineralocorticoid excess (AME), with an inactivating mutation in the glucocorticoid-metabolizing 11β-hydroxysteroid dehydrogenase type 2 enzyme (11HD2). In another group, abnormal adrenal steroid production leads to inappropriate stimulation of the mineralocorticoid receptor (MR) in the distal nephron. The pathophysiology may involve inappropriate production of aldosterone [in glucocorticoid-remediable aldosteronism (GRA) and familial hyperaldosteronism type II (FH II)], of cortisol (in familial glucocorticoid resistance), or of other steroid metabolites (in congenital adrenal hyperplasia and GRA). In contrast to earlier beliefs, hypertension in many of the inherited disorders may be mild, and electrolyte and acid-base abnormalities are often not present. Monogenic hypertension should therefore enter the differential diagnosis of any child or adolescent with hypertension. Plasma renin activity (PRA) is the appropriate screening tool for all types of inherited hypertension.

Results of one-year follow-up of steroid-free immunosuppression in pediatric renal transplant patients

Abstract:  Renal transplantation in children has traditionally required immunosuppression with multiple medications including glucocorticoids. Data collected over almost 30 yr suggest that although glucocorticoids are efficacious as part of a regimen to minimize the incidence of acute rejection episodes, their use is associated with increased risk for post‐transplant hypertension, hyperlipidemia, and reduced growth rates. We desired to reduce these complications and thus used an immunosuppressive protocol including daclizumab, tacrolimus, and mycophenolate mofetil and study the efficacy of this protocol in a population with a high percentage of African‐American recipients. No patient received glucocorticoids at any time post‐transplant. Our results show that at 1 yr post‐transplant, glomerular filtration rate, serum glucose, calcium and phosphorous metabolism, serum magnesium, and serum lipids were similar in patients receiving steroid‐free and those receiving steroid‐based immunosuppression. The incidence of acute rejection was similar in the two groups. Hematocrit and white blood count levels were lower 1 month after transplant in the steroid‐free patients but these levels increased within several months. Systolic blood pressure was similar in the two groups, although this was achieved, in part, in the patients who received steroids by the administration of medications to lower blood pressure. Finally, tacrolimus levels were similar in the two groups, but patients receiving steroids required higher doses of tacrolimus at several time points studied during the first post‐transplant year. Taken together, our data suggests that at one‐year follow‐up, steroid‐free immunosuppression is safe, and efficacious in pediatric renal transplant recipients.

Focal segmental glomerulosclerosis – epidemiology aspects in children and adults

The histologic features of idiopathic forms of focal segmental glomerulosclerosis (FSGS) were first described by Theodor Fahr in the Handbuch der speziellen pathologischen Anatomie und Histologie in 1925 [1]. Over the subsequent eight decades much has been written about the histologic features and clinical characteristics of patients with FSGS, but it is only in recent years that attention has been directed to the incidence and prevalence of the disorder in various populations. This article will provide an overview of the epidemiology of FSGS by reviewing published surveys of renal biopsies, experiences from clinical registries of children with renal insufficiency, and data from the U.S. Renal Data Systems (USRDS).

Developmental origins of adult hypertension: new insights into the role of the kidney.

It is now accepted that early life environment can modulate adult phenotype. One of the best documented examples is the effect of prenatal environment on adult hypertension and cardiovascular morbidity. Human epidemiologic studies have been complemented with experimental models showing, for example, that maternal dietary manipulations during pregnancy in the rat can be used to induce adult hypertension in the offspring. The weight of the emerging evidence suggests that abnormal Na handling by the kidney plays an important role in the pathogenesis of the hypertension. Although the number of nephrons is modestly reduced in most experimental models, there is very little change in total glomerular filtration rate, casting doubt on the hypothesis that restricted Na filtration is the major mechanism. Recent studies have instead strongly suggested that renal tubular handling of Na is altered, resulting in an altered set-point for Na balance. The mechanism may involve intrarenal inflammation and increased oxidative stress which disrupt the tubulointerstitial microenvironment, leading to constitutively upregulated Na reabsorption in the distal tubule. The upregulation may be mediated by autocrine and paracrine factors promoting distal tubule Na reabsorption. A similar mechanism has been hypothesized to be important in other types of hypertension and may hence be a common pathway in the genesis of volume-dependent hypertension.

Renal Function and Proteinuria after Successful Immunosuppressive Therapies in Patients with FSGS

BACKGROUND AND OBJECTIVES In the FSGS Clinical Trial, 22 cyclosporine-treated and 20 mycophenolate/dexamethasone-treated patients experienced a complete or partial remission after 26 weeks, completed 52 weeks of treatment, and were studied through 78 weeks. Herein, changes in the urine protein/creatinine ratio (UP/C) and estimated GFR (eGFR) throughout the entire study period are defined. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS The FSGS Clinical Trial, which was conducted from November 2004 to January 2010, enrolled patients aged 2-40 years, with eGFR ≥40 ml/min per 1.73 m(2) and UP/C >1 mg/mg after ≥4 weeks of corticosteroid therapy. Both groups received lisinopril or losartan throughout the study. UP/C and eGFR were measured at 0, 26, 52, and 78 weeks. RESULTS The median UP/C in the cyclosporine- and mycophenolate/dexamethasone-responsive patients fell by 89.8% and 82.7% at 52 weeks; the fall was largely sustained at 78 weeks (74.7% and 80.3%, respectively). The mean eGFR fell by 19.4% in the cyclosporine group and rose by 7.0% in the mycophenolate mofetil/dexamethasone group at 52 weeks, but subsequently rose by 16.4% and fell by 2.6%, respectively, in the two groups from 52 to 78 weeks. CONCLUSIONS In this subset of responding FSGS patients, the improvement in UP/C after cyclosporine or mycophenolate/dexamethasone treatment was largely sustained for 6 months after therapy. Reduction in eGFR in the cyclosporine group was improved 6 months after cyclosporine was stopped although the levels were lower than baseline in seven patients who entered the study with decreased eGFR.

Hodgkin lymphoma in a renal transplant recipient associated with low peripheral blood Epstein-Barr virus genome copies.

Posttransplant lymphoproliferative disorders are often accompanied by >500 Epstein-Barr virus (EBV) genome copies/10(5) lymphocytes, and they occur shortly after transplantation. Hodgkin lymphoma occurs rarely after transplantation, appearing a mean of 4.2 years posttransplant, and although Hodgkin lymphoma has strong associations with EBV, no quantitative analysis of peripheral blood EBV genome copies has been reported. A mixed cellularity Hodgkin lymphoma developed in a 17-year-old boy 4 years after a renal transplant. Serial EBV genome copy numbers from blood by competitive polymerase chain reaction had been obtained to assess for lymphoproliferative disease. Epstein-Barr virus genome copy numbers peaked at 500 copies/10(5) lymphocytes 8 months prior to Hodgkin lymphoma diagnosis but fell to 8 copies/10(5) lymphocytes at diagnosis. Reliance on EBV levels greater than 500 copies may result in delay of biopsy and diagnosis of Hodgkin disease in the posttransplant setting.

False-positive human immunodeficiency virus antibody test in a dialysis patient

A patient developed end-stage renal disease secondary to p-anti-neutrophil cytoplasmic antibody (p-ANCA) positive rapidly progressive glomerulonephritis. He subsequently had human immunodeficiency virus (HIV)-1 antibody screening performed as part of a pre-transplant evaluation. The HIV-1 enzyme immunoassay (EIA) antibody test was repeatedly reactive. The HIV-1 western blot was indeterminate. The western blot pattern revealed “non-specific staining obscuring bands in that region.” Another sample of serum was sent and the results were identical to the first result. An HIV-1 proviral qualitative polymerase chain reaction test was then performed several months later and no HIV-1 DNA was detected. One year later, an HIV-1 RNA test was negative. Thus, the positive antibody EIA test and the indeterminate western blot represent a false-positive result, most likely due to cross-reacting antigens in the patient’s serum with various HIV antibodies. Throughout this period and thereafter, the patient has exhibited no symptoms of HIV infection.