Bjørn Egil Vikse

Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease

Developmental programming of non-communicable diseases is now an established paradigm. With respect to hypertension and chronic kidney disease, adverse events experienced in utero can affect development of the fetal kidney and reduce final nephron number. Low birthweight and prematurity are the most consistent clinical surrogates for a low nephron number and are associated with increased risk of hypertension, proteinuria, and kidney disease in later life. Rapid weight gain in childhood or adolescence further compounds these risks. Low birthweight, prematurity, and rapid childhood weight gain should alert clinicians to an individuals lifelong risk of hypertension and kidney disease, prompting education to minimise additional risk factors and ensuring follow-up. Birthweight and prematurity are affected substantially by maternal nutrition and health during pregnancy. Optimisation of maternal health and early childhood nutrition could, therefore, attenuate this programming cycle and reduce the global burden of hypertension and kidney disease in the future.

Low Birth Weight Increases Risk for End-Stage Renal Disease

Case-control studies have shown an association between low birth weight and risk for renal failure. The Medical Birth Registry of Norway, which comprises data on all births in Norway since 1967, and the Norwegian Renal Registry, which comprises data on all patients who have developed ESRD in Norway since 1980, were used to examine whether birth-related variables were associated with risk for ESRD. Of the 2,183,317 children born between 1967 and 2004, 526 were found in the ESRD registry. Compared with birth weight in the 10th to 90th percentiles, births <10th percentile had a relative risk (RR) for ESRD of 1.7 (95% confidence interval 1.4 to 2.2; P < 0.001). Births with a weight for gestational age <10th percentile had an RR of 1.5 (95% confidence interval 1.2 to 1.9; P = 0.002). These associations were virtually identical after adjustment for birth-related confounders such as congenital malformations, multiple delivery, maternal age at birth, and maternal preeclampsia. Low birth weight was more strongly associated with development of ESRD during the first 14 years of life than after age 15. Low birth weight and low birth weight for gestational age were similarly associated with multiple causes of ESRD. In conclusion, in this cohort study with a maximum follow-up of 38 years, low birth weight and intrauterine growth restriction were associated with increased risk for ESRD.

Agalsidase Benefits Renal Histology in Young Patients with Fabry Disease

The effect of early-onset enzyme replacement therapy on renal morphologic features in Fabry disease is largely unknown. Here, we evaluated the effect of 5 years of treatment with agalsidase alfa or agalsidase beta in 12 consecutive patients age 7-33 years (median age, 16.5 years). We performed renal biopsies at baseline and after 5 years of enzyme replacement therapy; 7 patients had additional biopsies after 1 and 3 years. After a median of 65 months, biopsy findings from all patients showed total clearance of glomerular endothelial and mesangial cell inclusions, and findings from 2 patients showed complete clearance of inclusions from epithelial cells of the distal tubule. The 4 patients who received the highest dose of agalsidase exhibited substantial clearance of podocyte inclusions, and the youngest patient had nearly complete clearance of these inclusions. Linear regression analysis showed a highly significant correlation between podocyte globotriaocylceramide clearance and cumulative agalsidase dose (r=0.804; P=0.002). Microalbuminuria normalized in five patients. In summary, long-term enzyme replacement therapy in young patients can result in complete globotriaocylceramide clearance of mesangial and glomerular endothelial cells across all dosage regimens, and clearance of podocyte inclusions is dose-dependent.

Safety and Complications of Percutaneous Kidney Biopsies in 715 Children and 8573 Adults in Norway 1988–2010

BACKGROUND AND OBJECTIVES Skepticism about performing renal biopsies is often because of uncertainty regarding risk of complications. The aim of this study was to evaluate safety and relevant complications of renal biopsies in pediatric and adult patients in a large national registry study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Kidney biopsies reported in the Norwegian Kidney Biopsy Registry from 1988 to 2010 were included. Risk factors for major complications (blood transfusion and/or surgical or catheter intervention) were analyzed using logistic regression statistics. RESULTS Of the 9288 biopsies included, 715 were from children, and 8573 were from adults (≥18 years). Median age was 49 years (range=2 weeks to 94 years). Gross hematuria appeared after biopsy in 1.9% of the patients; 0.9% of patients needed blood transfusion, and 0.2% of patients needed surgical intervention/catheterization. The frequencies were 1.9%, 0.9%, and 0.2% in adults and 1.7%, 0.1% and 0.1% in children, respectively; 97.9% of the biopsies were without complications. In unadjusted analyses, risk factors for major complications were age>60 years, estimated GFR<60 ml/min per 1.73 m(2), systolic hypertension, acute renal failure, and smaller clinical center size (<30 biopsies/yr). Adjusted analyses (adjusted for age and/or estimated GFR) showed higher odds ratios (OR) only for smaller clinical center (OR=1.60 [1.02-2.50]) and low estimated GFR (estimated GFR=30-59 ml/min per 1.73 m(2) [OR=4.90 (1.60-14.00)] and estimated GFR<30 ml/min per 1.73 m(2) [OR 15.50 (5.60-43.00)]). CONCLUSIONS Percutaneous renal biopsy is a low-risk procedure in all ages. Reduced estimated GFR and smaller center size are associated with an increased risk of major complications.

Cardiovascular mortality after pre-eclampsia in one child mothers: prospective, population based cohort study

Objective To assess the association of pre-eclampsia with later cardiovascular death in mothers according to their lifetime number of pregnancies, and particularly after only one child. Design Prospective, population based cohort study. Setting Medical Birth Registry of Norway. Participants We followed 836 147 Norwegian women with a first singleton birth between 1967 and 2002 for cardiovascular mortality through linkage to the national Cause of Death Registry. About 23 000 women died by 2009, of whom 3891 died from cardiovascular causes. Associations between pre-eclampsia and cardiovascular death were assessed by hazard ratios, estimated by Cox regression analyses. Hazard ratios were adjusted for maternal education (three categories), maternal age at first birth, and year of first birth Results The rate of cardiovascular mortality among women with preterm pre-eclampsia was 9.2% after having only one child, falling to 1.1% for those with two or more children. With term pre-eclampsia, the rates were 2.8% and 1.1%, respectively. Women with pre-eclampsia in their first pregnancy had higher rates of cardiovascular death than those who did not have the condition at first birth (adjusted hazard ratio 1.6 (95% confidence interval 1.4 to 2.0) after term pre-eclampsia; 3.7 (2.7 to 4.8) after preterm pre-eclampsia). Among women with only one lifetime pregnancy, the increase in risk of cardiovascular death was higher than for those with two or more children (3.4 (2.6 to 4.6) after term pre-eclampsia; 9.4 (6.5 to 13.7) after preterm pre-eclampsia). The risk of cardiovascular death was only moderately elevated among women with pre-eclamptic first pregnancies who went on to have additional children (1.5 (1.2 to 2.0) after term pre-eclampsia; 2.4 (1.5 to 3.9) after preterm pre-eclampsia). There was little evidence of additional risk after recurrent pre-eclampsia. All cause mortality for women with two or more lifetime births, who had pre-eclampsia in first pregnancy, was not elevated, even with preterm pre-eclampsia in first pregnancy (1.1 (0.87 to 1.14)). Conclusions Cardiovascular death in women with pre-eclampsia in their first pregnancy is concentrated mainly in women with no additional births. This association might be due to health problems that discourage or prevent further pregnancies rather than to pre-eclampsia itself. As a screening criterion for cardiovascular disease risk, pre-eclampsia is a strong predictor primarily among women with only one child—particularly with preterm pre-eclampsia.

Adverse Perinatal Outcome and Later Kidney Biopsy in the Mother

Strong associations of adverse perinatal outcomes have been identified with later cardiovascular disease in the mother. Few studies have addressed associations with kidney disease. This study investigated whether perinatal outcomes are associated with later clinical kidney disease as diagnosed by kidney biopsy. The Medical Birth Registry of Norway contains data on all childbirths in Norway since 1967. The Norwegian Kidney Biopsy Registry contains data on all kidney biopsies in Norway since 1988. All women with a first singleton delivery from 1967 to 1998 were included. Pregnancy-related predictors of later kidney biopsy were analyzed by Cox regression analyses. A total of 756,420 women were included, and after a mean period of 15.9+/-9.4 yr, 588 had a kidney biopsy. Compared with women without preeclampsia and with offspring with birth weight of >or=2.5 kg, women with no preeclampsia and with offspring with birth weight of 1.5 to 2.5 kg had a relative risk (RR) for a later kidney biopsy of 1.7, women with no preeclampsia and with offspring with birth weight of <1.5 kg had an RR of 2.9, women with preeclampsia and with offspring with a birth weight of >or=2.5 kg had an RR of 2.5, women with preeclampsia and with offspring with a birth weight of 1.5 to 2.5 kg had an RR of 4.5, and women with preeclampsia and with offspring with a birth weight of <1.5 kg had an RR of 17. Similar results were found in adjusted analyses and after exclusion of women with diabetes, kidney disease, or rheumatic disease before pregnancy. The same risk patterns applied to any of the specific categories of kidney disease as well as specific kidney diseases investigated. Women who have preeclampsia and give birth to offspring with low birth weight and short gestation have a substantially increased risk for having a later kidney biopsy.

The Impact of Kidney Development on the Life Course: A Consensus Document for Action

Hypertension and chronic kidney disease (CKD) have a significant impact on global morbidity and mortality. The Low Birth Weight and Nephron Number Working Group has prepared a consensus document aimed to address the relatively neglected issue for the developmental programming of hypertension and CKD. It emerged from a workshop held on April 2, 2016, including eminent internationally recognized experts in the field of obstetrics, neonatology, and nephrology. Through multidisciplinary engagement, the goal of the workshop was to highlight the association between fetal and childhood development and an increased risk of adult diseases, focusing on hypertension and CKD, and to suggest possible practical solutions for the future. The recommendations for action of the consensus workshop are the results of combined clinical experience, shared research expertise, and a review of the literature. They highlight the need to act early to prevent CKD and other related noncommunicable diseases later in life by reducing low birth weight, small for gestational age, prematurity, and low nephron numbers at birth through coordinated interventions. Meeting the current unmet needs would help to define the most cost-effective strategies and to optimize interventions to limit or interrupt the developmental programming cycle of CKD later in life, especially in the poorest part of the world.

Relationship between chronic kidney disease prevalence and end-stage renal disease risk.

Purpose of reviewIncidence of end-stage renal disease has increased dramatically during the last 30 years and screening for early stages of chronic kidney disease is often suggested as a preventive measure. The relationship between chronic kidney disease and end-stage renal disease is complex, however, and recent studies have given some insights into this relationship. The review will summarize these studies and briefly discuss the clinical implications. Recent findingsWhile the prevalence of chronic kidney disease is high in most Western countries, the incidence of end-stage renal disease differs substantially. The general increase in the incidence of end-stage renal disease seen in recent years may be partially explained by a lower cardiovascular mortality, allowing more patients with chronic kidney disease to develop end-stage renal disease, and widening of entrance criteria for renal replacement therapy. Data do not, however, support these factors as explanatory for the existing international differences. These differences are better explained by different prevalences of diabetes and obesity as well as by differences in rate of progression from early chronic kidney disease stages to end-stage renal disease. Rate of progression seems to be affected by race, socioeconomic status and predialytic care. SummarySeveral mechanisms influence the relationship between chronic kidney disease and risk of end-stage renal disease. Decreased cardiovascular mortality and improved treatment availability may explain parts of the increase in the incidence of end-stage renal disease, and there are also large international differences in rates of progression from chronic kidney disease to end-stage renal disease that may be amendable by public health and predialytic care interventions.

A developmental approach to the prevention of hypertension and kidney disease: a report from the Low Birth Weight and Nephron Number Working Group

In 2008, the World Health Assembly endorsed the Global Noncommunicable Disease (NCD) Action Plan based on the realization that NCDs caused more deaths than communicable diseases worldwide. 1 This plan strongly advocates prevention as the most effective strategy to curb NCDs. The “Life Course Approach”, also recently highlighted in the Minsk Declaration, reflects the increasing recognition that early development impacts later-life health and disease. 1,2 Optimization of early development offers the opportunity for true primary prevention of NCDs. Developmental programming in the kidney has been recognized for over 2 decades but its contribution to the global burden of kidney diseases remains underappreciated by policy makers. 3 Given the many factors known to impact fetal kidney development, including maternal health and nutrition, exposure to stress, poverty, pollutants, drugs and infections during gestation, 3 a holistic strategy to prevent such programming effects is consistent with the “Life-Course” approach and aligns with the United Nations Sustainable Development Goals (SDG) to foster health. 2,4 Chronic kidney disease (CKD) is an important contributor to the NCD burden that has been relatively neglected in the Global NCD Action Plan, despite CKD being a major cause of hypertension, and a major risk multiplier of cardiovascular disease 1,5 While the prevalence of CKD in many lower-income countries remains unknown, CKD is more prevalent among disadvantaged populations within industrialized nations, e.g. African Americans and Aboriginal Australians. 6 People receiving dialysis or transplantation are projected to double from 2.6 million in 2010 to 5.4 million in 2030. 7 Between 2.3 and 7.1 million adult people died from lack of access to dialysis and transplantation in lower-income countries in 2010. 7 Given the clinical consequences and often prohibitively high costs of treatment, prevention and early detection are the only sustainable solutions to address this growing global burden. To address the neglected issue of developmental programming of kidney disease and hypertension, a multidisciplinary workgroup, including international expert obstetricians, neonatologists and nephrologists (see Appendix), was convened. We argue that the Global NCD Action Plan does not adequately address the impact of developmental origins of NCDs which is globally but is particularly important in low- and middle-income countries (LMICs) where developmental risk is highest and the burden of NCDs is growing fastest. 8 The working group identified the need to raise awareness of the role of developmental programming in renal disease, and suggests locally adapted preventive strategies that could have long-term benefits on health and heath cost savings worldwide, integrating obstetrical, neonatal and nephrology perspectives.

Familial Clustering of ESRD in the Norwegian Population

BACKGROUND AND OBJECTIVES Studies and clinical experience suggest that kidney disease clusters in families, but few population-based studies have been performed. This study investigates risks and causes of ESRD in Norwegians with and without a first-degree relative with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS On the basis of data from the Norwegian Population Registry, first-degree relatives for most Norwegians were identified. All Norwegians with ESRD (defined as chronic RRT) since 1980 have been registered in the Norwegian Renal Registry. All Norwegians born in Norway who were alive in 1980 and had at least one registered relative were included. For this study, data on ESRD were available through 2009, and individuals without ESRD were censored at December 31, 2009. Data were analyzed in a cohort design, with ESRD in a first-degree relative of the included person as the main explanatory variable. Risks of ESRD and different causes of ESRD were analyzed using Cox regression statistics. RESULTS In total, 5,119,134 individuals were included, of whom 8203 individuals developed ESRD during follow-up and 27,046 individuals had a first-degree relative with ESRD. Compared with individuals without a first-degree relative with ESRD, individuals with a first-degree relative with ESRD had a relative risk of ESRD of 7.2 (95% confidence interval, 6.5 to 8.1). Similar analyses showed that relative risk of ESRD caused by nonhereditary causes was 3.7 (95% confidence interval, 3.1 to 4.4), relative risk of ESRD caused by glomerular disease was 5.2 (95% confidence interval, 4.1 to 6.6), relative risk of ESRD caused by interstitial disease was 4.7 (95% confidence interval, 3.1 to 7.3), relative risk of ESRD caused by diabetic nephropathy was 2.6 (95% confidence interval, 1.6 to 4.1), and relative risk of ESRD caused by hypertensive nephrosclerosis was 2.6 (95% confidence interval, 1.6 to 4.1). Relative risk of nonhereditary parenchymal renal disease was 3.8 (95% confidence interval, 3.1 to 4.7). CONCLUSIONS As expected, ESRD clusters in families. Interestingly, ESRD without known hereditary cause also clusters in families.