Sarah L. White

Is Low Birth Weight an Antecedent of CKD in Later Life? A Systematic Review of Observational Studies

BACKGROUND There has been considerable interest in the hypothesis that low birth weight may be a marker of impaired nephrogenesis and that this is causally related to chronic kidney disease (CKD). STUDY DESIGN Systematic review and meta-analysis of observational studies. SETTING & POPULATION Studies of the relationship between birth weight and CKD published before February 1, 2008, were identified by using electronic searches. SELECTION CRITERIA All studies that had collected data for birth weight and kidney function at greater than 12 months of age were eligible for inclusion, except for studies of extremely low-birth-weight infants, very premature infants, or toxic exposure in utero. STUDY FACTOR: Birth weight. OUTCOMES CKD defined as albuminuria, low estimated glomerular filtration rate (<60 mL/min/1.73 m(2) or < 10th centile for age/sex), or end-stage renal disease. RESULTS We analyzed 31 relevant cohort or case-control studies with data for 49,376 individuals and data for 2,183,317 individuals from a single record-linkage study. Overall, 16 studies reported a significant association between low birth weight and risk of CKD and 16 observed a null result. The combination of weighted estimates from the 18 studies for which risk estimates were available (n = 46,249 plus 2,183,317 from the record linkage study) gave an overall odds ratio (OR) of 1.73 (95% confidence interval [CI], 1.44 to 2.08). Combined ORs were consistent in magnitude and direction for risks of albuminuria (OR, 1.81; 95% CI, 1.19 to 2.77), end-stage renal disease (OR, 1.58; 95% CI, 1.33 to 1.88), or low estimated glomerular filtration rate (OR, 1.79; 95% CI, 1.31 to 2.45). LIMITATIONS A reliance on published estimates and estimates provided on request rather than individual patient data and the possibility of reporting bias. CONCLUSIONS Existing data indicate that low birth weight is associated with subsequent risk of CKD, although there is scope for additional well-designed population-based studies with accurate assessment of birth weight and kidney function and consideration of important confounders, including maternal and socioeconomic factors.

Comparison of the Prevalence and Mortality Risk of CKD in Australia Using the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study GFR Estimating Equations: The AusDiab (Australian Diabetes, Obesity and Lifestyle) Study

BACKGROUND The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) is more accurate than the Modification of Diet in Renal Disease (MDRD) Study equation. We applied both equations in a cohort representative of the Australian adult population. STUDY DESIGN Population-based cohort study. SETTING & PARTICIPANTS 11,247 randomly selected noninstitutionalized Australians aged >or= 25 years who attended a physical examination during the baseline AusDiab (Australian Diabetes, Obesity and Lifestyle) Study survey. PREDICTORS & OUTCOMES Glomerular filtration rate (GFR) was estimated using the MDRD Study and CKD-EPI equations. Kidney damage was defined as urine albumin-creatinine ratio >or= 2.5 mg/mmol in men and >or= 3.5 mg/mmol in women or urine protein-creatinine ratio >or= 0.20 mg/mg. Chronic kidney disease (CKD) was defined as estimated GFR (eGFR) >or= 60 mL/min/1.73 m(2) or kidney damage. Participants were classified into 3 mutually exclusive subgroups: CKD according to both equations; CKD according to the MDRD Study equation, but no CKD according to the CKD-EPI equation; and no CKD according to both equations. All-cause mortality was examined in subgroups with and without CKD. MEASUREMENTS Serum creatinine and urinary albumin, protein, and creatinine measured on a random spot morning urine sample. RESULTS 266 participants identified as having CKD according to the MDRD Study equation were reclassified to no CKD according to the CKD-EPI equation (estimated prevalence, 1.9%; 95% CI, 1.4-2.6). All had an eGFR >or= 45 mL/min/1.73 m(2) using the MDRD Study equation. Reclassified individuals were predominantly women with a favorable cardiovascular risk profile. The proportion of reclassified individuals with a Framingham-predicted 10-year cardiovascular risk >or= 30% was 7.2% compared with 7.9% of the group with no CKD according to both equations and 45.3% of individuals retained in stage 3a using both equations. There was no evidence of increased all-cause mortality in the reclassified group (age- and sex-adjusted hazard ratio vs no CKD, 1.01; 95% CI, 0.62-1.97). Using the MDRD Study equation, the prevalence of CKD in the Australian population aged >or= 25 years was 13.4% (95% CI, 11.1-16.1). Using the CKD-EPI equation, the prevalence was 11.5% (95% CI, 9.42-14.1). LIMITATIONS Single measurements of serum creatinine and urinary markers. CONCLUSIONS The lower estimated prevalence of CKD using the CKD-EPI equation is caused by reclassification of low-risk individuals.

The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both?

The mammalian mitochondrial genome (mtDNA) is a small double-stranded DNA molecule that is exclusively transmitted down the maternal line. Pathogenic mtDNA mutations are usually heteroplasmic, with a mixture of mutant and wild-type mtDNA within the same organism. A woman harbouring one of these mutations transmits a variable amount of mutant mtDNA to each offspring. This can result in a healthy child or an infant with a devastating and fatal neurological disorder. Understanding the biological basis of this uncertainty is one of the principal challenges facing scientists and clinicians in the field of mitochondrial genetics.

Genetic Counseling and Prenatal Diagnosis for the Mitochondrial DNA Mutations at Nucleotide 8993

Mitochondrial genetics is complicated by heteroplasmy, or mutant load, which may be from 1%-99%, and thus may produce a gene dosage-type effect. Limited data are available for genotype/phenotype correlations in disorders caused by mtDNA mutations; therefore, prenatal diagnosis for mtDNA mutations has been hindered by an inability to predict accurately the clinical severity expected from a mutant load measured in fetal tissue. After reviewing 44 published and 12 unpublished pedigrees, we considered the possibility of prenatal diagnosis for two common mtDNA mutations at nucleotide 8993. We related the severity of symptoms to the mutant load and predicted the clinical outcome of a given mutant load. We also used the available data to generate empirical recurrence risks for genetic counseling, which may be used in conjunction with prenatal diagnosis.

How can we achieve global equity in provision of renal replacement therapy

There is a significant emerging burden of chronic and end-stage kidney disease in low- and middle-income countries, driven by population ageing and the global epidemic of type 2 diabetes. Sufferers of end-stage kidney disease require ongoing dialysis or kidney transplantation to survive; however, in many low- and middle-income countries, treatment options are strictly limited or unaffordable. Low numbers of maintenance dialysis patients and transplant recipients reflect profound economic and service provision challenges for health-care systems in low- and middle-income countries in sustaining renal replacement therapy programmes. Underdeveloped organ donor and transplant programmes, health system and financing issues, ethical regulation of transplantation and the cost of pharmaceuticals commonly pose additional barriers to the delivery of efficient and cost-effective renal replacement therapy. Development of locally appropriate transplant programmes, effective use of nongovernmental sources of funding, service planning and cost containment, use of generic drugs and local manufacture of dialysis consumables have the potential to make life-saving renal replacement therapy available to many more in need. Select low- and middle-income countries demonstrate more equitable provision of renal replacement therapy is possible outside high-income countries. For other low- and middle-income countries, education, the development of good public policy and a supportive international environment are critical. Prevention of end-stage kidney disease, ideally as part of an integrated approach to chronic vascular diseases, must also be a key objective.

The cost effectiveness of increasing kidney transplantation and home based dialysis

Background:  Renal replacement therapy (RRT) consumes sizable proportions of health budgets internationally, but there is considerable variability in choice of RRT modality among and within countries with major implications for health outcomes and costs. We aimed to quantify these implications for increasing kidney transplantation and improving the rate of home‐based dialysis.

Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue- or age-related variation

Two pathogenic mitochondrial DNA mutations, a T-to-G substitution (8993T>G) and a T-to-C substitution (8993T>C), at nucleotide 8993 have been reported. We describe 13 pedigrees with mitochondrial DNA mutations at nucleotide 8993; 10 pedigrees with the 8993T>G mutation and three with the 8993T>C mutation. Prenatal diagnosis of the nucleotide 8993 mutations is technically possible. However, there are three major concerns: (i) that there is variation in mutant loads among tissues; (ii) that the mutant load in a tissue may change over time; and (iii) that the genotype–phenotype correlation is not clearly understood. We have used the 13 pedigrees to determine specifically the extent of tissue- and age-related variation of the two mutations at nucleotide 8993 in the mitochondrial DNA. The tissue variation was investigated by analysing two or more different tissues from a total of 18 individuals. The age-related variation of the mutation was investigated by comparing the amount of both mutations in blood taken at birth and at a later age. No substantial tissue variation was found, nor was there any substantial change in the proportion of either mutation over periods of 8–23 years in the four individuals studied. In addition, we noted that two features were remarkably common in families with nucleotide 8993 mutations, namely (i) unexplained infant death (8 cases in 13 pedigrees), and (ii) de novo mutations (5 of the 10 8993T>G pedigrees).

Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy

The global nephrology community recognises the need for a cohesive plan to address the problem of chronic kidney disease (CKD). In July, 2016, the International Society of Nephrology hosted a CKD summit of more than 85 people with diverse expertise and professional backgrounds from around the globe. The purpose was to identify and prioritise key activities for the next 5-10 years in the domains of clinical care, research, and advocacy and to create an action plan and performance framework based on ten themes: strengthen CKD surveillance; tackle major risk factors for CKD; reduce acute kidney injury-a special risk factor for CKD; enhance understanding of the genetic causes of CKD; establish better diagnostic methods in CKD; improve understanding of the natural course of CKD; assess and implement established treatment options in patients with CKD; improve management of symptoms and complications of CKD; develop novel therapeutic interventions to slow CKD progression and reduce CKD complications; and increase the quantity and quality of clinical trials in CKD. Each group produced a prioritised list of goals, activities, and a set of key deliverable objectives for each of the themes. The intended users of this action plan are clinicians, patients, scientists, industry partners, governments, and advocacy organisations. Implementation of this integrated comprehensive plan will benefit people who are at risk for or affected by CKD worldwide.

Alcohol consumption and 5-year onset of chronic kidney disease: the AusDiab study

BACKGROUND Excessive alcohol consumption is a risk factor for hypertension and stroke; however, evidence for an association with chronic kidney disease is conflicting. METHODS A total of 6259 adults >or=25 years of age, without a history of alcohol dependence, participating in baseline (1999-2000) and follow-up (2004-2005) phases of an Australian population-representative study (AusDiab) were the subject of this analysis. Alcohol consumption status and volume/frequency were collected by standardized interviewer administered questionnaires and self-administered food frequency questionnaires. The outcomes were as follows: (i) 5-year decline in estimated glomerular filtration rate (eGFR) >or=10%, with baseline eGFR >or= 60 and final eGFR <60 mL/min/1.73 m(2), and (ii) 5-year doubling of albumin to creatinine ratio (ACR) with final ACR >or= 2.5 (males)/>or= 3.5 (females) mg/mmol, in the absence of albuminuria at baseline. RESULTS Self-identification as a moderate or heavy, versus light, drinker was associated with elevated risk of albuminuria in males and females <65 years of age (OR, 95% CI: males 1.87, 0.99-3.52; females 2.38, 1.37-4.14). Odds of de novo eGFR <60 mL/min/1.73 m(2) were 0.34 (95% CI 0.22-0.59) and 0.68 (95% CI 0.36-1.27) in males and females, respectively, who were moderate-heavy drinkers. Alcohol intake of >or=30 g/day was associated with an increased risk of albuminuria after adjustment for age, sex and baseline kidney function (OR = 1.59, 95% CI 1.07-2.36), but a reduced risk of eGFR <60 mL/min/1.73 m(2) (OR = 0.59, 95% CI 0.37-0.95), compared with consumption of <10 g/day. CONCLUSIONS Moderate-heavy alcohol consumption may be an important modifiable risk factor for albuminuria in the general population. The natural history of alcohol-induced kidney damage and how this relates to markers of kidney function in the general population warrant further research.

Diagnostic Accuracy of Urine Dipsticks for Detection of Albuminuria in the General Community

BACKGROUND Urine dipsticks, an inexpensive accessible test for proteinuria, are widely advocated for mass screening; however, their diagnostic accuracy in the general community is largely unknown. STUDY DESIGN Evaluation of diagnostic test accuracy in a cross-sectional cohort. SETTING & PARTICIPANTS AusDiab, a representative survey of Australian adults 25 years and older (conducted in 1999/2000). Stratified cluster random sampling from 11,247 individuals participating in the biomedical examination; complete urinalysis data available for 10,944. INDEX TEST Urine dipsticks (Bayer Multistix), with a positive result defined as ≥1+ or trace or higher protein. REFERENCE TEST Albumin-creatinine ratio (ACR), measured on a random spot urine sample. Reference test positivity was defined as ACR ≥30 mg/g or ACR ≥300 mg/g. RESULTS Numbers of participants with ACR <30, 30-300, and ≥300 mg/g were 10,219 (93.4%), 634 (5.8%), and 91 (0.8%), respectively. The area under the receiver operating characteristic curve (AUC) for dipstick detection of ACR ≥30 mg/g was 0.8451 ± 0.0129 (SE) in men and 0.7775 ± 0.0131 in women (P < 0.001). The AUROC for dipstick detection of ACR ≥300 mg/g was 0.9904 ± 0.0030 in men and 0.9950 ± 0.0016 in women (P = 0.02). Dipstick result ≥1+ identified ACR ≥30 mg/g with 57.8% sensitivity (95% CI, 54.1%-61.4%) and 95.4% specificity (95% CI, 95.0%-95.8%) and identified ACR ≥300 mg/g with 98.9% sensitivity (99% CI, 92.1%-100%) and 92.6% specificity (99% CI, 92.0%-93.3%). A dipstick result of trace or higher identified ACR ≥30 mg/g with 69.4% sensitivity (95% CI, 65.9%-72.7%) and 86.8% specificity (95% CI, 86.1%-87.4%) and identified ACR ≥300 mg/g with 100% sensitivity (99% CI, 94.3%-100%) and 83.7% specificity (99% CI, 82.8%-84.6%). A negative dipstick result (less than trace) had a negative predictive value of 97.6% (95% CI, 97.2%-97.9%) for ACR ≥30 mg/g and a negative predictive value of 100% (99% CI, 99.9%-100%) for ACR ≥300 mg/g. The probability of an ACR ≥30 mg/g confirmed on laboratory investigation was 47.2% (95% CI, 43.9%-50.5%) based on a dipstick result ≥1+ and 27.1% (95% CI, 25.1%-29.2%) based on a trace or higher result. LIMITATIONS Isolated urine samples precluded assessment of test reproducibility. Urine specific gravity and pH were not recorded; therefore, the effect of urine concentration on test performance was not assessed. CONCLUSIONS A dipstick test result <1+ or less than trace has a high negative predictive value in the general community setting, with minimal risk of a missed diagnosis of macroalbuminuria. High false-positive rates emphasize the need for laboratory confirmation of positive results.