Andrew Smyth

A Systematic Review and Meta-Analysis of Pregnancy Outcomes in Patients with Systemic Lupus Erythematosus and Lupus Nephritis

BACKGROUND AND OBJECTIVES Studies of the impact of systemic lupus erythematosus (SLE) and its pregnancy complications have yielded conflicting results. Major limitations of these studies relate to their small numbers of patients and retrospective designs. The aim of this study was to perform a systematic literature review of pregnancy outcomes in women with SLE and a meta-analysis of the association of lupus nephritis with adverse pregnancy outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We searched electronic databases from 1980 to 2009 and reviewed papers with validity criteria. Random-effects analytical methods were used to evaluate pregnancy complications rates. RESULTS Thirty-seven studies with 1842 patients and 2751 pregnancies were included. Maternal complications included lupus flare (25.6%), hypertension (16.3%), nephritis (16.1%), pre-eclampsia (7.6%), and eclampsia (0.8%). The induced abortion rate was 5.9%, and when excluded, fetal complications included spontaneous abortion (16.0%), stillbirth (3.6%), neonatal deaths (2.5%), and intrauterine growth retardation (12.7%). The unsuccessful pregnancy rate was 23.4%, and the premature birth rate was 39.4%. Meta-regression analysis showed statistically significant positive associations between premature birth rate and active nephritis and increased hypertension rates in subjects with active nephritis or a history of nephritis. History of nephritis was also associated with pre-eclampsia. Anti-phospholipid antibodies were associated with hypertension, premature birth, and an increased rate of induced abortion. CONCLUSIONS In patients with SLE, both lupus nephritis and anti-phospholipid antibodies increase the risks for maternal hypertension and premature births. The presented evidence further supports timing of pregnancy relative to SLE activity and multispecialty care of these patients.

Salt intake and cardiovascular disease: why are the data inconsistent?

Effective population-based interventions are required to reduce the global burden of cardiovascular disease (CVD). Reducing salt intake has emerged as a leading target, with many guidelines recommending sodium intakes of 2.3 g/day or lower. These guideline thresholds are based largely on clinical trials reporting a reduction in blood pressure with low, compared with moderate, intake. However, no large-scale randomized trials have been conducted to determine the effect of low sodium intake on CV events. Prospective cohort studies evaluating the association between sodium intake and CV outcomes have been inconsistent and a number of recent studies have reported an association between low sodium intake (in the range recommended by current guidelines) and an increased risk of CV death. In the largest of these studies, a J-shaped association between sodium intake and CV death and heart failure was found. Despite a large body of research in this area, there are divergent interpretations of these data, with some advocating a re-evaluation of the current guideline recommendations. In this article, we explore potential reasons for the differing interpretations of existing evidence on the association between sodium intake and CVD. Similar to other areas in prevention, the controversy is likely to remain unresolved until large-scale definitive randomized controlled trials are conducted to determine the effect of low sodium intake (compared to moderate intake) on CVD incidence.

Patterns of Alcohol Consumption and Myocardial Infarction Risk Observations From 52 Countries in the INTERHEART Case–Control Study

Background— Although moderate alcohol use is associated with protection against myocardial infarction (MI), it is not known whether this effect is generalizable to populations worldwide. It is also uncertain whether differences in the pattern of alcohol use (and in particular heavy episodic consumption) between different regions negate any beneficial effect. Methods and Results— We included 12 195 cases of first MI and 15 583 age- and sex-matched controls from 52 countries. Current alcohol use was associated with a reduced risk of MI (compared with nonusers: adjusted odds ratio, 0.87; 95% confidence interval, 0.80–0.94; P=0.001); however, the strength of this association was not uniform across different regions (region-alcohol interaction P<0.001). Heavy episodic drinking (≥6 drinks) within the preceding 24 hours was associated with an increased risk of MI (odds ratio, 1.4; 95% confidence interval, 1.1–1.9; P=0.01). This risk was particularly elevated in older individuals (for age >65 years: odds ratio, 5.3; 95% confidence interval, 1.6–18; P=0.008). Conclusions— In most participants, low levels of alcohol use are associated with a moderate reduction in the risk of MI; however, the strength of this association may not be uniform across different countries. An episode of heavy drinking is associated with an increased risk of acute MI in the subsequent 24 hours, particularly in older individuals.Background— Although moderate alcohol use is associated with protection against myocardial infarction (MI), it is not known whether this effect is generalizable to populations worldwide. It is also uncertain whether differences in the pattern of alcohol use (and in particular heavy episodic consumption) between different regions negate any beneficial effect. Methods and Results— We included 12 195 cases of first MI and 15 583 age- and sex-matched controls from 52 countries. Current alcohol use was associated with a reduced risk of MI (compared with nonusers: adjusted odds ratio, 0.87; 95% confidence interval, 0.80–0.94; P =0.001); however, the strength of this association was not uniform across different regions (region-alcohol interaction P 65 years: odds ratio, 5.3; 95% confidence interval, 1.6–18; P =0.008). Conclusions— In most participants, low levels of alcohol use are associated with a moderate reduction in the risk of MI; however, the strength of this association may not be uniform across different countries. An episode of heavy drinking is associated with an increased risk of acute MI in the subsequent 24 hours, particularly in older individuals. # CLINICAL PERSPECTIVE {#article-title-33}

Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study

BACKGROUND Alcohol consumption is proposed to be the third most important modifiable risk factor for death and disability. However, alcohol consumption has been associated with both benefits and harms, and previous studies were mostly done in high-income countries. We investigated associations between alcohol consumption and outcomes in a prospective cohort of countries at different economic levels in five continents. METHODS We included information from 12 countries participating in the Prospective Urban Rural Epidemiological (PURE) study, a prospective cohort study of individuals aged 35-70 years. We used Cox proportional hazards regression to study associations with mortality (n=2723), cardiovascular disease (n=2742), myocardial infarction (n=979), stroke (n=817), alcohol-related cancer (n=764), injury (n=824), admission to hospital (n=8786), and for a composite of these outcomes (n=11,963). FINDINGS We included 114,970 adults, of whom 12,904 (11%) were from high-income countries (HICs), 24,408 (21%) were from upper-middle-income countries (UMICs), 48,845 (43%) were from lower-middle-income countries (LMICs), and 28,813 (25%) were from low-income countries (LICs). Median follow-up was 4.3 years (IQR 3.0-6.0). Current drinking was reported by 36,030 (31%) individuals, and was associated with reduced myocardial infarction (hazard ratio [HR] 0.76 [95% CI 0.63-0.93]), but increased alcohol-related cancers (HR 1.51 [1.22-1.89]) and injury (HR 1.29 [1.04-1.61]). High intake was associated with increased mortality (HR 1.31 [1.04-1.66]). Compared with never drinkers, we identified significantly reduced hazards for the composite outcome for current drinkers in HICs and UMICs (HR 0.84 [0.77-0.92]), but not in LMICs and LICs, for which we identified no reductions in this outcome (HR 1.07 [0.95-1.21]; pinteraction<0.0001). INTERPRETATION Current alcohol consumption had differing associations by clinical outcome, and differing associations by income region. However, we identified sufficient commonalities to support global health strategies and national initiatives to reduce harmful alcohol use. FUNDING Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.

Canadian Society of Nephrology Commentary on the KDIGO Clinical Practice Guideline for CKD Evaluation and Management

We congratulate the KDIGO (Kidney Disease: Improving Global Outcomes) work group on their comprehensive work in a broad subject area and agreed with many of the recommendations in their clinical practice guideline on the evaluation and management of chronic kidney disease. We concur with the KDIGO definitions and classification of kidney disease and welcome the addition of albuminuria categories at all levels of glomerular filtration rate (GFR), the terminology of G categories rather than stages to describe level of GFR, the division of former stage 3 into new G categories 3a and 3b, and the addition of the underlying diagnosis. We agree with the use of the heat map to illustrate the relative contributions of low GFR and albuminuria to cardiovascular and renal risk, though we thought that the highest risk category was too broad, including as it does people at disparate levels of risk. We add an albuminuria category A4 for nephrotic-range proteinuria and D and T categories for patients on dialysis or with a functioning renal transplant. We recommend target blood pressure of 140/90mm Hg regardless of diabetes or proteinuria, and against the combination of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors. We recommend against routine protein restriction. We concur on individualization of hemoglobin A1c targets. We do not agree with routine restriction of sodium intake to <2g/d, instead suggesting reduction of sodium intake in those with high intake (>3.3g/d). We suggest screening for anemia only when GFR is <30mL/min/1.73m(2). We recognize the absence of evidence on appropriate phosphate targets and methods of achieving them and do not agree with suggestions in this area. In drug dosing, we agree with the recommendation of using absolute clearance (ie, milliliters per minute), calculated from the patients estimated GFR (which is normalized to 1.73m(2)) and the patients actual anthropomorphic body surface area. We agree with referral to a nephrologist when GFR is <30mL/min/1.73m(2) (and for many other scenarios), but suggest urine albumin-creatinine ratio > 60mg/mmol or proteinuria with protein excretion > 1g/d as the referral threshold for proteinuria.

The relationship between estimated sodium and potassium excretion and subsequent renal outcomes

Patients are often advised to reduce sodium and potassium intake, but supporting evidence is limited. To help provide such evidence we estimated 24 h urinary sodium and potassium excretion in 28,879 participants at high cardiovascular risk who were followed for a mean of 4.5 years in the ONTARGET and TRANSCEND trials. The primary outcome was eGFR decline of 30% or more or chronic dialysis. Secondary outcomes were eGFR decline of 40% or more or chronic dialysis, doubling of serum creatinine or chronic dialysis, an over 5%/year loss of eGFR, progression of albuminuria, and hyperkalemia. Multinomial logit regression with multivariable fractional polynomials, adjusted for confounders, determined the association between urinary sodium and potassium excretion and renal outcomes, with death as a competing risk. The primary outcome occurred in 2,052 (7.6%) patients. There was no significant association between sodium and any renal outcome (primary outcome odds ratio 0.99; 95% CI 0.89-1.09 for highest [median 6.2 g/day] vs. lowest third [median 3.3 g/day]). Higher potassium was associated with lower odds of all renal outcomes (primary outcome odds ratio 0.74; 95% CI 0.67-0.82 for highest [median 2.7 g/day] vs. lowest third [median 1.7 g/day], except hyperkalemia nonsignificant. Thus, urinary potassium, but not sodium, excretion predicted clinically important renal outcomes. Our findings do not support routine low sodium and potassium diets for prevention of renal outcomes in people with vascular disease with or without chronic kidney disease.

Obstetric Nephrology: Lupus and Lupus Nephritis in Pregnancy

SLE is a multi-organ autoimmune disease that affects women of childbearing age. Renal involvement in the form of either active lupus nephritis (LN) at the time of conception, or a LN new onset or flare during pregnancy increases the risks of preterm delivery, pre-eclampsia, maternal mortality, fetal/neonatal demise, and intrauterine growth restriction. Consequently, current recommendations advise that the affected woman achieve a stable remission of her renal disease for at least 6 months before conception. Hormonal and immune system changes in pregnancy may affect disease activity and progression, and published evidence suggests that there is an increased risk for a LN flare during pregnancy. The major goal of immunosuppressive therapy in pregnancy is control of disease activity with medications that are relatively safe for a growing fetus. Therefore, the use of mycophenolate mofetil, due to increasing evidence supporting its teratogenicity, is contraindicated during pregnancy. Worsening proteinuria, which commonly occurs in proteinuric renal diseases toward the end of pregnancy, should be differentiated from a LN flare and/or pre-eclampsia, a pregnancy-specific condition clinically characterized by hypertension and proteinuria. These considerations present challenges that underscore the importance of a multidisciplinary team approach when caring for these patients, including a nephrologist, rheumatologist, and obstetrician who have experience with these pregnancy-related complications. This review discusses the pathogenesis, maternal and fetal risks, and management pertinent to SLE patients with new onset or a history of LN predating pregnancy.

Sodium intake and renal outcomes: a systematic review

BACKGROUND Sodium intake is an important determinant of blood pressure; therefore, reduction of intake may be an attractive population-based target for chronic kidney disease (CKD) prevention. Most guidelines recommend sodium intake of < 2.3 g/day, based on limited evidence. We reviewed the association between sodium intake and renal outcomes. METHODS We reviewed cohort studies and clinical trials, which were retrieved by searching electronic databases, that evaluated the association between sodium intake/excretion and measures of renal function, proteinuria, or new need for dialysis. RESULTS Of 4,337 reviewed citations, seven (n = 8,129) were eligible, including six cohort studies (n = 7,942) and one clinical trial (n = 187). Four studies (n = 1,787) included patients with CKD. All four cohort studies reported that high intake (> 4.6 g/day) was associated with adverse outcomes (vs. moderate/low), while none reported an increased risk with moderate intake (vs. low). Three studies (n = 6,342) included patients without CKD. Two cohort studies (n = 6,155) reported opposing directions of association between low (vs. moderate) sodium intake and renal outcomes, and one clinical trial (n = 187) reported a benefit from low intake (vs. moderate) on proteinuria but an adverse effect on serum creatinine. CONCLUSIONS Available, but limited, evidence supports an association between high sodium intake (> 4.6g/day) and adverse outcomes. However, the association with low intake (vs. moderate) is uncertain, with inconsistent findings from cohort studies. There is urgent need to clarify the long-term efficacy and safety of currently recommended low sodium intake in patients with CKD.

The Safety of Eplerenone in Hemodialysis Patients: A Noninferiority Randomized Controlled Trial

BACKGROUND AND OBJECTIVES Mineralocorticoid receptor antagonism reduces morbidity and mortality in patients with heart failure, but the safety of these drugs in patients receiving dialysis is unclear. This study evaluated whether hyperkalemia and/or hypotension limited the use of eplerenone, a selective mineralocorticoid receptor antagonist, in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a randomized controlled trial of prevalent patients receiving hemodialysis at five Canadian centers. Participants were randomly allocated to 13 weeks of eplerenone titrated to 50 mg daily (n=77) or a matching placebo (n=77). The primary outcome was permanent discontinuation of the drug because of hyperkalemia or hypotension. Secondary outcomes included hyperkalemia, hypotension, and cardiovascular events. RESULTS Seventy-five eplerenone-treated patients and 71 placebo-treated patients were included in the per protocol population. The primary outcome occurred in three patients (4.0%) in the eplerenone group and two (2.8%) in the placebo group, for an absolute risk difference of 1.2 percentage points (95% confidence interval, -4.7 to 7.1 percentage points). Eplerenone was interpreted as noninferior to placebo with respect to the primary outcome (i.e., a discontinuation rate for these reasons >10% was excluded). In the eplerenone group, nine patients (11.7%) developed hyperkalemia (potassium level >6.5 mEq/L), compared with two patients (2.6%) in the placebo group (relative risk, 4.5; 95% confidence interval, 1.0 to 20.2). There was no significant effect on predialysis or postdialysis BP. CONCLUSION Eplerenone increased the risk of hyperkalemia but did not result in an excess need to permanently discontinue the drug. Further trials are required to determine whether mineralocorticoid receptor antagonism improves cardiovascular outcomes in patients receiving long-term dialysis.

Page Kidney: Etiology, Renal Function Outcomes and Risk for Future Hypertension

J Clin Hypertens (Greenwich). 2012;14:216–221. ©2012 Wiley Periodicals, Inc.