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The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
ACUTE AND CHRONIC KIDNEY DISEASE
Early initiation of renal replacement therapy (June 2016)
It is unclear if the early initiation of renal replacement therapy (RRT) (ie, without an obvious indication such as severe hyperkalemia, metabolic acidosis, pulmonary edema or advanced uremic symptoms) provides any benefit to critically ill patients with acute kidney injury (AKI) compared with later initiations of RRT. Two new randomized trials have evaluated this in somewhat different patient populations. In the larger trial, 620 critically ill patients with severe AKI were randomized to early or delayed RRT . There was no difference in 60-day mortality, and nearly one-half of patients in the delayed RRT group recovered without requiring RRT. In contrast, a second trial of 231 critically ill patients with more moderate AKI showed reduced 90-day mortality with earlier RRT . In the delayed initiation group, only 11 patients ended up not requiring RRT, and early RRT reduced the duration of AKI and length of stay. However, we have lower confidence in the results of the smaller trial, because it is possible that the relatively small size of the trial resulted in an overestimate of the treatment benefit. It is otherwise difficult to understand how minor differences in the protocols and patient populations could achieve such dramatically different outcomes. Until further data are available, UpToDate suggests that RRT not be initiated in the absence of obvious clinical indications. (See "Renal replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose", section on 'Timing of elective initiation'.)
Proton pump inhibitors and chronic kidney disease (May 2016)
Two observational studies suggest that protein pump inhibitors (PPIs) may increase the risk of chronic kidney disease (CKD). In one study, data were analyzed from over 10,000 participants in the Atherosclerosis Risk in Communities (ARIC) study, and from a large integrated health care system in the United States . In an analysis adjusted for multiple variables, PPI use was associated with increased risk of CKD compared with no PPI use (hazard ratio [HR] 1.5), and compared with use of H2 receptor antagonists (HR 1.4). In a study of over 170,000 new PPI users and 20,000 new H2 receptor antagonist users followed for over five years, the PPI group had an increased risk of CKD (HR 1.3) and end-stage renal disease (HR 2.0), and increasing duration of use was associated with a progressively higher CKD risk . The mechanism underlying the association between PPIs and risk of CKD is not known, nor is it clear whether decreasing PPI use decreases the risk of CKD. Moreover, PPIs are used to prevent gastroduodenal mucosal injury from nonsteroidal anti-inflammatory agents (NSAIDs), and only one of the two studies evaluated NSAID use and found that it was higher among PPI users compared with PPI nonusers . Additional studies are needed to define a causal relationship between PPI use and the development and worsening of CKD. (See "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders", section on 'Kidney disease'.)
Metformin use and reduced kidney function (April 2016)
The use of metformin is contraindicated in patients with factors predisposing to lactic acidosis, including impaired renal function. The precise renal thresholds for the safe use of metformin remain uncertain. Improved clinical outcomes with metformin have been reported in observational studies of patients with diabetes and renal impairment (estimated glomerular filtration rate [eGFR] 45 to 60 mL/min). On the basis of these studies, the US Food and Drug Administration (FDA) revised its labeling of metformin, which previously had identified metformin as contraindicated in women and men with serum creatinine levels ≥1.4 mg/dL (124 micromol/L) and ≥1.5 mg/dL (133 micromol/L), respectively . The use of metformin is contraindicated in patients with an eGFR <30 mL/min, and the initiation of metformin is not recommended in patients with an eGFR between 30 and 45 mL/min. For patients taking metformin whose eGFR falls below 45 mL/min, the benefits and risks of continuing treatment should be assessed, whereas metformin should be discontinued if the eGFR falls below 30 mL/min. For patients with eGFR between 30 and 60 mL/min, we typically reduce the metformin dose by half (no more than 1000 mg per day), although there are no data to support this approach. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications'.)
Increased body weight and chronic kidney disease (March 2016)
Increased body weight is known to be associated with a higher risk of chronic kidney disease (CKD), which has been attributed to its association with conditions that cause CKD. A prospective cohort study from Korea now suggests that, compared with those of normal weight, even metabolically healthy overweight or obese individuals who are free from diabetes, hypertension, hypertriglyceridemia, and insulin resistance at baseline have a higher five-year cumulative incidence of CKD . (See "Screening for chronic kidney disease", section on 'Risk factors for chronic kidney disease'.)
Medication to prevent contrast nephropathy (March 2016)
A meta-analysis evaluated the effectiveness of multiple interventions to reduce the risk of contrast nephropathy. Compared with saline alone or saline plus placebo, both low- and high-dose N-acetylcysteine given with saline reduced the risk of contrast nephropathy . In addition, analysis of five studies (n = 1477) revealed that statins given with N-acetylcysteine and intravenous saline reduced the risk of contrast nephropathy compared with N-acetylcysteine and intravenous saline alone. The strength of the evidence in the meta-analysis was considered low, however, and we do not believe that there are sufficient data to support the use of statins solely for the prevention of contrast nephropathy. For at-risk patients, we suggest administration of acetylcysteine based upon its potential for benefit and low toxicity and cost. (See "Prevention of contrast-induced nephropathy", section on 'Acetylcysteine'.)
Choice of contrast agent to prevent contrast nephropathy (March 2016)
The type of contrast agent affects the risk of contrast nephropathy. Nonionic agents tend to be safer with respect to contrast nephropathy compared with ionic contrast agents. It is not known, however, whether nonionic iso-osmolal agents are safer than nonionic low-osmolal agents. A meta-analysis that included 25 randomized trials comparing the nonionic iso-osmolal agent iodixanol with a diverse group of nonionic low-osmolal agents reported a slight reduction in the risk of nephropathy with iodixanol that did not meet study criteria for clinical importance . There was no difference between groups in the risk for renal replacement therapy, cardiovascular outcomes, or death, and the strength of the evidence was only moderate. These findings are consistent with our recommendation to use either iodixanol or nonionic low-osmolal contrast agents. (See "Prevention of contrast-induced nephropathy", section on 'Nonionic iso-osmolal agents'.)
Erythropoiesis-stimulating agents may not improve quality of life in chronic kidney disease (February 2016)
While many clinicians believe that maintaining hemoglobin levels above 10 to 12 g/dL with erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease (CKD) improves quality of life, particularly in younger individuals with active lifestyles, a meta-analysis calls this into question. The meta-analysis included studies that examined the effect of ESAs on changes in health-related quality of life using validated instruments including the 36-item Short Form Health Survey (SF-36; 13 studies) and the Kidney Disease Questionnaire (KDQ; four studies) . The achieved hemoglobin was 7.4 to 12 g/L in the placebo-treated and/or lower hemoglobin target group and 10.2 to 13.6 g/L in the higher hemoglobin target group. Overall, there were no significant differences between groups in any SF-36 or KDQ domains. These data suggest that the use of ESAs to treat anemia may not result in significant changes in health-related quality of life among CKD patients. (See "Anemia of chronic kidney disease: Target hemoglobin/hematocrit for patients treated with erythropoietic agents", section on 'Quality of life'.)
Dialysis and survival outcomes in older adults (May 2016)
Older patients may derive little survival benefit from dialysis. A well-designed retrospective study from the Netherlands compared survival outcomes among patients >70 years who opted for conservative care versus dialysis . Survival was calculated from different starting points including the time at which the treatment decision was first made and from times at which the estimated glomerular filtration rate (eGFR) was first <20, <15, and <10 mL/min/1.73 m2. The overall median survival was higher for those patients who opted for dialysis. However, the survival advantage conferred by dialysis was substantially reduced among patients >70 years who had cardiovascular or other severe comorbidity, and there was no difference between groups among patients older than 80 years. (See "Conservative care of end-stage renal disease", section on 'Who should be offered conservative care'.)
Cool-temperature dialysis and hemodynamic stability (April 2016)
Using cool-temperature dialysate may increase the hemodynamic stability of selected patients during hemodialysis. A recent meta-analysis showed that, compared with standard dialysis, cool-temperature dialysis reduced the risk of intradialytic hypotension by 68 percent . Patients on cool-temperature dialysis were more likely to have uncomfortable symptoms during dialysis, such as chills, shivering, or cramps, although there was no effect on overall quality of life or dialysis adequacy, as assessed by the 36-question health survey assessment form. Cool-temperature dialysis is an effective strategy to increase hemodynamic stability in patients with intradialytic hypotension. (See "Intradialytic hypotension in an otherwise stable patient", section on 'Second-line approach'.)
Venous thromboembolism risk with central versus peripheral insertion of central venous catheters (January 2016)
There is accumulating evidence that peripherally-inserted central venous catheters (PICCs) are associated with a greater risk for upper extremity deep vein thrombosis (UEDVT) compared with centrally-inserted central venous catheters (CICCs). The Medical Inpatients and Thrombosis (MITH) Study evaluated catheter use in 299 venous thromboembolism cases compared with controls without venous thromboembolism at a single institution . Central catheter use was associated with a 14-fold increased risk for UEDVT, without a significantly increased risk for pulmonary embolism. PICCs were associated with a higher cumulative risk compared with CICCs (8.1 versus 4.8 per 1000 admissions). Given the higher risk for UEDVT with PICCs, we generally avoid them in patients for whom maintaining vascular patency and integrity for long-term vascular access options (eg, future hemodialysis access) is essential. (See "Catheter-related upper extremity venous thrombosis", section on 'Peripheral versus central insertion' and "Overview of central venous access".)
GLOMERULAR DISEASE AND VASCULITIS
Potential mechanism of malignancy-associated membranous nephropathy (June 2016)
The production of antibodies produced against tumor antigens that also recognize similar or identical molecules present on podocytes is a possible mechanism for malignancy-associated membranous nephropathy (MN). In a case report of a patient with anti-PLA2R-negative MN and concomitantly diagnosed adenoneuroendocrine carcinoma of the gallbladder, the expression of thrombospondin type-1 domain-containing 7A (THSD7A) was detected by immunohistochemistry on tumor cells but not on normal gallbladder tissue . The patient also had elevated plasma levels of anti-THSD7A antibodies, which the authors proposed were formed against abnormally expressed THSD7A by tumor cells. Treatment with chemotherapy led to the disappearance of THSD7A antibodies in the plasma within two weeks and a marked reduction in proteinuria. In a series of 24 other patients with MN and THSD7A antibodies, six were found to have a malignancy. (See "Causes and diagnosis of membranous nephropathy", section on 'Malignancy'.)
Goal blood pressure in older adults (June 2016)
Goal blood pressure in older adults was examined in the Systolic Pressure Intervention Trial (SPRINT) . SPRINT enrolled a subgroup of more than 2600 ambulatory adults aged 75 years or older, including 349 categorized as being fit, 1456 as less fit, and 815 as frail according to a validated frailty index. At 3.1 years, rates of both the primary cardiovascular endpoint and all-cause mortality were significantly lower among those assigned more intensive (goal <120 mmHg) versus less intensive (goal <140 mmHg) systolic blood pressure lowering. The benefit from more intensive blood pressure control was present in both fit and frail older adults. Serious adverse events were similar in the two treatment groups, and did not depend upon frailty. (See "Treatment of hypertension in the elderly patient, particularly isolated systolic hypertension", section on 'Goal blood pressure'.)
Antihypertensive therapy in patients not at high cardiovascular risk (April 2016)
The benefit of antihypertensive therapy in patients at low or moderate cardiovascular risk, including those who are normotensive, is unclear. The Third Heart Outcomes Prevention Evaluation trial (HOPE-3) randomly assigned 12,705 patients at moderate risk for cardiovascular disease (only 38 percent were hypertensive at baseline) to receive a fixed-dose combination of candesartan plus hydrochlorothiazide or placebo . At 5.6 years, there was no significant difference in cardiovascular events. However, among a hypertensive subgroup (ie, those whose initial systolic pressure was in the highest tertile, or greater than 143 mmHg), antihypertensive therapy significantly reduced the incidence of major cardiovascular events (5.7 versus 7.5 percent, absolute benefit of 1.8 percent). Thus, antihypertensive therapy reduced cardiovascular events in patients with mild hypertension and low overall cardiovascular risk. (See "What is goal blood pressure in the treatment of hypertension?", section on 'Benefit in those with mild hypertension'.)
Meta-analysis of goal blood pressure trials (March 2016)
A meta-analysis of goal blood pressure trials (ie, comparing a more intensive versus a less intensive goal) included 16 studies (including the SPRINT trial) and 52,235 patients . A standardized 10/5 mmHg reduction in systolic/diastolic pressure resulted in reductions in the relative risks of stroke, coronary heart disease, and cardiovascular death. A trend, that did not reach statistical significance, was also seen for reduction in heart failure and all-cause mortality. The absolute (as opposed to relative) risk reductions varied according to baseline cardiovascular risk. The absolute benefit from blood pressure reduction was substantially greater among patients who, at baseline, were considered high-risk for having a cardiovascular event over the subsequent 5 to 10 years. (See "What is goal blood pressure in the treatment of hypertension?", section on 'Evidence of benefit from treating hypertension'.)
Cardiovascular benefits from blood pressure lowering (February 2016)
A meta-analysis of 123 randomized trials of antihypertensive therapy including 613,815 patients found that a standardized 10 mmHg reduction in achieved systolic pressure reduced the risk of death (relative risk [RR] 0.87, 95% CI 0.84-0.91), as well as risk of coronary heart disease, stroke, or heart failure . The benefit was consistent regardless of the baseline blood pressure (including in patients whose initial systolic pressure was less than 130 mmHg). In addition, patients with both low initial systolic pressure and preexisting cardiovascular disease benefited from lower blood pressure. (See "What is goal blood pressure in the treatment of hypertension?", section on 'Evidence of benefit from treating hypertension'.)
Early volume expansion in STEC-hemolytic uremic syndrome (January 2016)
Fluid management of patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) has been based on assessment of intravascular volume, which can be increased or decreased. However, a prospective Italian study of 38 children with STEC-HUS from 2012 and 2014 compared with historical controls from 2006 to 2009 reported that routine early volume expansion targeted to increase body weight by 10 percent improved outcome (lower rate of renal replacement therapy, shorter hospital course, and shorter duration of intensive care) . Although these results are promising, further investigation is needed due to the potential bias from the use of historical controls and the relatively small number of patients and adverse events in the study. Until confirmatory data are available, we recommend assessment of intravascular volume status and renal function, with administration of fluids to rapidly correct documented volume depletion. We recommend not routinely providing volume expansion, especially if there is evidence of increased intravascular volume. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children", section on 'Fluid management'.)
Survival of recipients of HLA-mismatched kidneys (March 2016)
The success of human leukocyte antigen (HLA)-mismatched kidney transplantation is reduced compared with HLA-matched kidneys. However, a multicenter study suggests higher survival rates for recipients of HLA-incompatible living-donor kidneys compared with waitlisted controls who either never receive a kidney or who receive an HLA-compatible deceased-donor kidney after a prolonged time on the waiting list . The observed survival benefit persisted despite the presence of high donor-specific antibody (DSA) levels and independent of the desensitization protocol utilized. However, a few factors may have influenced these findings: data were reported from highly effective transplant centers and may not be generalizable to all centers, and the comparator group came from all patients on the waiting list rather than just active patients who would be considered suitable for transplantation, which may overestimate the apparent benefit of transplantation. (See "HLA matching and graft survival in kidney transplantation", section on 'Survival compared with waiting list'.)
Zika virus and tissue/gamete donation (March 2016)
Zika virus has been detected in a number of tissues and body fluids. To avoid possible transmission of Zika virus infection, the US Food and Drug Administration (FDA) has issued donor deferral recommendations for hematopoietic stem cells, tissues, and donor sperm or eggs; the recommendations do not apply to solid organs . Living donors with Zika virus infection or relevant epidemiologic exposure (residence in or travel to an area where mosquito-borne transmission of Zika virus infection has been reported, or unprotected sexual contact with a person who meets these criteria) should be considered ineligible for donation for six months. Deceased donors with Zika virus infection in the preceding six months should also be considered ineligible. The deferral period recommended by the FDA for blood donors with risk factors for Zika virus infection remains at four weeks. (See "Zika virus infection: An overview", section on 'Blood/tissue donation'.)
BENEFIT trial comparing belatacept and cyclosporine in kidney transplant patients (February 2016)
The final results of the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) have been published . BENEFIT was a phase III trial that compared a more intensive (MI) or less intensive (LI) regimen of a T cell inhibitor, belatacept, versus cyclosporine in adults receiving a kidney transplant from living or standard criteria deceased donors. Of the 660 patients initially treated, only 128 (MI group), 136 (LI group), and 92 (cyclosporine group) completed the 84-month study. Patients who dropped out of the trial were ineligible to continue, declined the extension study, withdrew consent, had an adverse effect, or died; others were lost to follow-up, or were nonadherent and not included in the analysis. Of the patients who were evaluated, at 84 months, the risks of death or graft loss and the development of donor-specific antibodies were lower among patients treated with belatacept compared with cyclosporine. However confidence in these data are limited because of the large number of patients who were excluded from the final analysis. (See "Maintenance immunosuppressive therapy in renal transplantation in adults", section on 'Belatacept'.)
Microvascular outcomes with empagliflozin in patients with type 2 diabetes (July 2016)
There are few trials evaluating microvascular outcomes in patients taking sodium-glucose co-transporter 2 (SGLT2) inhibitors. Microvascular disease was a prespecified secondary outcome in a recent trial designed specifically to evaluate cardiovascular morbidity and mortality in patients with type 2 diabetes and established cardiovascular disease (CVD) . In this trial, 7028 patients with type 2 diabetes and established CVD were randomly assigned to empagliflozin or placebo once daily; the majority of patients were also taking metformin, antihypertensives, and lipid-lowering agents. Incident or worsening nephropathy occurred in 12.7 and 18.8 percent of patients in the empagliflozin and placebo groups, respectively. The reduction in nephropathy drove the improved composite microvascular endpoint (the initiation of retinal photocoagulation, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy) for empagliflozin. The mechanism behind the reduction in incident or worsening nephropathy with empagliflozin is likely multifactorial, but is thought to be largely related to a direct renovascular effect of empagliflozin. Whether other SGLT2 inhibitors have similar renal effects is unknown. There have been reports of acute kidney injury, some requiring hospitalization and dialysis, in patients taking canagliflozin or dapagliflozin. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'SGLT2 inhibitors'.)
Elbasvir-grazoprevir for chronic HCV infection (February 2016)
Despite the proliferation of interferon-free regimens for the treatment of chronic hepatitis C (HCV) infection, safety concerns have limited options for patients with severe renal impairment, who have been excluded from trials of most available regimens. In January 2016, the US Food and Drug Administration approved the new combination regimen elbasvir-grazoprevir for the treatment of patients with genotypes 1 and 4 HCV infection, including those with any degree of renal impairment (including dialysis dependence) . In a randomized, placebo-controlled trial of genotype 1-infected patients with estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m2, the sustained virologic response (SVR) rate was 94 percent among the 122 patients who received elbasvir-grazoprevir for 12 weeks, and adverse event rates were similar between treatment and placebo groups . These results were comparable to those among patients with normal renal function. Elbasvir-grazoprevir is given for 12 to 16 weeks with or without ribavirin, depending on the presence of pre-existing resistance-associated variants in the NS5A protein and prior exposure to HCV protease inhibitors. (See "Treatment of chronic hepatitis C infection in adults with renal impairment", section on 'Regimens with direct-acting antivirals'.)
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