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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
Migalastat and Fabry disease (August 2016)
The treatment of patients with Fabry disease primarily focuses upon replacing the missing or deficient enzyme (alpha-galactosidase A). Enzyme replacement therapy (ERT) is limited by infusion reactions and the development of antibodies against the drug. Migalastat hydrochloride is an oral pharmacologic chaperone that binds to and stabilizes specific mutant forms of alpha-galactosidase and is a potential alternative therapy. In a double-blinded trial, 67 patients with Fabry disease who were not on ERT were randomly assigned to treatment with migalastat or placebo for six months, followed by open-label migalastat for up to an additional 18 months . Although enrolled patients were required to have mutant forms of alpha-galactosidase that were suitable for migalastat, only 50 of the 67 patients ultimately were confirmed to have amenable mutations. At six months, there was difference in the primary endpoint, defined as the percent of patients with a ≥50 percent reduction in the number of Gb3 inclusions per kidney interstitial capillary. However, in a secondary analysis of the 50 patients confirmed to have migalastat-suitable mutations, there was a greater reduction in the mean number of Gb3 inclusions per kidney interstitial capillary in patients treated with migalastat compared with placebo. Further studies evaluating long-term outcomes in patients with amenable mutations are still needed. (See "Treatment of Fabry disease", section on 'Alternatives to ERT'.)
Plant-based low protein diet in chronic kidney disease (July 2016)
A randomized trial compared a very low protein, plant-based diet supplemented with ketoanalogues (KD) with a mixed source (plant- and animal-based) low-protein diet (LPD) among patients with a stable estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 . At 18 months of follow-up, compared with the LPD group, fewer patients in the KD group reached the composite endpoint of >50 percent reduction in eGFR or initiation of renal replacement therapy (RRT) (42 versus 13 percent, respectively). Compared with the LPD group, fewer patients in the KD group required RRT (30 versus 11 percent).
Caution is warranted in interpreting these results, however. While there were no differences between groups in nutritional parameters, other studies have shown increased mortality among patients treated with a keto acid- and amino acid-supplemented very low protein diet. Concerns have also been raised about delayed registration of the trial in the public trials registry until after enrollment of some participants. (See "Dietary recommendations for patients with nondialysis CKD", section on 'Source of protein intake'.)
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'.)
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'.)
GLOMERULAR DISEASE AND VASCULITIS
B7-1 blockade does not improve posttransplant nephrotic syndrome in patients with recurrent FSGS (August 2016)
Primary idiopathic focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and the optimal treatment is unknown. An initial report demonstrated that the protein B7-1 is more highly expressed within kidneys of patients with recurrent FSGS and could serve as a therapeutic target. However, in a series of nine patients with recurrent idiopathic FSGS following transplantation, treatment with a B7-1 inhibitor (abatacept or belatacept) did not induce remission of proteinuria . Among all nine patients, expression of B7-1 within podocytes was undetectable in kidney biopsies performed at the time of disease recurrence. B7-1 expression in podocytes was similarly absent from the biopsies of 22 additional patients with recurrent FSGS. Thus, in contrast with the prior study, B7-1 was not expressed during FSGS recurrence and B7-1 blockade was not effective in the treatment of recurrent idiopathic FSGS. (See "Focal segmental glomerulosclerosis in the transplanted kidney", section on 'Abatacept'.)
Rituximab in primary membranous nephropathy (July 2016)
Rituximab may have benefit among patients with idiopathic membranous nephropathy with a moderate risk of progression. In one unblinded trial, 75 patients with persistent proteinuria greater than 3.5 g/day after six months of treatment with angiotensin inhibition, diuretics, and a statin (nonimmunosuppressive therapy) were randomly assigned to rituximab or no rituximab . Nonimmunosuppressive therapy was continued in all patients. At six months, there was no significant difference in the primary composite endpoint of complete or partial remission of proteinuria between patients. However, in a post-trial observational phase that followed patients for an additional 12 months, the rate of complete or partial remission was higher among patients treated with rituximab (65 versus 34 percent). In addition, patients treated with rituximab had less proteinuria and higher serum albumin levels. The role of rituximab for patients with primary membranous nephropathy is uncertain and further data are awaited. (See "Treatment of idiopathic membranous nephropathy", section on 'Rituximab'.)
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'.)
Intensive blood pressure control and long-term outcomes in CKD (August 2016)
Several trials have compared more versus less intensive blood pressure control in patients with chronic kidney disease (CKD); however, follow-up during these trials was four years or less. A meta-analysis that combined patient-level information on long-term follow-up from the two largest of these trials (AASK and MDRD, with 14 to 19 years of follow-up) found that more intensive blood pressure control during the trial was associated with reduced overall mortality (hazard ratio 0.87) . The reduction in death was similar in patients with and without proteinuria. Aggressive blood pressure lowering also reduced the progression to ESRD, but the benefit was confined to those with proteinuric CKD. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Meta-analyses'.)
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'.)
Calcineurin inhibitor-sparing strategies following kidney transplantation (July 2016)
A number of different immunosuppressive approaches have been evaluated to reduce the risk of developing chronic allograft nephropathy related to calcineurin inhibitor therapy after kidney transplantation. A systematic review and meta-analysis of 88 randomized controlled trials involving renal transplant recipients evaluated the outcomes of four strategies (minimization, conversion, withdrawal, and avoidance) to limit exposure to calcineurin inhibitors among renal transplant recipients . Minimization of the calcineurin inhibitor dose, when combined with mycophenolate mofetil, resulted in better renal function, a lower risk of biopsy-proven acute rejection, and a lower rate of graft loss compared with standard calcineurin inhibitor doses. In general, conversion (primarily to a mammalian target of rapamycin inhibitor) and avoidance strategies did not provide benefit, whereas withdrawal strategies increased the risk of acute rejection. Thus, consideration should be given to calcineurin inhibitor therapy minimization to help prevent the development and progression of chronic renal allograft nephropathy. (See "Chronic renal allograft nephropathy", section on 'Reducing calcineurin inhibitor exposure'.)
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'.)
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".)
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