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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
Metformin use in patients with diabetes and renal impairment, heart failure, or chronic liver disease (January 2017)
The US Food and Drug Administration (FDA) recently revised its labeling of metformin, which will increase its use in patients with renal impairment. This change is supported by the findings of a systematic review of 17 observational studies comparing diabetes regimens with and without metformin; metformin use was associated with lower all-cause mortality among patients with heart failure, renal impairment, or chronic liver disease with hepatic impairment . In addition, metformin use in patients with renal impairment or heart failure was associated with fewer heart failure readmissions. Metformin remains contraindicated in patients with estimated glomerular filtration rate (eGFR) <30 mL/min, concurrent active or progressive liver disease, or unstable or acute heart failure with risk of hypoperfusion and hypoxemia. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications'.)
Thrombotic microangiopathy from interferon (October 2016)
Drug-induced thrombotic microangiopathy (DITMA) has been described with a number of chemotherapeutic, immunosuppressive, and other drugs. Unlike thrombotic thrombocytopenic purpura (TTP), DITMA is not associated with severely reduced ADAMTS13 activity, and the principal treatment is drug discontinuation rather than plasma exchange. A new report has provided strong evidence for interferon as a cause of TMA . Patients receiving interferon who develop signs of a TMA should have the drug discontinued promptly before organ failure develops. (See "Drug-induced thrombotic microangiopathy", section on 'Immunosuppressive agents'.)
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 no 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. Migalastat has been approved for use in Europe but not in the United States. (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'.)
Regional anesthesia for hemodialysis arteriovenous fistula creation (November 2016)
Regional anesthesia during the creation of hemodialysis arteriovenous fistulas causes arterial and venous dilation, which may improve early fistula patency. In a trial that randomly assigned 126 adults receiving primarily radiocephalic or brachiocephalic fistulas to brachial plexus block or local anesthesia, brachial plexus block resulted in a higher rate of primary fistula patency and a trend toward a higher rate of functional patency at three months . Based upon these findings, we suggest brachial plexus block for the creation of arteriovenous fistulas, rather than using local anesthesia alone. (See "Creating an arteriovenous fistula for hemodialysis", section on 'Type of anesthesia'.)
Predialysis education and choice of modality (November 2016)
Predialysis education regarding different dialysis modalities may increase the number of patients who opt for peritoneal dialysis. In a systematic review and meta-analysis, structured educational interventions were associated with a twofold increase in the odds of choosing peritoneal dialysis compared with standard care . (See "Dialysis modality and patient outcome", section on 'Selection of dialysis modality'.)
GLOMERULAR DISEASE AND VASCULITIS
Durability of remission in idiopathic membranous nephropathy (November 2016)
Among patients with idiopathic membranous nephropathy (MN), the durability of remission (spontaneous or treatment-associated) is associated with improved renal survival. In a prospective study of 376 patients with idiopathic MN who achieved complete or partial remission of nephrotic-range proteinuria, persistent remission at 3, 6, 12, and 24 months, compared with disease relapse at those time points, was associated with a lower risk of the primary endpoint (end-stage renal disease or 50 percent reduction in estimated glomerular filtration rate) . (See "Treatment of idiopathic membranous nephropathy", section on 'Prognosis'.)
Accuracy of the spot urine protein to creatinine ratio in patients with kidney disease (October 2016)
A spot urine protein to creatinine ratio (UPCR) is frequently used to estimate 24-hour proteinuria and to follow the effects of treatment in patients with proteinuric kidney diseases. However, a longitudinal study of patients with biopsy-proven glomerular disease  and a systematic review of studies of patients with lupus nephritis  have demonstrated that a spot UPCR may not accurately predict the result of a 24-hour urine, particularly in patients with lower degrees (<1 g/day) of proteinuria. These findings support our recommendation that a 24-hour urine collection should be the method of choice for initial quantification of proteinuria and for verification of changes in proteinuria before therapy is altered in patients with kidney disease. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Accuracy of spot urine estimates'.)
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'.)
Effect of antihypertensive drug class on fracture rates (January 2017)
Thiazide diuretics stimulate distal tubular reabsorption of calcium, leading to a decrease in urinary calcium excretion and a possible benefit on bone mineral density. The rates of hip or pelvic fractures among patients treated with thiazide-like diuretics, angiotensin converting enzyme (ACE) inhibitors, or calcium channel blockers were compared in a post-hoc analysis of the ALLHAT trial . At approximately five years, those randomly assigned chlorthalidone had fewer hip or pelvic fractures as compared with those assigned either lisinopril or amlodipine. Thus, if monotherapy is appropriate in a patient with hypertension and osteoporosis, thiazide-like diuretics may have advantages over ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers. (See "Choice of drug therapy in primary (essential) hypertension", section on 'Thiazide diuretics'.)
Outcomes in severe asymptomatic hypertension (hypertensive urgency) (November 2016)
There is no proven benefit from rapid reduction of blood pressure in patients with severe asymptomatic hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg). In one retrospective study of over 59,000 patients who presented in the ambulatory setting with severe asymptomatic hypertension, there was no difference in major adverse cardiovascular events, or prevalence of uncontrolled hypertension six months later, for patients sent to the emergency department or sent home from the office for outpatient blood pressure management . Hospitalization rates were higher for those sent to the emergency department. This cohort study suggests that most patients with asymptomatic hypertensive urgency who present in the ambulatory setting can be managed as outpatients. (See "Management of severe asymptomatic hypertension (hypertensive urgencies) in adults", section on 'Rapidity of blood pressure lowering'.)
Angioplasty in renal artery stenosis (November 2016)
In patients with atherosclerotic renal artery stenosis, a meta-analysis of trials comparing percutaneous transluminal renal angioplasty (PTRA) with stent placement plus medical therapy with medical therapy alone found no benefit from PTRA on mortality, end-stage renal disease, major cardiovascular events, or blood pressure control . One or more major periprocedural complications occurred in 7.1 percent of patients who underwent PTRA. Thus, in patients with renal artery stenosis and clinical characteristics similar to those enrolled in these trials, we suggest not revascularizing and instead treating with medical therapy alone. (See "Treatment of unilateral atherosclerotic renal artery stenosis", section on 'Revascularization versus medical therapy alone'.)
J-shaped relationship between blood pressure and cardiovascular outcomes (November 2016)
There may be a blood pressure threshold below which tissue perfusion is reduced and risk is increased for cardiovascular and renal events and mortality (a J-shaped curve between blood pressure and event rate). In a large international prospective observational study of patients with stable coronary artery disease and treated hypertension, achieved diastolic pressures below 70 and above 80 mmHg were independently associated with increased risk for adverse outcomes (figure 1) . Similarly, achieved systolic pressures below 120 and above 140 mmHg were independently associated with increased risk for adverse outcomes (figure 2). However, these data are observational, and other evidence disputes the importance of these J-shaped curves, particularly for systolic pressure. Based upon the available evidence and the physiology of coronary perfusion, we generally try to avoid lowering the diastolic blood pressure to a value of <60 mmHg in most patients. (See "What is goal blood pressure in the treatment of hypertension?", section on 'J-shaped diastolic curve'.)
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'.)
Dietary protein and the risk of kidney stones (November 2016)
Different types of dietary protein may have different effects on the risk of kidney stones. Earlier studies have found an association between high animal protein intake and an increased incidence of stone disease, at least in men, while vegetable protein intake has not been associated with stone risk. A new study suggests that the risk of stones may vary depending upon whether the source of the animal protein is dairy or nondairy . Higher nondairy animal protein intake was associated with a trend toward an increase in stone risk, whereas higher dairy protein intake in young women was associated with a lower risk of stone disease. (See "Risk factors for calcium stones in adults", section on 'Protein'.)
Acute kidney injury in critically ill children (November 2016)
Children cared for in intensive care units (ICUs) are at increased risk of acute kidney injury (AKI). In a large prospective multicenter study of patients 3 months to 25 years of age cared for in over 30 pediatric ICUs worldwide, approximately 27 percent developed AKI and 12 percent developed severe AKI (stage 2 or 3 AKI) (table 1) . Severe AKI was independently associated with an increased risk of death, and increasing severity was associated with increasing risk of death. These data reinforce the need to identify patients at risk for AKI or with mild AKI so that interventions to prevent further injury can be implemented. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Critically ill children'.)
Screening for cardiovascular disease before kidney transplantation (October 2016)
Cardiovascular disease is the leading cause of mortality in kidney transplant recipients. Although pretransplant cardiac evaluation is recommended for potential transplant candidates, the optimal screening strategy has not yet been identified. In a prospective study comparing clinical risk factor assessment with coronary artery calcium (CAC) scores among 138 pretransplant patients, CAC scores were not superior to risk factor assessment in identifying patients who would benefit from noninvasive testing for coronary heart disease (CHD) . Both clinical risk factor assessment and CAC scores had a poor positive predictive value but a high negative predictive value for identifying patients with CHD. (See "Evaluation of the potential renal transplant recipient", section on 'Coronary heart disease'.)
Pretransplant kidney biopsies in liver transplant candidates with renal dysfunction (September 2016)
Among liver transplant candidates with renal dysfunction, a pretransplant kidney biopsy can help to identify patients who should be considered for simultaneous liver-kidney transplantation (SLK). A small retrospective study found that when pretransplant kidney biopsy criteria (>40 percent glomerulosclerosis and/or >30 percent interstitial fibrosis) were used to select SLK candidates, allocation of a kidney could be avoided in 70 percent of liver transplant candidates with renal dysfunction . Post-transplant glomerular filtration rates were similar over the first year for SLK and liver alone transplant patients; further studies and longer-term follow-up are indicated. (See "Renal function and nonrenal solid organ transplantation", section on 'Approach in liver transplant candidates'.)
Biopsy gene expression profiling in kidney transplant recipients to predict risk of chronic injury (September 2016)
Gene expression analysis may provide a new method of identifying kidney transplant recipients who are at risk of developing chronic allograft nephropathy. In a prospective study of 101 renal transplant recipients, a microarray analysis performed on three-month posttransplant renal allograft biopsies identified a set of 13 genes that independently predicted the development of histologic injury at 12 months and risk of renal allograft loss at two and three years post-biopsy . Although further studies are needed, this gene set represents a promising approach that could be used to identify patients who may benefit from therapeutic strategies to prevent the progression to fibrosis. (See "Chronic renal allograft nephropathy", section on 'Future directions'.)
Perioperative complications in minimally invasive live donor nephrectomy (September 2016)
Minimally invasive donor nephrectomies account for more than half of live donor nephrectomies performed for kidney transplantation. A systematic review of over 32,000 minimally invasive live donor nephrectomies demonstrated a low operative mortality rate of 0.01 percent and low rates of intraoperative and postoperative complications (primarily bleeding and infections) . Comparison of the different minimally invasive techniques found similar complication rates between hand-assisted versus non-hand-assisted, laparoscopic versus retroperitoneoscopic, and multiport versus single-port procedures. (See "Benefits and complications of minimally invasive live-donor nephrectomy", section on 'Donor morbidity'.)
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'.)
Prognostic implications of albuminuria remission in type 1 diabetes (December 2016)
In patients with type 1 diabetes who have moderately increased albuminuria (formerly "microalbuminuria"), progression and stabilization of albuminuria are associated with high and intermediate risks, respectively, for a decline in glomerular filtration rate (GFR), but whether remission of albuminuria can further improve chronic kidney disease risk has not been known. Among patients with type 1 diabetes in the DCCT study who developed moderately increased albuminuria, the risk of GFR decline at 18 years was the same for those whose albuminuria persisted compared with those whose albuminuria remitted . These data suggest that moderately increased albuminuria is an important risk marker for progression of kidney disease, even if remission of albuminuria can be achieved. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'Regression to normoalbuminuria'.)
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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