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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
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'.)
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'.)
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'.)
GLOMERULAR DISEASE AND VASCULITIS
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'.)
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'.)
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'.)
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".)
- Kavanagh D, McGlasson S, Jury A, et al. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood 2016.
- Germain DP, Hughes DA, Nicholls K, et al. Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. N Engl J Med 2016; 375:545.
- Garneata L, Stancu A, Dragomir D, et al. Ketoanalogue-Supplemented Vegetarian Very Low-Protein Diet and CKD Progression. J Am Soc Nephrol 2016; 27:2164.
- Gaudry S, Hajage D, Schortgen F, et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med 2016; 375:122.
- Zarbock A, Kellum JA, Schmidt C, et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA 2016; 315:2190.
- Lazarus B, Chen Y, Wilson FP, et al. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Intern Med 2016; 176:238.
- Xie Y, Bowe B, Li T, et al. Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD. J Am Soc Nephrol 2016; 27:3153.
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494829.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery (Accessed on April 11, 2016).
- Verberne WR, Geers AB, Jellema WT, et al. Comparative Survival among Older Adults with Advanced Kidney Disease Managed Conservatively Versus with Dialysis. Clin J Am Soc Nephrol 2016; 11:633.
- Hogan MC, Reich HN, Nelson PJ, et al. The relatively poor correlation between random and 24-hour urine protein excretion in patients with biopsy-proven glomerular diseases. Kidney Int 2016.
- Medina-Rosas J, Yap KS, Anderson M, et al. Utility of Urinary Protein-Creatinine Ratio and Protein Content in a 24-Hour Urine Collection in Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis. Arthritis Care Res (Hoboken) 2016; 68:1310.
- Delville M, Baye E, Durrbach A, et al. B7-1 Blockade Does Not Improve Post-Transplant Nephrotic Syndrome Caused by Recurrent FSGS. J Am Soc Nephrol 2016; 27:2520.
- Dahan K, Debiec H, Plaisier E, et al. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up. J Am Soc Nephrol 2016.
- Hoxha E, Wiech T, Stahl PR, et al. A Mechanism for Cancer-Associated Membranous Nephropathy. N Engl J Med 2016; 374:1995.
- Ku E, Gassman J, Appel LJ, et al. BP Control and Long-Term Risk of ESRD and Mortality. J Am Soc Nephrol 2016.
- Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial. JAMA 2016; 315:2673.
- O'Connell PJ, Zhang W, Menon MC, et al. Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective study. Lancet 2016; 388:983.
- Kortram K, Ijzermans JN, Dor FJ. Perioperative Events and Complications in Minimally Invasive Live Donor Nephrectomy: A Systematic Review and Meta-Analysis. Transplantation 2016.
- Sawinski D, Trofe-Clark J, Leas B, et al. Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta-Analysis. Am J Transplant 2016; 16:2117.
- Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375:323.