Disclosures: Alice M Sheridan, MD Employee of UpToDate, Inc. John P Forman, MD, MSc Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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
Combination ACE inhibitor plus ARB no benefit in autosomal dominant polycystic kidney disease (November 2014)
Combination therapy with an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) provides no benefit to patients with many forms of chronic kidney disease, but this has not been shown among patients with autosomal dominant polycystic kidney disease (ADPKD). Lisinopril plus placebo was compared with lisinopril plus telmisartan in a large randomized trial of ADPKD patients with reduced estimated glomerular filtration rate (eGFR) . There was no difference between groups in the composite endpoint of death, end-stage renal disease, or 50 percent reduction in estimated GFR. (See "Hypertension in autosomal dominant polycystic kidney disease", section on 'Angiotensin-converting enzyme inhibitor plus angiotensin receptor antagonist'.)
Blood pressure target in autosomal dominant polycystic kidney disease (November 2014)
The optimal blood pressure target for patients with autosomal dominant polycystic kidney disease (ADPKD) is not known. A low blood pressure target (defined as <95/60 to 110/75 mmHg) was compared with a standard blood pressure target (defined as 120/70 to 130/80 mmHg) in a large randomized trial . Patients in the low blood pressure target group had a lower rate of increase in total kidney size. However, side effects including lightheadedness and dizziness were more common in the low target group. (See "Hypertension in autosomal dominant polycystic kidney disease", section on 'Blood pressure goal'.)
Long-term effect of intensive glycemic control on macrovascular outcomes in type 2 diabetes (October 2014)
The ADVANCE trial randomly assigned 11,140 patients with long-standing type 2 diabetes to either standard therapy or modified release gliclazide plus other drugs as required to achieve an A1C of <6.5 percent, and found no benefit of intensive therapy on the primary composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke after a median of five years. Of the 10,082 surviving trial participants, 8494 enrolled in a post-trial monitoring study . A 2000-patient random subset of the surviving cohort that agreed to participate in the post-trial monitoring study had periodic laboratory testing for A1C, fasting blood glucose, serum creatinine, blood pressure, and weight. Mean A1C, which had been significantly different during the trial, became similar by the first post-trial visit and remained similar throughout the monitoring period (7.2 and 7.4 percent in the original intensive and standard groups, respectively). After a median total follow-up of 9.9 years, similar to the findings in the randomized trial, there was no benefit of intensive therapy on macrovascular outcomes. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'ADVANCE'.)
Renal prognosis in patients with type 1 diabetes and nephropathy (October 2014)
Historically, the majority of patients with type 1 diabetes who develop severely increased albuminuria (urine albumin excretion >300 mg per day, formerly "macroalbuminuria" or "overt nephropathy") progressed to end-stage renal disease (ESRD). However, with modern management, severely increased albuminuria may regress, and rates of ESRD may be less than 20 percent at 10 years. In the DCCT/EDIC type 1 diabetes cohort, 123 patients developed severely increased albuminuria that was persistent at two consecutive study visits . During the subsequent 10 years, 58 percent of these patients regressed to <300 mg of albuminuria per day, and 12 percent regressed to <30 mg per day. The 10-year rates of reduced estimated glomerular filtration rate (eGFR, <60 mL/min/1.73 m2) and ESRD in these patients with severely increased albuminuria were 34 and 18 percent, respectively. Lower HbA1c and blood pressure values were associated with a greater frequency of albuminuria regression and a lower incidence of reduced eGFR and ESRD. Thus, even patients who develop overt nephropathy can avoid progressive renal impairment. (See "Overview of diabetic nephropathy", section on 'Type 1 diabetes'.)
Fenoldopam does not improve outcomes in cardiac surgery patients with early acute kidney injury (October 2014)
Fenoldopam, a dopamine receptor-1 agonist, has been studied for the prevention and treatment of acute kidney injury (AKI) following cardiac surgery with inconsistent results from small studies. A large multicenter randomized trial compared fenoldopam to placebo in 667 patients admitted to an intensive care unit with acute kidney injury (AKI) following cardiac surgery . Compared with placebo, there was no decrease in the need for renal replacement therapy or in 30-day mortality in patients who received fenoldopam. However, hypotension occurred more frequently in the fenoldopam group compared with placebo. We agree with the 2012 KDIGO guidelines that fenoldopam not be used to treat acute kidney injury. (See "Possible prevention and therapy of postischemic (ischemic) acute tubular necrosis", section on 'Fenoldopam'.)
Smoking and asbestos exposure increase risk of retroperitoneal fibrosis (September 2014)
Exposure to asbestos and tobacco smoke may result in a multiplicative increase in the risk of retroperitoneal fibrosis. This was suggested by a case control study that matched patients with idiopathic retroperitoneal fibrosis with control patients of similar age, sex, and geographic region . Both smoking alone and asbestos alone increased the risk of retroperitoneal fibrosis. However, the combination of smoking and asbestos was associated with a much greater increase in risk (about eight- to 12-fold) than that conferred by either smoking (about threefold) or asbestos exposure (about fourfold) alone. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis", section on 'Etiology and risk factors'.)
Elevated troponin levels and mortality in chronic kidney disease (September 2014)
A large meta-analysis examined the diagnostic and prognostic capability of cardiac troponins T (cTnT) and I (cTnI) among chronic kidney disease (CKD) patients [7-9]. Both cTnT and cTnI were shown to have low specificity for the diagnosis of acute myocardial infarction (AMI) . However, among CKD patients who did not have AMI, elevated cTnT was associated with a threefold increase in all-cause mortality and cTnI was associated with a 2.7-fold increase in all-cause mortality . (See "Serum cardiac biomarkers in patients with renal failure", section on 'Troponins' and "Serum cardiac biomarkers in patients with renal failure", section on 'Use of troponins in prognosis'.)
GLOMERULAR DISEASE AND VASCULITIS
THSD7A as a novel antigen in idiopathic membranous nephropathy (November 2014)
Approximately 70 to 80 percent of patients with primary (idiopathic) membranous nephropathy (MN) have a positive test for anti-phospholipase A2 receptor (PLA2R) antibodies. Thrombospondin type-1 domain-containing 7A (THSD7A) is, like PLA2R, a transmembrane protein expressed on podocytes. THSD7A may be the responsible antigen in approximately 10 percent of patients with idiopathic MN who are negative for anti-PLA2R antibodies. The association of THSD7A with membranous nephropathy was examined in a study of 154 patients with anti-PLA2R-negative idiopathic MN, 74 patients with anti-PLA2R-positive idiopathic MN, 76 patients with other glomerular disease, and 44 healthy controls . Autoantibodies specific for THSD7A were identified in sera from 15 of 154 patients with anti-PLA2R-negative idiopathic MN, but not in the sera from other individuals. (See "Causes and diagnosis of membranous nephropathy", section on 'Thrombospondin type-1 domain-containing 7A'.)
Rituximab as maintenance therapy in ANCA-associated vasculitis (November 2014)
Azathioprine and methotrexate are conventionally considered the preferred drugs for maintenance therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial compared rituximab with azathioprine as maintenance therapy in 115 patients who had achieved remission after induction therapy with cyclophosphamide and glucocorticoids . Major relapse rates at 28 months were lower for rituximab (5 versus 29 percent). Rates of adverse events were also similar. However, the dosing of azathioprine in this trial was not consistent with the practice of many experts, and this may have contributed to the excess relapse rate. In addition, most patients had GPA, a positive PR3-ANCA, and were newly diagnosed rather than relapsed patients. It is not clear whether or not these data apply to other groups of patients with ANCA-associated vasculitis or to patients induced with rituximab rather than cyclophosphamide. Thus, either rituximab or azathioprine (or methotrexate although it was not evaluated in this trial) can be used as maintenance therapy in patients with GPA or MPA while awaiting further data to confirm these findings. (See "Maintenance immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis", section on 'Rituximab'.)
Abatacept in patients with proliferative lupus nephritis (November 2014)
CTLA4-Ig (abatacept) is a fusion protein that competitively inhibits CD28-B7 T cell costimulation. In the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study (ACCESS), 134 patients with proliferative lupus nephritis (half also had membranous lupus) were treated with cyclophosphamide and glucocorticoids and were randomly assigned to also receive abatacept or placebo . All patients received azathioprine after the conclusion of cyclophosphamide until week 24. The complete response rate at 24 weeks was 33 percent with abatacept and 31 percent with placebo. The total response rate at 24 weeks (complete or partial) was 59 percent in both groups. At one year, 64 percent of patients in the abatacept group and 68 percent in the placebo group had a complete or partial remission. Adverse events were similar between the two groups. Thus, these data do not support the use of abatacept in the initial treatment of proliferative lupus nephritis. (See "Therapy of diffuse or focal proliferative lupus nephritis", section on 'Costimulatory blockade with CTLA4-Ig'.)
Combination tacrolimus and mycophenolate mofetil in patients with lupus nephritis (November 2014)
Cyclophosphamide or mycophenolate mofetil (MMF), in combination with glucocorticoids, are the preferred agents for initial therapy in patients with focal or diffuse proliferative lupus nephritis (LN). A “multitarget” regimen that combined tacrolimus, low-dose MMF, and prednisone was compared with high-dose cyclophosphamide and prednisone in 368 Chinese patients with LN . At 24 weeks, the rate of complete remission, defined as 24-hour urine protein excretion of 0.4 g or less, serum albumin of 3.5 g/dL or more, normal serum creatinine, and absence of an active urine sediment, was greater in the multitarget group (46 versus 26 percent) as was the overall response rate (complete or partial remission; 84 versus 63 percent). Serious adverse events, particularly infections, were more common with multitarget therapy (7 versus 3 percent), as was dropout due to adverse events (6 versus 2 percent). The study was limited by the lack of long-term follow-up of kidney function and by the fact that tacrolimus can reduce proteinuria through a hemodynamic mechanism (which may be unrelated to immunologic recovery). Since all of the patients in this trial had a normal serum creatinine at baseline, proteinuria reduction without immunological recovery could have been classified as a remission. Pending further data, we do not advise this multitarget regimen as induction therapy for most patients with proliferative lupus nephritis. (See "Therapy of diffuse or focal proliferative lupus nephritis", section on 'Tacrolimus'.)
Antihypertensive therapy provides benefit in mild hypertension (January 2015)
The benefit of antihypertensive drug therapy has been questioned in patients with mild hypertension (systolic 140 to 159 mmHg and/or diastolic 90 to 99 mmHg) and no preexisting cardiovascular disease. A meta-analysis including 15,266 such patients reported that, compared with placebo or a less intensive regimen, antihypertensive therapy or a more intensive regimen for five years produced significantly lower rates of all-cause mortality (3.9 versus 4.8 percent) and stroke (1.6 versus 2.1 percent), and similar rates of myocardial infarction . Thus, low-risk patients with mild hypertension and no preexisting cardiovascular disease who fail to reduce their blood pressure with lifestyle modification should receive antihypertensive therapy. (See "Hypertension: Who should be treated?", section on 'Low-risk patients'.)
Cardiovascular risk and benefit of antihypertensive therapy (October 2014)
Although the severity of hypertension or magnitude of cardiovascular risk do not affect the relative risk reduction of major cardiovascular events with antihypertensive therapy, the absolute benefit of antihypertensive therapy is greater in patients with more severe hypertension or greater overall cardiovascular risk. In a meta-analysis of 11 randomized trials comparing antihypertensive therapy with placebo, patients were risk-stratified according to their estimated five-year risk of having a major cardiovascular event . In patients with the highest overall cardiovascular risk (ie, five-year risk >21 percent), the absolute risk reduction was 3.8 percent (number needed to treat, 26 patients for five years). In patients with the lowest overall cardiovascular risk (ie, five-year risk approximately 6 percent), the absolute risk reduction was 1.4 percent (number needed to treat, 71 patients for five years). (See "What is goal blood pressure in the treatment of hypertension?", section on 'Benefit according to overall cardiovascular risk'.)
Long-term effect of antihypertensive therapy in diabetic patients (October 2014)
The ADVANCE trial randomly assigned 11,000 diabetic patients to a fixed combination of perindopril-indapamide or placebo for approximately four years. The trial included both patients with and without hypertension, and concomitant therapy with other blood pressure medication during the trial was at the discretion of the patient's physician. Patients in the perindopril-indapamide group had lower rates of cardiovascular mortality (3.8 versus 4.6 percent) and all-cause mortality (7.3 versus 8.5 percent). A post-trial, open-label cohort (8500 patients) were followed for an additional six years . Blood pressures between the treatment and placebo groups, which were different during the trial (135/74 versus 140/76 mmHg), became similar within six months after completion of the trial and remained similar throughout the cohort phase. Compared with those originally assigned placebo, those who had received perindopril-indapamide had a lower death rate during the cohort phase (15.3 versus 16.7 percent), as well as a lower incidence of major cardiovascular events (13.3 versus 14.2 percent). Combining both the trial and cohort phases together (approximately 10 years of follow-up), all-cause mortality was significantly lower among those in the treatment group (hazard ratio 0.91, 95% CI 0.84-0.99). Thus, blood pressure lowering is associated with long-term benefits on mortality and cardiovascular disease in diabetic patients. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'ADVANCE trial'.)
Initial imaging in patients with suspected nephrolithiasis (September 2014)
Computerized tomography (CT) and ultrasonography as initial imaging strategies were compared in a large multicenter randomized trial . Patients presenting to an emergency department (ED) with suspected nephrolithiasis (but without signs of another serious diagnosis) were assigned to initial imaging with a non-contrast helical CT scan, ultrasonography performed by a radiologist, or ultrasonography performed at the bedside by an ED physician. Subsequent evaluation and care was at the discretion of the treating clinicians. The sensitivity for stone detection was lower for ultrasonography than CT scan (54 percent if performed by an ED physician or 57 percent performed by a radiologist compared with 88 percent for CT). A CT scan was performed in 41 percent of patients who initially underwent ultrasonography while 5 percent of patients who initially had a CT subsequently had ultrasonography. Despite the lower sensitivity of ultrasonography, the rates of important missed diagnoses that resulted in complications, such as pyelonephritis with sepsis or diverticular abscess, were similar (0.5 percent with ultrasonography versus 0.3 percent with CT). Serious adverse events and return visits to the ED after discharge were also similar. Patients assigned to receive an initial CT were exposed to more than twice as much radiation during the initial ED visit than those assigned ultrasonography although, because many patients assigned ultrasonography ultimately underwent CT, the differences in cumulative radiation exposure at six months were less dramatic. While we previously suggested a non-contrast helical CT scan as the test of choice for most patients with suspected nephrolithiasis, we now consider that both CT and ultrasonography are acceptable initial imaging modalities in patients with suspected nephrolithiasis who have a low clinical suspicion for an alternative serious diagnosis. In such patients, ultrasonography leads to less radiation exposure than CT and equivalent overall outcomes. (See "Diagnosis and acute management of suspected nephrolithiasis in adults", section on 'Tests of choice: Non-contrast CT scan or ultrasonography'.)
Sirolimus and mortality in kidney transplant recipients (December 2014)
The mechanistic target of rapamycin (mTOR) inhibitor, sirolimus, is commonly used for immunosuppression among transplant recipients, and may be associated with a decreased risk of malignancy. A systematic review and meta-analysis of randomized trials demonstrated a decreased risk of malignancy but an increased risk of death associated with sirolimus among kidney and kidney pancreas transplant recipients . (See "Mechanistic target of rapamycin (mTOR) inhibitors in renal transplantation", section on 'Mortality'.)
Levofloxacin does not decrease BK virus infection in kidney transplant recipients (December 2014)
BK virus infection causes allograft failure in kidney transplant recipients and has few effective therapies. The prophylactic effect of the quinolone antibiotic, levofloxacin, on BK viral infection was studied in a randomized placebo-controlled trial including recipients of kidney allografts transplanted between 2011 and 2013 . Compared with placebo, levofloxacin did not decrease the risk of BK infection, allograft rejection, or patient or allograft survival. (See "Management of BK virus-induced (polyomavirus-induced) nephropathy in kidney transplantation", section on 'Quinolone antibiotics'.)
Risk of gestational hypertension or preeclampsia in kidney donors (November 2014)
The assessment of risk conferred by living kidney donation is critically important in determining the suitability of individual donor candidates. A retrospective cohort study demonstrated an increased risk of gestational hypertension or preeclampsia compared with well-matched nondonors . Women of childbearing age who wish to donate a kidney should be advised of this increased risk. (See "Evaluation of the living kidney donor and risk of donor nephrectomy", section on 'Maternal and fetal outcomes'.)
Alemtuzumab induction regimen for immunosuppression in renal transplantation (October 2014)
The optimal immunosuppression induction therapy for renal transplant recipients is not known. In a randomized trial that compared a steroid-free regimen of alemtuzumab induction followed by low-dose tacrolimus and mycophenolate with basiliximab induction followed by standard-dose tacrolimus, mycophenolate and steroids, patients who received alemtuzumab had a lower rate of biopsy-proven rejection . There was no difference between groups in transplant failure or infection. These findings require confirmation by additional studies before steroid-free regimens should be considered a routine option for maintenance therapy in transplant recipients. (See "Induction immunosuppressive therapy in renal transplantation in adults", section on 'Alemtuzumab'.)
mTOR inhibitors and antiphospholipid syndrome in kidney transplant recipients (September 2014)
Mechanistic target of rapamycin (mTOR) inhibitors may decrease the recurrence of antiphospholipid syndrome (APS)-associated vascular lesions among kidney transplant recipients . The activation of mTOR signalling pathways was demonstrated in cultured vascular endothelial cells treated with IgG antibodies from patients with APS. Allograft biopsies from transplant recipients with antiphospholipid antibodies who were receiving sirolimus, an mTOR inhibitor, showed decreased hyperplasia of endothelial cells, compared with biopsies from patients with antiphospholipid antibodies who did not receive sirolimus. Additionally, allograft function appeared to be better preserved among APS patients who received sirolimus. (See "Antiphospholipid syndrome and the kidney", section on 'Renal transplantation'.)
Trimethoprim-sulfamethoxazole and sudden death (December 2014)
While trimethoprim-sulfamethoxazole (TMP-SMX) has generally been felt to be well tolerated, a case-control study found an association between sudden death, possibly due to hyperkalemia, and prescription of TMP-SMX among older patients who were also receiving an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) .Those who received TMP-SMX had an increased seven-day risk of sudden death compared with those who received amoxicillin (adjusted odds ratio 1.38, 95% CI 1.09-1.76). However, other factors that affected the choice of antibiotic may have confounded these results, and higher quality evidence is needed to determine whether this association is causal. (See "Trimethoprim-sulfamethoxazole: An overview", section on 'Life threatening effects'.)
Patiromer for hyperkalemia in patients with chronic kidney disease (November 2014)
Patiromer is a nonabsorbable organic polymer, formulated as a powder for oral suspension, which binds potassium in the colon in exchange for calcium. In OPAL-HK, a phase III randomized placebo-controlled trial, 243 outpatients with chronic kidney disease and persistent hyperkalemia while receiving a stable dose of an ACE inhibitor or ARB were treated with either 4.2 or 8.4 g of patiromer twice daily for four weeks . The mean decrease in serum potassium was 0.6 and 1.2 meq/L with lower and higher doses, respectively; approximately 75 percent of patients achieved the target serum potassium of 3.8 to 5.0 meq/L. Patients whose baseline serum potassium was 5.5 meq/L or greater and who achieved the target serum potassium during the initial four-week period were randomly assigned to patiromer or placebo for another eight weeks. Serum potassium remained the same in patients continuing patiromer and increased by 0.7 meq/L in those assigned placebo. Serious adverse events were rare. The long-term efficacy and safety of patiromer are unknown, as are the effects in patients with acute hyperkalemia or end-stage renal disease. Patiromer is an investigational drug at this time. (See "Treatment and prevention of hyperkalemia in adults", section on 'Patiromer'.)
Zirconium cyclosilicate for hyperkalemia (November 2014)
Sodium zirconium cyclosilicate (ZS-9) is an orally administered inorganic, nonabsorbable crystalline compound that exchanges both sodium and hydrogen ions for potassium throughout its intestinal transit. The efficacy of ZS-9 in chronically hyperkalemic outpatients was evaluated in two nearly identical phase III randomized placebo-controlled trials [24,25]. ZS-9 doses of 5 to 10 g thrice daily reduced the mean serum potassium by 0.3 to 0.6 meq/L as compared with placebo. Edema was more common with higher doses of ZS-9, although serious adverse events were similar. The steepest decline in serum potassium occurred during the first four hours of therapy. This suggests an acute effect on intestinal potassium secretion, rather than simply a reduction in potassium absorption. Neither trial evaluated the long-term efficacy and safety of ZS-9, and neither studied patients with acute hyperkalemia or end-stage renal disease. ZS-9 is not currently approved or available for clinical use. (See "Treatment and prevention of hyperkalemia in adults", section on 'Zirconium cyclosilicate'.)
Discontinuation of eculizumab therapy for complement-mediated hemolytic uremic syndrome (September 2014)
Eculizumab, a humanized recombinant monoclonal antibody targeting complement protein C5, is an effective therapy for the majority of patients with complement-mediated hemolytic uremic syndrome (HUS), a life-threatening condition. However, it is unknown if discontinuation of eculizumab therapy, an expensive intervention with significant adverse effects, results in a high relapse rate and if lifelong therapy is thus needed. Limited data from a small observational study suggest that discontinuation may be feasible, as 7 of 10 patients remained in remission after eculizumab therapy was stopped . In three patients, relapse occurred within six weeks of stopping therapy, but all three patients completely recovered when therapy was resumed. Additional studies are needed to confirm if eculizumab therapy can be discontinued and, if so, to define the optimal setting. (See "Complement-mediated hemolytic uremic syndrome", section on 'Adverse effects'.)
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