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What's new in nephrology and hypertension
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What's new in nephrology and hypertension

Disclosures: Alice M Sheridan, MD Nothing to disclose. John P Forman, MD, MSc Nothing to disclose.

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.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2015. | This topic last updated: Nov 12, 2015.

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.


Effect of finerenone in diabetic nephropathy (October 2015)

Mineralocorticoid receptor antagonists (MRAs) reduce proteinuria in patients with diabetic nephropathy, whether used alone or in combination with an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Finerenone, an investigational nonsteroidal MRA that may be associated with less hyperkalemia than other MRAs, was evaluated in a phase 2 dose-finding trial of 823 patients with type 2 diabetes treated with an ACE inhibitor or ARB [1]. A dose-dependent effect was observed at 90 days, with albuminuria reductions ranging from 21 to 38 percent at doses ranging from 7.5 mg/day to 20 mg/day. The incidence of hyperkalemia with finerenone treatment was low (1.5 percent); acute reductions in glomerular filtration rate were mild and were reversible after cessation of the study drug. The long-term effects of MRAs, including finerenone, in patients with diabetic nephropathy is unknown, and they should not be routinely used in these patients until such data are available. (See "Treatment of diabetic nephropathy", section on 'Mineralocorticoid receptor antagonism'.)

Terlipressin versus midodrine and octreotide for hepatorenal syndrome (July 2015)

Terlipressin, a vasopressin analog, is used for the treatment of hepatorenal syndrome, but is not approved for use in the United States. In a trial that randomly assigned 49 patients with hepatorenal syndrome to terlipressin plus albumin or to midodrine and octreotide plus albumin, the rate of complete response (a decrease in serum creatinine to less than 1.5 mg/dL [133 micromol/L] at 14 days) was significantly greater with terlipressin plus albumin (56 versus 5 percent) [2]. However, the partial response rate was greater with midodrine and octreotide plus albumin, and mortality rates did not differ; in addition, the dose of midodrine used was lower than often employed in clinical practice, and blood pressures were lower in the group who received midodrine and octreotide plus albumin. Thus, despite this and other limited trials showing benefit from terlipressin, it remains unclear whether this therapy is superior to the combination of midodrine and octreotide. (See "Hepatorenal syndrome", section on 'Terlipressin plus albumin where available'.)

Remote ischemic preconditioning protects against ischemic acute kidney injury (June 2015)

Remote ischemic preconditioning (RIPC) is a method by which the induction of transient ischemia of an organ (usually an upper arm) protects against subsequent ischemic injury of another organ. A randomized trial including 240 patients has suggested a protective benefit of RIPC on the incidence of acute kidney injury (AKI) [3]. Increases in urinary biomarkers following RIPC were associated with reduced AKI in this trial. The benefit of RIPC on renal outcomes, morbidity, and mortality needs to be studied in other multicenter trials before it is used clinically. The safety of repeated episodes of transient ischemia has not been conclusively demonstrated. (See "Possible prevention and therapy of postischemic (ischemic) acute tubular necrosis", section on 'Remote ischemic preconditioning'.)


Trends in permanent arteriovenous fistula usage at hemodialysis initiation (June 2015)

Excessive numbers of patients continue to initiate hemodialysis with catheters in spite of the 1997 National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (K-DOQI) recommendations that primary arteriovenous (AV) fistula be constructed in at least 50 percent of all new patients electing to receive hemodialysis as their initial form of renal replacement therapy (Fistula first). A review of the United States Renal Data System identified 510,000 patients, of whom 83 percent initiated hemodialysis with a catheter, 14 percent with an AV fistula, and 3.4 percent with an AV graft [4]. Functioning permanent access at initiation of hemodialysis was associated with lower mortality rates compared with those initiating hemodialysis with a catheter, including patients using a temporary catheter while awaiting maturation of an AV access. (See "Arteriovenous fistulas and grafts for chronic hemodialysis access", section on 'Recommended strategy for chronic hemodialysis access'.)

Cinacalcet and calciphylaxis in hemodialysis patients (June 2015)

Calciphylaxis (calcific uremic arteriolopathy, CUA) is a serious disorder that afflicts hemodialysis patients and is characterized by systemic medial calcification of arterioles resulting in ischemia and subcutaneous necrosis. An analysis of adverse event reports collected during the Evaluation of Cinacalcet (EVOLVE) trial suggested that the use of cinacalcet may reduce the risk of calciphylaxis [5]. However, our confidence in these results is limited, due to a high drop-out rate in the cinacalcet group and a high rate of crossover in the placebo group: nearly 20 percent of patients in the placebo group ended up taking commercially available cinacalcet. Additionally, although cinacalcet reduced the risk of hyperparathyroidism, the decrease in the risk of CUA appears to have been unrelated to cinacalcet's effect on parathyroid hormone (PTH). Further study is needed before providing recommendations regarding the use of cinacalcet to prevent calciphylaxis in high-risk individuals. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Epidemiology and risk factors' and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients", section on 'Efficacy studies'.)


SPRINT trial on goal blood pressure (November 2015, Modified November 2015)

Goal blood pressure in most hypertensive patients had been <140/90 mmHg, or <150/90 mmHg in older adults. The potential benefit of lowering the systolic blood pressure goal in nondiabetic older adults with risk factors for cardiovascular disease or with chronic kidney disease was evaluated in the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter, randomized, open-label trial performed in 9361 hypertensive patients in the United States [6]. Patients were randomly assigned to a standard treatment group (target systolic pressure <140 mmHg) or an intensive treatment group (target systolic pressure <120 mmHg). Blood pressure during the trial was measured using automated oscillometric blood pressure (AOBP) and not using manual (ausculatory) blood pressure, which is more commonly used in routine practice. AOBP involves a device that averages multiple consecutive readings taken with the patient at rest and typically yields readings that are 5 to 10 mm lower than with manual measurement. After a median of 3.26 years, intensive as compared with standard treatment reduced the rate of the primary end point, a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death (5.2 versus 6.8 percent), and also reduced mortality (3.3 versus 4.5 percent). Intensive treatment increased the rates of acute kidney injury, syncope, and hyponatremia, but not orthostatic hypotension or falls resulting in hospitalization. As a result of the SPRINT trial, UpToDate now recommends lower systolic pressure goals for nondiabetic older adults at high risk for cardiovascular events. In addition, the new goals depend upon the method of measurement. (See "What is goal blood pressure in the treatment of hypertension?", section on 'Benefit according to overall cardiovascular risk' and "Goal blood pressure in patients with cardiovascular disease or at high risk".)

New guidelines on screening and diagnosis of hypertension (October 2015)

New guidelines from the United States Preventive Services Task Force (USPSTF) and the Canadian Hypertension Education Program (CHEP) have been released and suggest that, in nearly all patients who have an elevated blood pressure measured in the office, out-of-office blood pressure readings should be obtained to confirm the diagnosis [7,8]. For out-of-office blood pressure measurement, 24-hour ambulatory blood pressure monitoring (ABPM) is preferred, and home blood pressure monitoring is an acceptable alternative if ABPM is not possible. These guidelines are consistent with our recommendations for confirming elevated blood pressure readings. (See "Overview of hypertension in adults", section on 'Diagnosis'.)

Spironolactone in resistant hypertension (October 2015)

The effect of spironolactone in patients with resistant hypertension has been evaluated in several randomized trials. The best data come from the PATHWAY-2 trial, a randomized crossover study comparing spironolactone (25 to 50 mg/day) with placebo, doxazosin, or bisoprolol in 285 patients with resistant hypertension (mean clinic blood pressure 157/90 mmHg and mean home blood pressure 148/84 mmHg despite therapy with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, a calcium channel blocker, and a diuretic) [9]. Spironolactone significantly reduced mean home systolic pressure at 12 weeks (by 10, 5, and 6 mmHg compared with placebo, doxazosin, and bisoprolol, respectively). Spironolactone (or another mineralocorticoid receptor antagonist) is the treatment of choice in patients with resistant hypertension. (See "Treatment of resistant hypertension", section on 'Mineralocorticoid receptor antagonists'.)

Chlorthalidone and indapamide for hypertension treatment (July 2015)

Two meta-analyses compared thiazide-like diuretics (chlorthalidone and indapamide) with hydrochlorothiazide for the treatment of hypertension.

In a meta-analysis of 14 trials that compared the blood pressure reduction with one of three dose levels of hydrochlorothiazide (low, intermediate, high) to a corresponding dose level of one of the thiazide-like diuretics, systolic pressure reduction was greater with chlorthalidone and indapamide (by 3.6 and 5.1 mmHg, respectively) [10].

In a multiple-treatment (network) meta-analysis of 21 trials that indirectly compared thiazide-type diuretics (such as hydrochlorothiazide) with thiazide-like diuretics (such as chlorthalidone) by evaluating their efficacy against placebo or common comparator drugs, thiazide-like diuretics significantly lowered the relative risk of cardiovascular events by 12 percent and heart failure by 21 percent [11].

If a diuretic is chosen for treatment of hypertension, we suggest chlorthalidone or indapamide rather than hydrochlorothiazide.

(See "Choice of drug therapy in primary (essential) hypertension: Recommendations", section on 'Thiazide-like versus thiazide-type diuretics'.)

Renal denervation in patients with resistant hypertension (July 2015)

An open-label randomized trial (DENERHTN) compared stepped antihypertensive therapy alone with stepped antihypertensive therapy plus renal denervation in 106 patients with confirmed resistant hypertension despite therapy with indapamide, amlodipine, and ramipril (or irbesartan if allergic to angiotensin converting [ACE] enzyme inhibitors) [12]. Stepped antihypertensive therapy consisted of spironolactone, bisoprolol, prazosin, and rilmenidine added (in that order) at monthly intervals as needed. At six months, the change in 24-hour ambulatory systolic pressure decreased significantly more in the denervation group (-15.4 versus -9.5 mmHg). However, there was no sham intervention, and the baseline blood pressure was higher in the denervation group, suggesting that the results could be due in part to regression to the mean. Given the negative findings from SYMPLICITY-HTN-3 (a blinded trial), further studies are needed before renal denervation can be widely recommended for resistant hypertension. (See "Treatment of resistant hypertension", section on 'Catheter-based radiofrequency ablation of renal sympathetic nerves'.)

Mortality in frail older adults taking combination antihypertensive therapy (May 2015)

In a cohort of 1127 frail nursing home residents from France and Italy (aged 80 years and older), the two-year mortality rate (32 percent) was highest among those who were treated with two or more antihypertensive drugs and had a systolic pressure less than 130 mmHg [13]. Mortality was lower (about 20 percent) among individuals who had higher blood pressures despite taking two or more antihypertensive drugs, and among those taking fewer medications regardless of blood pressure. Increased mortality for those who had a systolic pressure less than 130 mmHg while being treated with two or more drugs may have been due to a higher prevalence in this group of heart failure (35 versus 14 percent) and coronary heart disease (35 versus 18 percent). (See "Treatment of hypertension in the elderly patient, particularly isolated systolic hypertension", section on 'Problem of frailty'.)


Tamsulosin or nifedipine for acute nephrolithiasis (May 2015)

Meta-analyses of randomized trials have found that therapy with an alpha blocker or calcium channel blocker ("medical expulsive therapy" or MET) in patients with small ureteral calculi increases both the likelihood and speed of stone passage. A subsequent trial randomly assigned 1167 adult patients presenting with ureteric colic caused by small stones (10 mm or less) to four weeks of therapy with tamsulosin, nifedipine, or placebo [14]. The primary endpoint, which was the need for further intervention (such as lithotripsy) within four weeks, and all secondary endpoints (including days until stone passage and pain), were assessed by self-administered questionnaires at four weeks; follow-up imaging was not routinely performed. There was no benefit from tamsulosin or nifedipine for any endpoint. However, patients with small stones infrequently require intervention, and self-reported stone passage is likely to be inaccurate. These concerns seriously limit the usefulness of this trial. For patients with stones ≤10 mm in diameter, we consider MET an option to facilitate spontaneous stone passage. (See "Diagnosis and acute management of suspected nephrolithiasis in adults", section on 'Facilitating stone passage'.)


Retrieval of kidneys under hypothermic versus normothermic conditions (August 2015)

The standard protocol for management of deceased-donor kidneys mandates that retrieval of organs be done under normothermic conditions. Therapeutic hypothermia (or targeted temperature management) may decrease the risk of delayed graft function. This was shown in a study in which 370 organ donors (resulting in 572 kidney transplants) were randomly assigned after declaration of brain death to organ retrieval under normothermic or hypothermic conditions [15]. Delayed graft function occurred less frequently in the hypothermic compared with the normothermic group, even after adjusting for donor type, creatinine, and age; kidney cold ischemia time; and organ procurement agency. The long-term effects of hypothermia on graft survival or acute rejection were not tested by this trial. However, these data suggest an inexpensive and safe intervention that may increase graft survival. (See "Deceased and living donor renal allograft recovery", section on 'Therapeutic hypothermia'.)


Thrombotic microangiopathy caused by a defect in cobalamin metabolism (September 2015)

A number of thrombotic microangiopathies (TMAs) must be considered in a patient with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, including thrombotic thrombocytopenic purpura (TTP) and Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS). A recent case report describes a previously healthy 18-year-old who presented with MAHA, thrombocytopenia, and renal failure with negative testing for TTP and ST-HUS [16]. He was found to have cobalamin C deficiency, with elevated plasma homocysteine and methylmalonic acid (MMA) levels and a mutation in MMACHC, a gene involved in cobalamin (vitamin B12) metabolism. Treatment with vitamin B12, betaine, and folinic acid resulted in a dramatic recovery. His brother had died of a similar syndrome at the same age. Patients with unexplained MAHA and thrombocytopenia should be evaluated for this disorder, which has an unknown prevalence and for which a safe and inexpensive therapy is readily available [17]. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Overview of primary TMA syndromes'.)

Long-term patiromer therapy for hyperkalemia in chronic kidney disease (July 2015)

Patiromer is an investigational agent that appears promising for long-term control of hyperkalemia in patients with chronic kidney disease. It is a spherical, nonabsorbable organic polymer, formulated as a powder for suspension, which binds potassium in the colon in exchange for calcium. In a phase II, open-label dose-finding trial (AMETHYST-DN), 306 diabetic patients with an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2 and either mild or moderate hyperkalemia were randomly assigned to a range of initial patiromer doses [18]. At four weeks, the change in serum potassium from baseline ranged from -0.35 mEq/L with a dose of 4.2 g twice daily to -0.97 mEq/L with a dose of 12.6 g twice daily. At 52 weeks, serum potassium concentrations remained in the normal range with continued patiromer therapy. Discontinuation of patiromer resulted in an increase in the serum potassium within three days. The most common treatment-related side effects included constipation and hypomagnesemia. Severe hypomagnesemia (a serum magnesium <1.2 mg/dL) developed in 13 patients. (See "Treatment and prevention of hyperkalemia in adults", section on 'Patiromer'.)

International consensus on management of IgG4-related disease (July 2015)

The optimal treatment for immunoglobulin G4-related disease (IgG4-RD) has not been established, nor have randomized trials been performed to inform treatment approaches. Nonetheless, broad international consensus has been achieved among experts on several major management strategies [19]. These include the importance of biopsy confirmation of the diagnosis to exclude malignancy and other disorders that may mimic IgG4-RD; the need to treat symptomatic patients, sometimes urgently, as well as some asymptomatic patients; use of glucocorticoids as first-line therapy; use of maintenance therapy in certain patients; and retreatment strategies for patients who relapse after successful remission induction. Consensus was not reached on the use of steroid-sparing immunosuppressive agents from the start of treatment, and largely reflects different practice styles between countries. (See "Overview of IgG4-related disease", section on 'Diagnostic studies' and "Overview of IgG4-related disease", section on 'Treatment principles and observations'.)

Combination renin-angiotensin system inhibition in diabetic patients (June 2015)

Several randomized trials that directly compared dual versus single renin-angiotensin system inhibition in diabetic patients found that dual therapy produced no benefit and an increase in adverse effects. Findings are similar in a subsequent network meta-analysis [20]. In this analysis in patients with diabetes and hypertension, dual therapy with an angiotensin-converting enzyme (ACE) inhibitor plus an angiotensin II receptor blocker (ARB) was superior to placebo in preventing end-stage renal disease, but monotherapy with either an ACE inhibitor or an ARB, also compared with placebo, produced similar benefits while dual therapy produced more adverse effects. Combination renin-angiotensin system inhibition with an ACE inhibitor and ARB or direct renin inhibitor is not recommended in diabetic patients. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Avoid combination renin-angiotensin system inhibition'.)

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  1. Bakris GL, Agarwal R, Chan JC, et al. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA 2015; 314:884.
  2. Cavallin M, Kamath PS, Merli M, et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial. Hepatology 2015; 62:567.
  3. Zarbock A, Schmidt C, Van Aken H, et al. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA 2015; 313:2133.
  4. Malas MB, Canner JK, Hicks CW, et al. Trends in incident hemodialysis access and mortality. JAMA Surg 2015; 150:441.
  5. Floege J, Kubo Y, Floege A, et al. The Effect of Cinacalcet on Calcific Uremic Arteriolopathy Events in Patients Receiving Hemodialysis: The EVOLVE Trial. Clin J Am Soc Nephrol 2015; 10:800.
  6. SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015.
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  9. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015.
  10. Roush GC, Ernst ME, Kostis JB, et al. Head-to-head comparisons of hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects. Hypertension 2015; 65:1041.
  11. Olde Engberink RH, Frenkel WJ, van den Bogaard B, et al. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertension 2015; 65:1033.
  12. Azizi M, Sapoval M, Gosse P, et al. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet 2015; 385:1957.
  13. Benetos A, Labat C, Rossignol P, et al. Treatment With Multiple Blood Pressure Medications, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents: The PARTAGE Study. JAMA Intern Med 2015; 175:989.
  14. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet 2015; 386:341.
  15. Niemann CU, Feiner J, Swain S, et al. Therapeutic Hypothermia in Deceased Organ Donors and Kidney-Graft Function. N Engl J Med 2015; 373:405.
  16. Grangé S, Bekri S, Artaud-Macari E, et al. Adult-onset renal thrombotic microangiopathy and pulmonary arterial hypertension in cobalamin C deficiency. Lancet 2015; 386:1011.
  17. George JN. Cobalamin C deficiency-associated thrombotic microangiopathy: uncommon or unrecognised? Lancet 2015; 386:1012.
  18. Bakris GL, Pitt B, Weir MR, et al. Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial. JAMA 2015; 314:151.
  19. Khosroshahi A, Wallace ZS, Crowe JL, et al. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis Rheumatol 2015; 67:1688.
  20. Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet 2015; 385:2047.
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