What's new in nephrology and hypertension

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

Kidney effects of different glucose-lowering agents in patients with type 2 diabetes (July 2023)

In prior studies, glucagon-like peptide 1 (GLP-1) receptor agonists reduced albuminuria and slowed estimated glomerular filtration rate (eGFR) decline among patients with diabetic kidney disease, and these agents are therefore used in such patients if additional glucose control is needed. By contrast, in a large trial in over 5000 individuals with type 2 diabetes on metformin monotherapy that directly compared the kidney effects of the GLP-1 receptor agonist liraglutide with a dipeptidyl peptidase 4 inhibitor, insulin, and glimepiride, there were no significant differences among the groups at five years in terms of eGFR decline or development of chronic kidney disease [1]. However, the patients enrolled had normal kidney function and well-controlled blood pressure at baseline, and the number of events was small. Thus, GLP-1 receptor agonists are still appropriate in patients with diabetic kidney disease whose glycated hemoglobin is far from their goal despite therapy with metformin. (See "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)

Nicotinamide for the treatment of hyperphosphatemia in chronic kidney disease (April 2023)

Nicotinamide, a widely available and inexpensive metabolite of nicotinic acid (niacin, vitamin B3), has generated interest as a potential treatment for hyperphosphatemia in patients with end-stage kidney disease. However, in a placebo-controlled randomized trial including over 700 patients on hemodialysis, add-on nicotinamide therapy had only a short-term effect on phosphate levels that was not maintained at 52 weeks [2]. In addition, nicotinamide therapy was associated with higher rates of diarrhea, pruritus, and thrombocytopenia. Based on these results, we do not use nicotinamide to treat hyperphosphatemia in patients on dialysis. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Dose and specific agents'.)

Detecting tolvaptan-associated liver injury in patients with ADPKD (February 2023)

Due to the risk of drug-associated liver injury, treatment of patients with autosomal dominant polycystic kidney disease (ADPKD) with tolvaptan requires participation in a Risk Evaluation and Mitigation Strategy (REMS) that monitors liver function tests for the duration of therapy, with more frequent testing in the first 18 months. The utility of this REMS was evaluated in a retrospective analysis of data from randomized trials that included over 2900 tolvaptan-treated patients, 2300 of whom had 18 months or more of tolvaptan exposure [3]. Alanine aminotransferase elevations associated with tolvaptan therapy (>3 times the upper limit of normal in approximately 5 percent of patients) most often occurred within 18 months after tolvaptan initiation and normalized after treatment interruption or discontinuation. These data support the current REMS protocol as a way of detecting early liver injury and preventing severe liver injury in tolvaptan-treated patients with ADPKD. (See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment", section on 'Monitoring'.)

DIALYSIS

Effect of hemodiafiltration or hemodialysis on mortality in patients with end-stage kidney disease (June 2023)

Although several studies suggest patients with end-stage kidney disease (ESKD) may benefit from chronic intermittent high-dose hemodiafiltration (HDF) as compared with hemodialysis (HD), these data are limited and HDF remains largely unavailable in the United States. In an open-label pragmatic trial in which nearly 1400 patients with ESKD were randomly assigned to either high-dose HDF (convection volumes of at least 23 L per session) or to conventional high-flux HD, all-cause mortality was lower in the HDF group compared with the HD group at a median of 30 months (17 percent versus 22 percent) [4]. However, these results may have been affected by lower baseline rates of cardiovascular disease, diabetes mellitus, and current smoking in the HDF group, and the mortality benefit of HDF was limited to patients without pre-existing cardiovascular disease or diabetes mellitus. Further study is required to determine the optimal role for HDF in ESKD care. (See "Alternative kidney replacement therapies in end-stage kidney disease", section on 'Mortality'.)

Timing of exercise during hemodialysis and intradialytic hypotension (May 2023)

Aerobic exercise improves physical function and health-related quality of life for patients on dialysis. Some dialysis centers offer exercise programs during hemodialysis (eg, stationary cycling), but use of these programs has been limited by concerns that exercise towards the end of dialysis may precipitate intradialytic hypotension. In a crossover trial in which nearly 100 patients on hemodialysis were randomly assigned to two sequential two-week intradialytic stationary cycling regimens that occurred either during the first or second half of the dialysis session, the timing of intradialytic cycling had no appreciable effect on the rate or severity of intradialytic hypotension [5]. Most patients may safely exercise during the last half of dialysis, and allowing them to do so can maximize the use of intradialytic exercise program resources. (See "Uremic myopathy and deconditioning in patients with chronic kidney disease (including those on dialysis)", section on 'Patients on dialysis'.)

Patient decision aids and conservative kidney management (January 2023)

Patient decision aids (PDAs) are tools used to facilitate informed decision-making and have been proposed as a way to promote conservative kidney management (CKM), an underutilized alternative to dialysis for many older patients with end-stage kidney disease (ESKD). In a trial that randomly assigned over 360 patients aged 70 years or older with nondialysis stage 4 or 5 chronic kidney disease to dialysis education with an interactive web-based PDA (Decision-Aid for Renal Therapy [DART]) or to usual care, scores assessing decisional quality and knowledge about ESKD were better in the DART group at three and six months of follow-up [6]. The preference for CKM increased from approximately 12 percent at baseline to 20 percent at six months in the DART group but remained stable for patients in the usual care group; however, differences in CKM preference between groups were not statistically significant. Although additional studies are required, PDAs such as DART may hold promise as a way of increasing the use of CKM. (See "Kidney palliative care: Conservative kidney management", section on 'Timing and content of the discussion'.)

FLUID, ELECTROLYTES, AND ACID-BASE BALANCE

Diabetes insipidus terminology change (February 2023)

Confusion between diabetes insipidus and diabetes mellitus has led to occasional medication errors resulting in patient-safety concerns; in addition, the name "diabetes insipidus" does not reflect the underlying pathophysiology of disease. As a result, the Endocrine Society, European Society of Endocrinology, Pituitary Society, Society for Endocrinology, European Society for Paediatric Endocrinology, Endocrine Society of Australia, Brazilian Endocrine Society, and Japanese Endocrine Society all proposed to change the names of these disorders [7]. Arginine vasopressin deficiency (AVP-D) is the new name for central diabetes insipidus, and arginine vasopressin resistance (AVP-R) is the new name for nephrogenic diabetes insipidus. (See "Arginine vasopressin deficiency (central diabetes insipidus): Clinical manifestations and causes" and "Arginine vasopressin deficiency (central diabetes insipidus): Treatment" and "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Clinical manifestations and causes" and "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment".)

GLOMERULAR DISEASE AND VASCULITIS

Cardiovascular disease and ANCA-associated vasculitis (June 2023)

Some of the increased risk of cardiovascular disease in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis may be due to nontraditional risk factors. In a retrospective, multinational study of over 2000 patients with ANCA-associated vasculitis, risk factors for myocardial infarction and stroke included vasculitis affecting the lungs or kidneys, in addition to older age and history of smoking [8]. Patients with pulmonary or kidney manifestations of ANCA-associated vasculitis may require more aggressive modification of traditional cardiac risk factors. Whether this increased cardiovascular risk can be mitigated by specific immunosuppressive strategies bears further scrutiny. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Prognosis and other outcomes'.)

Sparsentan for patients with IgA nephropathy (April 2023)

Patients with immunoglobulin (Ig)A nephropathy (IgAN) generally receive a renin-angiotensin inhibitor to reduce proteinuria, but proteinuria may persist in spite of maximally tolerated therapy. The efficacy and safety of sparsentan, a dual angiotensin II receptor and endothelin-1 receptor antagonist, are being evaluated in a phase III trial in which over 400 adults with biopsy-proven IgAN and persistent proteinuria after three months of supportive therapy were randomly assigned to sparsentan or irbesartan once daily [9]. In a prespecified interim analysis of 280 patients, those receiving sparsentan had a greater reduction in proteinuria from baseline at week 36; rates of serious treatment-related adverse events were similar between the groups. Longer-term effects of sparsentan on kidney function decline, mortality, and safety in this ongoing trial are expected in late 2023. Sparsentan received conditional approval by the US Food & Drug Administration pending verification of clinical benefit in the ongoing trial. (See "IgA nephropathy: Treatment and prognosis", section on 'Dual endothelin angiotensin receptor antagonists'.)

Mycophenolate mofetil for progressive IgA nephropathy (March 2023)

For patients with IgA nephropathy (IgAN) who are at high risk for disease progression, mycophenolate mofetil (MMF) is an alternative immunosuppressive therapy for those unable to receive oral glucocorticoids, but supportive data have come from trials that included limited patient populations. In a recent trial in which 170 patients with IgAN and persistent proteinuria after three months of supportive therapy were randomly assigned to treatment with MMF plus supportive care or supportive care alone, fewer patients in the MMF group experienced a doubling of serum creatinine (7 versus 21 percent); rates of end-stage kidney disease and death due to cardiovascular cause were low and not significantly different between the groups [10]. During posttrial follow-up, patients who discontinued MMF had an accelerated annual loss of kidney function compared with those who continued MMF. For patients with high-risk IgAN who cannot tolerate or who do not wish to receive high-dose glucocorticoids, MMF is our preferred alternative option. (See "IgA nephropathy: Treatment and prognosis", section on 'Other regimens'.)

Novel investigational therapy for patients with FSGS and two APOL1 variants (March 2023)

Patients with gain-of-function APOL1 variants are at increased risk of proteinuric chronic kidney disease including focal segmental glomerulosclerosis (FSGS); however, specific therapies for these patients are lacking. The efficacy and safety of inaxaplin, an investigational oral small molecule inhibitor of APOL1 channel function, were evaluated in a single-arm phase 2a study in 16 adults with two APOL1 variants and biopsy-proven FSGS who received the drug for 13 weeks along with standard care [11]. At 13 weeks, patients had a mean reduction in urine protein-to-creatinine ratio of nearly 50 percent compared with baseline; adverse events were experienced by nearly all patients but were mostly mild or moderate in severity. While these findings are promising, additional controlled studies are needed to determine longer-term efficacy and safety. (See "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Investigational therapies'.)

Cardiovascular risk in patients with granulomatosis with polyangiitis and microscopic polyangiitis (February 2023)

Patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) have an increased risk of cardiovascular events, although data on long-term outcomes are limited. In a large cohort study that examined cardiovascular events among over 2300 patients with GPA or MPA and nearly 7000 control patients over a median of 9.5 years, a diagnosis of GPA or MPA was associated with an increased risk of ischemic heart disease, heart failure, myocardial infarction, atrial fibrillation, ventricular arrhythmia/defibrillator implantation, ischemic stroke, percutaneous coronary intervention, and in-hospital cardiac arrest [12]. These findings highlight the importance of monitoring and preventing cardiovascular disease in this patient population. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Prognosis and other outcomes'.)

Targeted-release budesonide for IgA nephropathy (February 2023)

An oral targeted-release formulation of the glucocorticoid budesonide (TRF-budesonide) has been designed to release the drug in the distal ileum in patients with immunoglobulin A nephropathy (IgAN) to target the presumed site of production of aberrantly galactosylated IgA1 while limiting systemic glucocorticoid absorption. The efficacy and safety of this agent were evaluated in a randomized phase 3 trial of 199 patients with IgAN and persistent proteinuria despite optimized renin-angiotensin system blockade [13]. Treatment with TRF-budesonide, compared with placebo, resulted in a greater reduction in proteinuria from baseline and a slower rate of estimated glomerular filtration rate decline at nine months; while rates of adverse effects were similar between the groups, rates of adverse events leading to treatment discontinuation were higher in the TRF-budesonide group. Pending data on longer-term outcomes with TRF-budesonide, we continue to suggest initial therapy with oral systemic glucocorticoids plus supportive care for patients with IgAN at high risk for disease progression. (See "IgA nephropathy: Treatment and prognosis", section on 'Other regimens'.)

HYPERTENSION

Social determinants of health and disparities in hypertension control (July 2023)

Among patients treated for hypertension, rates of control are lower in Black individuals as compared with White individuals. As an example, in a large cohort of over 14,000 Black and White adults treated for hypertension, the rate of control (defined as a blood pressure <140/90 mmHg) was 64 percent among Black adults and 75 percent among White adults [14]. Compared with White adults, Black adults had lower annual household incomes and education levels, were less likely to have health insurance, and resided in more economically disadvantaged neighborhoods and regions with a shortage of health professionals; in adjusted analyses, differences in these social determinants accounted for one-third of the racial disparity in hypertension control. Differences in control rates are therefore likely due, at least in part, to social determinants of health. (See "Burden of hypertension in Black individuals", section on 'Control disparity'.)

Lack of validation among most commonly purchased home blood pressure devices (May 2023)

Self-measured blood pressure monitoring (eg, home blood pressure) is recommended for confirmation of hypertension when 24-hour ambulatory blood pressure monitoring is unavailable and also for longitudinal monitoring of blood pressure among patients treated for hypertension. However, less than 15 percent of commercially available blood pressure devices worldwide have published information on device accuracy; in addition, a multinational study found that only about 20 percent of the most commonly purchased devices have been validated [15]. Because self-measured blood pressure is a key part of appropriate hypertension management, patients should be supplied with lists of validated home-use devices, which can be found on websites hosted by the International Society of Hypertension, the American Medical Association, and Hypertension Canada. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring", section on 'Performance and interpretation of self-measured blood pressure (SMBP)'.)

Interindividual heterogeneity in the response to different antihypertensive medications (May 2023)

When patients with hypertension do not achieve blood pressure control on monotherapy, options include stepped care (adding a second medication) or sequential monotherapy (replacing the existing medicine with an agent from a different class). Support for sequential monotherapy comes from the interindividual heterogeneity in the blood pressure response to specific antihypertensive medications. In one study, for example, 270 patients with hypertension were treated sequentially with a medication from four different antihypertensive drug classes in random order; it was concluded that, on average, individualizing monotherapy could lead to an addition 4 mmHg lowering of systolic pressure [16]. However, trials comparing stepped care with sequential monotherapy found better blood pressure with stepped care, and therefore we suggest this approach rather than sequential monotherapy. (See "Choice of drug therapy in primary (essential) hypertension", section on 'Sequential monotherapy versus adding a second drug'.)

Therapeutic inertia in older adults with uncontrolled blood pressure (March 2023)

Therapeutic inertia, defined as the failure by clinicians to intensify antihypertensive treatment when blood pressure rises or remains above therapeutic goals, is an important contributor to low rates of hypertension control in the population. A large population-based study examined rates of antihypertensive initiation (or antihypertensive intensification) in older adults in the United States who had an ambulatory care visit in which their blood pressure was above goal (according to the American College of Cardiology/American Heart Association guidelines) [17]. In 2018, appropriate initiation of antihypertensive medication among untreated individuals occurred in less than 20 percent of visits, and appropriate addition of another antihypertensive agent among those already treated occurred in less than 10 percent of visits, representing a decrease in prescribing compared with data from 2008. These findings indicate that therapeutic inertia continues to be a major impediment to attaining hypertension control. (See "The prevalence and control of hypertension in adults", section on 'Methods to improve control rates'.)

Renal denervation in untreated patients with hypertension (March 2023)

Denervation of the renal sympathetic nerves lowers blood pressure in patients with hypertension. In a sham-controlled trial of over 200 patients with hypertension taking no antihypertensive therapy, ultrasound-based renal denervation lowered 24-hour ambulatory blood pressure by 6/4 mmHg at two months compared with the sham procedure and increased the rate of attaining goal blood pressure [18]. These findings, as well as those of other trials, demonstrate that renal denervation can be used to lower blood pressure in patients with hypertension. (See "Treatment of resistant hypertension", section on 'Renal denervation'.)

Ultrasound renal denervation in patients with resistant hypertension (January 2023)

Denervation of the renal sympathetic nerves reduced blood pressure in patients with resistant hypertension in one sham-controlled trial. In a second sham-controlled trial (RADIANCE-HTN TRIO), 136 patients with resistant hypertension despite treatment with a three-drug single-pill combination were randomly assigned to renal denervation or sham procedure [19,20]. At two months, renal denervation produced a larger decrease in daytime ambulatory systolic pressure; thereafter, medication adjustment was permitted and, at six months, the daytime ambulatory systolic pressures were similar between the groups. Patients in the denervation group were prescribed less antihypertensive medication at six months, but this difference was not statistically significant. These data suggest that renal denervation might reduce the number of medications needed to control blood pressure in patients with resistant hypertension. (See "Treatment of resistant hypertension", section on 'Renal denervation'.)

NEPHROLITHIASIS

Displacement of lower pole kidney stones during stone removal surgery (June 2023)

Due to their anatomical location, lower pole kidney stones are more technically challenging to treat surgically and have the lowest stone-free rates (SFRs). Prior observational studies have suggested that displacement of lower pole stones during ureteroscopy (URS) to a more accessible location within the kidney (such as the upper pole or kidney pelvis) may help facilitate stone fragmentation. In a randomized trial in nearly 140 patients who underwent URS for lower pole stones, those assigned to laser lithotripsy following basket displacement of their stones had higher SFRs compared with those assigned to laser lithotripsy without displacement (95 versus 74 percent) [21]; operative time, laser energy usage, and complication rates were similar between the groups. For patients who are undergoing URS for surgical removal of lower pole kidney stones, we suggest displacement of the lower pole stones prior to laser lithotripsy rather than performing lithotripsy without displacement. (See "Kidney stones in adults: Surgical management of kidney and ureteral stones", section on 'Displacement of lower pole stones'.)

Hydrochlorothiazide and prevention of recurrent kidney stones (March 2023)

Thiazide therapy can lower urinary calcium excretion and has been shown in prior randomized trials to reduce the risk of kidney stone recurrence in patients with calcium stones. A recent trial in over 400 patients with recurrent calcium kidney stones found that once daily hydrochlorothiazide (HCTZ; 12.5, 25, or 50 mg), compared with placebo, did not reduce the risk of a composite of symptomatic or radiologic stone recurrence over a median of three years [22]. However, there was a reduction in the rates of radiologic stone recurrence in patients receiving higher doses of HCTZ. For patients with recurrent calcium oxalate stones and higher than desired urine calcium, we continue to suggest treatment with a thiazide diuretic to lower urinary calcium excretion. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'High urine calcium'.)

TRANSPLANTATION

No benefit of sodium bicarbonate for kidney transplant recipients with metabolic acidosis (March 2023)

Metabolic acidosis is common among kidney transplant recipients and associated with graft loss and mortality. While correction of metabolic acidosis with alkali therapy (eg, sodium bicarbonate) has been shown to slow the decline of kidney function in nontransplant patients with chronic kidney disease, a similar benefit in kidney transplant recipients has not been demonstrated. In a recent trial in nearly 250 long-term kidney transplant recipients with stable graft function and metabolic acidosis, treatment with oral sodium bicarbonate, compared with placebo, increased serum bicarbonate levels but did not slow the decline of estimated glomerular filtration rate over two years [23]. Based on these results, sodium bicarbonate should not be given to preserve graft function in kidney transplant recipients with metabolic acidosis. (See "Kidney transplantation in adults: Overview of care of the adult kidney transplant recipient", section on 'Metabolic acidosis'.)

Machine perfusion versus hypothermia for deceased-donor kidney recovery (February 2023)

Among kidney transplant recipients, ex situ kidney hypothermic machine perfusion and therapeutic hypothermia during deceased-donor kidney retrieval have each been shown to reduce the risk of delayed graft function (DGF; defined as need for dialysis in the first week after transplant), but direct comparative data have been lacking. In a recent trial in which 1349 kidneys from 725 brain-dead donors were randomly assigned to machine perfusion, therapeutic hypothermia, or both before transplantation, the incidence of DGF was lower with machine perfusion than with hypothermia (19 versus 30 percent), with no additional benefit from the combination [24]. Rates of one-year allograft survival were similar among groups. Although machine perfusion adds significant expense to kidney retrieval, the reduction in DGF would mitigate this cost. (See "Deceased- and living-donor kidney allograft recovery", section on 'Pulsatile perfusion'.)

OTHER NEPHROLOGY

Comparison of the EKFC and CKD-EPI equations for estimating glomerular filtration rate (March 2023)

To calculate estimated glomerular filtration rate (eGFR), we and others recommend using the 2021 Chronic Kidney Disease Epidemiology (CKD-EPI) equation. Other equations have been developed using standardized serum creatinine assays, such as the European Kidney Function Consortium (EKFC) equation, which was developed predominantly in White populations and uses a race-specific Q value. In one study, the EKFC creatinine equation was slightly more accurate than the 2021 CKD-EPI creatinine equation in both White and Black populations [25]. However, because this equation takes race into account, we continue to recommend using the 2021 CKD-EPI creatinine equation. (See "Assessment of kidney function", section on 'eGFR from creatinine (primary approach)'.)