#NephMadness 2020: Hyperkalemia Region

Submit your picks! | NephMadness 2020 | #NephMadness | #HyperKRegion

Selection Committee Member: Deborah Clegg

Deborah Clegg is Associate Dean of Research in the College of Nursing and Health Professions at Drexel University. Her basic science laboratory has determined how sex hormones, estrogens in particular, impact food intake, body weight, and energy homeostasis. Her goal in her new position is to assist and mentor faculty in obtaining research funding.


Writer: Ryann Sohaney @RyannSohaney

Ryann Sohaney is a clinical research fellow at the University of Michigan and is currently pursuing a Master of Science in Clinical Research Design and Statistical Analysis. Her clinical and research interests include acute kidney injury and critical care nephrology, with a particular interest in mitigating adverse health outcomes following acute kidney injury.

Competitors for the Hyperkalemia Region

Potassium Binders in CKD vs Potassium is Good in CKD

Exercise Causes Hyperkalemia vs Exercise Prevents Hyperkalemia

Hyperkalemia is the most common electrolyte disturbance among patients with CKD. It affects 14%-20% with increasing prevalence associated with declining estimated glomerular filtration rate (eGFR). Careful nephrologist intervention is warranted, as hyperkalemia may provoke fatal cardiac dysrhythmias and is associated with increased all-cause mortality. Common treatments for chronic hyperkalemia include potassium restriction, the use of diuretics, elimination or reduction in medications which raise serum potassium, and the use of potassium binding resins. In practice, this can be challenging for several reasons: 

  • Potassium-restricted diets limit access to many nutrient rich foods.
  • The patients most likely to benefit from the renal and cardioprotective effects of renin angiotensin system inhibitors (RAASi) and mineralocorticoid receptor antagonist (MRA) (such as those with CKD, heart failure, and diabetes mellitus) are also at the greatest risk for elevated potassium.
  • Sodium polystyrene sulfonate (SPS) can cause serious gastrointestinal side effects.

In the scouting report for the Hyperkalemia Region, we will review the most recent binders to come on the market as well as the potential role for a potassium-rich diet in patients with CKD. 

Potassium Binders in CKD vs Potassium is Good in CKD

 


 

Potassium Binders in CKD

Adapted Figure 7 from Palmer and Clegg et al, AJKD © National Kidney Foundation.

Sodium polystyrene sulfonate
SPS, a Na+/K+ cation exchange resin, is the longest reigning potassium binder, having received FDA approval in 1958. While often scrutinized for the lack of large, randomized controlled trials to prove its efficacy, there are a host of retrospective data suggesting it works. Mikrut and Brockmiller-Sell showed that 30 g of SPS resulted in an average reduction in potassium of approximately 1 mmol/L (from an average of 5.5 mmol/L) and 60 g resulted in a reduction of 1.7 mmol/L (from an average of 6.2 mmol/L). A study by Kessler et al suggested a possible direct dose response in a larger cohort of hospitalized patients, while Sandal et al suggested that the reduction of potassium following the administration of SPS occurs even in the absence of other potassium reducing therapies (such as diuretics or renal replacement therapy) or a decrease in serum creatinine.

SPS for treatment of hyperkalemia has also been assessed in a single-center, double-blind, placebo-controlled trial among 33 patients with CKD and mild hyperkalemia (serum K+5.0-5.9 mmol/L). In this study, 30 g of SPS daily over 7 days was superior to placebo, with 73% of patients randomized to SPS achieving normokalemia and a difference in mean reduction in serum potassium of 1 mmol/L between groups. 

Despite its long history of use, the unfavorable side effect profile of SPS has given it a bad reputation among patients and clinicians alike. SPS commonly causes constipation when given alone. Thus, it is often administered in sorbitol. The sorbitol component has been implicated in a rare, but serious complication of colonic necrosis. Interestingly, a systematic review by Harel et al of 30 articles reporting 58 cases of serious adverse gastrointestinal events involving the use of SPS revealed that nearly a third of cases occurred in those not receiving sorbitol. These findings strongly suggest that SPS itself may be toxic.

A retrospective cohort study by Watson et al reported the incidence of colonic necrosis among outpatients and hospitalized patients receiving SPS was low, at 0.14% compared to 0.07% among non-users (the number needed to harm being 1,395). The requirement of colonic biopsy to confirm the diagnosis in this study may, however, have underestimated the potential for harm.

In a 2019 study, a large, population-based, retrospective cohort of 20,020 patients over 65 years of age prescribed SPS were matched to non-users. In this analysis, the authors reported a higher risk of an adverse gastrointestinal event (ie, hospitalization or emergency department visit with intestinal ischemia/thrombosis, gastrointestinal ulceration/perforation, or resection/ostomy) within 30 days of initial SPS prescription (0.2% compared to 0.1%). However, until an alternative binder is readily available (and affordable!), many nephrologists are unlikely to completely abandon its use. 

Visual Abstract by @MarioFunesMD on Noel et al

Patiromer
A new generation of potassium binders have stepped onto the court. Patiromer is a non-absorbed polymer powder made up of small, spherical beads. It is designed to be fully ionized at the physiologic pH of the colon, thereby enhancing the binding of potassium in exchange for calcium where the concentration of potassium is highest. Patiromer (Veltassa) received FDA approval for use in adults with hyperkalemia in October 2015 following the results of AMETHYST-DN. In this landmark phase 2 trial, patients with diabetic nephropathy (eGFR 15-59 ml/min/1.73 m2) receiving an angiotensin-converting enzyme (ACE), angiotensin receptor blocker (ARB), or both, with a serum potassium >5.0 mmol/L, were stratified according to baseline serum potassium and then randomized to several starting doses of patiromer. Patiromer starting dosages of 8.4-33.6 g daily resulted in statistically significant reductions in serum potassium at week 4 that were sustained through week 52 of treatment. Overall, adverse events were mild, and included constipation as well as hypomagnesemia in 7.2% of patients.

Visual Abstract by @whatsthegfr on Bakris et al

Patients with a history of bowel obstruction, severe gastrointestinal disorders, and major gastrointestinal surgery were excluded from the clinical trials, and precaution is advised when prescribing to this group. An important aspect of patiromer is that it works in the colon, so reduction in potassium can be delayed for up to 7 hours after ingestion. The starting dose of patiromer is 8.4 g daily with a maximum dose of 25.2 g daily. While the package insert says that patiromer should not be taken with other drugs, empiric data show that most medications are not affected by co-administration. Drugs that were not affected by co-administration with patiromer include amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil, and warfarin, while metformin, ciprofloxacin, and levothyroxine have decreased absorption. 

Summary of selected randomized clinical trials of patiromer in patients with CKD

Trial/Design Patient population Intervention Primary endpoint(s) Summary of findings
AMETHYST-DN

Phase 2, prospective, randomized, open-label, dose-ranging clinical trial

306 patients with diabetic nephropathy (eGFR 15 to <60 ml/min/1.73 m2) and serum [K+] >5.0 mmol/L on RAASi therapy Patients stratified by baseline K+ level into: 

-mild hyperkalemia (>5.0 to 5.5 mmol/L)

OR

-moderate hyperkalemia (>5.5 to <6.0 mmol/L) 

…and then randomized to receive one of several starting doses of patiromer:

– 4.2 g bid (mild hyperkalemia)

– 8.4 g bid

– 12.6 g bid

– 16.8 g bid (moderate hyperkalemia)

Change in K+ from baseline to week 4.

Adverse events though 52 weeks. 

Patiromer reduced K+ at 4 weeks which persisted through week 52. 

Hypomagnesemia was the most common adverse event (7.2%), followed by constipation (6.3%). Hypokalemia occurred in 5.6% of patients. 

OPAL-HK:

Phase 3, two phase, randomized, placebo-controlled trial

237 with CKD 4 and 5 receiving RAASi with a K+ of 5.1 to 6.4 mmol/L 

Withdrawal phase: Patients entered 2nd phase of study at week 4 if K+ is 3.8-5.0 mmol/L

Initial treatment phase: Patiromer 4.2 or 8.4 g/d for 4 weeks

Withdrawal phase: Continue patiromer

OR

switch to placebo through week 8

Treatment phase: Mean change in K+ from baseline to week 4

Withdrawal phase: change in K+ from the start of withdrawal to week 8 

Treatment phase: 76% of patients achieved a normal K+

Withdrawal phase: K> 5.5 recurred in 60% of placebo compared to 15% of patiromer group

AMBER:

Phase 2 randomized, double-blind, placebo-controlled trial

295 patients with eGFR 25 to ≤ 45 ml/min/1.73 m2 and resistant hypertension with a K+ of 4.3-5.1 mmol/L Spironolactone (open label) + patiromer 8.4 g daily

OR

Spironolactone (open label) + placebo

Proportion of patients on spironolactone at week 12 Patiromer enabled more patients to continue treatment with spironolactone (between group difference 19.5%) but this did not result in a difference in blood pressure.

Sodium zirconium cyclosilicate 
SZC, formerly known as ZS-9, consists of a crystal lattice structure that is highly selective for potassium and exchanges potassium for hydrogen and sodium ions. SZC received FDA approval for the treatment of hyperkalemia in May 2018 under the trade name Lokelma and is formulated as a powder. Clinical trials have demonstrated rapid and sustained normokalemia with SZC, with an average time to normokalemia (from a single dose of 10 g) of 2.2 hours, from a mean baseline of 5.6 mmol/L. Most patients maintain normokalemia with daily doses of 5-15 g daily. The recommended dose is 10 g three times daily for 48 hours, followed by a 10 g daily. Similar to SPS and patiromer, SZC should be taken either 2 hours before or 2 hours after other medications. Overall, SZC is well tolerated. However, a single 10 g dose of SZC contains 800 mg of sodium, making sodium retention and edema a potential concern. In the HARMONIZE trial, 14% of participants receiving 10 g SZC experienced edema as compared to 2.2% receiving 5 g daily. It is unclear from current literature if this translates into a higher need for diuretics or antihypertensive agents. For now, there is some reassurance that among patients with end-stage kidney disease (ESKD), intradialytic weight gain did not differ between those receiving SZC versus placebo

Summary of selected trials of zirconium cyclosilicate for the treatment of hyperkalemia

Trial/design Patient Population Intervention Primary endpoint Major Findings
HARMONIZE:

Phase 3, multicenter, randomized, double-blind, placebo-controlled trial

258 outpatients with K+ of ≥5.1 mmol/L Open label phase: Patients treated with SZC 10 g three times daily. 

Randomized phase: Patients achieving normokalemia were randomized to SZC 5 g, 10 g, 15 g or placebo for 28 days

Difference in K+ between placebo and each treatment group during days 8 through 29 of the randomized phase Median time to normalization of serum potassium was 2.2 hours, with 98% of patients achieving normokalemia by 48 hours. 

All three doses of SZC resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days

Hypokalemia developed in 10% of patients randomized to 10 or 15 g of SZC.

Packham et al:

Phase 3, two-stage, double-blind, dose-ranging trial

753 outpatients with hyperkalemia (K+ 5.0 to 6.5 mmol/L) Initial phase: SZC (1.25 g, 2.5 g, 5 g, or 10 g) or placebo three times daily for 48 hours

Maintenance phase: Patients with normokalemia at 48 hours randomly assigned to continue SZC or placebo once daily until day 14

Initial phase: Change in K+ at 48 hours

Maintenance phase: between-group difference in K+ level during the 12-day maintenance phase

There was a significant reduction in potassium levels at 48 hours in patients taking SZC.

Effect of treatment was observed within one hour of administration. 

In patients who continued SZC in the maintenance phase, normokalemia was maintained. 

 

Spinowitz et al:

Phase 3, two-phase, open-label trial

751 outpatients with hyperkalemia (K+ ≥5.1 mmol/L) Correction phase: Patients received SZC 10 g three times daily until normokalemia was achieved. 

Maintenance phase: Patients achieving nomokalemia received SZC 5 g daily titrated to maintain normokalemia for up to 12 months

Correction phase: restoration of normal serum potassium 

Maintenance phase: Proportion of patients maintaining serum potassium of ≤5.1 mmol/L

99% of patients achieved normokalemia during correction phase. 

99% of patients maintained a K+ ≤5.5 mmol/L during 12 months of follow up.

 

Future directions: patiromer and sodium zirconium cyclosilicate
A common struggle as a nephrologist treating patients with CKD is continuing medications with evidence-based indications while simultaneously avoiding hyperkalemia. Using potassium binders to enable patients to remain on RAASi or MRA may translate into improved cardiovascular and renal outcomes. The Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure (DIAMOND) trial is anticipated to be completed in 2022 and will study whether adding patiromer to RAASi blockade can allow continuation of these latter medications, leading to a reduction in the hard clinical outcomes of death and cardiovascular events. 

Resistant hypertension, defined as having elevated blood pressure that does not respond to the use of three antihypertensive agents from different classes, or having controlled blood pressure on four or more agents, occurs in approximately a quarter of patients with an eGFR <60 ml/min/1.73 m2. Unfortunately, the presence of hyperkalemia often limits the use of effective treatment options in this group.

Recently, the results of the AMBER trial were published. In this 12-week, double-blind, randomized, placebo-controlled trial, patients with CKD and resistant hypertension were treated with open-label spironolactone 25 mg and randomized to either placebo or patiromer 8.4 g daily. Patients receiving patiromer were more likely to remain on spironolactone and experienced less hyperkalemia. Despite enabling the continued use of spironolactone, there was no difference in mean change in systolic blood pressure between patients randomized to patiromer. However, a difference in blood pressure may not have been observed due to the relatively short follow up of the study (as more than half of spironolactone discontinuations in the placebo group occurred after 6 weeks).

Visual Abstract by @Vernisartan on Agarwal et al

Overall, these findings have important implications for the treatment of resistant hypertension in a population with high prevalence. Unfortunately, with an average retail price of $1,032 per month, the cost of patiromer is often prohibitive. Recently, I completed several successful prior authorizations, only to later learn that my patient is expected to pay nearly $500 a month! Despite promising trial results, our patients are unlikely to experience the potential health benefits of new potassium binders until their cost is substantially reduced.


 

Potassium is Good in CKD

There is an abundance of observational and interventional data highlighting the health benefits of diets rich in potassium. For example, high potassium diets are associated with lower blood pressure and reduced risk of cardiovascular mortality and stroke. Whether the health benefits of high potassium diets outweigh the risk of hyperkalemia in those with CKD, however, has been the topic of recent debate.

First, let us take a closer look at the mechanisms by which the kidney handles increased dietary potassium load. The majority of potassium filtered by the kidney is reabsorbed in the proximal tubule and thick ascending limb. Nearly all the potassium excreted by the kidney results from excretion along the aldosterone-sensitive distal nephron. Epithelial Na+ channels (ENaC) reabsorb Na+ in response to increased luminal flow, distal sodium delivery, and aldosterone stimulation in response to an increase in plasma K+. The influx of Na+ provides an electronegative luminal gradient which allows secretion of K+ through the renal outer medullary potassium channel (ROMK) to occur. 

Following an increased dietary load of potassium, kaliuresis and natriuresis are also believed to occur even before plasma potassium and aldosterone increase. This mechanism may be mediated by the inactivation of the Na+/Cl cotransporter (NCC) in the distal convoluted tubule, facilitating an increase in urine flow rate and sodium delivery to the distal nephron. As kidney function declines, these mechanisms become less effective and the colon attempts to compensate by increasing colonic secretion of potassium mediated by the apical large conductance K+ (BK) channel.

Adapted Figure 3 from Palmer and Clegg et al, AJKD © National Kidney Foundation.

Many potassium-rich foods, namely fruits and vegetables, are also excellent sources of fiber, alkali, and other micronutrients. Incorporating a diet low in potassium but sufficient in alkali and fiber can be a challenge. This is important as metabolic acidosis may potentiate hyperkalemia, and metabolic acidosis may contribute to further progression of renal disease. Additionally, the increase in alkali (namely citrate and acetate) which accompany a diet high in potassium may, in turn, reduce the risk for nephrolithiasis  and have important implications for bone health.

Large observational cohorts examining diets low in potassium and incident CKD or the progression of CKD have been conflicting in their results.

The PREVEND study cohort suggests that low urinary potassium excretion (a surrogate for a low potassium diet) is associated with a higher risk for incident CKD.

Visual Abstract by @edgarvlermamd on Kieneker et al

In Chronic Renal Insufficiency Cohort (CRIC), a large CKD cohort, low urinary potassium excretion was associated with increased risk of CKD progression, while a post hoc analysis of the MDRD study revealed no association. The most recent observational cohort to address this question, the Korean Cohort Study for Outcome in CKD (KNOW-CKD), revived hope for dietary potassium slowing CKD progression. It remains uncertain if the observed benefits from high potassium diets are explained by potassium or a healthy dietary pattern. Patients with higher urinary potassium in the KNOW-CKD cohort also had significantly higher eGFR at baseline which may further bias results, although they adjusted for this phenomenon. 

Few clinical trials have assessed the direct effect of dietary potassium intake among patients with CKD. The “K+ in CKD Study,” which aims to investigate the renoprotective effects of dietary potassium, is currently recruiting patients with hypertension and CKD 3b/4 with an average decline in eGFR of greater than 2 ml/min/1.73 m2 for randomization to 40 mmol of potassium chloride, potassium citrate, or placebo. The primary study endpoint is the difference in eGFR after 2 years of treatment, while secondary endpoints include other renal outcomes (ie, > 30% decrease in eGFR, doubling of serum creatinine, ESKD, albuminuria), blood pressure, cardiovascular events, all-cause mortality, and incidence of hyperkalemia.

There have been several trials assessing diets high in fruits and vegetables, and likewise, high in potassium and alkali, for the treatment of metabolic acidosis in CKD. Among patients with CKD stage 4 with hypertensive kidney disease and a serum HCO3 <22, patients were randomized to sodium bicarbonate tablets or to a diet high in fruits and vegetables. During the year of follow up, mean serum bicarbonate was higher in the sodium bicarbonate group; however, there was no increase in plasma potassium or decline in eGFR from baseline in either group.

A second trial assessed the use of prescribed diet in fruits and vegetables, sodium bicarbonate, or usual care among patients with hypertensive CKD stage 3 on the outcome of eGFR decline and metabolic acidosis. Improvement in metabolic acidosis and preservation of eGFR decline between patients prescribed fruits and vegetables and those treated with sodium bicarbonate.

Visual Abstract by @edgarvlermamd on Goraya et al

While the results are encouraging, patients at highest risk for hyperkalemia, such as those with diabetes or those with a starting serum potassium greater than 4.6 mmol/L, were excluded from both of these trials, and all patients with CKD stage 4 were on furosemide for blood pressure control, limiting generalizability. 

Check out this podcast episode of The Curbsiders featuring Deborah Clegg, @RyannSohaney, and @kidney_boy:

#199 NephMadness: Hyperkalemia, Diet, K+ Binders, Exercise

 

Exercise Causes Hyperkalemia vs Exercise Prevents Hyperkalemia

There is no doubt that exercise has numerous health benefits – we featured a whole Exercise Nephrology region last year. Regular exercise increases high-density lipoprotein cholesterol, improves blood pressure control and insulin sensitivity, and lowers cardiovascular disease risk. Further benefits of exercise include improved balance and coordination, thereby lowering the risk for falls and increasing longevity. There is also some evidence that regular exercise among patients with CKD may slow the rate of renal function decline. Recognizing the numerous health benefits of exercise, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that patients with CKD exercise for at least 30 minutes, 5 times weekly. Today we ask ourselves: how does exercise influence serum potassium?


 

Exercise Causes Hyperkalemia

Most of the body’s potassium is in the intracellular space, of which 80% is contained in skeletal muscle. As the body’s largest potassium reservoir, skeletal muscle plays an important role in maintaining normal potassium balance. The skeletal muscle action potential starts with depolarization due to the influx of sodium through voltage-gated Na+ channel in the sarcolemma surrounding muscle fibers. This is followed by repolarization as potassium exits through voltage gated K+ channels, inactivating the voltage-gated sodium channels and leading to muscle fatigue. Repeated skeletal muscle contractions can thus lead to considerable potassium release into the extracellular space. In fact, during short bursts of exhaustive sprinting, arterial potassium concentrations rose by 4.3±0.2 mmol/L, leading to a near doubling in potassium! This rapid rise in blood potassium concentration has been well documented in numerous studies and is directly proportional to exercise intensity.


 

Exercise Prevents Hyperkalemia

Following vigorous exercise, plasma potassium falls below previous resting levels. Atanasovska et al examined the dynamics of plasma potassium during and following an intense 2,000 m rowing event in 10 athletes by measuring potassium concentrations every 30 seconds during the event, and up until 30 minutes post-exercise. Potassium concentrations rose during the first 90 seconds to a mean of 6.1 mmol/L and remained at this level for the remainder of the exercise.  After exercise, the potassium fell to a mean of 3.3 mmol/L, which was sustained for 30 minutes. 

It is the skeletal muscle Na+/K+ATPase which is responsible for restoring intracellular and extracellular ion balance, actively exchanging intracellular sodium for extracellular potassium. Na+/K+-ATPase activity is tightly regulated, with activity being enhanced by insulin and catecholamines. The upregulation of Na+/K+-ATPase by catecholamines such as epinephrine takes effect within minutes and counteracts the hyperkalemic effect of skeletal muscle action potentials. This stimulation of Na+/K+-ATPase is mediated by β2-adrenoreceptor, the same mechanism by which inhaled albuterol is effective for the treatment of acute hyperkalemia.  

The effects of exercise on serum potassium may be longer lasting. In addition to enhancing the activity of Na+/K+-ATPase, exercise also increases the number of this ion pump in the cell membrane. Also, since exercise improves insulin resistance, this could also allow exercise to improve potassium metabolism in CKD. Insulin resistance (as well as diabetes) is an independent predictor of increased potassium and hyperkalemia. 

Can we leverage exercise to prevent hyperkalemia among patients with ESKD on hemodialysis? 

Mustafa et al did a 3-month study of exercise after dialysis and saw an improvement in arterial stiffening (the primary goal of the study), but also noted that pre-dialysis potassium fell from 5.2 mmol/L to 4.5 mmol/L over the 3 months of the study. The changes could not be explained by improvement in insulin sensitivity, which was not affected. 

In ESKD, excess potassium must be sequestered in skeletal muscle to buffer the total potassium overload and prevent profound hyperkalemia between dialysis sessions. Hemodialysis, as we know, does not have direct access to the body’s potassium stores and relies upon continued solute release from the intracellular compartment into plasma for adequate clearance. In a sample of 11 patients, a 60-minute intradialytic exercise program decreased potassium rebound following hemodialysis, perhaps by increasing skeletal muscle blood flow, and possibly enhanced by exercise-induced potassium efflux from cells. A meta-analysis of three small studies evaluating this same question, however, did not see a difference in potassium levels with intradialytic exercise. It is possible that an effect was not seen due to variations in the time in which potassium was measured. Nevertheless, exercise, both intradialytic and otherwise, has numerous benefits and should be encouraged.

– Executive Team Member for this region: Joel Topf, AJKD Social Media Advisory Board member. Follow him @kidney_boy.

 

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC point for reading this region.

  1. Register/log in to the NKF’s Professional Education Resource Center (PERC). If you select “Physician” in the drop-down menu during registration, the ABIM ID will pop up – make sure to complete this during registration to receive MOC points after course completion.
  2. Review the activity, disclosure, and accreditation information.
  3. Click “Continue” and review Course Instructions.
  4. Complete Post-Test. Please note: By selecting “Yes” to the participation questions for each region, the corresponding Post-Test questions will appear. Click “Save Draft” to save your responses and finish later. When you are ready to submit your answers, click “Preview” to review all responses, then click “Submit.”
  5. Click “Next” to complete the Evaluation form, then click“Submit.”
  6. Claim 1.0 CME credit and 1.0 MOC point per region (up to 8.0 total for 8 regions of NephMadness).
  7. Save/print your certificate.

The CME and MOC activity will expire on June 13th, 2020.

Submit your picks! | #NephMadness | @NephMadness | #HyperKRegion

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.