Concept Map: Hypokalemia and HTN workup

 

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Content edited: Dr Rondon and Dr Sharma

Concept Map: Oral Agents to treat Hyperkalemia- a summary

This is a concept map of the 3 oral GI agents used to treat hyperkalemia.

Topic Disciussion: Bold and BRASH

Bold and BRASH

As we all know, one of the cornerstones of nephrology is the intimate relationship between the ever-present and masterfully made kidneys and that other thing less important thing a little higher up that pumps blood (remember this is a nephrology blog.) In all seriousness though, we can never forget that renal disease inevitably begets cardiac disease and vice versa and must always be vigilant about that relationship. And of course, there are many ways that this phenomenon called cardiorenal syndrome comes to exist. I want to touch upon a special phenomenon called BRASH syndrome.

BRASH syndrome which stands for Bradycardia, Renal Failure, AV-nodal blocking agents, Shock, Hyperkalemia is a phenomenon that usually occurs (but not necessarily required) in the setting of AV-nodal blockers that cause bradycardia which leads to poor renal perfusion which progresses to renal failure which causes hyperkalemia which in turn leads to worsening bradycardia and the cycle continues. It is an incredibly interesting scenario in that seemingly unrelated or previously thought unrelated components are very closely related.

Looking back, people have described a phenomenon whereby people who have bradycardia end up in renal failure.  Physiologically this makes perfect sense when thinking about cardiac output as seen below:

 Cardiac Output = Heart Rate X Stroke Volume

As heart rate drops stroke volume is not always enough to keep up with cardiac output especially if a patient has pre-existing cardiac disease and cannot mount a good volume response to drop in HR. Patient’s with kidney disease are also susceptible to this. Eventually, patients will go into shock from this perpetual cycle.

Treatment for this disease really hinges on two things: restoring sinus rhythm at appropriate which should in turn start to relieve acute kidney injury by restoring renal perfusion and temporizing patients with hyperkalemia. In most cases invasive measures like transvenous pacing are NOT necessary unless advanced heart blocks are present however medications such as dopamine or isoproterenol or even epinephrine can be used to try and restore perfusion to the kidney. If patient’s have suspected AV-nodal blocking agent toxicity even conventional methods like glucagon or insulin drip are not usually necessary. Next, IV calcium should be used to help stabilize cardiac membrane to prevent further bradycardia. Then, kaluresis is important as well to help stop bradycardia. If a patient is hypovolemic fluid resuscitation is very important and Lactated Ringers or Bicarbonate infusion can be used based on the patient’s acid-base status. Also, if patient is anuric, diuretics can be tried to help open up kidneys to eliminate potassium however if patient’s do not respond, dialysis may be required to intervene in this cycle to prevent further bradyarrhythmia and/or arrest.

Overall, BRASH syndrome is a sometimes-overlooked entity which can be resolved quickly if caught early and usually can prevent worsening renal and cardiac disease.

Major Take Away Points:

1)      BRASH Syndrome - Bradycardia, Renal Failure, AV-nodal blocking agents, Shock, Hyperkalemia

2)      Vicious cycle where one entity (sometimes started by AV-nodal blockers) usually leads to another

3)      Occurs due to drop in cardiac output from bradycardia without appropriate response of stroke volume to compensate

4)      AKI occurs in low flow state causing renal hypoperfusion leading to pre-renal state and possible ATN causing build-up of potassium

5)      Treatment relies on managing bradycardia to restore renal perfusion, and cardiac membrane stabilization along with kaluresis

For more information, there is a great review here:

http://emcrit.org/pulmcrit/brash-syndrome-bradycardia-renal-failure-av-blocker-shock-hyperkalemia/

 image courtesy: https://spongebob.fandom.com/wiki/Bold_and_Brash

Post by
Rushang Parikh, MD

Concept Map: Distal Renal Tubular Acidosis

Distal RTA is the true Nephrogenic RTA and can be truly divided into two variants- the hypokalemic and the hyperkalemic types. Here is a concept map of the topic

Hyperkalemia meets their new K-busters

      Hyperkalemia is a challenge in CKD and ESRD patients. The treatment agents for this complication have been limited to bowel resins, diuretics and dialysis.  There has been some recent interest in novel agents as some evidence suggesting the efficacy of Kayexalate and side effects leading to colonic necrosis in some settings.

Three articles published this week (2 in NEJM and 1 in JAMA) give us trials of using novel K lowering agents in three different settings.

The first trial looked at patiromer use for hyperkalemia in CKD patients on RAAS inhibitors. The active moiety of patiromer for oral suspension is a nonabsorbed polymer that binds potassium in exchange for calcium in the distal colon leading to highest K excretion possible. Patiromer is a dry powder, primarily a spherical bead that is not absorbed and that binds potassium when mixed in small amounts of water. It exchanges potassium for calcium, which would be of some concern if the drug were absorbed. It appears, however, that the drug is not absorbed and that the amount of calcium absorbed is small. In A RCT with placebo, patiromer treatment was associated with a decrease in serum potassium levels and, as compared with placebo, a reduction in the recurrence of hyperkalemia. Mild-to-moderate constipation was the most common adverse event (in 11% of the patients); hypokalemia occurred in 3%.

The second trial looked at zirconium cyclosilicate (ZS-9), a novel selective cation exchanger, could lower serum potassium levels in patients with hyperkalemia. ZS-9 is a compound with a crystalline structure that traps potassium  10 times as much potassium as kayexalate does. It is insoluble and remains in the intestine during transit. This was in a variety of diagnosis leading to hyperkalemia in over 700 patients. There was an initial phase and then a maintenance phase. Patients with hyperkalemia who received ZS-9, as compared with those who received placebo, had a significant reduction in potassium levels at 48 hours, with normokalemia maintained during 12 days of maintenance therapy per their conclusion

The third trial titled HARMONIZE was a phase 3, multicenter, randomized,

double-blind, placebo-controlled trial evaluating zirconium cyclosilicate in outpatients with hyperkalemia (serum potassium_5.1mEq/L) . Among outpatients with hyperkalemia, sodium zirconium cyclosilicate reduced serum potassium to normal levels within 48 hours; compared with placebo, all 3 doses of zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days.

Two accompanying editorials are in NEJM and JAMA as well

Few questions still remain and are a concern:

Since all 3 trials were pharmaceutical company sponsored, placebo was used to compare the agents for efficacy. Why not kayexalate?- it works and it’s cheaper. The authors in one study did state that the agent was not compared to sodium or calcium polystyrene  since prospective studies are lacking in the later and also agents cause bowel necrosis.

But there are significant years of experience and pathophysiology that it works.  Side effects are part and parcel of every agent. The above agents had constipation as side effect, and some might have calcium and magnesium concerns if used long term given how they work. Also all three trials were very short term and long term trials are needed still.  FDA approval is also warranted before any use.

Nevertheless, the patients we have that have CKD and or heart failure and we really want them to be on ACEI, ARB or aldactone but cannot due to K related concerns and or require diuretics with them:- now we may have an alternative option for the situation. 

Pseudohyperkalemia: Some questions and possible answers?

Pseudohyperkalemia- what’s the mechanism and why?

Classically, we observe this in patients who have thrombocytosis or leukocytosis. Potassium is released from WBCS and platelets when a blood sample is allowed to clot in vitro.   When we use a plasma sample, the tube it gets drawn is heparinized and hence clotting doesn’t occur and plasma K levels are usually lower than serum K levels. When you have thrombocytosis or leukocytosis, this process is even more prominent.   In thrombocytosis, platelet granules release K.

Besides the clotting leading to lysis and K release, prolonged storage of blood at room temperature or in cold before performing the test and lead to impair N/K ATPase pump in WBCS and lead to spurious K levels.

Some researchers have defined pseudohyperkalemia when serum potassium concentration exceeded that of plasma by more than 0.4 mmol/L provided that samples are collected under strict techniques, remain at room temperature and are tested within 1 hour from blood specimen collection.

The phenomenon of pseudohyperkalemia was first reported by Hartmann and Mellinkoff in 1955 as a marked elevation of serum potassium levels in the absence of clinical evidence of electrolyte imbalance. They also found that in particular, the lag time between blood collection and potassium determination was confined to a maximum of 30 minutes, and a positive correlation between platelet count and serum, but not plasma potassium concentration, was found. Other causes of this entity is from fist clenching and use of tourniquet as well.

With leukemia, many cases are now reported leading to false elevation of K.  If plasma and serum are separated quickly ( within 30 min), the normal K levels can be seen.  Potassium normally is now measured in heparinized tubes, so why does K still get elevated?  Lysis of cells can still occur.  Because of the high WBCS counts seen in some cases of CLL, spurious K can still be found. It is possible that its due to the impaired N/K pump in that state of elevated WBCs that contribute to the release of K from cells.  Trauma is the major cause. Drawing in a tube without shaking may help as well.

What about Stat ABG draws? The fragile WBCs are prone to mechanical stress frequently. The K measurements in many cases of CLL may be inaccurately elevated if sample of blood are not analyzed quickly and in absence of lysis inducing events. Arterial analysis done by ABG draws is quicker and perhaps less mechanical stress and may allow for more accurate K readings than venous draws.  In addition, perhaps it also doesn’t allow for that fist clenching and tourniquet use that might be leading to pseudohyperkelamia.

Is plasma K better than serum K?  A letter in NEJM in 1991 showed that elegantly that plasma K was superior to serum K in getting the more accurate K level in patients who had experienced trauma.

What is reverse pseudohyperkalemia? It is when the plasma K is higher than serum K and still is spurious in nature. Few cases reports have highlighted this entity as well. It is possible that this is due to a hiegtened sensitivity to heparin induced membrane damage in setting of a blood malignancy. 

Hypercalcemia and hypokalemia- is there a link?

Interestingly, we do encounter this combination sometimes and likely has no connection.  This was indeed studied in a 1977 paper in Annals of Internal Medicine. They studied 103 patients with hypercalcemia in a cancer hospital with normal renal function and no history of taking potassium depleting agents. Interestingly, 32% were hypokalemic.  The cause of hypercalcemia is most cases was malignancy followed by primary hyperparathyroidism. Also, as the calcium levels were higher, the frequency of hypokalemia was greatest.

Why does hypercalcemia cause hypokalemia?

Perhaps the calcium delivery increases the na delivery to the distal tubule which in turn results in na-k exchange with loss of potassium. This is what might be postulated based on animal studies and prior human trials.  This above study was only done in the cancer ward and hence might have many other confounders that were not accounted for such as chemotherapy agents that cause low K, diarrhea in setting of infections, chemotherapy and so forth.  While the pathophysiology is plausible, the more likely explanation might be true-true and unrelated.

Topic Discussion: Hyperkalemia in Bartter Syndrome

Bartter syndrome is an autosomal recessive disorder characterized by renal salt wasting, hypokalemic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism. Five variants of Bartter syndrome have been identified depending on the affected protein in the thick ascending limb of the loop of Henle:

·        Type 1: Inactivating gene mutation that encodes the  Na+-K+-2Cl- contransporter (NKCC2)

·        Type 2: Inactivating gene mutation that encodes the apical  K+ channel (ROMK)

·        Type 3: Inactivating gene mutation that encodes the  basolateral Cl- channel (ClCNKB)

·        Type 4: Inactivating gene mutation that encodes a basolateral accessory Cl- channel subunit Barttin (BSND)

·        Type 5: Inactivating gene mutation that encodes the  basolateral Calcium sensing receptor (CASR)

Apical ROMK ensures functioning of the NKCC2 cotransporter by recycling potassium back into the renal tubular lumen so hypokalemia in patients with defects in ROMK (Bartter's type II) is relatively mild compared with that in the other forms of Bartter's syndrome.

The mechanism of hypokalemia in Bartter syndrome is thought to be increased distal potassium secretion in the CCD caused by increased distal Na+ delivery in the setting of high aldosterone levels and also by activation of the flow-mediated K+ channels (Maxi-K or BK channels).

However, it has been recognized that Type 2 Bartter syndrome can sometimes course with hyperkalemia. The reason for this can be found in the developmental aspects of potassium secretion. Satlin et al have shown that CCDs isolated from newborn rabbits and studied by in vitro microperfusion show no net K+ secretion until after the third week of postnatal life; net K+ secretory rates increase to adult levels by 6 weeks of age. The role of the maxi-K channels appears to assume great importance in regulating K+ homeostasis under conditions where ROMK K+ secretion is limited like in Type 2 Bartter syndrome. Maxi-K channels are not consistently detected in the CCD until the 4th week of life. This is worsened by the fact that children with type 2 Bartter syndrome are usually born prematurely.

Although patients with type 2 Bartter syndrome may exhibit severe hyperkalemia during the first few days of life, the hyperkalemia is usually transitory. In fact, these patients typically exhibit modest hypokalemia beyond the neonatal period probably due to maturation and presence of Maxi-K channels after the 4^th week.

Hyperkalemia during neonatal period has also been described in type I pseudohypoaldosteronism (type I PHA). However, in type I PHA hyperkalemia is sustained beyond the neonatal period and is associated with metabolic acidosis

Post by

Dr. Helbert Rondon

Nephrology Crosswords: Dyskalemias

Try the next crossword in Kidney International:  The theme this time is Dyskalemias
http://www.nature.com/ki/journal/v81/n8/full/ki20125a.html

Hypokalemia quiz answer

Labs on presentation: Na 117, K 1.5, Normal renal function. Exam consistent with volume depletion. EKG changes consistent with hypokalemia. Hyponatremia is asymptomatic

Treatment?

A. Treat hyponatremia first and then hypokalemia

B. Treat hyponatremia and hypokalemia simultaneously

C. Treat hypokalemia first and then hyponatremia  

Any thoughts? What would you do?
Here is what you all said:

" C,  but I believe that, in practice, we'd probably end up doing B."

"I would think treat both. As you improve distal tubular flow with saline , hypokalemia can worsen"

"How about KCl, NaCl and DDAVP with water restriction."

"Treat hypokalemia first.”

”In this case the hyponatremia may be at least partly explained by the huge deficit in total body potassium stores, thus causing intracellular shift of sodium in exchange for potassium. Given that this patient is asymptomatic, option C is probably the safest. Aggressive repletion of K w/150-200 mEq daily for 2-3 days will be necessary to replete his K and the patient's Na may slowly improve as well."


"Treat hypokalemia with IV KCL (ECG abnormalities make it urgent). Repleting volume would probably take care of hyponatremia."

"Patient should only be treated for Hypokalemia first as hypokalemia correction itself will cause improvement in hyponatremia. The theory behind it is with K repletion, there is translocation of K in the cell and Na will move out. Mich. Halperin book has an excellent article on this."

I think all responded practically the right answer. Correction of hypokalemia is very important in setting of hyponatremia and one has to be watchful of not over correcting Na too fast in this setting as correcting the K will correct the Na as one of the commenters pointed out. There have been cases reported of osmotic demyelination from just aggressive correction of K leading to fast Na correction.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/20338465

http://www.ncbi.nlm.nih.gov/pubmed/8192171

CONSULT ROUNDS: Hypokalemia and Osmotic Demyelination Syndrome

Labs on presentation: Na 117, K 1.5, Normal renal function. Exam consistent with volume depletion. EKG changes consistent with hypokalemia. Hyponatremia is asymptomatic

Treatment?

A. Treat hyponatremia first and then hypokalemia

B. Treat hyponatremia and hypokalemia simultaneously

C. Treat hypokalemia first and then hyponatremia  

Any thoughts? What would you do?

TOPIC DISCUSSION: Hypokalemic Nephropathy

Yes... Hypokalemia that is chronic can lead to decrease in GFR and nephropathy. How so?
Also known as kaliopenic nephropathy
1. Hypokalemia can lead to a renal concentrating defect leading to polyuria and polydipsia- DI
2. Chronic tubular damage can occur as a result and lead to proximal tubular damage as well
3. Tubular interstitial disease develops
4. Proteinuria can be seen
5. Renal cysts can be noted
6. There is also impairment of  renal angiogenesis, evidenced by progressive capillary loss, reduced endothelial cell proliferation, and loss of VEGF expression in one study.
7. Histologically:- tubular atrophy, interstitial infiltration of macrophages, and fibrosis
Ref:
http://www.ncbi.nlm.nih.gov/pubmed/18178802
http://www.ncbi.nlm.nih.gov/pubmed/17928827
http://www.ncbi.nlm.nih.gov/pubmed/20828906

Nephsap review: Fluids Electrolytes

Another interesting Nephsap teaching point by a question was an under recognized cause of acquired apparent mineralcoritcoid access.
Liver cirrhotic patients with elevated bilirubins and sickle cell crisis patients who have elevated bilirubins have this happen to them.  When total bilirubin levels are very high, it is hypothesized that worsening cholestasis led to greater bile acid inhibition of 11B - HSDH type II in the distal nephron and this allows for K wasting via cortisol mediation and HTN as well.
Case reports have been reported in liver cirrhosis and sickle cell crisis patients?
Wonder if we see this or its noticed in Post BMT - VOD syndrome?

Nephsap review: Fluids Electrolytes

Interesting thing we learned at our Nephsap about why hypomagnesemia causing hypokalemia
1. Intracellular Mg has inhibitory effects on the K secretion of ROMK channels in the distal nephron.
2. A decrease in Intracellular Mg will release this inhibitory effect and cause Renal K excretion.
3. Also Low Mg can lead to increase distal Na delivery and increased aldo as well and K excretion increases.