Detective Nephron: Next venture

 

Check out the next Detective Nephron as we tackle a fun case

Detective Nephron: Next Venture

 Here is another mystery electrolyte disorder with Detective Nephron

https://www.kidneynews.org/view/journals/kidney-news/14/12/article-p16_12.xml 

Detective Nephron: Next Venture

 Check out the next electrolyte venture of Detective Nephron in Kidney News

In the NEWS: Immunotherapy and the Kidney( new data in 2021)- AKI and electrolytes

Immune checkpoint inhibitors (ICI) are a novel class of immunotherapy drugs that have vastly improved cancer care for patients. Data on AKI has been evolving. 

In a multicenter international study just published in JITC by Gupta et al involving 30 sites across 10 countries, researchers collected data on 429 patients with ICI-AKI and 429 control patients who did not develop ICI-AKI. Armed with the largest ICI-AKI database to date, the team of researchers was able to identify predictors, recovery potential and survival outcomes of those patients with ICI-AKI.

One of the most important findings from the two-year study reveals that among patients who take ICI again – even after an episode of ICI-AKI – only 16.5 percent developed recurrent ICI-AKI, which shows that most patients can still take these life-saving medications safely.

Additional findings show that in renal-recovery occurs in approximately two-thirds of patients with ICI-AKI. Early treatment with corticosteroid is associated with a higher likelihood of renal recovery. Lower baseline kidney function, proton pump inhibitor use and extrarenal immune-related adverse events are independent risk factors for developing ICI-AKI.

A related paper recently published in the journal Kidney International by Wanchoo et al looking at the scope of electrolyte disorders that are seen with ICI. Hyponatremia, hypokalemia and hypercalcemia were the most common findings. SIADH is the most common cause of hyponatremia and adrenal disorders led the way in the cause of hypercalcemia. 

Topic Discussion: Electrolytes Disorders with COVID19

AKI has been reported with COVID19 ,electrolyte disorders have been less well described. A recent paper in CKJ describe the full spectrum of electrolyte disorders seen with COVID19.

The most common presentation was hyponatremia and hypochloremia together (second vertical bar) in 1289 (12.4%), followed by hyponatremia alone (third vertical bar) in 1150 (11.1%).

What about patients with eGFR<60 but >15? 30.3% had hyponatremia, 11.1% had hyperkalemia, and 19.7% had hypochloremia. Hypocalcemia was seen in 19.2% of patients. Hyperphosphatemia (13.9%) and hypermagnesemia (12.2%) were seen in fewer patients.

What about ESKD patients?

In these patients the most common disorders were hypochloremia (62%), hyponatremia (40.9%), and hyperkalemia (23.4%). Hyperphosphatemia was seen in 45.7% of patients but we had some missing phosphorus data.

What about kidney transplant recipients? The most commonly seen were hyponatremia (42.4%), hyperkalemia (16.7%), and hypochloremia (19%).

Limitations: Purely descriptive.

But highlights for the first time and the largest to date on the various electrolyte disorders in hospitalized COVID-19 patients. Further studies are needed to look at mortality outcomes related specifically to each electrolyte disorder.

Prevalence of Hyponatremia related to COVID19 has been described in the NY region. Looking at the spectrum of both hyponatremia and hypernatremia and it's relation to patient outcomes has not been well studied.

To take this further, Na disorders were evaluated in detail with outcome of mortality. This is published in NDT. Among 9946 patients included in the study ,4808 (48.3%) had normonatremia, 3532 (35.5%) had mild hyponatremia, 904 (9.1%) had moderate/severe hyponatremia, 319 (3.2%) had mild hypernatremia, and 383 (3.8%) had moderate/severe hypernatremia. When examined by decile of age, dysnatremia occurred in 46-54% of patients in each group, with hyponatremia the predominant disorder across all age groups. The proportion of patients who experienced in-hospital death was highest for those with moderate/severe hypernatremia (232/383 [60.6%]), followed by mild hypernatremia (163/319 [51.1%]), moderate/severe hyponatremia (261/904 [28.9%]), mild hyponatremia (818/3532 [23.2%]) and normonatremia (1089/4808 [22.6%]), a trend seen across all age groups. 

U-shaped pattern was seen in the relationship between admission serum sodium level and the odds of in-hospital death, with hyponatremia and hypernatremia both significantly associated with mortality, even after full adjustment for demographics, comorbid conditions and illness severity. Compared to hyponatremia, hypernatremia carried a strong association with in-hospital death, in both mild and moderate/severe categories, and across all ages, a relationship that persisted even following correction for serum glucose. While hypernatremia has  been shown to be  a strong predictor of mortality in prior studies, this finding is novel for COVID-19. 

Both hyponatremia and hypernatremia were also associated with a prolonged hospital length of stay. The magnitude of the odds ratio was substantial, especially for moderate/severe hypo- and hypernatremia, and was not substantively changed after multivariable adjustment. This suggests that at least a portion of the prolonged hospitalization may be directly related to electrolyte disorder management. 

This is the largest study to describe prevalence and outcomes of both hyponatremia and hypernatremia in a diverse population of almost 10,000 patients hospitalized with COVID-19. Other similar studies just published in the endocrine literature as well.

Topic Discussion: Chloride in Cardio-Renal Syndrome

At recent ASN Kidney Week 2020, Dr. Amir Kazory really gave a great lecture highlighting the importance of an important ion that often is ignored in CHF and Cardio-renal syndrome.

We should perhaps move away from the Na centric view of CHF.

Some interesting points made in his talk and overall what we know.

1. Hyponatremia is a predictor of CHF outcomes. But when we correct the Na, mortality doesn't improve. - classic V2R antagonist EVEREST trial showed no benefit

2. When we give 3% saline as shown by the Yale group recently in JACC, there is significant weight loss in diuretic resistant patients. 

3. The Na restriction in diet has limited evidence that it works

Some interesting data on Cl in CHF.

One of the first studies done looking at Cl in CHF found that for every 4.1meq/L of drop in Cl, there is 25-30% increase in 5 year-mortality. 

Contemporary advanced CHF cohort suggest that serum chloride levels at admission are independently and inversely associated with mortality in this one study. The prognostic value of serum sodium in CHF was diminished compared with chloride.

Why does this matter? 
Two physiological reasons:

1. Low Chloride can stimulate renin release in macula densa

2. Low intracellular chloride can increase TAL NKCC activity and DCT NCC activity

Interestingly, low chloride patients are also diuretic resistant. 

It would be fascinating to see if increasing Cl, without Na really has a good effect on diuresis. Azetazolamide trials are ongoing as a potential way to do this. Could SLGT2i be potentially working via this mechanism? It is very possible that Cl is a more important player than Na in CHF and Cardio-renal syndrome. Fascinating!!

Check out this excellent review. ( also for figure source)

Topic Discussion: Zytiga (Abiraterone) induced hypernatremia, and HTN

Zytiga (Abiraterone) is a hormonal chemotherapy agent used to treat prostate cancer. It selectively and irreversibly inhibits CYP17 (17 alpha-hydroxylase/C17,20-lyase), an enzyme required for androgen biosynthesis which is expressed in testicular, adrenal, and prostatic tumor tissues. Inhibits the formation of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione.

Interestingly. it has a high rate of hypernatremia as a known renal complication. In several studies, hypernatremia (33%), hypokalemia (17% to 30%) were reported as known complications. Why? It is postulated that it can increase mineralocorticoids due to CYP17 inhibition may result in hypertension, hypokalemia, and fluid retention (including grade 3 and 4 events) and perhaps some component of hypernatremia as well- almost like a Cushing's state. Per package insert, concomitant administration with corticosteroids reduces the incidence and severity of these adverse events.

In the LATITUDE trial, which used prednisone 5 mg daily in combination with 1000 mg abiraterone acetate daily, grades 3-4 hypokalemia were detected in 10% of patients on the zytiga arm and 1% of patients on the placebo arm, grades 3-4 hypertension were observed in 20% of patients on the zytiga arm and 10% of patients on the placebo arm. Grades 3-4 fluid retention occurred in 1% of patients each arm.

It is recommended that patients get monitored for hypertension, hypokalemia, and fluid retention at least once a month. Treatment of hypertension is recommended, choice of drug is not defined.

This is an interesting toxicity that as nephrologist seeing prostate cancer with CKD and perhaps new onset hypertension, hypokalemia or hypernatremia should consider in the differential diagnosis.

Concept Map: Sickle Cell Disease and the Kidney

Concept Map: Oral Agents to treat Hyperkalemia- a summary

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

Concept Map: Hypomagnesemia and it's effect on other electrolytes

Topic Discussion: Icodextrin and it's important pseudo-lab effects

Icodextrin is a glucose polymer used in peritoneal dialysis to help in improved clearance and ultrafiltration. Laboratory and metabolic effects of icodextin is important to know( especially the effect on glucose, Na and serum osmolarity)

There are a few that are important to remember

1.      The predominant circulating metabolites of icodextrin are maltose , maltotriose , and maltotetraose, with little glucose released in the systemic circulation due to the absence of circulating maltase. The release of glucose from the metabolized polymers occurs predominantly during the intra-cellular metabolism of maltose or other polymers by way of cellular enzymes involved in carbohydrate metabolism.

2.       The “glucose load” arising from the use of icodextrin is “functionally invisible” to the peritoneal cavity and systemic circulation, and its predominant systemic exposure is intracellular.

3.      In contrast to the acute hyperglycemia and hyperinsulinemia associated with glucose-based solutions, icodextrin does not lead to hyperglycemia or hyperinsulinemia following its intraperitoneal administration. 

4.      Point of care glucose testing might not be accurate when using icodextrin and serum glucose values should be used for insulin management.  Maltose interferes with glucose assays that utilize glucose dehydrogenase enzymes of the pyrroloquinolinequinone class (GDH PQQ), causing falsely elevated readings. The overestimation of glycemia is likely due to the presence of maltose and other oligosaccharide metabolites of icodextrin in the systemic circulation and the reaction of GDH-PQQ with the free reducing group of the glucose molecule located at the end of each saccharide chain.

5.      The decline in serum sodium and chloride associated with icodextrin therapy is caused mainly by a dilutional effect resulting from blood levels of icodextrin metabolites, particularly maltose and maltotriose. The presence of osmotically active particles in the vascular compartment is sufficient to cause a slight shift in water from the interstitial and cellular compartments to the vascular compartment, resulting in the dilutional hyponatremia (sometimes called hypertonic hyponatremia). It is like having hyperglycemia or mannitol induced hyponatremia.  

6.      Use of icodextrin has been associated with a slight increase in plasma osmolality in some studies. It can last up to 2 weeks after discontinuing icodextrin

7.      A small increase in mean serum alkaline phosphatase  has been reported in some studies of icodextrin Increases in alkaline phosphatase are not associated with true liver or billiary disease.

8.      Icodextrin interferes with amylase activity measurements by acting as a competitive inhibitor in the amylase activity assay.

Detective Nephron Next Venture

Check out the next adventure of the Detective on a case of hypophosphatemia in the latest issue of ASN Kidney News 

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

Concept Map: Low Anion Gap

Here is a summary of various causes and mechanisms of a Low Anion Gap

Consult Rounds: Toxic alcohol ingestions

A summary of all potential alcohol toxicities ( Renal perspective)

Name	Metabolic Acidosis	Osmolar Gap	Anion Gap	Ketones	Ca Oxolate Stones	Reduced Vision
Alcohol	Yes	Yes	Yes( lactate also)	Yes	No	No
Methanol	Yes	Yes( earlier on and then disappears)	Yes	No	No	Yes
Ethylene Glycol	Yes	Yes	Yes	No	Yes	No
Isopropyl Alcohol	No	Yes	No	Yes	No	Yes
Propylene Glycol	Yes	Yes(initially)	Yes(converted to lactate)	No	No	No

Topic Discussion: Interesting HTN, hypokalemia and Met Alk syndromes: a summary

There are certain syndromes that lead to HTN, hypokalemia and metabolic alkalosis that are very rare but often confusing. Here is a breakdown of the 3 ones that often can get confusing.

Syndrome	Defect	Pathophysiology	Treatment	Comments
Liddle Syndrome	Missense mutation in ENaC channel	Constitutive activation of the ENaC channel	Triamterene or Amiloride	Low renin and low aldosterone level, no response to spironolactone
Congenital Adrenal hyperplasia	11-B hydroxylase deficiency	Leading to excessive mineralocorticoid production	Life-long steroids to help shut off ACTH	Diagnosis is confirmed by elevations of 11-deoxycortisol and 11-deoxycorticosterone
Glucocorticoid remediable Aldosteronism	Chimeric gene crossover of ACTH and Angio-11 genes	Normal ACTH controls cortisol and AngII controls Aldo. In this gene mutation, ACTH starts controlling Aldo and hence causing HTN and ongoing changes Leading to excessive aldosterone production.	Life-long steroids to help shut off ACTH	Low renin but high Aldo in these cases.
Syndrome of Apparent mineralocorticoid excess	11-B hydroxysteroid dehydrogenase type 2 mutation or inhibition	Normally, 11-B hydroxysteroid dehydrogenase in-actives cortisol via making to cortisone. This avoids cortisol mediated mineralocorticoid activity to maintain it’s specificity to aldosterone. If this is blocked, then cortisol activates mineralocorticoid activity	Amiloride or spironolactone	Diagnosis made via free urinary cortisol to cortisone ratio Renin and Aldo levels are low Licorice that has glycyrrhic acid that can also inhibit 11-B hydroxysteroid dehydrogenase.