Unusual causes of non-anion gap metabolic acidosis: chlorine gas

Chlorine gas inhalation happened this week-end at a water park in Michigan. Link

Fact sheet on chlorine here.

Great potassium links

Potassium Intake of the U.S. Population
What We Eat in America, NHANES 2009-2010
by Mary Hoy and Joseph Goldman

Link (PDF)

What we eat in America Individuals 2 years and over day 1 dietary intake data, weighted.
NHANES 2009-2010
National Research Council. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: The National Academies Press, 2005.


Link (PDF)

Hypokalemic periodic paralysis - an owner's manual

#NephJC Preview: Hyperosmolarity drives hypertension and CKD

On Tuesday, July 8th, at 9 pm we are doing our sixth nephrology journal club and it is on Johnson et al's Perspective in July's Nature Reviews Nephrology.

The article begins with a discussion with the ongoing epidemic of CKD in Sri Lanka and Central America. Actually people in the know are calling it Mesoamerica, a term I had not heard before.

From Wikipedia

Mesoamerica is a region and cultural area in the Americas, extending approximately from central Mexico to Belize, Guatemala, El Salvador, Honduras, Nicaragua, and northern Costa Rica, within which a number of pre-Columbian societies flourished before the Spanish colonization of the Americas in the 15th and 16th centuries.[1][2] It is one of six areas in the world where ancient civilization arose independently, and the second in the Americas after Norte Chico (Caral-Supe) in present-day northern coastal Peru.

Characteristics of the CKD epidemic:

• Men are predominant affected
• Victims work and line in hot tropical agricultural communities
• They are manual workers
• Largely asymptomatic
• Elevated creatinine without (significant) proteinuria

The second paragraph is critical to the rest of the review. It states that numerous of studies and researchers have looked for nephrotoxins like pesticides or heavy metals none have been found. This chart is from Dan Weiner's free and excellent CJASN review.

The Johnson editorial focuses on recurrent dehydration as the etiology. This explains the male:female mismatch and explains why high altitude appears to be protective. The article suggests that it is the hyperosmolality not the volume depletion that may be important in the disease:

In this Perspectives article, we present the hypothesis that changes in osmolarity induced by an imbalance in water and salt intake, rather than the amount of salt or water ingested per se, drives the development of dehydration-related hypertension and kidney disease.

This theory is in contrast to the more conventional view of repeated episodes of volume depletion causing pre-renal AKI and this resulting in CKD as described by Weiner et al:

Recently, a new paradigm has been gaining favor that AKI, even with apparent recovery in kidney function, may not be innocuous (27). In this paradigm, either repair attempts themselves or ongoing insults with subsequent repair at- tempts lead to a self-perpetuating cycle of inflammation and repair, resulting in kidney fibrosis and clinically recognizable CKD. Accordingly, we hypothesize that repeated ischemic insults to the kidney caused by severe volume depletion with or without hyperthermia and potentially in conjunction with other kidney insults result in progressive kidney fibrosis and ultimately, kidney failure.

The article then describes the body's defense against hyperosmolality, the first path is the familiar release of ADH and the concentration of urine and reclamation of water from the collecting tubules. The second limb is one I was not familiar with.

The second process involves activation of the polyol metabolic pathway, in which hyperosmolarity increases the activity of aldose reductase, which in turn converts glucose into sorbitol. Sorbitol is an osmolyte that protects tubular cells and interstitial medullary cells from the hyperosmotic environments that drive water reabsorption, especially under conditions of dehydration and plasma hyperosmolarity.

The rest of the article describes the science behind how these two pathways, when chronically activated, can promote  CKD.

ADH antagonists have been shown to prevent/decrease albuminuria in rat models of diabetic nephropathy. In another experiment, forced water drinking reduced a number of measures of diabetic kidney disease in rat models (e.g. proteinuria, nephrosclerosis, renin activity, etc). The article describes some potential mechanisms for this toxicity including the possibility that ADH drives hypertension, increased metabolic demand and mitochondrial dysfunction. The authors provide links to two reviews of ADH as a progression factor in CKD:

1. Nature Reviews Nephrology: Vasopressin: a novel target for the prevention and retardation of kidney disease?
2. Current Opinion in Nephrology and Hypertension: Vasopressin beyond water: implications for renal diseases

The article then turns to the aldose reductase pathway. Aldose reductase generates sorbitol which is used to protect the tubular and medullary cells from hyperosmolarity. The proposed toxicity comes from the metabolism of sorbitol to fructose and then the metabolism of fructose. Fructose kinase rapidly consumes ATP in the conversion of fructose to glyceraldehyde 3-P and the consumption of ATP can cause ATP depletion and ischemic damage.

A depiction of fructose metabolism alongside glycolysis. The first step of fructose metabolism is wholly unregulated so ATP will be consumed until either there is no ATP or fructose available.

The article points out that KHK-C, enzyme that burns ATP in the metabolism of fructose, is primarily located in the liver (hence all the liver disease associated with high sugar intake) but is also found in the proximal tubule. High fructose intake has been associated with renal disease in animal models.

So the purported chain of events is:

1. increased osmolality leads to
2. increased aldolase activity which leads to
3. increased sorbitol
4. Sorbitol is metabolized to fructose
5. Fructose metabolism causes local ATP depletion and renal damage

This chain of events was demonstrated to occur in animal models in a recent KI article. The increased osmolality was created by heat exposure, further modeling the presumed injury in Mesoamerica. Renal dysfunction, from the increase in osmolality, was demonstrated via increases in creatinine, NGAL, blood pressure and histologic change. The experiment also used fructose kinase knock out mice and they were protected from these changes, implicating this enzyme as the bad actor.

Johnson et al, logically extends this data to one possible implication:

The observation that dehydration-induced hyperosmolarity results in renal injury mediated by endogenous fructose (which is produced by the polyol pathway) also raises the question of whether rehydration with fructose-containing drinks, or the chewing of sugarcane (which is rich in fructose), might exacerbate renal injury.

the aminoglycoside of our time?

The article then turns its attention to the pro-inflammatory aspects of hyperosmolality. This has been demonstrated with increased cytokine release form peripheral blood monocytes and increased TGF-beta from smooth muscle cells. Increased osmolality stimulates the sympathetic nervous system which in turn stimulates angiotensin 2. All of these could be important mechanisms in causing or extending CKD with increased osmolality.

The authors conclude by briefly reviewing some of the data on salt intake and hypertension. They suggest that some of the variable results may have been because we have been looking at salt intake and ignoring the possibility that the mechanism of hypertension may not be entirely due to increased extracellular volume and that increases in osmolality may be important. Would it be possible to replace the puritanical instruction to minimize sodium with a simpler instruction to wash that sodium down with a lot of water? Exploring this will require careful attention to be paid to the timing of water administration:

Specifically, plasma osmolarity will be affected by both the amount of salt ingested and the timing of ingestion. For example, drinking water followed by eating salty food might have worse consequences than the reverse. Eating salty foods and then drinking fluids to quench the resulting thirst might not be ideal, as the thirst response occurs after vasopressin is released.[ 82 , 83 ]

This is a fascinating and novel look at emerging models of renal failure and shows the how a remote epidemic can stimulate fresh looks at old problems.

#NephJC this Tuesday, we dive into MesoAmerican Nephropathy

Readers of PBFluids know that I have been on the uric acid is the source of hypertension and hypertensive nephropathy beat ever since Richard Johnson came to the Townsend to speak at a gout symposium. Johnson's lecture on the link between uric acid and hypertension is the single best lecture I have ever seen.

Before that lecture I thought I was a pretty good lecturer, that lecture taught me that I was a baby. I knew nothing. If you ever get a chance to hear Dr. Johnson, move heaven and earth to hear him, he is amazing.

You can see some of my posts relating to uric acid, fructose and kidney disease here:

• DreamRCT submission: Prove the uric acid-CKD connection
• My hour long presentation on the subject for the Michigan ACP 
• Use of Mendelian Randomization to determine the effect of uric acid on blood pressure
• Summary of the introduction to The Sugar Fix, Richard Johnson's diet book
• My summary of the Goicoechea data showing the protective effect of allopurinol in CKD
• Editorial I wrote about obesity, fructose and uric acid.

Though not covered extensively on PBFluids one of the most interesting stories in nephrology for the last year has been the emergence of a newly recognized epidemic of renal disease in Central America. I first learned about it following this tweet:

.@pbjpaulito Did you know about this? http://t.co/ttcnT21GCz cc @kidney_boy
— Meenakshi Budhraja (@gastromom) June 29, 2013

and I was recently reminded about this when this tweet crossed my stream:

"@Amazing_Maps: The disease most likely to kill you Source: http://t.co/8tqGkI3KRv - pic.twitter.com/IFswcuu3Fb” Kidneys in Central America
— Joel Topf (@kidney_boy) June 24, 2014

Here is a close up of the only country in the world where Nephritis and nephrosis is the leading cause of death, Nicaragua.

The one time I blogged about this. Though I haven't been fastidious about the MesoAmerican Nephropathy beat, eAJKD has:

• MesoAmerican Nephropathy: A New Entity. Biopsy results from the endemic area.
• Three Epidemics Across 10,000 Miles: Can We Connect the Dots? Editorial on the disease, focusing on the possibility of pesticides as the etiologic agent.

Interestingly, these two intrigues subjects, the toxicity of uric acid/fructose and MesoAmerican Nephropathy collided in a recent editorial by Richard Johnson et. al. This editorial is the subject of this week's NephJC on Tuesday, July 8th at 9:00 Eastern.

The article is a perspective review titled: Hyperosmolarity drives hypertension and CKD-water and salt revisited. (PMID: 24802066)

I was told that Nature Reviews Nephrology was going to make the article open access and it was a few weeks ago but for now it is closed. Make nice to your local medical librarian.

More background and a summary of the article tomorrow.