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Sometimes the simplest things…

I just had a great patient encounter.

An 83 y.o. African American gentleman was referred to me for a creatinine of 1.7 mg/dL (eGFR 50 mL/min). On the initial visit he had a positive review of systems for obstruction. I added a PSA to my normal laboratory work-up of CKD and it ended up grossly positive at 42. We referred him on to urology and they diagnosed prostate Ca. He is currently getting hormone therapy.

Today he came in for his first visit with me since the cancer diagnosis. He was so appreciative. He hugged me. He acted like I saved his life. There was a strange asymmetry to the experience, I felt that I had done almost nothing more than a routine diagnosis while he was treating me like William Osler.

Sometimes the simplest things. . .

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Former Felllow makes good


Rakesh Lattupalli just graduated from our fellowship in June. He was an exceptional fellow. He just finished a scientific article on the Melamine outbreak. Rakesh was the person who got me interested in the subject. The article is a nice overview of some of the scientific data on melamine toxicity.

Like me, he feels that melamine is not likely to be the entire story and a second co-factor will be identified that is critical to the development of nephrolithiasis. He suggests cyanuric acid as a possible candidate.

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Melamine milk poisoning continues to make headlines


White Rabbit candies are being pulled from the shelves for failing to have less than 2.5 mg/kg melamine.

The Chinese press reported another 380 sick children in Beijing at the same time as they are declaring the milk safe. Though this seems to be a contradiction, my feeling is that stones in children will be showing up for months after the milk supply is clean as kidney stones can lie asymptomatic for months (years?) in the renal pelvis before spontaneously moving into the ureters where they cause pain, obstruction and hematuria.

The Taiwanese press provides a shockingly sophisticated article on the problems with our current toxicity knowledge of melamine and the associated debate on limits of safety. In addition to discuss limits of tolerability it goes into the differing methods of detection including high performance liquid chromatography (HPLC), liquid chromatography-tandem mass spectrometry (LC-MS/MS), gas chromatography-mass spectrometry (GC-MS). The LC-MS/MS method is apparently the most sensitive assay. One confusing aspect of the article is they swithc freely between mg/kg and ppm. One mg/kg is equal to 1 ppm.

A friend was staying with us over the week-end. She and her husband adopted a little girl from China. She was drinking chinese formula 6 months ago. She is doing well, no symptoms and when she came over she had a “kidney test.” The mother asked me if she should do anything. My answer was that her daughter likely was exposed to melamine as it looks like this practice of spiking milk with melamine has been going on for awhile. I added that since her daughter was doing well and not having colicky pain, a diagnosis of nephrolithiasis would not change what you do. I recommended against doing a renal ultra-sound and wait for any symptoms which would likely never occur.

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Acid-Base lecture for ER residents

Yesterday I gave a great lecture on interpreting ABG results. I added a problems set for gap-gap analysis and added a section on the osmolar gap. I also improved the anion gap section with my new favorite nemonic. Forget PLUMSEEDS, forget MUDSLEEPS, forget MUDPILES. The new hotness is GOLD MARK:

  • M Methanol
  • A Aspirin
  • R Renal failure
  • K Ketoacidosis
This new nemonic was published in a letter in the Lancet (thanks vincent bourquin). I love that it drops the silliness of paraldehyde that no one uses anymore and drops isoniazid and iron which hardly ever cause an anion gap.
I also stumbled across a cool article on the sensitivity of the anion gap for lactic acidosis. Surprisingly an anion gap is only found in 58% of patients with an anion gap.
Additionally I cleaned up a bunch of the lecture. I still have not reformatted it for the iPhone so the handout is traditional 8.5×11 without a booklet form.
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Bumex, same short pharmacokinetics of lasix with better bioavailability

I’m working more at Providence Hospital and I find that the intensivists and cardiologists love the Bumex. This opinion is shared by some prominant nephrologists. Unfortunately bumetanide suffers from the same short pharmacokinetics as furosemide: half life of about 90 minutes after oral or IV dosing. The big advantage bumetanide has over furosemide is more predictable bioavailability after oral dosing. Torsemide trumps both of them with excellent bioavailablity and a half-life of 210 minutes.

The reason that bumex is preferred is the beleif that it is a more potent diuretic than furosemide. According to Brater, all of the loop diuretics have similar potency and decisions among the loops should be based on pharmaokinetics (as opposed to pharmacodynamics). Here is the statement in his NEJM review of diuretic therapy.


Phamacokinetics of torsemide, bumetanide and furosemide from the package inserts. And here is the table from Brater’s reveiw:

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Journal Club: Aspirin and FGF-23

The first article was an intriguing look at various renal function parameters and how they respond to various doses of aspirin. All the patients were pre-treated with enalepril and a thiazide diuretic for 6 days. Then they were given one of four doses of aspirin:

  1. placebo
  2. 80 mg
  3. 160 mg
  4. 320 mg

They found decreased GFR, decreased sodium clearance, decreased solute clearance and decreased free water clearance with 160 mg and 320 mg but the effect was transient with all factors returning to baseline 4 hours after the aspirin was administered.

The article has a long introduction and discussion outlining all of the heart failure studies which have shown that aspirin can be harmful or can decrease the effectiveness of ACEi in heart failure.

The study is small (n=16, with each participant randomized to two doses of aspirin with a 2 week washout between doses) and the authors fail to fully describe the cohort. The primary weakness is the authors want to extrapolate there findings over 6 hours to the effect of aspirin taken chronically for years. Additionally they make the leap of using aspirin-induced changes in renal function to be a proxy for interference with ACEi effect on heart failure survival.

Nonetheless it will change the way I practice. I had previously given my patients (who essentially all are on diuretics and ACEi) the green light to take aspirin any way they want. I will now suggest they limit themselves to 81 mg for CAD protection.

The second article was the NEJM article on FGF-23 and the risk of mortality in hemodialysis patients. FGF-23, or fibroblast growth factor-23, is a newly discovered molecule which regulates the phosphorous in the body. It is one of the primary phosphatonins, signals which increase the renal excretion of phosphorous. Additionally they suppress 1-alpha hydroxylase lowering the amount of 1,25 dihydroxy-vitamin D.

This is prospective cohort with nested case-control of incident dialysis patients in the U.S. The investigators looked at 200 patients who died (cases) in the first year and compared them to 200 patients who survived one year (control). FGF-23 was measured on the first day of dialysis. They divided the cohort into quartiles based on phosphorous and found that patients who subsequently died had increased FGF-23. They found a graded increase in the risk of death with increased FGF-23 level that was signifigant in the whole cohort and inevery quartile of phosphorous except the highest.They also showed a dose responce of mortality to FGF-23 levels in the whole cohort in the crude data, case-mix adjusted and multivariate adjusted.


The authors in the discussion point out that the association of FGF-23 with mortality is stronger than that found with phosphorous and mortality. They found FGF-23 levels were 22% lower in African-Americans than in Caucasians. The authors leave a tease that this lower level of FGF-23 level may explain the improved survival found in African Americans on dialysis.

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Melamine Milk Poisoning and Kidney Stones


Nephrology rears its ugly head in the news cycle.

The NYT weighs in. China Says Complaints About Milk Began in 2007

The top food official resigns. I bet he is happy to get away with a forced resignation compared to Zheng Xiaoyu, former head of the chinese FDA who was executed for corruption following the tainted phamaceutical debacle last year.

The interesting is that the same toxin, melamine, was implicated in the pet food renal failure problem in 2007. At that time, the US FDA provided lots of assurances that malamar is not that toxic. Is this a pediatric issue? In some of the articles following the pet food issue a second compound, cyanuric acid, was implicated in the pathophysiology. I have not read anything about cyanuric acid.

More on this as it develops.

The only data I could find on the concentration of melamine in the milk products comes from this ChinaDaily article.

The highest concentration of melamine was found in Sanlu products. Tests show every kg of Sanlu milk food contains 2.56 g of melamine, which can make milk appear rich in protein in quality tests. The chemical is usually used to make plates, bowls, mugs and sundry other products, but is banned from being used in the food industry.

The other tainted products contain between 0.09 mg to 619 mg of melamine per kg.

During the pet food scare of 2007, there was concern that some of the melamine contaminated pet-food reached live-stock and ended up contaminating the food supply. The FDA estimated the tolerable daily intake of melamine at 0.63 mg/kg.

The point of departure (POD) is the NOAEL of 63 mg/kg/day from the rodent subchronic bioassay. This POD was then divided by two 10-fold safety/uncertainty factors (SF/UF) to account for inter- and intra-species sensitivity, for a total SF/UF of 100. The resulting Tolerable Daily Intake (TDI) is 0.63 mg/kg bw/day. The TDI is defined as the estimated maximum amount of an agent to which individuals in a population may be exposed daily over their lifetimes without an appreciable health risk with respect to the endpoint from which the NOAEL is calculated.

Using the concentrations from the China Daily article and the FDA limits on tolerability a 7 kg baby would need to ingest 1.7 liters of Sanlu milk to exceed this safe limit (of note, at the highest concentration only 7 mL would exceed the safe limit). Either the safety estimate was off or there is an additional compound causing the toxicity.

Google search for melamine

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Teaching Medical Students


Last Friday I started teaching third year medical students. This is the first time I have taught medical students (in isolation, there are always medical students at my lectures for the residents) since 2003, when I ran a teaching section for renal physiology for first year medical students at Pritzker School of Medicine, University of Chicago with John Asplin.

I am now teaching the medical students two lectures every rotation, the first on sodium and the second on potassium and calcium. I hope to expand this to ABGs and another electrolyte lecture so I can isolate potassium and spend an entire hour on it.

I modified my Don’t Panic handout for the students. During the lecture I realized that the SIADH section was weak and too complex for the students. I will probably change it to focus on the fact that ADH reduces water excretion and that this can be adaptive (early CHF, volume depletion, hyperosmolar) or maladaptive (SIADH). I will change the section on the dilution of urine to a background box as I think it is important but only interesting to nephrologists and similar wierdos.

I will add a focus on a few clinical scenarios with increased ADH.

I still need to expand the hypernatremia section.

Handout
iPhone version