Over collection or just a big guy

A patient came to my office with a creatinine of 2.2 indicating a GFR of 33mL/min by the MDRD formula. 

His primary care doctor ordered a 24 hour urine for creatinine and protein as part of her work-up for CKD:

• 24-hour urine creatinine was 3,232 mg 
• 24-hour urine protein was below the level of detection (<183>

To calculate the CrCl multiply the urine cr (total mass, not the concentration) by 100 then divide the product by 1440 (the number of minutes in 24-hours) and then by the serum creatinine (in mg/dl).

• His CrCl is 102 mL/min

This is a huge discrepancy: 

• Advanced Stage 3b CKD by MDRD
• Normal kidney function by 24-hour urine collection
  

The first thing you should do is determine if the 24-hour urine was an adequate sample. Usually I worry about under-collections of urine due to a missed void or spillage. In this case I worried that an over-collection was masking renal failure.  (i.e. Did he collect his urine for more than 24-hours? Did his wife join in and contribute to the collection?) The average man produces 23 mg/kg of creatinine. The average woman produces 18 mg/kg. I am unaware of the proper figures for children.

His body weight is 123 kg and the 24-hour creatinine collection was 3,232 mg. This yields 23 mg/kg, right on the money for an average adult male.

This is just a big guy and this is where the MDRD can fail us.

Supporting the diagnosis of CKD stage zero was a normal renal ultrasound, a lock of proteinuria and a normal U/A and microscopic exam.

reference: Current Critical Care

Melamine makes the big time: The Journal

The New England Journal of Medicine this week did a Perspective piece on Melamine. Its amazing to me how a health crisis this big has been essentially ignored up to now by the core medical journals.

The article is in depth and insightful. It suggests, as my former fellow did, that the combination of both melamine and cyanuric acid produced the latest epidemic.

The article continues the obscurity and confusion that comes from mixing parts per million and mg per kilogram.

Since there are insufficient data from humans, the WHO meeting recommended a tolerable daily intake (TDI) of 0.2 milligrams per kilogram of body weight for melamine and 1.5 milligrams per kilogram of body weight for cyanuric acid. The executive summary stated that the TDI is "applicable to the whole population, including infants." However, exposure to both melamine and cyanuric acid may confer a higher risk, and there are unknowns about long-term renal and other risks. The current limit set by the FDA for melamine in food is 2.5 parts per million, calculated on the basis of ingestion by a person weighing 60 kg.

The article links to a report produced by the above mentioned WHO meeting. It provides exposure data from the Chinese Centers for Disease Control and Prevention:

The dietary exposure based on the consumption of melamine-adulterated infant formula in China at the median levels of melamine reported in the most contaminated brand was estimated to range from 8.6 to 23.4 mg/kg body weight per day, based on data provided by the Chinese Center for Disease Control and Prevention.

Klotho information

I went to an afternoon of lectures at ASN on Klotho and its relationship to calcium. I thought they talked about klotho being involved with proximal tubule transcellular calcium reabsorption via TRPV5/6 but after posting a comment about that here, I find that my memory failed me.

It looks like Klotho binds FGF-23 receptor and makes it more specific for binding FGF-23 which then increases the production of calcitriol. Additionally free Klotho in the urine increases expression of TRPV5/6 which enhances DCT and connecting tubule transcellular calcium absorption.

Great explanatory abstract:

the Recent advances that have given rise to marked progress in clarifying actions of alpha-Klothootho (alpha-Klotho) and FGf23 can be summarized as follows:

1. alpha-Klotho binds to Na, K-ATPase, and Na, K-ATPase is recruited to the plasma membrane by a novel alpha-Klotho dependent pathway in correlation with cleavage and secretion of alpha-Klotho in response to extracellular Ca.
   
2. The increased Na gradient created by Na, K-ATPase activity drives the transepithelial transport of Ca in the choroid plexus and the kidney, this is defective in alpha-Klotho(-/-) mice.
   
3. The regulated PTH secretion in the parathyroid glands is triggered via recruitment of Na, K-ATPase to the cell surface in response to extracellular Ca concentrations.
   
4. alpha-Klotho, in combination with FGF23, regulates the production of 1,25 (OH) Vitamin D in the kidney. In this pathway, alpha-Klotho binds to FGF23, and alpha-Klotho converts the canonical FGF receptor 1c to a specific receptor for FGF23, enabling the high affinity binding of FGF23 to the cell surface of the distal convoluted tubule where alpha-Klotho is expressed.
   
5. FGF23 signal down-regulates serum phosphate levels, due to decreased NaPi-IIa abundance in the apical membrane of the kidney proximal tubule cells.
   
6. alpha-Klotho in urine increases TRPV5 channel abundance at the luminal cell surface by hydrolyzing the N-linked extracellular sugar residues of TRPV5, resulting in increased Ca influx from the lumen. 
   

These findings revealed a comprehensive regulatory scheme of mineral homeostasis that is illustrated by the mutually regulated positive/negative feedback actions of alpha-Klotho, FGF23, PTH and 1,25 (OH) Vitamin D. In this regard, alpha-Klotho and FGF23 might play pivotal roles in mineral metabolism as regulators that integrate calcium and phosphate homeostasis, although this concept requires further verification in the light of related findings. Here, the unveiling of the molecular functions of alpha-Klothootho and FGF23 has recently given new insight into the field of calcium and phosphate homeostasis. Unveiled molecular functions of alpha-Klotho and FGF23 provided answers for several important questions regarding the mechanisms of calcium and phosphate homeostasis that remained to be solved, such as :

1. What is the non-hormonal regulatory system that directly responds to the fluctuation of extracellular Ca? 
   
2. How is Na, K-ATPase activity enhanced in response to low calcium stimuli in the parathyroid glands?
   
3. What is the exact role of FGF23 in calcium and phosphorus metabolism?
   
4. How is Ca influx through TRPV5 controlled in the DCT nephron?
   
5. How is calcium homeostasis regulated in cerebrospinal fluid?
   

However, several critical questions still remain to be solved. So far reported,alpha-Klotho binds to Na, K-ATPase, FGF receptors and FGF23, and alpha-Klotho hydrolyzes the sugar moieties of TRPV5. Does alpha-Klotho recognize these proteins directly or indirectly?Is there any common mechanism?How can we reconcile such diverse functions of alpha-Klotho?What is the Ca sensor machinery and how can we isolate it?How do hypervitaminosis D and the subsequently altered mineral-ion balance lead to the multiple phenotypes?What is the phosphate sensor machinery and how can we isolate it? How does the Fgf23/alpha-Klotho system regulate phosphorus homeostasis? How are serum concentrations of Ca and phosphate mutually regulated?

Good looking review article

Fluid and Electrolyte lecture at Providence from Tuesday Dec 16

I did a lecture at Providence last week.

I was scheduled to just give a electrolyte lecture without any further guidance. I pulled out two interesting cases I had seen in the last few weeks. Both patients have a non-anion gap metabolic acidosis, but one is hypokalemic and the other is hyperkalemic.

Here is the native Powerpoint files for you to use or edit.

Here is the SlideShare for online viewing

Non-anion gap Metabolic Acidosis (NAGMA)

View SlideShare presentation or Upload your own. (tags: acid base)