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)

Great cases on call

I'm running the on-call gauntlet.

I was on call Sat and Sun December 6,7

Sat December 13

Sat and Sun December 20,21

Thursday through Sunday December 25-28

four straight week-ends, with Christmas thrown in for the Jew. Ughh.

That said this week-end has had a few great cases:

• IgM Cold-agglutinin hemolytic anemia in need of plasmapheresis.
• Fluconazole induced hyperkalemia
• Urinary obstruction induced electrogenic type 1 RTA (Hyperkalemic variety of type 1 RTA)
• Primary hyperaldosteronism induced hypertensive emergency
  

I'll elaborate on some (all) of these cases in the next few days.

Happy holidays

Propofol induced lactic acidosis

I was consulted on a patient with acute renal failure and severe acidosis without an obvious source. The intensivist postulated this could be propofol induced B-type lactic acidosis. I had not previously encountered this entity.

Apparently propofol can block the electron transport train of the mitochondria causing lactic acidosis. Clinically the patients present with lactic acidosis, rhabdomyolysis and acute renal failure.

Propofol Infusion Syndrome Associated with Short-Term Large-Dose Infusion During Surgical Anesthesia in an Adult

Interesting article showing propofol decreasing oxygen utilization in animal model

Pediatric case in which the doctors captured increased levels of various types of carnitine indicative of altered mitochondrial oxygen utilization.

Craven et al found 24% rate of unexplained metabolic acidosis with propofol use, suggesting a much more common mild form of the disease.

My patient was exposed to only a single dose of propofol so I am skeptical but the lack of an alternative compelling etiology is leaving me considering this disease.

Patient information: over-the-counter medications

What over the counter medications should I be careful about with my kidney disease?

All over-the-counter medications have the potential to be harmful and so they should only be taken according to the labels and if you have any questions you should call you doctor. However, there are a few over-the-counters that are particularly problematic for patients with weak kidneys. Here they are:

1. Ibuprofen (Advil, Motrin), Naproxen (Naprosyn)
2. Sodium phosphorous solutions (Fleets enemas or fleets oral cathartics)
3. Magnsesium citrate (MagCitrate)
4. Pseudophedrine

Ibuprofen (Advil, Motrin), Naproxen (Naprosyn). Both of these medications are non-steroidal anti-inflammatory drugs or NSAIDs. There are a number of other NSAIDs that are prescription only including indomethacin, Celebrex and others. The problems with NSAIDs goes for all of these agents, not just the over-the-counter ones. NSAIDs block the production of prostaglandins that trigger inflammation in the body. Unfortunately, in the kidneys, prostaglandins help maintain blood flow. Blocking prostaglandins can decrease the blood flow to the kidney and cause the kidney to shut down. This is more common when patients are also taking diuretics (water pills) and blood pressure medicines called ACE inhibitors or ARBs. (Common ACE inhibitors include Vasotec, Zestril benazapril, Altace or any drug which ends with –pril. Common ARBs include Cozaar, Diovan, and Atacand or any drug which ends with –sartan.)

NSAIDs can also interfere with blood pressure medicines and cause patients to retain fluid.

Sodium phosphorous cathartics. Fleets enemas and oral solutions are used to treat constipation or prepare patients for surgery or colonoscopy. Recently we have learned that these medications can cause severe permanent kidney damage. Little is known about how often this occurs and appears to be rare but people with normal kidney function have developed severe renal failure requiring dialysis or transplant following exposure to these medications. Unfortunately not all doctors are aware of this complication and are still prescribing these medications. A clear picture of who is at risk for this complication has not emerged but experts agree on the following risk factors:

1. Advanced age
2. Chronic kidney disease
3. Use of diuretics (water pills)
4. Use of ACE inhibitors or ARBs

In addition to the risk of damaging the kidneys with sodium phosphorous, patients on dialysis who take these drugs are at risk of severe elevations in phosphorous that may kill them.

Magnesium citrate is sold under the brand names Citro-mag and Citroma. Magnesium citrate is used to treat constipation and to cleanse the bowels before surgery. In patients with severe kidney disease (CKD stage 4 and 5 and dialysis) it can cause harmful levels of magnesium.

Pseudoephedrine is the active ingredient in some cold medicines (Actifed, Sudafed) that are now kept behind the counter due to the fact that pseudoephedrine is one of the ingredients needed to manufacture methamphetamine (crystal meth). Pseudoephedrine raises the blood pressure by about one point and the heart rate by about 2 beats per minute in patients with normal blood pressure or people with well-controlled high blood pressure. This should not cause any problems. However, in patients with poorly controlled or untreated hypertension, pseudoephedrine may cause larger changes in blood pressure and should only be used after speaking with your doctor.

Scrubs: On renal failure

Great bit on refusing dialysis

Tip o'the hat to Stacy without an e

Patient information: Nephrogenic Fibrosing Dermopathy

Are MRIs safe for patients with kidney disease?

Sometimes. In 2000 a new skin disease was discovered that caused patients to develop thick skin around their joints, especially the knees. The thickened skin prevented people from bending their legs so they can’t walk. The disease was initially only found in patients on dialysis.The condition was named nephrogenic fibrosing dermopathy or NFD for short.

For a long time doctor’s had no idea what caused NFD. Then in 2006 some doctors in Europe noticed that only patients who received gadolinium during an MRI developed NFD. Other physicians verified this association and now it is generally accepted, though not proven, that gadolinium is at least part of the cause of NFD.

Gadolinium is used as contrast for patients receiving an MRI when doctors want a better view of the blood vessels. It is always used in a related imaging technique called an MRA. The FDA has identified people at risk of developing NFD. The list includes people with:
1. Acute renal failure
2. CKD stages 4 or 5
3. Cirrhosis induced kidney disease (called hepatorenal sndrome)
4. End-stage renal disease on dialysis

There is no proven strategy to prevent NFD except to avoid exposure to this agent. New contrast agents are being developed that do not have gadolinium. If your medical condition absolutely requires a gadolinium MRi then your doctor may schedule special dialysis sessions to remove the toxin right after MRI.

If you are on dialysis or have any of the other risk factors you should make sure your doctor knows about NFD and you should coordinate the MRI with your nephrologist.

There is no risk of NFD if you do not receive contrast with your MRI.

Patient information: Contrast nephropathy

I am writing some patient information articles to go on our SCSP's website, scsp.net.

I am including them here as I fine tune them. I have been in contact with Dr. Shah, a nephrologist who has produced some gorgeous patient information booklets that we will be posting online also.

I have heard that getting a dye for a cardiac catheterization or CAT scan can damage my kidneys. Is that true?

Yes. X-ray dye is usually made with iodine and is sometimes called iodinated contrast. The dye allows doctors to see the blood vessels and used when using x-rays to diagnose a number of medical problems. The dye that can damage the kidneys is always given intravenously. Another type of dye is given as a oral liquid. This oral contrast is not harmful to the kidneys.

If you have healthy kidneys the IV dye is almost never harmful; however if you have weak kidneys (chronic kidney disease stage 3, 4 or 5) and especially if you also have diabetes or are also over the age of 65 you are at risk of kidney damage from the contrast.

The kidney damage is called radiocontrast nephropathy. The damage is usually temporary (7-10 days) but sometimes it can cause permanent renal failure requiring dialysis.

There are ways to reduce the risk of developing radiocontrast nephropathy, though even in expert haqnds the risk cannot be eliminated. Protective strategies include:
1. Stopping diuretics
2. Hydrating the patient with saline solution
3. Taking an anti-oxidant called N-acetyl cysteine
4. Reducing the dose of contrast
5. Using a contrast agent with less toxicity

It is important, that if you are at risk of radiocontrast nephropathy and are going to get IV contrast that you notify your nephrologist beforehand so she can coordinate the protective strategy to spare your kidneys.

Giving patients good news

I was rounding at one of the rehab/sub-acute hospitals today. One of the patients was a 70 y.o. African American man who had undergone a kidney transplant 12 days ago. He had delayed graft function and so he had continued right along with his normal dialysis schedule. He had been on dialysis for 3 years.

Over the week-end, his kidney opened up (recovered renal function in his transplant kidney) and so we held his dialysis on Sunday (patients on the TTS schedule received the Saturday dialysis on Sunday due to a Thanksgiving schedule shift). Today his creatinine fell further and I told him he was done with dialysis.

He immediately began to cry and convulse. I wasn't sure if these were tears of joy or a seizure. After a few minutes he was able to speak again and told me how happy and grateful he was to be off dialysis.

It was one of those moments the makes being a doctor special.

From the trenches of the consult service...

Me: If a bicarb of 6 and an anion gap of 35 doesn't get you excited you shouldn't be a nephrologist.

My fellow: Yeah, its the ST-elevation MI of nephrology.

The fall of cholesterol

The cholesterol theory of heart disease has been getting knocked around a bit these days.

Just writing that sentence feels rebelous. To call cholesterol's causative link with heart disease a theory seems blasphemous. I started thinking about this when I looked over some summaries of the Jupiter data.



The results of the JUPITER trial indicate that rosuvastatin is associated with a significant reduction in major cardiovascular events, including death, in apparently healthy persons with LDL cholesterol less than 130. The reduction in risk was roughly twice as high as one would predict from the reduction in the LDL:

Moreover, the results were quite different from those of trials that recruited on the basis of elevated LDL.

Those trials "generally reported a 20% reduction in vascular risk for each 1 mmol/L (38.7 mg/dL) absolute reduction in the LDL cholesterol level, an effect that would have predicted a proportional reduction in the number of events in our study of approximately 25%," the investigators wrote.

"However, the reduction in the hazard seen in our trial, in which enrollment was based on elevated high-sensitivity C-reactive protein levels rather than on elevated LDL cholesterol levels, was almost twice this magnitude and revealed a greater relative benefit than that found in most previous statin trials," they added.

This mismatch with reduction in LDL and reduction is risk is similar to the findings of with ezetimibe which showed no reduciton in the progression of atherosclerosis despite dramatic reductions in cholesterol.

Add to that the increase rather than reduction in first major cardiovascular events associated with torcetrapib which successfully increased HDL and reduced LDL. Another nail in the coffin also comes with torcetrapib which despite increasing HDL and reducing LDL failed to reduce atheroma volume.

It seems that large swaths of the cholesterol theory need to be revised and updated to account for this new data. While we wait for this new hypothesis it is important to reevaluate all of the conclusions and health recommendations we make based on intermediate end-points rather than on clinical outcomes. The primary health recommendations that I have in my sites are dietary. Low fat diets have repeatedly failed studies on endpoints and are propagated on their ability to improve the lipid profiles. Well, both ezetimibe and torcetrapib improve the lipid profiles and do little else of benefit to patients.

From a 2002 JAMA review:

In the Minnesota Coronary Survey,⁵¹ cardiovascular events were not significantly reduced by a high-polyunsaturated-fat diet despite a decrease in serum cholesterol, but the mean duration of dietary intervention was only about 1 year. Two secondary prevention trials testing the approach of total fat reduction did not find a significant reduction in serum cholesterol or CHD events.^52-53

A more recent reveiw from Circulation comes to a similar conclusion. It reminds me of a NYT magazine article about the Atkins diet. This wonderful article has a section that looks at the lack of correlation between Heart Healthy diets and actually reducing cardiac events.

It began in January 1977, when a Senate committee led by George McGovern published its ''Dietary Goals for the United States,'' advising that Americans significantly curb their fat intake to abate an epidemic of ''killer diseases'' supposedly sweeping the country. It peaked in late 1984, when the National Institutes of Health officially recommended that all Americans over the age of 2 eat less fat. By that time, fat had become ''this greasy killer'' in the memorable words of the Center for Science in the Public Interest, and the model American breakfast of eggs and bacon was well on its way to becoming a bowl of Special K with low-fat milk, a glass of orange juice and toast, hold the butter -- a dubious feast of refined carbohydrates.

In the intervening years, the N.I.H. spent several hundred million dollars trying to demonstrate a connection between eating fat and getting heart disease and, despite what we might think, it failed. Five major studies revealed no such link. A sixth, however, costing well over $100 million alone, concluded that reducing cholesterol by drug therapy could prevent heart disease. The N.I.H. administrators then made a leap of faith. Basil Rifkind, who oversaw the relevant trials for the N.I.H., described their logic this way: they had failed to demonstrate at great expense that eating less fat had any health benefits. But if a cholesterol-lowering drug could prevent heart attacks, then a low-fat, cholesterol-lowering diet should do the same. ''It's an imperfect world,'' Rifkind told me. ''The data that would be definitive is ungettable, so you do your best with what is available."