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."

ACTH for membranous nephropathy

Once you go beyond the modified Ponticelli, the treatment of idiopathic membranous feels like hunting in the woods. I have a woman in her late thirties who I have been treating for almost three years. She has between 6 and 10 grams of proteinuria, no renal failure (Cr or 0.8 and stable) no hypertension, and a middling albumin with terrible lipids. She doesn't get much edema and is able to limit her use of loop diuretics to very occasionally.

We started with conservative therapy for 6 months to see where the proteinuria is going. After that we decided to give treatment a try because of the heavy proteinuria. She also had high levels of urinary IgG and urine beta-microglobulin.

She was reluctant to use cyclophosphamide because of concerns about future fertility. And I'm reluctant to use it in a young patient especially for a disease which is causing her minimal problems right now.

We started with MMF. Little effect.

We then gave a trial of CSA. Little effect.

We gave a trial of Pentoxifylline (Trental). little effect

What now? Tacro? Rituximab?

Anyone have any experience with ACTH?


I must say I have been seduced by the preliminary data (case series, rct) on ACTH. To me it looks more compelling than the alternatives (rituximab and tacro). The fact you have to go to a specialty pharmacy to get the stuff is a little intimidating.

Link to a description of membranous nephropathy from a lecture I give on Hep B, C and HIV associated renal pathology.

Renal Vitamins

Just saw this post on the Renal Fellow's Network. I appreciate his flippant attitude toward renal vitamins as they are so routine as to invite disregard but they may have an effect on mortality.

This 2004 article based on the DOPPS database shows a significant reduction in mortality (RR 0.84) associated with use of water soluble vitamins.


I always have a healthy skepticism for DOPPS data as they have been on the wrong side of the anemia, Kt/V and statin debate. Each time being refuted by the RCT. But I'll take the position that since no one will ever do a randomized controlled trial we should go forward with the renal vitamins.

I first heard about this data on renal vitamins during the at the Easterling Lecture given by Eric Young for the Michigan NKF in 2003. At the time this was explained by the reduction of homocysteine induced by the folate in the vitamin. Since that has also fallen to the blade of the RCT, I wonder what componant of the renal vitamin explains the benefit.

CKD in the NYT

Kidney Disease a Takes a Growing Toll

Nice article on the increasing prevelance of chronic kidney disease. They even mention the controversy of geriatric CKD, one of my newest interests.

The article mentions the NKF of Michigan's project to raise awareness of CKD by using hair dressers. I am the newest member of the NKF of Michigan's Scientific Advisory Board.

Also the article has a quote by Steven Fadem, a nephrologist I shared a limo with last week at the EVOLVE Primary Investigator's Meeting. Crazy small world.

MBD and Clinical Practice

Glen Chertow on MBD and clinical practice.

Starts with the high mortality of CVD in ESRD slide shown at every gatheriong of nephrologists.

MBD as a non-traditional risk factor for CVD

HEMO, 4D, Wrone on homocysteine, D-COR all RCT, All negative. [should add correction of anemia study]

45% drop out in D-COR lead to a loss of power and contributed to negative trial.

Cinacalcet approved based on its ability to get the PTH down and get patient to guidelines but we are missing the information on whether this helps patients.

Power is the probablity of detecting the treatment affect if it really exists. 90% power means that 9 out of 10 times you will detect a treatment effect if it exists.

With 3883 patients EVOLVE had 88% power to detect 20% reduction in cardiovascular disease. If the benefit is 15%, which would phenomenally important to our patients, we may not be able to detect it.

KDIGO

bill goodman talking on KDIGO. Goodman wrote the article that interested me in the topic of vascular calcification and binder choice.




What is KDIGO
Kidney Disease Improving Global Outcomes
established in 2003

Independent non-profit, established by the NKF
The concept was to take K/DOQI and generalize the guidelines for a global audience.

The KDIGO mission is to provide:

• Clinical Practice Guidelines
• Guideline database
• Work groups
• Controversy conferences
• Mineral and bone inititative (in draft)
• Hepatitis C in kidney disease (coming)
• Care of transplant patient (coming)
• Acute kidney disease (coming)
  

CKD Mineral and Bone Disease
A rose from the perception that international perspective needed to define renal osteodystrophy

use the phrase ROD exclusively to define: alterations in bone morphology in patients with CKD
classification based on bone histology, bone turnover, mineralization and volume.

CKD-MBD is a systemic disorder of mineral and bone metabolism due to ckd manifested by either one or a combination of the following:

• abnormalities of Ca, Phos, PTH, Vitamin D
• abnormal bone turnover, mineralization, volume, linear growth or strength
• vascular or soft tissue calcification

KDIGO revisited the concept of guidelines
They graded evidence and created their guidelines by limitting the data to:

• RCT of at least six months in duration
  
• N>50 excepts for pediatrics and bone biopsy
• Intermediate endpoints including: BMD, bone biopsy, vascular calcification and biochemical endpoints are not considered unless they have been validated prospectively [unclear if any surrogates have been validated]
  
• Observational studies acceptable if a clinical outcome examined conducted with a high methodological quality and had a relative risk of >2.0 or <0.5

treatment of CKD-MBD

• lowering high phos
• abnormal PTH levels in CKD-MBD
• treatment of bone and bisphosphonates, other osteoporosis medication and growth hormone
• evaluation and treatment of kidney transplant bone disease

there is little evidence to provide guidance for a specific therapeutic target range for any biochemical parameter

• extreme values are associated with greater mortality risk
• little evidence to support preferred treatments

KDIGO concluded that PTH guidelines are mainly opinion based and not informed by randomized clinical trials

150-300 is based on evidence just not rct and outdated

phos and calcium guidelines are loose

repeated emphasis through out document on the lack of evidence from RCT with hard outcomes


Data Gaps


Evolve is really important, largest prospective clinical trial on dialysis population

Fellow talk: interesting case

Dr. Dhungal did the interesting case conference this morning. He did a great job.

Primary Hyperadosteronism

View SlideShare presentation or Upload your own. (tags: aldosterone hypertension)

Fellow talk on anion gap metabolic acidosis

Here are the slides used by Dr. Kayal to support his comprehensive talk on anion gap metabolic acidosis.

Gap Acidosis

View SlideShare presentation or Upload your own. (tags: anion gap)

Renal Adventures in Imaging

One of my favorite lectures. I'm supposed to give an hour lecture on contrast nephropathy but I find that the residents have excellent knowledge and instincts on this topic so I expand it in two other areas they are less well versed:

1. Oral sodium phosphorous and nephrocalcinosis
2. Nephrogenic fibrosing dermopathy

iPhone version
Booklet for printing

The blog is sort of a mess.

I tried doing some "live" blogging of the ASN and use the blog to take notes during some of the lectures I attended. I would judge that effort to be a failure. I'll spend the next few days trying to clean up some of these posts.

Renal Week 2008: Clotho

Makoto Kuro

Emerging role of Klotho

Klotho mouse has accelerated aging
due to insertion of gene missiong gene X by accident.
first model of human aging with multiple phenotypes.Question what is gene X
single pass transmembrain protein
it has some siaqlidase activity
gene expressed predominant\ly in the kidney and a little in the brain

does over expression of klotho surpress aging?
over expression extends mouse life by 30%
expressed in the distal convoluted tubules with weak expression in PT
the extracellular domain is clipped by ADAM 10 and then is a soluble factor

klotho -/- has similar phenotypes as FGF23 -/-

FGF is phophaturic hormone from the bones
gain of function causes hypophosphatemic rickets (vit D resistant)

FGF23 binds to FGF23 receptor plus Klotho

FGF23 requires klotho to activate FGF signaling
FGF lowers 1-alpha hydroxylase and increases 24-hydroxylase (deacticvate 1,25)
`
FGF?Klotho system surpresses PTH

agiing like phenotypes are caused by phosphate toxicity

soluble/secreted klotho independent of FGF23 increases renal phosphate wasting

sialidase activity activates TRPV5 which increases Ca current.

Link between |Klotho and CKD.

Mice lacking Klotho and ESRD share: casc calcification and hyperphosphatemia

mice with over expression of klotho are more resistant to vasc calcification and hyperphosphatemia in CKD model.

Renal Week 2008: Acute Kidney Injury Lecture: Can staging guide therapy

Claudio Ronco

We have no data. thank-you.

Various definitions of AKI change the prevalence and prognosis of AKI.

In RIFLE use the worse of cr or u.o to define category

States 200,000 patients have been used to validate RIFLE.

Systemic review of RIFLE in KI in 2008 by Ronco.

AKIN changes R to include increase in Cr of 0.3. Otherwise just sw2ithches I to 2 and F to 3.

Also the two creatines used to determine the 5change must be measured within 48 hours of each other.

Early initiation of RRT has theoretical benefits
Defintion on how to measure/define this are not established

He feels the failure of the ATN is due to Pagamini's high, medium and low severity argument.

Much better talk

Renal Week 2008: Acute Kidney Injury

Mehta

Need to adjust serum Cr for fluid balance. He states that this will allow Cr to determine renal failure 24 hours earlier. He fails to give an equation to do this. Is creatinine distributed in total body water or extracellular water? My guess is total body water.

eGFR would be more helpful in eliminating the curvelinear relationship of GFR and Cr but not validated in ARF.

Jelliffe method takes into account Cr generation and is better in ARF. Fails to provide information on calculating the eGFR by Jelliffe method.

Mentions Thurau's article on Acute renal success. Am J Med 1976

Shaw in Nephron Physiology article on the time course of AKI as determined by differing etiologies.

Oliguria is bad
diuretic matter, but he wont tell us how.

Mehta is the worst lecturer. He throws a ton of data up and fails to describe any of the implications.

Total crap.

Renal Week 2008: CVD and CKD: Case 7

66 yo woman with ESRD due to analgesic nephropathy. Hx of Crohn's Disease. Extended criteria deceased donor allograft transplant 1.5 yrs ago.

Now SBP of 160.

Next Speaker Ojo. Greatest name in Nephrology.

CVD and CKD in Transplantation

Progressive reduction of acute rejection since 2000 from 17.4 to 10.3% at one year. This should improve outcome of graft and patient; however post-transplant life-span has decreased from 14 in 1995 to 12.7 in '06.

CVD is the explanation for this conundrum.

After the first year the most common cause of loss of graft is: death with a functioning graft (56%). This is twice as common as number 2, chronic rejection (21%).

43.5% die of CVD.

Hypertension, DM, hypercholesterolemia, obesity, and anemia are all more prevalent in transplant patients than transplant candidates or prevalent dialysis patients.

Focus on immunosupressant drugs

• In HIV patients with lower cd4 have higher higher CVD death rate
• Same relationship of CD4 to CVD is seen in patients with radiation exposure (Hiroshima) causing lower cd4 counts
• also seen in transplant patients.

Rabbit data showing that increased cholesterol plaques with concurrent CSA, without change in lipid profile. Roselaar jci 1995 96 1389.

Steroids are dangerous even at low doses in the normal population.

CSA increase BP.

CSA also causes endothelial dysfunction.

Sirolimus is antiatherogenic, as seen in cardiac stents.
MMF also appears to reduce cholesterol plaque Romero Atherosclerosis 2000: 152:127-133.

Cr alone is a predictor of CVD independent of immunosupression and traditional risk factors.

Renal Week 2008: CKD and CVD: Antihypertensive therapy

Case report of a patient with HTN
Ray Townsend is the MC (sweet). He presnts a patient with HTN and modest CKD. Cr 1.4 up from 0.9 in 2001.

Ray passes off to Domenic Sica.

Antihypertensive Drug Therapy in patients with HTN and CKD.

Volume expansion

• Patient was on 25 mg of HCTZ. No need to change to loop if the patient is euvolemic. Chlorathalidone vs hctz
• Ernst HTN 2006. chlorathalidone reduced 24hr mean bp more (7 vs 12) non-ckd patients. night time bp drop was even more pronounced 6 vs 13 mmHg.
• Recommends switch within class from hctz to chlorthalidone
• the increase in calcium may help with PTH. interesting.
• elison JCI 83: 113; 1989 images of hypertrophy of DCT with loop diuretics
• He's pushing torsemide
• Using FeNa to determine if patient is responding to loops (look for fena>3%)
• Why is there variability in bioavailability of furosemide: floculation of pills stops some absorption. Use of liquid furosemide doesn't help because of only a limited area of absorbtion: early duodenum only.
• He likes the torsemide

Drug accumulation

At gfr 30-50 need to think about dose adjustment.
Renally cleared: atenolol, nadolol, betaxolol

Hepatically cleared
propanolol, metoprolol, carvedilol

Dose response to beta-blockers is flat in CKD.

Don't titrate atenolol. It is renally cleared and patients are already retaining the drug before you increase the dose. Though the BP effect is not dose dependent, the adverse effects are.

Aldosteronism

• 20% of patients with CKD.
• Likely this patient will have aldo level of 14-20 and renin less than 1
• Aldosterone antagonists (AA) reduce proteinuria
• Need diuretic on board to get much BP effect
• Half-life of spironolactone is 24 hours, in liver disease 120 hours, and in CKD multiple days. These figures include active metabolites. He feels eplerenone is safer because you won't get accumulation.
• Consider qod dosing of spironolactone. Consider 12.5 mg qd
• beware of heparin causing hyperkalemia with AA
• Similar warning for ACEi, ARB, TMP/SMX

Clonidine

• in CKD clonidine is renally cleared. This decreases rebound htn by extending the half life
• initially clonidine has a steep dose responce at low doses but then flattens
• causes dose dependent volume retension. this is worse with TTS
• at higher doses the peripheral alpha stimulation will overcome the central reduction in alpha activity so patients get increase in BP. This is seen in clonidine OD or with autonomic dysfunction.
  

CCB

• Amlodipine has half-life of 40 hours
• nifedipine's half-life goes from 2 to 4 hours in renal failure
• Edema with CCB is worse in patients with CKD because they already have increased volume

ACEi

• 10 in the US
• fosinopril and trandolopril have significant hepatic clearance
• ARB are not renally excreted
• dialyzable: captopril, enalepril, lisinopril. Use in overdose.

Statin

• AUC of simva increases 4 fold with diltiazem
• Cool case report of a patient on 80 of simva who was admitted for A-fib with RVR and gets started on a diltiazem gtt. He developed rhabdo a few days later.
  

That's it. Question time.

Using NephSAP for teaching on the consult service.

New month. Back on the consult service.

Dr. Jabri is the consult fellow and we are going to read the NephSAP on GNs. Should be good.

Melamine in the eggs, melamine in pesticide

Hong Kong discovers high levels of melamine in chinese eggs:

Hong Kong said last week it would test meat, vegetables and processed food for melamine, a move that underlines concerns about food safety in the former British colony which returned to Chinese rule in 1997.

It imposed a cap on melamine in September, restricting it to no more than 2.5 milligrams per kilogram, while melamine found in food meant for children under three and lactating mothers should be no higher than one mg per kg.
The level of melamine found in the eggs was 4.7 mg per kg, the newspapers said.

The newest revelations on melamine toxicity involves vegetables that are sprayed with the insecticide cyromazine. This derivative of melamine degrades back into melamine resulting in the contamination.

Recently, experts have investigated and confirmed that melamine has also been found in lettuce, water cress, tomatoes, mushrooms, potatoes and other agricultural products. There is 17 milligrams (0.000037 lbs) of melamine per kilogram (2.20 lbs) of mushrooms.

Cyromazine itself apparently has very little toxicity:

Cyromazine is practically nontoxic (acutely) to mammals and birds. Exposure estimates for these organisms are 0.05 ppm. Acute toxicity for birds is 1785 ppm maximum. Safety factor is 105-106 for birds. Acute toxicity for mammals is 1000 ppm maximum. Safety factor is again 105 - 106.

Cyromazine

melamine

How much bicarb is in baking soda

My fellow says there is 60 mEq in every tsp of baking soda.

That sounds like a lot.

Important links

Abstracts from the NKF Spring Meeting 2008

Journal Club: Campath and ACE/ARB and AKI in CABG

The first article was an analysis of campath for induction with tacrolimus.

Patients were randomized to either

• Methylpred 250 mg and Campath 20 mg immediately following surgery followed by Tacrolimus Group
• Tacrolimus, prednisone, and MMF (no induction therapy)
  

Primary outcome was biopsy proven rejection at 6 months.
Secondary outcome was biopsy-proven rejection at 12 months, time to first rejection, patient and graft survival, incidence of corticosteroid resistant rejection.

n= 131 deceased donor, kidney transplant in patients with PRA ≤ 25%. All patients were receiving their first kidney. Age 18-65.


No episodes of humoral rejection was found in either group.

The figure above I think is particularly informative as it becomes obvious that all the difference is in the first month. This is a study of induction vs. no induction and they demonstrate a huge reduction in early rejection with induction.

Big picture: large reduction early reduction but no difference in serum creatinine at one year.

The second article was a retrospective analysis of the risk of acute kidney injury based the presence or absence of ACEi/ARB.

A VA study looking at chronic use of ACEi or ARB and the risk of acute kidney injury following cardiovascular surgery. SUNY Buffalo looked at 1,358 patients with CV surgery from 2001-2005. 50% were on ACE/ARB

• 40% had AKI (essentialy all Modified RIFLE: Stage 1, Cr rise ≥0.3 or 50-100%)
  
• 7 patients Stage 2 (Cr rise 2-3x the baseline)
  
• 2 patients Stage 3 (Cr greater than 4 or >3x the baseline)

They found that use of ACEi/ARB had a 27.6% increase in risk of AKI.

Of note 18% of the patients who had AKI, their creatinine had not returned to baseline at 3 months post surgery and still qualified as AKI. This does not jive with the natural history of AKI, especialy relatively mild AKI. This makes me wonder if the baseline creatinine were abnormally low in some of the patients and the increase documented was not AKI but actually resolution of the creatine falling.

The primary concearn I have is that the study had 543 patients with AKI and only 9 had more than a doubling of creatinine. They used a very sensitive definition of AKI and like any test, when you increase the sensitivity you decrease the specificity. It is very possible that a large proportion of those patients defined as AKI didn't actually have AKI, throwing the study into doubt.

Some details on one of the deaths from the melamine milk contamination

This article talks about the family of the first infant to die from melamine milk contamination. The child, Yi Kaixuan was only 6 months old. He died back in May, months before any information about the contamination came out.

But on April 20, the baby wouldn't stop crying and had problems urinating. Jiao took him to the village clinic, but they couldn't pinpoint a problem.

Alarmed, Yi left his construction job and returned home. The family headed for the Gansu provincial capital, Lanzhou. On April 30, they took the baby to two city hospitals. Doctors were stunned, Yi said. They said they'd never seen a child with so many kidney stones, and the situation was critical.

A frenzy of testing followed, and the bills piled up past $145. The parents didn't sleep all night, waiting.

Around noon the next day, a doctor came to tell them their baby had died.

Tragic.

iPhone Medical Applications

I have four medical applications on my iPhone, of which I use two. Here is a quick review.

To show how the iPhone equipped physician approaches clinical problems I will use the DB's Medical Rants most recent acid-base problem. He presents a case with the following information:

49-year-old man, previously in good health, presents after a few weeks of progressive weakness and dizziness. He admits to polyuria. Your job is to extensively discuss his lab tests.

The first step in my mind is to fully interpret the ABG. To do this we will use the application ABG.

ABG

This simply named program is an ABG calculator that runs through the standard algorithms for detecting multiple primary acid-base abnormalities. Can't remember Winter's Formula. As long as you don't have boards coming up you can just plug'n chug and turn DB's ABG into the following:

This does two of the calculations that DB describes at length:

1. Winter's formula (16 * 1.5 + 8 ±2) shows that the predicted pCO2 is 30-34. The patient's CO2 is 33 so the patient has isolated and appropriately compensated pCO2 of 33. ABG displays this information in the second line when it describes the acid-base disorder as "Compensated metabolic acidosis." It does not describe a second primary condition such as respiratory acidosis or alkalosis.
   
2. Gap-Gap or delat-delta. The patient has a dramatically elevated anion gap at 27 (15 over the upper limit of normal of 12) but his bicarb of 16 is only 8 below normal. The difference between the delta gap and the delta anion gap is 7 (15-8) when this is added to the normal bicarbonate you get 31; so the patient had a pre-existing metabolic alkalosis with a bicarbonate of 31. ABG displays this information as the corrected bicarbonate.

The next step is adjusting his sodium for the hyperglycemia. To do this we will use Mediquations though Medical  Calc works just as well.

Mediquations

DB, in his discussion, states that he has unpublished data proving that no formula is effective at adjusting the serum sodium for the hyperglycemia. For those of us without his unpublished data should adjust the sodium using Katz's traditional conversion (pdf of a letter to JAMA discussing adjusting sodium for hyperglycemia in DKA. Katz's original conversion was discussed in a letter to the NEJM) of a drop in Na of 1.6 for every 100 the glucose is over 100 mg/dL. Nephrology fellows should additionally be aware of Hillier's data showing the sodium falling 2.4 for every 100 of glucose. Both Mediquations and Medical calculator adjust the sodium using Katz's conversion.

Of coarse you wouldn't know it was Katz's conversion because even if you tap on "More Info," Mediquation does not provide the reference. Likewise you will not get the reference with Medical Calc.

Though DB did not explore free water defecits in his discussion of the case this is a clinically relevent point. You can use Mediquation to calculate the water deficit.

I feel that using ABG and Mediquations will make you a more effective physician without forcing you to memorize equations used only periodically.

New Virus. Killing people. Scarrier than Lehman Brothers.

These emerging viral illnesses always scare the crap out of me. From the WHO:

13 October 2008 -- The results of tests conducted at the Special Pathogens Unit, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service in Johannesburg, and at the Special Pathogens and Infectious Disease Pathology branches of the Centers for Disease Control in Atlanta, USA, provide preliminary evidence that the causative agent of the disease which has resulted in the recent deaths of 3 people from Zambia and South Africa, is a virus from the Arenaviridae family.

Analysis continues at the NICD and CDC in order to characterize this virus more fully. CDC and NICD are technical partners in the Global Outbreak Alert and Response Network (GOARN).

Meanwhile, a new case has been confirmed by PCR in South Africa. A nurse who had close contact with an earlier case has become ill, and has been admitted to hospital. Contacts have been identified and are being followed-up

Love the name GOARN. Reminds me of the alien Kirk had to battle mano-a-mano.

Salt restriction in dialysis

I need to learn more about this.

Also check out The Salt Blog. Unfotunately, it looks like only one post, but a lot of comments.

Interesting.

Teaching Medical Students: Potassium

A couple of Fridays ago I did my second lecture for the medical students at Providence Hospital. I lectured on potassium.

The handout is good but gets a little light on content towards the end. I will revise this before the next lecture.

Potassium for Med Students

Publish at Scribd or explore others: Other money credit

Potassium booklet form for printing
Potassium handout for iPhone

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. . .

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.

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.

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:

• G Glycols
• O 5-Oxoproline (pyroglutamic acid)
• L L-Lactic acid
• D D-Lactic acid

• 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 8.5x11 without a booklet form.

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:

When does the melamine story progress from the tragic to the absurd. Gorillas?

The latest victims of the melamine incident: gorillas.

Melamine Crisis: "There is no problem"

"There is no problem," Xiang Yuzhang, the national quality watchdog's chief inspection official, told reporters in Beijing.

Love the close of this article with a quote by the Chinese equivalent of Baghdad Bob.

This on the same day that 5 cases of kidney stones in children surfaced in Taiwan.