Nephrology Fellowship: by the numbers

We have come to that time once again. Time to interview a gaggle of highly qualified candidates for a few spots in our nephro fellowship. Here is is how it looks by the numbers:


The number of new nephrologists is just under 400 per year.

30% are woman and 51% are US medical graduates. This is a decrease in the number of foreign medical grads from 50% in 1999 to 40% in 2005.
757 applicants applied for 372 spots in at 135 accredited programs in 2007.

Nephrology is the fourth most popular internal medicine sub-specialty after cards, Heme/Onc and Pulmonary/Critical care (look at the bottom of the list and add that to the combined Pulm/Crit Care).

42 kidney transplant programs are available.

There are 19 programs in interventional nephrology however, only 6 are certified by the American Society of Diagnostic and Interventional Neophrology (ASDIN).

More info.

What’s going on with diabetes

VADT is yet another negative trial showing a lack of benefit from controlling blood sugars.

That makes three negative trials in the last 12 months.

  • ADVANCE trial: 11,140 people randomized to gliclazide in order to lower the A1c to 6.5, the control group achieved 7.3%. This lowered combined micro- and macrovascular complications by 10% 18.1% vs 20% after a median of 5 yrs (p=0.01). However the difference was entirely driven by a 21% reduction in nephropathy, with no reduction in retinopathy, macrovascular complications or reduction in CV death or death from any cause.
  • ACCORD Trial: 10,251 people randomized to usual care (A1c 7.0-7.9) or intensive care (A1c under 6%). There was no difference in the primary composite outcome of non-fatal heart attack and strokes and CV mortality. Unfortunately there was a significant increase in total mortality (p=0.04) with high mortality in the intensive therapy group.

All three of these trials were looking to prove that better glycemic control could reduce strokes and heart attacks. We have known since the early nineties that good glycemic control prevents or delays microvascualr complications (kidney disease, blindness, neuropathy) but the data on cardiovascular disease was lacking. This is important because relatively few diabetics develop ESRD and most patients die of heart disease, a macrovascular complication. For example in type 1 diabetics the 20 year risk of developing ESRD is only 2.2%, while the risk of death is four times that at around 10%.

Unfortunately, this looks like a bust. Not one of the trials have shown any sign that improved glycemic control translates into reduced heart attacks or strokes.

Here is a powerpoint lecture on DM I gave a year ago. SlideShare kind of butchers the formatting so if you are really interested download it rather than whatch in the online viewer.

2008 the year in Review

My list (with help from my partners and fellows) of the Top Nephrology Stories of 2008

  1. Melamine!
  2. Heparin!
  3. ATN trial shows no benefit to high dose dialysis in acute kidney injury
  4. FDA finally validates concerns of oral sodium phosphorous solutions for colonoscopy prep
  5. FGF-23
  6. Concerns with the COOPERATE trial
  7. ASTRAL
  8. Home blood pressure monitoring
  9. Reduction of proteinuria with aliskren
  10. No CERA for USA

Top unique keywords that lead people to this blog:

  1. PBFluids
  2. iPhone Medical Apps
  3. Lecture Seder Style
  4. Nephsap
  5. Melamine Milk Poisoning
  6. Dysnatremia
  7. Acid-Base Lecture
  8. IV Fluids Lecture
  9. KDIGO
  10. PICARD Study

Top blog entries by traffic

  1. iPhone medical applications
  2. Melamine milk poisoning and kidney stones
  3. Acid-base lecture for ER-residents
  4. Getting ready for fluids and electrolyte lecture
  5. Bumex same short pharmacokinetics of lasix with better bioavailability
  6. Bevacizumab and acute renal failure
  7. Melamine milk poisoning continues to make headlines
  8. Acid-base lecture for residents of St John
  9. Teaching on two-Ell: acute renal failure and GFR
  10. Teaching on two-Ell: anemia and ckd

Renal Revascularization: The Astral Trial

One of the important studies released at Renal Week 2008 was the ASTRAL Trial (Angioplasty and STent for Renal Artery Lesions). This is the largest trial ever done on renal angioplasty. This seems like one my constant battles with cardiologists. I get a consult a month regarding whether patients should get a renal agioplasty done. I am almost always fighting against this based on prior information which showed marginal improvements in blood pressure control with the therapy and no change in the level of kidney function. However this data was questionable due to a high cross-over rate (i.e. 22 of the 28 patients initially randomized to drug therapy alone underwent angioplasty after 3 months).
This shows that the 806 patients randomized to ASTRAL dwarves all of the previous work on the subject. (source)

ASTRAL was billed as the definitive study to determine if angioplasty and stent preserved renal function, improved blood pressure, prevented hospitalizations, or reduced CV mortality. Patients were followed for 27 months. The enrolled cohort is representative of that are typical candidates for renal revascularization. Here are the graphs from the Investigator Newsletter:

GFR

The bulk of patients had moderately severe renal disease. It is important that they did not select patients too late in the disease where revascularization may be too late to save the kidney. Similarly you wouldn’t wat to intervene too early where the splay between the groups may take longer than 27 months to materialize.

The average GFR was 40 mL/min.

Of note: if you just looked at patients with an initial GFR<25, size="4">Length

The fact that the affected kidney size was pretty good goes against the potential criticism that they were revascularizing too late after permanent infarction and scarring has ocured.

Stenosis
Most of the patients had severe stenosis, a high grade that if found during a diagnostic angiogram would be followed by an intervention.

  • 93% of interventions included use of a stent.
  • The mean stenosis was 76%

Results:
At follow-up, no difference in creatinine, blood pressure, time to first renal event, or mortality (p = ns for all outcomes)

The authors emphasized that there was no benefit for the entire cohort but they feel that the therapy is likely helpful for some subset of the population. I agree, like every nephrologist, I have seen patients have dramatic improvements in renal function following angioplasty for RAS. With the immense ASTRAL database it will be exciting to see if the authors can tease out which subgroups benefit from this technology.

Despite having seen multiple patients benefit from renal artery angioplasty I have remained a skeptic of the technology. Part of this comes from the older flawed and small trials and partly due to the ineffectiveness of cardiac angioplasty to help patients except in regards to reducing angina (a condition that doesn’t have a renal analog) or in patients having an active infarct.

Kidney Stones and Chronic Kidney Disease

One of the biggest stories coming out of Renal Week 2008 was this abstract which linked kidney stones to the development of CKD. This is an important study but I filed it under “no duh.” Patients with kidney stones tend to be heavier, have more hypertension, get episodes of acute renal failure and have repeated instrumentation on the kidneys. They also have gout, and associated hyperuricemia, an increasingly important progression factor for CKD and hypertension.

The most important aspect of this is the question that was left unanswered: do kidney stones cause CKD. The association makes sence but causality would be much more important because we have good tools to prevent kidney stones and it would be wonderful if by preventing kidney stones we could also be preventing future kidney failure.

Hopefully this question will be answered in the near future.

[F-FC202] Kidney Stones Are Associated with an Increased Risk of Developing Chronic Kidney Disease

Andrew Rule, Eric Bergstralh, L. Joseph Melton, Xujian Li, Amy Weaver, John Lieske Nephrology, Mayo Clinic; Health Sciences Research, Mayo Clinic

Background: Kidney stones lead to chronic kidney disease (CKD) in patients with rare genetic diseases (e.g., primary hyperoxaluria), but it is less clear if kidney stones are an important risk factor for CKD in the general population.

Methods
: A cohort of all Olmsted County, MN residents with incident kidney stones in the years 1984-2003 were matched 3:1 to controls in the general population based on index date (first stone diagnosis for stone formers and any clinic visit for controls), age, and sex. Diagnostic codes (yrs: 1935-2007) and serum creatinine levels (yrs: 1983-2006) were captured with the linkage infrastructure of the Rochester Epidemiology Project. Risk of incident chronic kidney disease was assessed using clinical diagnostic codes, end-stage renal disease (dialysis, transplant or death with CKD), sustained (>90 days) elevated serum creatinine (>1.3 mg/dl in men, >1.1 mg/dl in women), and sustained estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Proportional hazards models adjusted for age, sex, and baseline and time-dependent co-morbidities (diabetes, obesity, gout, hypertension, hyperlipidemia, alcohol, tobacco, coronary artery disease, heart failure, cerebral infarct, and peripheral vascular disease).

Results
: After excluding persons with prevalent CKD, 4424 stone formers and 10995 controls were identified with a mean follow-up of 8.4 and 8.8 years, respectively. Stone formers had an increased risk of developing a clinical diagnosis of CKD [hazard ratio (HR)=1.6, 95% CI: 1.4-1.8, see figure], end-stage renal disease (HR=1.4, 95% CI: 0.9-2.2), a sustained elevated serum creatinine (HR = 1.4, 95% CI: 1.2-1.7), and a sustained reduced eGFR (HR = 1.4, 95% CI: 1.2-1.6).

Conclusions
: These data argue kidney stones to be an important risk factor for chronic kidney disease.

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.

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.

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?

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

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