Year: 2009

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Dose of DIalysis

Everything I learned in fellowship has turned out wrong. When I was a fellow I was taught:

  • Higher Kt/V were beneficial for patients
  • Increasing the hemoglobin reduced LVH and improved outcomes in CKD
  • Using non-calcium based binders saved lives
  • and most importantly: increasing the dose of dialysis in AKI improved survival

The last point was an area that was emphasized in my education. I heard Dr. Murray spend so much time going over the preliminary evidence that I was honed to proselytize the gospel of early and often dialysis for acute kidney injury. I loved working with Murray, he’s a great speaker, a great teacher and the only man with more board certifications than years in middle school (internal medicine, nephrology, critical care, clinical pharmacology).

Since finishing fellowship it has been humbling watching each of these truths fall to the blade of the RCT (though I still believe that calcium based binders are harmful).

The results of the ATN Trial this past summer has been especially heartfelt because I was so invested in the outcome. I had argued and fought so many times to get an access and initiate dialysis, to get an extra-treatment, all this time being smugly self confident that I was helping the patient. Confident that I was fighting the good fight. Ughh.

So here it is, a review of the article that kicked me in the chest…
The objective was to determine if more intensive dialysis for acute kidney injury would improve survival in critically ill people. Unique to this trial, the protocol allowed patients to get either conventional hemodialysis or hemofiltration depending on the hemodynamic status of the patient at any time during the trial. This innovation allows the trial to better track actual practice. Additionally, it allows the trial to get past the eternal debate of which modality is better, and answer the question of what dose to target regardless of the modality.

The study was conducted from 2003 to 2007.

The trial was run at 27 institutions.

Enrollment criteria:

  • Critically ill adult
  • Age: 18 or older
  • Renal failure plus at least one other organ system failure or sepsis

Patients who were hemodynamically stable were provided hemodialysis (prescribed Kt/V 1.2-1.4). If they were unstable, CVVH or SLED was provided. The decision between CVVH and SLED was determined by individual site preference.

Patients were randomized to one of two dosing schemes:

Less-intensive strategy:

  • Stable: Intermittent hemodialysis: 3 days a week effluent
  • Unstable: Continuous therapy: effluent of 20 mL/kg/hr

Intensive strategy:

  • Stable: Intermittent hemodialysis: 6 days a week effluent
  • Unstable: Continuous therapy: effluent of 35 mL/kg/hr

These definitions for dose come from Ronco’s paper (continuous therapy) and Schiffl’s paper (intermittent therapy) two studies which are (were?) frequently invoked as support for high dose dialysis in acute kidney injury.

Dialysis was continued until recovery of renal function, discharge from the ICU or 28-days of therapy or death. Recovery of renal function was defined by 6-hour CrCl of >12 mL/min and investigator discretion or >20 mL/min.

Primary Endpoint: All-cause mortality at day 60.

Secondary endpoints:

  • In-hospital death
  • Recovery of renal function (CrCl>20). Recovery was defined as complete if Cr was <0.5>0.5 over the baseline creatinine.
  • Duration of renal replacement therapy
  • Dialysis free at 60 days
  • Duration of ICU stay
  • Return to previous home at day 60.

Power analysis

  • Estimated mortality with less-intensive strategy 55%
  • Estimated mortality with intensive strategy 45%

The authors estimated 10% loss to follow-up and all patients lost were assigned to “alive” for analysis. 90% power with a sample size of 1164.

Enrollment was below the power analysis goal of 1164 at 1124 but the study had better retention with 29 being lost for various reasons and 5 being lost and analyzed as “alive.” The power analysis anticipated 112 people being lost.


The all important table 1. shows a cohort that looks similar to the patients I take care of. 60% sepsis and 80% ventilated. Appache 26. All and all, a sick cohort.

The protocol was adhered to extremely well with extra treatments occurring on 0.5% of days in the high dose group and .5% of days with less-intensive strategy. Missed treatments occurred on 1.9% of days in the intensive strategy and 1.1% in less-intensive strategy. Surprisingly, the delivered dose of dialysis with intermittent therapy was a Kt/V of 1.3, right in the middle of the prescribed target. ICU patients are classically difficult to dialyze and previous analysis of delivered dose have shown it to lag well behind prescribed dose.

With continuous therapy the delivered dose like-wise correlated well with prescribed dose: 36.2 mL/kg with intensive strategy and 21.5 mL/kg with less-intensive strategy.

Primary outcome: 53.6% 60-day mortality with less-intensive strategy and 51.5% mortality with intensive strategy (p=0.47).

Secondary outcomes:

  • In-hospital mortality: 48.0% less-intensive strategy, 51.2% intensive strategy
  • Complete recovery of renal function (day 28): 18.4% less-intensive strategy, 15.4% intensive strategy
  • Return to home by day 60: 16.4% less-intensive strategy, 15.7% intensive strategy

Complications: Patients on the intensive strategy required vasopressor support during renal-replacement therapy more often, 14.4% vs 10.0% (p=0.02) and required interventions for hypotension more often, 37.7% vs 30.0% (p=0.006). However, in intermittent dialysis both groups reported similar rates of dialysis associated hypotension 18.5% with intensive vs 18.0% with less-intensive) and similar drops in blood pressure (MAP from 86 to 75 with intensive and from 86 to 74 with less-intensive). The increase in dialysis associated events maybe related to the increased frequency of dialysis (more exposures to dialysis) with intensive strategy.

Hypophosphatemia (17.6% vs 10.9%, p=0.001) and hypokalemia (7.5% vs 4.5%, p=0.03) were both more common with intensive therapy than with less-intensive therapy.

The editorial by Bonventre that was published with the article was okay. I would re-direct interested readers to the Hume, et al. editorial in AJKD which was better.

Some points from the Bonventre article include:

  • Increased numbers of men in the study
  • Lack of CKD patients
  • Questions about the changing of modalities allowed by the protocol
  • Increased amount of SLED in the intensive therapy group compared to the less-intensive strategy

Some choice quotations from the Hume article:

This report currently should be viewed as the definitive study defining dialysis dosing in critically ill patients with AKI.

During the maintenance phase of AKI, while hemodialysis/hemofiltration techniques are being utilized, the patient dies from multi-organ failure while in exquisite electrolyte and fluid balance.

Our group has focused on 2 major areas of evaluation. The first is the recognition that current renal substitution therapy only provides the small-solute clearance function of the kidney but not the metabolic and endocrine functions of the kidney. Similar to the clinical evidence that kidney transplantation markedly prolongs survival and improves health related quality of life compared to dialysis, the replacement of renal parenchymal cell functions in AKI may change the natural history of this disorder.

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Comment on Loin Pain Hematuria Syndrome

The Renal Fellow Network did a nice pocket review of Loin Pain Hematuria Syndrome recently. However they left off an important diagnosis which also presents with hematuria and unilateral pain, Nut Cracker Syndrome. This refers to impingement of the left renal vein between the aorta and superior mesenteric artery.

These patients usually come to the nephrology office with a history of mysterious kidney stones which have been difficult to visualize.

In Nut Cracker Syndrome the pain is always on the left side.

Nice review with imaging studies are found in this NDT article from 1995.

(a) MRI revealed a dilated left renal vein (black arrows) after passing between the aorta (A) and superior mesenteric artery (white arrowhead).
(b) MRA showed that the diameter of the left renal vein (black arrow) was larger in the left part adjacent to the aorta (A) compared with the right adjacent part. A prominent left ovarian vein (white arrow), implicating formation of a collateral circulation, was also noted. IVC = inferior vena cava.
(c) Digital subtraction MRA found the impingement of the left renal vein (LRV) between the aorta (A) and superior mesenteric artery (white arrowhead).

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Great case in the office


45 y.o. referred for 4+ proteinuria. Patient is asymptomatic without edema but the FLP shows total cholesterol to be pushing 300. The patient reports for one month he has seen bubbles in his urine. A 24-hour urine showed 2,500 mg of protein on an adequate specimen.

PMHx is significant for gout which has been treated with allopurinol without much improvement. Over the last couple of years he has gone from 100 mg to 300 mg, during this time his uric acid has stayed a midling 7-9 mg/dL. Two months ago he was started on probenecid, a uricosuric agent. This is appropriate as his renal function is great (S Cr of 0.9 in a male who works out).

His physical exam is benign.

No additional relevent data can be gleaned from his labs.

What’s the diagnosis?

Proteinuria due to probenecid. The patient stopped the offending agent and within ten days the U/A showed 1+ proteinuria and the PCR was 0.37.

In the exam room I told him it was a membranous nephropathy but according to this letter to NDT from 2007 the pathology is not typically membranous at all. This jives with the rapid recovery from proteinuria after the medicine is withdrawn.

Here is the mechanism of action of probenecid from UpToDate:

MECHANISM OF ACTION — Competitively inhibits the reabsorption of uric acid at the proximal convoluted tubule, thereby promoting its excretion and reducing serum uric acid levels; increases plasma levels of weak organic acids (penicillins, cephalosporins, or other beta-lactam antibiotics) by competitively inhibiting their renal tubular secretion

Cool case.

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Articles that changed the way I practice: Gonzalez and Steroids for AIN

Acute interstitial nephritis (AIN) is a drug induced renal failure.

Patients classically have fever, rash and eosinophilia.

During my fellowship there was little data to support the use of steroids and I came down opposed to steroids. Last year Gonzales Et al. published a retrosprective analysis of 61 patients with biopsy proven AIN. 9 were not given steroids and the remiander were given a hodge-podge of different steroid protocols.

In addition to providing data on the question of steroids the article is a goldmine of data regarding AIN.

The culprit was usually an antibiotic:

  • Antibiotic in 34 cases
  • Cephalosporin in 15 cases
  • Quinolone in 12 cases
  • Penicillin in 7 cases
  • NSAID in 23 cases
  • Allopurinol in 1 case
  • Ranitidine in 1 case
  • Omeprazole in 1 case
  • Pimozide in 1 case

Only 8 patients (13%) had the classic triad of fever, rash and eosinophilia. Table 1:

The key result was a signifigant difference in the need for long-term dialysis and a reduction in the final creatinine with steroids.


The data is not the most compelling (It’s retrospective, the control group was tiny compared to the intervention group) but it is by far best we have on the subject and it changed the way I treat AIN.

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Student lecture on Acid-Base

I gave a lecture to the third-year medical students at Providence hospital on Friday. I thought the lecture went well but on saturday I was going over an admit note by one of the students in the class. The patient was admitted with DKA but had a combined metabolic acidosis and respiratory alkalosis. This student didn’t do the Winter’s formula calculation and missed the respiratory disease. Of course so did everyone else on the admitting team.

Frustrating.

Here is the handout. I added a couple of things since giving the lecture on Friday.

Update: I corrected a mistake in one of the delta bicarb questions. Sorry.

Acid Base Handout (Student)

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Craig Langman’s Editorial on the Melamine Crisis from The Journal


Craig Langman (who has made a previous appearance on PBFluids) wrote an editorial for the Melamine article and pair of letters to The Journal (one from Wang et al. from Taiwan and the other from Ho et al. from Hong Kong).

He recommends the same advice I have been giving for Americans who have adopted Chinese infants:

How should physicians in other parts of the world care for Chinese infants who may have been exposed to melamine-contaminated powdered infant formula? The American Society of Pediatric Nephrology suggests a conservative approach in asymptomatic infants,PDF since stones presumed to have been induced by melamine ingestion appear to be passed easily after hydration, and there are currently no follow-up reports on the children studied by Guan et al. and Wang et al. Performance of abdominal ultrasonography in all potentially exposed Chinese children living in the United States would be likely to cost many millions of dollars, an expenditure difficult to justify, given that both unaffected and affected children may have no symptoms and that the meaning of a stone in an asymptomatic child is uncertain.

Langman emphasizes that each study is unable to estimate a true incidence because the populations studied were not representative of the population at risk.

He also teases the reader by mentioning that stones, which are increasing in frequency among adults, seem to be increasingly common among children. He states that this may be due to dietary and lifestyle issues but doesn’t even entertain the possibility that melamine exposure here in the U.S. and around the world may be responsible. This possibility was first suggested in an insightful article in Slate. We know that melamine is found in the U.S., we don’t know how long it has been here.

My personal sense is that the Slate article is just scaring people unnecessarily. if the increase in stones was do to melamine we would know it. We would know it because stones that are removed by interventions are always analyzed in a stone lab. The stones in China that were due to melamine were made of uric acid and melamine. If even a single stone in the U.S. was found to be melamine the whole medical world would go ape.

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The Jounal Delivers a Bumper Crop of Melamine Articles.

The primary article is an analysis of 589 children by Na Guan

Methods

All of the children’s parents were given a survey to establish demographic data and judge exposure. The investigators questioned parents on the brand and amount of formula ingested and matched it up to government data on the amount of melamine in each brand. Children were then put through varying degrees of biochemical and ultrasound testing.

All the children were under 36 months of age, the population most at risk of melamine stones.

The primary outcome was the presence of kidney stones.
The General Administration of Quality Supervision and Quarnatine of the PRC analyzed 22 brands of formula and reported the amount of melamine. The researchers then categorized each formula as:
  1. High melamine (over 500 ppm)
  2. Moderate melamine (less than 150 pm)
  3. No-melamine.
Ultrasounds were reported as:
  1. Definite stones
  2. Suspected stones (increased sporadic, punctiform echogenicity in the kidneys or pyelocalyceal system)
  3. No stones
Result
The all important table 1.
In 589 exams they found definite 50 stones, 112 suspected stones and 427 children were stone free.

Most of the children with stones did not oliguria, dysuria or edema. Only two of 34 stone formers (6%) had hematuria and only 1 had leukoturia (3%). None of the children with suspected stones had hematuria and only one had leukocyturia (1.3%).

Microalbuminuria was found in more of the children with stones (10%) or suspected of having stones (13.6%) compared to the stone free children (5.6%). Symptoms were not helpful in distinguishing stone formers from the stone free.

Fifty-six children had serum creatinine checked (22 with stones, 21 with suspected stones and 13 without). All of the creatinines were normal.

Interestingly 62 of 404 children had a calcium to creatinine ratio that exceeded age based targets. The 15% rate of hypercalciuria was not associated with stone risk in this study (p=0.34).

In multivariate analysis exposure to high-melamine milk (7x as likely) and pre-term birth (4.5x as likely) were significantly associated with stone formation.

The primary conclusion is that the physical and biochemical lab add nothiong to the evaluation of melamine stones. The birth history and the melamine exposure assessment are critical but need to be followed up by an ultra-sound.

The authors note that only 23 of 121 children exposed to high-melamine formula developed stones

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NephSAP on the iPhone


Last week on the fellow education day we did the ESRD NephSAP. Dr. Bellovich showed me that the complete text is available through iTunes as a podcast. Sweet. I have started to listen to the NephSAP in the car. Seems like a pretty cool way to get the info.