Tag: acute kidney injury

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Monday was the highest traffic day on this site. Ever.

My post on Everything I learned in fellowship is wrong was featured on the home page of renalWEB.

It feels weird that my post was listed at the top under “News Headlines.” The ATN article came out in July and I just got around to writing about it six months later. I wrote it so that when I discuss the findings on rounds, I have a way to quickly find an abstract of the study with my personal observations. And I will discuss it with the fellows because even though the study was a negative study it is a benchmark study in nephrology. The article is a negative study but it is negative in the way that HEMO was negative, not the way that DCOR was.

  • HEMO is usually listed as a disappointing study because we were not able to help patients by ratcheting up their dose of dialysis from 1.16 to 1.53 (eKt/V).
    But as Glen Chertow argued persuasively, the HEMO trial was a triumph of evidence based medicine. We were able to definitively argue against the desire to incrementally enhance three-times a week day-time dialysis. The increasing evidence for daily and in-center nocturnal dialysis are by-products of the failure of HEMO. If HEMO had been a positive trial we would probably be focusing on a HEMO II with a targetted eKt/V of 1.8. The negative result has sparked innovation and a search for novel ideas.
  • DCOR on the other hand has almost nothing definitive to show despite being “the largest outcomes study ever done in the hemodialysis population.” The failure of DCOR can be attributed to a low event rate, a high but undefined cross-over rate and a 50% drop-out rate. All of these conspired to produce an under-powered study and clinicians are left in a sea of phosphorous binder marketing without near term hope for better guidance.

So the negative finding of the ATN group advances the science of nephrology, removes an important question and will allow us to move on to new strategies to help patients with acute kidney injury.

A final note to the editor of RenalWEB, my bullet on the dose of dialysis referred to the HEMO trial, which did not look at frequency of dialysis or radical increases in dose. The jury is still out on those techniques but I’m with you. Those two strategies seem right and beneficial.

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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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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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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.

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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.

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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

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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.

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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.

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Hepatorenal syndrome Journal Club

Journal club today reviewed this article on the treatment of hepatorenal syndrome (HRS) with terlipressin. What a breath of fresh air in the field of HRS, a real randomized double blind placebo controlled trial!

Terlipressin is part of the new wave of HRS that focus on splanchnic vasoconstriction to reverse one of the initiating events in the pathologic cascade that results in HRS. I have been using the combination of octreotide and midodrine to exploit the same therapeutic target. I have had mixed results. I am not aware of any prior controlled trials of this therapeutic target.

Enrollment criteria:

  • Age ≥18
  • Liver disease
  • Doubling of serum cr to ≥2.5 mg/dL in less than 2 weeks with no responce to stopping diuretics and giving plasma expansion

Exclusion criteria

  • Obstructive nephropathy
  • Parenchymal renal disease (ATN, glomerular disease, interstitial nephritis)
  • Use of renal toxic medications
  • Shock
  • Uncontrolled bacterial infection
  • Uncorrected fluid losses
  • Liver disease due to factors which are also nephrotoxic (e.g. acetominophen)
  • Severe cardiovascular disease (investigators discretion)

Intervention: Patients were randomized to either 1 mg terlipressin q6h or matching placebo. If after 3 days the patients had not had a decrease in Cr of 30% the study drug was doubled to 2 mg q6h. The protocol recommended daily albumin infusions (100 g on day one and 25 g daily after that). The protocol prohibited concomitant use of vasocontrictors (dopamine, norepinephrine) prostaglandin, NSAIDs.

Primary end-point: percent of patiens with a serum Cr ≤1.5 on two measurements 48 hours apart without dialysis, death or recurrence of HRS.

Secondary end-points:

  1. Change in serum Cr from baseline to day 14
  2. incidence of treatment failure (Cr ≥ baseline after day 7, dialysis, death)
  3. Combined incidence of treatment success and partial response (Cr decreased by >50% but not ≤ 1.5) without diqalysis or recurrence of HRS
  4. Survival [Yay!] at 60 days (though they did not show the results)
  5. Transplant-free survival at 60 days (though they did not show the results)
  6. Survival at 180 days
  7. Transplant-free survival at 180 days

Results:

They randomized 112 patients from 35 centers.
More patients in the terlipressin group had a Cr > 7, though the average creatinine was 3.96 in the experimental group and 3.85 in the control group.

The Table 1 did not have p values to allow you to compare differences between the two groups.

The primary outcomes were summarized in Table 2:
The primary outcome is the first line “Treatment success at day 14” and unfortunately they “Missed it by that much” with a p value of 0.093. The next line is HRS reversal which according to the article is the traditional definition of response to therapy in prior investigations of HRS. It is interesting that if the authors had used this “traditional” end-point we would be dancing in the streets about a positive therapy but since they selected a more stringent criteria of response (under pressure from the FDA?) they have a negative trial. The power analysis they provided states they predicted a 50% response rate for terlipressin and a 5% response for the placebo. They actually found a 25% response for terlipressin and 12.5% for placebo. So one cold look at this as an underpowered study because they did not meet the effectiveness they estimated in the power analysis.

The authors then provide an intriguing figure which shows that the patients who recovered in the placebo group, all recovered very early while the recoveries in the terlipressin group occurred through the period the drug was administered.
I believe the point was to show proof of efficacy, implying that the early spontaneous recoveries in the placebo group were due to misdiagnosis or lack of serious disease while the recovery of patients in the terlipressin’s group increased with increasing duration of therapy. I find this fairly compelling.

One of the secondary outcomes was survival (Yay!). There was no difference in survival between the two groups.

Though I love investigators that have the cojones to look at survival, it is a little strange in HRS because the renal failure is secondary to another life threatening primary illness, liver failure. Even if the therapy is perfectly effective at reversing the renal failure, the long-term survival is dependent on getting a liver transplant or spontaneous recovery of the liver disease. One might argue that curing the renal failure would extend the life of the patient making a transplant more likely but since renal failure is a large component of the MELD score, curing the renal failure actually pushes patients down the list for a liver transplant. So in my mind, the lack of a survival benefit in the treatment of HRS is not nearly as damaging as it normally is.

My final conclusion is that though the study did nt reach scientific signifigance for its primary outcome it did demonstrate compelling evidence for positive biologic activity and since all of the alternative therapies have worse data I would use terlipressin if it was available. My guess though is this negative trial will mean that it will not be licensed and distributed in the U.S.