Tag: journal club

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Geriatric nephrology hits the NEJM

The introduction references the following study and states that in 1999:
  • Nursing home residents represented 4% of the people starting dialysis
  • Nursing home residents represented 11% of the people initiating dialysis over the age of 70
  • First year mortality is 35% for patients older than 70
  • First year mortality is 50% for patients older than 78
The investigator used the USRDS and The Minimum Data Set, a database of nursing home residents that all Medicare and Medicaid certified nursing homes must participate contribute to. The study cohort consisted of people who were in the nursing home prior to starting dialysis. Patients were included if they had a functional status assessment prior to initiating dialysis. This resulted in a cohort of 3,702 residents.
Functional status was measured by grading the following skills on a scale from 0 (total independence) to 4 (dependence):
  1. eating
  2. dressing
  3. toileting
  4. maintaining personal hygiene
  5. walking
  6. getting up out of a chair
  7. moving around in bed
Increases in scores A second measure of functional status, MDS-ADL, was also used. Demographic, co-morbidity data was collected from the Form 2728 genereated by the nephrologist at the time of the initiation of dialysis.
200 patients were excluded from the analysis because they failed to have a funcrional status assessment prior to starting dialysis. These patients were healthier than the study cohort. I don’t feel this is a critical bias as this represented a rather small fraction of the cohort. My guess is the results of this study fairly represent the population of dialysis nursing home residents.

The key points are beautifully rendered in two charts. The first shows the mortality of the cohort following the initiation of dialysis:
The bars represent the timing of the ADL assessment. The dotted line is cummulative mortality. The red arrow is the half-life of this population. Half the cohort is dead before 9months!
Looking at the mortality alone one must wonder if the patients are receiving any survival benefit from dialysis. It is hard to imagine the mortality is much worse if they didn’t get dialyzed.
The meat of the article is in next graph that shows the distribution of functional status every 3 months. It goes back a year prior to initiating dialysis and follows forward for the first year after initiating dialysis. Patients demonstrate a stable functional status until the 3 months prior to starting dialysis. In the three months prior to initiation there is some subtle decreases in functional status but that really accelerates as soon as they start dialysis.
The combined end points of death and deterioration are shown in a bleak graph:

What a depressing study, both mortality and morbidity. It forces nephrologists to question the role of dialysis in nursing home residents. This is a population that does terrible on dialysis.
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Journal Club: Aggrenox and AVG for TZDs in HD

Dixon et al. Effect of dipyridamole plus aspirin on hemodialysis graft patency. N Engl J Med (2009) vol. 360 (21) pp. 2191-201 (PDF)

Randomized placebo controlled double blind trial of patients on hemodialysis or to start hemodialysis in the next 6 months with a new AVG.

Primary outcome was loss of primary unassisted graft patency. thrombosis, 50% stenosis. Patients underwent regular site monitoring and referred for angiography if qB was less than 600 or less than 1000 and a greater than 25% reduction of qB.

Power analysis required 1054 patients.

results: 321 randomized to Aggrenox
328 assigned to placebo

No difference in bleeding or cardiovascular events.

Take home message: modest benefit from expensive drug in underpowered but well designed and executed study.

Brunelli et al. Thiazolidinedione use is associated with better survival in hemodialysis patients with non-insulin dependent diabetes. Kidney Int (2009) vol. 75 (9) pp. 961-8 (pdf)

Thiazolidinediones (TZDs)

  • bind peroxisome proliferator-activated receptor gamma
  • increase insulin sensitivity in peripheral tissues
  • increase HDL
  • decrease triglycerides
  • decrease visceral fat
  • improve endothelial function

This study is a retrospective analysis of hemodialysis patients in the ArMORR cohort.
ArMORR is a cohort of incident dialysis patients at FMC units. The total cohort includes 10,044 patients.

This analysis restricted to patients with diabetes surviving at least 30 days on dialysis.

Patients on pioglitazone (Actos) or rosiglitazone (Avandia) were placed in the TZD group. Primary outcome was time to death from any cause. Maximum follow-up was one year.

Results: 5,290 patientss were eligible for inclusion.
9.6% were treated with a TZD


Improved survival was seen among patients on TZDs, especially patients not also on insulin. Interestingly the survival benefit came from a reduction of non-CV end-points.

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Journal Club: ECLIPSE Trial and Membranous Lupus

Clevipidine
Aronson et al. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg (2008) vol. 107 (4) pp. 1110-21

Clevipidine is a short-acting, IV, calcium channel blocker licensed for blood pressure control. The ECLIPSE Trial is a randomized, multi-center, open-label, prospective trial of perioperative blood pressure control for cardiac surgery. clevidipine was compared to nitroglycerine, sodium-nitroprusside and nicardipine in three parallel trials. The primary outcome was safety with a secondary outcome of efficacy.

Efficacy was measured by a method I have never seen before. The key measure of efficacy was keeping the blood pressure in the normal range so the authors measured the area under the curve for time versus SBP outside of the target blood pressure:

The authors found no difference in safety among the four drugs, though there was a pesky P=0.04 for increased death with sodium nitroprusside compared to clevidipine:

Clevidipine was significantly more efficacious than all competitors as individuals (except nicardipine) and when compared to all comparators.

Lupus Membranous Nephritis
Austin et al. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol (2009) vol. 20 (4) pp. 901-11

Prospective randomized controlled trial to compared cyclosporin for 11 months, to alternate-month cyclophosphamide for 11 months, to alternate-day prednisone alone.

Primary outcome was time to remission (less than 0.3 g of protein).Both CSA and prednisone were significantly better at achieving remission (complete and partial) than oral prednisone:
As we have seen in prior trials of cyclosporin in proteinuric renal disease (see FSGS), when the cyclosporin is stopped the proteinuria returns:
A well done, but small trial. Good to see an RCT in this rare entity because evidence based data on how to handle membranous lupus has been scant.

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Journal Club: Dry weight adjustment in dialysis

Agarwal continues his streak of important studies on blood pressure in dialysis patients. This study shows that reducing the dry weight results in reductions in ambulatory blood pressures done between dialysis sessions. Agarwal had previously demonstrated that in-center blood pressure readings poorly correlated with ambulatory blood pressure. One of the key findings was that the systolic fell twice as much as the dialtolic blood pressure. This means they did not only reduce the blood pressure but they also reduced the pulse pressure, something which we really are unable to do with antihypertensive drug therapy (which reduces both the systolic and diastolic blod pressure and have little affect on the pulse pressure).

Personal note: Agarwal was one of my attendings when I was a resident and wrote one of my letters of recommendation for fellowship.
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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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Journal Club: Aspirin and FGF-23

The first article was an intriguing look at various renal function parameters and how they respond to various doses of aspirin. All the patients were pre-treated with enalepril and a thiazide diuretic for 6 days. Then they were given one of four doses of aspirin:

  1. placebo
  2. 80 mg
  3. 160 mg
  4. 320 mg

They found decreased GFR, decreased sodium clearance, decreased solute clearance and decreased free water clearance with 160 mg and 320 mg but the effect was transient with all factors returning to baseline 4 hours after the aspirin was administered.

The article has a long introduction and discussion outlining all of the heart failure studies which have shown that aspirin can be harmful or can decrease the effectiveness of ACEi in heart failure.

The study is small (n=16, with each participant randomized to two doses of aspirin with a 2 week washout between doses) and the authors fail to fully describe the cohort. The primary weakness is the authors want to extrapolate there findings over 6 hours to the effect of aspirin taken chronically for years. Additionally they make the leap of using aspirin-induced changes in renal function to be a proxy for interference with ACEi effect on heart failure survival.

Nonetheless it will change the way I practice. I had previously given my patients (who essentially all are on diuretics and ACEi) the green light to take aspirin any way they want. I will now suggest they limit themselves to 81 mg for CAD protection.

The second article was the NEJM article on FGF-23 and the risk of mortality in hemodialysis patients. FGF-23, or fibroblast growth factor-23, is a newly discovered molecule which regulates the phosphorous in the body. It is one of the primary phosphatonins, signals which increase the renal excretion of phosphorous. Additionally they suppress 1-alpha hydroxylase lowering the amount of 1,25 dihydroxy-vitamin D.

This is prospective cohort with nested case-control of incident dialysis patients in the U.S. The investigators looked at 200 patients who died (cases) in the first year and compared them to 200 patients who survived one year (control). FGF-23 was measured on the first day of dialysis. They divided the cohort into quartiles based on phosphorous and found that patients who subsequently died had increased FGF-23. They found a graded increase in the risk of death with increased FGF-23 level that was signifigant in the whole cohort and inevery quartile of phosphorous except the highest.They also showed a dose responce of mortality to FGF-23 levels in the whole cohort in the crude data, case-mix adjusted and multivariate adjusted.


The authors in the discussion point out that the association of FGF-23 with mortality is stronger than that found with phosphorous and mortality. They found FGF-23 levels were 22% lower in African-Americans than in Caucasians. The authors leave a tease that this lower level of FGF-23 level may explain the improved survival found in African Americans on dialysis.

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Journal Club: Bicarb for contrast nephropathy and calcitriol for CKD 3 and 4

The first article was a retrospective study on the use of calcitriol in patients with CKD stage 3 and 4. The outcome was mortality and mortality plus dialysis. The authors were able to demonstrate a significant reduction in both outcomes with the use of calcitriol. Some interesting points were the lack of a dose effect and the effect was independent of PTH. The authors suggest that the benefit of activated vitamin D therapy is not due to its affect on PTH.

Association of oral calcitriol with improved survival.

The second article was the latest study on contrast nephropathy.

Sodium bicarbonate vs sodium chloride.

This well done randomized, single-blinded, controlled trial showed no difference between isotonic NaCl and nearly isotonic bicarbonate.

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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.

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Teaching on the Consult Service: ARF The PICARD Study Group

The first article that was pulled from the reading sessions in NephSAP is this retrospective review of ARF by the PICARD Group.

PICARD Study

The introduction begins by setting the scene: Acute renal failure is lethal with over 50% mortality in most series. Additionally, we haven’t seen any major improvement in mortality for these patients in the last 30 years. Then they authors state that the ANP ARF trials were well designed. This is almost laughable as the ANP trials are the poster child on how not to do a clinical trial on ARF. After that they go over the fact that ARF research is hard because the patients are sick and we lack a standardized methodology for talking about the severity of illness. APACHE II scores are notoriously bad at predicting mortality in renal failure. And the storied Cleaveland clinic ARF score has not been validated outside that institution. Then the authors layout the problem they are trying to answer:

To prepare for future clinical trials in ARF, it is essential that valid, generalizable models for risk adjustment be developed, both for stratification in patient selection and for covariate adjustment in the event of imbalanced randomization.

So in order to accurately risk stratify patients and successfully balance study groups we will not be able to properly evaluate new therapies. This study group was created to do a RCT of CVVH vs IHD and hence captured lots of prospective data of patients in ARF. Only 166 of the 851 were enrolled and randomized in the trial (negative and tragic because they were unlucky with their randomization and they had a significantly higher severity of illness in the CVVH group.). This paper uses all 851 patients to look for predictors of mortality in ARF.

Enrollment criteria:

  • ARF + ICU + Nephrology consult
  • No CKD Cr > 2 or BUN > 40
  • CKD: Cr increased by 1.0
  • No prior dialysis, kidney transplant, obstructive uropathy or pre-renal azotemia

Severity of illness scores (they calculated 13 different scores besides creating their own score) were calculated on the day of nephrology consult. Using the day of consult seems arbitrary and prone to variations in local practice patterns, i.e. if the study is done in an area where early consult is the norm then presumably the patients will have less severe disease and hence have better outcomes, hence a score derived with this methodology will underestimate the mortality in a center with a culture which leans towards later consultation (and presumably sicker patients).

After excluding subjects that had missing data that prevented them from calculating the scores they were left with a cohort of 605 patients.

Half of the cohort received dialysis while in the ICU and 51.9% died in the hospital.

They created a risk score based on:

  • Age
  • Gender
  • Respiratory failure
  • Liver failure
  • Hematologic failure
  • Creatinine
  • BUN
  • Log urine output
  • Heart rate

They then showed that their new model beating the crap out of the old models with an AUC on the ROC of 0.832. The best other scoring system, SAPS2, received only a 0.766. The APACHE II had an AUC of only 0.634. (Perfect AUC is 1.0 and a worthless value is 0.5).

The biggest weakness is that the Mehta score (the eponyminous name for the score created with The PICARD Data) was able to predict outcomes well when you tested it using the data used to define the score. This is the ultimate home field advantage. Levey in the MDRD group divided their cohort into a derivation group and a validation group. This current authors did not do that.

This will be a moot point if the score is validated in a new independent study. I wonder if the ATN group did that? I bet they did, or will publish on this soon.

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Journal Club: Albuminuria

Today’s journal club was on Aliskiren (Tekturna)combined with Losartan versus Losartan alone from the NEJM and Benazepril + Amlodipine (Lotrel) versus ACEi + HCTZ (Lotensin HCT) from KI. Both studies use change in albuminuria for the primary endpoint.

The Aliskiren study had an expected outcome. The shocker would have been if it had gone the other way. The surprising thing was how close they came to showing an actual decrease in progression (p=0.07) in only 6 months and with only 600 patients. Looks like aliskiren + ARB is a lock to slow the progression to doubling of creatinine and prevention of dialysis.

The Guard study was a surprise because the old generic lowered albuminuria more than the new hotness Lotrel. A lot of spin in the discussion on why that may have occurred.