Tag: dialysis

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Journal Club: dialysis time, not the critical factor in graft survival

One of the inherent truths in transplant is that the longer someone is on dialysis the worse the outcome after transplant. Patient with higher dialysis vintage prior to transplant are more likely to lose their graft and die following transplant. This was first shown by Cosio Et al. and subsequently verified by other researchers.

Cosio’s primary figure showing dramatically increased mortality with increasing time on dialysis

Though Cosio et al. was the first (?) to find this association the most elegant data comes from Meier-kreiesche, Et al. who looked at graft survival when a paired sets of cadaveric kidneys is donated to recipients with differing duration of dialysis. By looking at paired kidneys they were able to neutralize any confounding factors from the donor. The primary analysis looked at kidneys that were split between one recipient with less than 6-months of dialysis and another with more than 2-years of dialysis. The end-point was graft survival:

They also calculated patient survival and they likewise found a significant splay based on time on dialysis:

Five- and ten-year unadjusted overall patient survival for paired kidneys was 89% and 76%, respectively, in the group on dialysis less than 6 months compared to 76% and 43%, respectively, in the group on dialysis for more than 2 years (P<0.001 each).

The obvious implication was that dialysis was bad for you. The longer you were on dialysis the more baggage you were carrying at the time of transplant and that baggage comes back to haunt the recipient with a shorter life and shorter kidney survival. From the conclusion:

…the longer patients wait on dialysis for a transplant the longer patients are exposed to the chronic effects of end-stage renal failure and dialysis. It is well documented that patients on dialysis have alterations in the concentration of a number of substances (e.g., homocysteine, advanced glycosylation end products, and lipoproteins) that may predispose these patients to both cardiovascular and renal allograft vascular damages. In addition, the poor nutrition, chronic in- flammatory state, altered immunologic function, and inade- quate clearance that often accompanies patients with ESRD on dialysis may predispose these patients to poorer toler- ance to the immunosuppressive agents after transplantation.

On our journal club last week we looked at a study by Schold, et al. that analyzed time on dialysis prior to transplant by dividing it into time prior to wait list and time after being listed. They found that all of the risk from prolonged dialysis comes from the time prior to being placed on the transplant wait list:

The data was more dramatic for graft loss than for mortality. The intersting part of this is trying to explain this discrepancy.  Why would time on dialysis prior to wait listing be any different that time on dialysis after wait listing? There is no biological difference so the authors conclude that the difference must be in a subtle, previously unmeasured difference in co-morbidity or access to care. The authors go on to pre-suppose that efforts to reduce patient exposure to dialysis may not yield the benefits one might expect if these other factors are not also corrected.

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Hyperkalemia as an indication for dialysis

A few weeks ago we admitted a patient who has been approaching ESRD for a number of years. Most of her medical care had been provided in the hospital as she bounced from admission to admission. Though we tried to get her into our CKD clinic she always failed to show up. You can track the progression of her CKD from hospitalization to hospitalization with a gradually increasing baseline creatinine.

On this most recent admission, she came in with the triple 8s:

  • Hemoglobin 8.8
  • Creatinine 8.1
  • Potassium 8.6

Here is her initial EKG with that potassium:

The most remarkable part of the EKG was the profound bradycardia, heart rate of 30. Also she has beautifully peaked T waves. I’m surprised by the lack of a prolonged QRS. She had a great response to medical management with her K falling to the 5s. The repeat EKG was rather unremarkable.
The patient received dialysis on the day of admission and the following day I set her up for chronic dialysis. Whenever a patient progresses to chronic dialysis from CKD I always try to remind myself of how rare this event is. As nephrologists it is too common and seeing that unfortunate outcome alters our perception so that we may overestimate its frequency. End-stage renal disease is an exceptional, not a routine outcome of CKD. The vast majority of patients with CKD ultimatly expire of something other than renal failure. Let’s review three important studies to emphasize this:
Keith et al looked at the five-year outcome of 28,000 patients with chronic kidney disease. He divided them by CKD stage and found that of the 11,278 patients with CKD stage 3, only 1.1% of then received dialysis and 0.2% received a transplant. A quarter of them died (24.3%). The authors summarized the results:

The likelihood of renal replacement therapy, either transplant or dialysis, was near zero (≤1.3%) for patients in all stages except stage 4, where 2.3% ± 1.1% of patients received a transplant and 17.6% ± 2.7% had dialysis initiated.

Eriksen et al found similar results in a 10-year study, with a 4% risk of renal failure for patients with CKD stage three compared to a 51% risk of death.
And lastly, O’Hare, et al’s VA study that looked explicitly at renal failure and the competing outcome of death. They asked, “At what age and GFR is renal failure more likely than death?”. Obviously, at a younger age, when death is a more remote possibility, a higher GFR will have the time to deteriorate to the point of requiring renal replacement therapy. The results showed surprisingly low GFRs:
To read the graph, find your patients age and then line it up with their GFR. If the intersection is in the black, they are more likely to die, if it is in the grey then hello Mr. Fresenius, nice to meet you Ms. Tacrolimus. Note, that in a 75 year old with a GFRas low as 16 mL/min, death is still more likely than ESRD.
So, the next time you see a patient initiating dialysis after a long run of chronic kidney disease don’t be frustrated by the fact that they didn’t do enough to prevent this, be amazed that they survived to this outcome. 
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My first shot at a nephrology checklist

This month I am attending on the dialysis floor. As you can imagine it is a high volume experience with a lot of patient turnover. Patients get admitted from six or seven large dialysis units around the area and our group alone has a dozen nephrologists. This leads to communication problems. Coordinating care with the dialysis units, the outpatient nephrologists, the specialists and primary care docs; it can be overwelming.

This checklist actually acts more as a list of important contact numbers for each patient. Gawande, specificaly mentions that improved communication is one of the key ways that checklists improve outcomes.

At the bottom are some basic items that all dialysis patients need and can get missed on a busy service.

It is all contained on a 3×5 card.

Admitting Checklist 4up


The native Pages file (.zip)

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I’m reading the January NephSAP on primary care for the working nephrologist

There is some great stuff in there. This line on the futility of cancer screening among dializers struck me as particularly interesting:

[Kajbaf et al.] calculated the maximum increase in life expectancy (for a 60-yr-old woman) from routine Papanicolaou (Pap) testing and mammography to be 3 and 2 days, respectively.

Wow. (Ref PDF)

I feel like dialysis is always geting beat up over the high yearly mortality rate, and admittedly it is high. So it was interesting to see this table of some other conditions and there associated mortality. I didn’t realize dialysis had such familiar company.

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Monitoring therapeutic Dilantin in renal failure requires looking at the free not total Dilantin.

My fellowship director was the Great Brain, Dr Patrick Murray. Pat is quadruple boarded:

  1. internal medicine
  2. critical care
  3. nephrology 
  4. clinical pharmacology

Pretty intimidating. (If you have the time, check out his 179-slide presentation. Wow!)

One of the side effects of doing my fellowship under a professor in clinical pharmacology is that I learned more about drug monitoring in renal failure than any innocent nephrology fellow should.

One of the pearls he taught regarded the monitoring of therapeutic Dilatin (phenytoin) levels. the Renal Fellow Network discussed Dilantin pharmacokinetics twice but neither of the posts noted the change in protein binding that occurs with renal failure.

Dilantin is highly protein bound (90%) and only the free dilantin is therapeutically active. Uremia is associated with plasma molecules which displace Dilantin from albumin. This increases the active fraction of Dilantin, so sub-therapeutic total levels of Dilantin may represent appropriate free levels in the presence of renal failure.

I currently have a dialysis patient in the ICU who was seizing following a cardiac arrest. He was loaded with Dilantin and a few days later his labs showed:

Total phenytoin level of 5 mcg/mL, below the therapeutic target of 10-20. Simultaneously his free level was 1.14 mg/L. (Rant: How can the EMR express the total level as mcg/ml and the free level as mg/L. THEY ARE EQUIVALENT. Don’t hide it.)

So in this case the free dilantin is 23% of the total, rather than the normal 10%. Note that the total level appears sub-therapeutic but this patient would be poorly served by a re-loading of Dilantin as his free level is therapeutic.

Summary: in uremia always use the free dilantin level and don’t trust the total Dilantin level.

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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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What’s new in Potassium: sudden cardiac death

As the Nephrology Fellow Network recently covered the etiology of cardiovascular disease in dialyzors is unique from the general public. Use of statins, the foundation of preventative cardiology, has repeatedly failed to prevent cardiovascular vascular disease (CVD) among dialyzors. One reason for this, is the propensity for these patients to die of sudden cardiac death (a lethal heart rhythm requiring a shock of electricity or luck to reverse) rather than acute myocardial infarction (heart attacks). In this study (PDF), from Italy, the investigators found that nearly half of the cardiovascular deaths were due to sudden cardiac death (SCD). The authors retrospectively looked at their data to find risk factors for SCD.

They prospectively looked at 476 patients in 5 Italian hemodialysis units. The cohort was tracked for 3 years and had 167 deaths (35%), 32 due to SCD and 35 due to other CVD. On multivariate analysis they found the following risk factors for SCD:
As important as what was significant, is what was not significant. Left ventricular hypertrophy, heart failure and valvular heart disease, all important risk factors for SCD among non-dialysis patients were not associated with SCD in their cohort.

The most interesting analysis was when they parsed out the day of the week the patients died of SCD. Instead of looking at the absolute day they related the day to the patients dialysis schedule. I have modifed their chart to reflect this, with twin X-axis: one for MWF and another for TTS patients.
The red line indicates how high the bars would be if there was no relationship to the dialysis schedule. The highest risk periods were the 24 hours before dialysis at the beginning of the week and the 24 hours after the dialysis at the beginning of the week. Not dialyzing for the two days over the week-end put patients at risk for SCD both before and after subsequent dialysis.

This sounds like an electrolyte associated complication rather than a uremic toxin because of the risk after dialysis, indicating the change in the toxin, not just the high level, is a risk-factor. This is supported by studies (1, 2) of potassium modeling in which the potassium in the dialysate is lowered sequentially during dialysis. By modeling the potassium, the speed of potassium removal is decreased. This has been shown to decrease pre-mature ventricular contractions (a benign momentary disturbance in the heart rhythm that is being used as a proxy for more serious arhythmias, like SCD. Medicine has gotten in trouble with this proxy in the past so it may not be appropriate.).

Summary: modestly high potassiums are associated increased SCD and the two day dialysis holiday on traditional three day a week dialysis is likewise associated with SCD. Hello daily dialysis!

The lecture on Potassium that this entry was drawn from:

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Statins fail again

Statins have a tortured relationship with nephrology. Our patients have accelerated atherosclerosis and they die overwhelmingly of cardiovascular disease. So one of my primary jobs is to continually optimize cardiovascular risk factors to save my patients

Control blood pressure, start an aspirin, and maximize the statin are the lather, rinse, repeat of my world.

That said we have little data that this makes a whit of difference, at least in our dialysis patients.

Aspirin

  • No randomized trials have been done on the role of aspirin to prevent cardiovascular events among dialysis patients.
  • Aspirin was found to increase acute coronary syndrome in an unbadjusted analysis but was not significant in multivariate analysis.
  • Berger et al. (PDF), however found a dramatic reduction in 30-day mortality for patients with acute myocardial infarction given aspirin. Unfortunatly fewer dialysis patients received ASA and other standards of heart-attack care (beta-blocker and ACEi) than patients not on dialysis.
The survival of patients based on whether they received ASA for their acute MIThe use of standard therapies for acute myocardial infarction was lower among dialysis patients, even patients deemed ideal candidates for the therapy.


Blood pressure

  • Hypertension, along with cholesterol and obesity, is subject to reverse epidemiology in dialysis patients. This means that observed epidemiology trends are the opposite of what you would expect from data on non-dialysis patients. Lower blood pressure leads to high mortality, lower cholesterol leads to higher mortality, increased BMI yields better observed survival. The observational data, however, does not mean that interventions to lower blood pressure will lead to the same bad outcomes.
  • A recent meta-analysis (PDF) of 8 randomized trials of anti-hypertensive therapy gives credence to the practice of treating hypertension in dialysis patients.

  • One thing high lighted by the trial, though, is the paucity of evidence for this treatment: They were able to find only 1,679 patients. Terrible.

Statins

  • The 4D study is one of the few randomized controlled trials in dialysis patients and unfortunately did not show any improvement in mortality with atorvastatin. The study randomized 1,255 hemodialysis patients to either 20 mg of atorvastatin or placebo. After 4 years they found the statin was safe and effective in reducing the median serum LDL cholesterol level by 42%. However, the primary endpoint—cardiac death, nonfatal MI, and stroke—was reduced by insignificant 8% (P=0.37).

  • The authors found a significant increase in fatal strokes among the patients randomized to atorvastatin. (RR 2.03, P=0.04).
  • Today came word that another randomized controlled trial on statins among hemodialysis patients, AURORA, was also a bust. Published yesterday in The Journal, AURORA randomized 2,776 dialysis patients to 10 mg of rosuvastatin (Crestor) or matching placebo. The end-point was a composite of CV death, non-fatal MI, and non-fatal stroke. Average follow-up was 3.8 years and there was no difference in the primary outcome (396 outcomes with rosuvastatin versus 408 on placebo, P=0.51).

  • AURORA found no increased risk of strokes as found in the 4D study.
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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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Lead time bias

As I go through the literature on early nephrology referral, I am troubled by the possibility of lead time bias. This was a large issue in the debate surrounding the optimal time to initiate dialysis. The problem comes from measuring survival from the initiation of dialysis.

Patients with good nephrologic care regularly get started on dialysis earlier than their counterparts with poor or non-existent CKD care. This is evidenced by the lower creatinines at the time of initiation of dialysis in patients with early referral seen in multiple studies.

This is consistent with my practice where I tell my patients that we “…want to delay dialysis as long as possible, but not longer than possible…” because if they have profound malnutrition or advanced heart disease due to the delay of dialysis they will do poorly once they transition to dialysis.

Because of this skew in the initiation of dialysis it is important to account for that in any analysis of survival on dialysis. I hope this short slide show makes this clear.

Note: I do not know if lead time bias is responsible for the prolonged survival with early referral to nephrology I just know that it needs to be accounted for and most literature ignores this potential source of error.