AKI QUIZ

32 yo man presented with kidney failure.  His tox screen was positive for cocaine. He was normotensive and physical exam was unremarkable. BUN was 52 mg/dL and Cr 8.1 mg/dL.  Sodium was 139 mEq/L, potassium 4.9 mEq/L, chloride 103 mEq/L and bicarbonate 17 mEq/L.  Calcium was 8.0, Urinalysis had 1+ protein, 3-5 WBC/hpf and 1-3 RBC/hpf.  Envelope shaped and needle-like crystals were noted on sediment. Renal ultrasound was negative for obstruction.

The renal biopsy proves that the diagnosis is:

A. Kappa light chain cast nephropathy

B. Acute phosphate nephropathy

C. Ethylene glycol toxicity

D. Primary hyperoxaluria, Type I

E. Rhabdomyolysis

Dear Mr President: "Tear Down This Wall"

President Barack Obama

"The Immunosuppression Coverage Wall"

The White House

Washington D.C. 20500

Dear Mr. Obama,

We cheered you when, against the odds, you introduced health care reform. Now we need your help in supporting a bipartisan effort on behalf of kidney transplant recipients.

As you know, since 1972 Medicare has covered patients with end-stage renal disease (ESRD). While there is no Medicare time limit for coverage of a dialysis patient, kidney transplant recipients lose their Medicare coverage 36 months after a transplant¹. Medicare covers 80% of immunosuppressant costs for 3 years post-transplant, while patients and/or insurers cover the rest. Patients who are >age 65 and/or disabled are legally exempt from these limitations in coverage.

On September 20^th 2011, Congressman Michael C. Burgess, M.D. (R--Texas) and Congressman Ron Kind (D--Wisconsin) introduced the “Immunosuppressive Drug Coverage for Kidney Transplant Patients Act” (H.R. 2969). 

U.S. Senators Dick Durbin (D--Illinois), Thad Cochran (R--Mississippi) and Scott Brown (R--Massachusetts) have introduced companion legislation in the Senate.

This bipartisan legislation will allow individuals who are eligible for immunosuppressive drugs under Medicare Part B to continue to receive their vital treatment past the 36-month cutoff. The proposed legislation has the strong support of the American Society of Transplantation, the National Kidney Foundation, Dialysis Patient Citizens, among others.

The current system increases the risk of patient's stopping their immunosuppressive drugs and losing their kidney graft because they are unable to cover the costs of their immunosuppressant’s following loss of Medicare coverage. This is a particular problem for low income and minority patients. Extending Medicare coverage for immunosuppressive drugs would prevent this from happening.

Reducing the number of kidney transplant patients returning back to dialysis makes both clinical and economic sense¹. Kidney transplantation provides superior outcomes and better quality of life as compared to chronic dialysis². Transplantation is also nearly 8 times less expensive than chronic hemodialysis^3,4. Having patients return back to the transplant waiting list and go in line again for a re-transplant makes no sense – aside from the human cost, it increases overall health care costs and escalates an already critical shortage in kidneys.

Respectfully,

__________________

References

1. Gordon EJ, Prohaska TR, Sehgal AR. The financial impact of immunosuppressant expenses on new kidney transplant recipients. Clin Transplant. 2008 Nov-Dec;22(6):738-48. Epub 2008 Jul 31. PubMed PMID: 18673373; PubMed Central PMCID: PMC2592494.Open access

2. Laupacis A, Keown P, Pus N, Krueger H, Ferguson B, Wong C, Muirhead N. A study of the quality of life and cost-utility of renal transplantation. Kidney Int. 1996;50:235. [PubMed]

3. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341:1725. [PubMed]

4. Loubeau PR, Loubeau JM, Jantzen R. The economics of kidney transplantation versus hemodialysis. Prog Transplant. 2001;11:291. [PubMed]

Editorial

Wait Wait… Don’t Tell Me - Is More Dialysis Better?
Ajay K. Singh, MBBS, FRCP, MBA 
Brigham and Women's Hospital/Harvard Medical School

In the United States, on National Public Radio there is a cute little radio show called Wait Wait Don’t Tell Me. It pits your knowledge against some of the best and brightest in the news and entertainment world while figuring out what's real news and what's made up. Well, in the world of kidney failure, the real news is that dialysis dose does matter and that more is better. In my view, what’s made up is that a urea reduction ratio (URR) of >65% or kT/V>1.2 is "adequate dialysis".

Could shortening the interdialytic interval by adding one or more dialysis treatments to the schedule make a difference? Yes, the evidence from Foley and co-workers (1) that was published in the New England Journal of Medicine presents a compelling case for changing the way we currently schedule dialysis. The authors discuss the importance of more frequent dialysis. Perhaps abrupt volume changes (going from too much volume to perhaps too little) and/or solute (changes in potassium or middle or small molecules) might be important after all. I discussed this paper here a few days ago.

Treatment of pregnant patients with more dialysis is better for both maternal and fetal outcomes. Both nocturnal dialysis and daily dialysis seem to result in better outcomes compared to thrice weekly dialysis; and a higher dose of dialysis does seem to make a difference. Two recent papers make this point (2,3) [discussed on this site yesterday], and the standard of care is now to provide 20 to 24 hours each week of high flux dialysis to pregnant patients – whether it’s regular or nocturnal delivery of dialysis (4). Of course, like Johnson and Johnson baby oil, one could also argue that if it’s good for babies it can’t be half bad for adults.

The paper in the New England Journal of Medicine by Glen Chertow and colleagues (5) provides strong evidence that greater frequency of dialysis improves outcomes. Chertow and colleagues published the Frequent Hemodialysis Network’s Daily Dialysis Trial. This was a prospective, multicenter, parallel-group clinical trial randomized of 245 dialysis-dependent adults who were randomized to either frequent (6 times per week) or standard (3 times per week) in-center hemodialysis for one year. What did they find? Frequent dialysis was significantly superior for both co-primary outcomes: The composite of death or change in left ventricular mass (“death/LVM”; Hazard ratio 0.61, 95%CI 0.46-0.82), as well as the composite of death or change in RAND Physical Health Composite from the SF-36 (“death/PHC”; HR 0.70, 95%CI 0.53-0.92). Secondary outcomes of hypertension and hyperphosphatemia were also improved, although patients in the frequent hemodialysis arm were more likely to undergo vascular access interventions (HR 1.71, 95%CI 1.08-2.73).

Of course you should ask how much evidence is there to indicate that more dialysis is better? Cited in the References section are a handful of studies that suggest exactly that (6-9), and I’ve only scratched the surface in reviewing what is out there.

What about the results of the HEMO study? It was also published in the New England Journal of Medicine (10); 1846 patients undergoing thrice-weekly dialysis were randomly assigned (using a two-by-two factorial design) to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer. In the standard-dose group, the mean (±SD) urea-reduction ratio was 66.3±2.5 percent, the single-pool Kt/V was 1.32±0.09, and the equilibrated Kt/V was 1.16±0.08; in the high-dose group, the values were 75.2±2.5 percent, 1.71±0.11, and 1.53±0.09, respectively. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment: the relative risk of death in the high-dose group as compared with the standard-dose group was 0.96 (95% CI, 0.84,1.10; P=0.53), and the relative risk of death in the high-flux group as compared with the low-flux group was 0.92 (95% CI, 0.81,1.05; P=0.23). However, the HEMO study evaluated the intensity of dialysis not its frequency and not total duration of dialysis. In fact, as Chertow and colleagues mention in their paper in NEJM: “solute removal can be dramatically augmented by increasing the frequency of hemodialysis sessions” (11).

The truth is that many nephrologists are adding their support to the idea of longer and/or more frequent dialysis (12,13). An excellent review by JR Lacson and Mike Lazarus published in March 2011 makes a persuasive case (14). 

About 8 years ago, I visited Andreas Peirratos in his dialysis unit at Humber Hospital in Toronto Canada and interviewed several of his patients on nocturnal dialysis. While not a scientific study, I came away convinced that longer dialysis makes a difference, and should be offered to patients, and most importantly, should be reimbursed. Andreas Peirratos is a spectacular kidney doctor, and his 14 year experience is published elsewhere (15). 

Naysayers of nocturnal dialysis will point to the results of the Nocturnal Hemodialysis trial published in Kidney International in July 2011 (16). Rocco and colleagues randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. However, the study's results for the two co-primary end-points: death or left ventricular mass were null. But surely, by any objective measure, we should agree that the study sample was too small, and the study was under-powered to observe a significant difference. 

Do you remember Isaac Asimov? He was a Russian-born American author and professor of biochemistry who died in 1992. Growing up in England, I read a few of his science fiction books – I’m sure you did too. He wrote in I Robot: “It is the obvious which is so difficult to see most of the time. People say 'It's as plain as the nose on your face.' But how much of the nose on your face can you see, unless someone holds a mirror up to you?”

Bottom-Line: For years we’ve squandered the opportunity to make a real difference in the lives of our dialysis patients by doing the bidding of payors or policy makers in prescribing a minimally acceptable dose of dialysis, rather than doing the bidding of our patients and finding ways to maximize dialysis dose. The narrative has been about the high cost of dialysis. Perhaps costs are higher because of under-dialysis. Data supports the notion that under-dialyzed patients' are more likely to be hospitalized, and more likely to need higher dosages of drugs like epo and vitamin D, which cost a lot of money. By increasing the dialysis dose through higher frequency and/or duration of dialysis, costs may actually come down as patient's have improved outcomes, a reduced need for drugs, better quality of life, and lower hospitalization rates. Although we do need additional trials - with larger sample sizes and harder end-points, we also need to manage patients with the information that we have now. Therefore, increasing the frequency and/or duration of dialysis seems sensible. So the answer to the Wait, Wait...Don't Tell Me question is: Yes, more dialysis is better.

References
1. Foley, Robert N., Gilbertson, David T., Murray, Thomas, Collins, Allan J. Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis. New England Journal of Medicine 2011 365:12, 1099-1107 
2. Luders C, Castro MC, Titan SM, De Castro I, Elias RM, Abensur H, Romão JE Jr. Obstetric outcome in pregnant women on long-term dialysis: a case series. Am J Kidney Dis. 2010 Jul;56(1):77-85. Epub 2010 Apr 10. PubMed PMID: 20382457.
3. Barua M, Hladunewich M, Keunen J, Pierratos A, McFarlane P, Sood M, Chan CT.Successful pregnancies on nocturnal home hemodialysis. Clin J Am Soc Nephrol. 2008 Mar;3(2):392-6. PubMed PMID: 18308997; PubMed Central PMCID: PMC2390936.
4. Hou S. Pregnancy in women treated with dialysis: lessons from a large series over 20 years. Am J Kidney Dis. 2010 Jul;56(1):5-6. PubMed PMID: 20620681.
5. Chertow GM, Levin NW, Beck GJ, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010;363:2287-2300[Erratum, N Engl J Med 2011;364:93.]
6. Owen WF Jr, Lew NL, Liu Y, Lowrie EG, Lazarus JM. The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993;329:1001-1006
7. Held PJ, Port FK, Wolfe RA, et al. The dose of hemodialysis and patient mortality. Kidney Int 1996;50:550-556
8. McClellan WM, Soucie JM, Flanders WD. Mortality in end-stage renal disease is associated with facility-to-facility differences in adequacy of hemodialysis. J Am Soc Nephrol 1998;9:1940-1947
9. Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription on patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med 1981;305:1176-1181
10. Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002;347:2010-2019
11. Depner TA. Daily hemodialysis efficiency: an analysis of solute kinetics. Adv Ren Replace Ther 2001;8:227-235
12. Suri RS, Nesrallah GE, Mainra R, et al. Daily hemodialysis: a systematic review. Clin J Am Soc Nephrol 2006;1:33-42
13. Walsh M, Culleton B, Tonelli M, Manns B. A systematic review of the effect of nocturnal hemodialysis on blood pressure, left ventricular hypertrophy, anemia, mineral metabolism, and health-related quality of life. Kidney Int 2005;67:1500-1508
14. Lacson E Jr, Lazarus M. Dialysis time: does it matter? A reappraisal of existing literature. Curr Opin Nephrol Hypertens. 2011 Mar;20(2):189-94. Review. PubMed PMID: 21178614.
15. Ouwendyk M, Pierratos A. Reflecting on 14 years of nocturnal home hemodialysis in Canada. CANNT J. 2008 Jul-Sep;18(3):55-7. PubMed PMID: 19010027.
16. Rocco MV, Lockridge RS Jr, Beck GJ, et al The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int. 2011 Jul 20. doi: 10.1038/ki.2011.213. [Epub ahead of print] PubMed PMID: 21775973.

COMMENTARY

Management of the Pregnant Dialysis Patient

Case Presentation

An outside nephrologist calls you to arrange transfer of dialysis care for a 31 year old woman who has been on dialysis for 3 months and has become pregnant. She is 16 weeks pregnant by ultrasound. The high risk OB visit is essentially unremarkable. The patient is on dialysis 3 times each week, M-W-F via a left arterio-venous fistula. Time on dialysis (Qt) is 3.5 hours, on an F8 dialyzer. Her recent monthly labs show a BUN of 72 mg/dL, creatinine of 8.1 mg/dL, K 4.6 mEq/L, calcium and phosphorus 9.8 and 5.2 mg/dL, respectively. Her Hgb is 11.6 g/dL, WCC 6.0x10⁹/L, plats 192,000. Her urea reduction ratio (URR) is 68%, KT/V of 1.24.  Her beta HCG level is highly positive. What are the next steps?

Discussion

Pregnancy is uncommon and usually unplanned in patients undergoing chronic hemodialysis. Only 42% of pre-menopausal women on dialysis have normal menstrual periods; most women are in fact anovulatory. Other reproductive endocrine abnormalities in female dialysis patients include hyperprolactinemia, low serum progesterone levels, and absent LH/FSH surges. The overall conception rate in dialysis patients is 0.3-1.4%/year, and the pregnancy rate is greater for patients on hemodialysis than those on peritoneal dialysis.

Claudio Luders and colleagues from São Paulo, Brazil published their experience on the management and outcomes of pregnant women on dialysis in AJKD in 2010. This is a fantastic paper because of the size of the study, the details that they provide, and the uplifting results.

In their paper, Luders et al present retrospective data for all pregnancies that occurred in 1988-2008 in women undergoing maintenance hemodialysis at the São Paulo University Medical School (São Paulo, Brazil). They analyzed maternal and fetal outcomes of all of these 52 pregnancies, as well as their relationship with various clinical, laboratory, and hemodialysis parameters, such as preeclampsia, pregnancy before or after dialysis therapy, hemodialysis dose, polyhydramnios, anemia, and predialysis serum urea level. In addition, they performed logistic regression models for a composite adverse fetal outcome (perinatal death or extremely premature delivery) and linear regression models for birth weight.

The main findings of their study were:

87% overall rate of successful delivery, with a mean gestational age of 32.7+/- 3.1 weeks.

Preeclampsia was associated with a poor prognosis compared with pregnancies without pre eclampsia:

• a successful delivery rate of 60% versus 92.9% (P <0.02)
• extremely premature delivery rate of 77.8% versus 3.3% (P <0.001)
• lower gestational age (P <0.001), and birth weight (P <0.001).

Patients with an adverse composite fetal outcome had:

• a higher frequency of preeclampsia (P <0.001)
• lower frequency of polyhydramnios (P<0.03)
• lower third-trimester hematocrit (P< 0.03),
• higher predialysis serum urea level (P <0.03).

Luders et al in their paper explain their approach to managing the dialysis prescription. Essentially, they use a short frequent dialysis schedule that is adjusted initially for whether the patient has residual renal function and the body weight. They dialyze their patients 6 times weekly on a high-flux, high-efficiency dialyzer. For patients with a urine output >1,000 mL/day, who are less <1 year on dialysis therapy, and have a body weight <70 kg, they start off with a 1.5- to 2.0-hour dialysis treatment 6 times/weekly. In contrast, for patients with a urine output<1,000 mL/day, who are > 1 year on dialysis therapy, or have a body weight >70 kg they start initially with a 2.0- to 3.0-hour dialysis treatment 6 times weekly. They say that they individualize the dialysis prescription based on laboratory, ultrasonographic, and clinical parameters. They also indicate that for complications, such as severe hypertension, anorexia, frequent nausea or vomiting, uncontrolled edema, excessive weight gain, and persistent polyhydramnios, the dialysis time is increased by 30-minutes.

The other study that has generated considered interest is from Barua et al (2)

They describe their experience with five patients (age range, 31 to 37 yr) who had seven pregnancies while on nocturnal hemodialysis and delivered six live infants. In all patients, the amount of hemodialysis was increased (from a weekly mean of 36 ± 10 to 48 ± 5 h; P < 0.01) after pregnancy was diagnosed. Mean predialysis blood urea and mean blood pressure were maintained within normal physiological parameters. The mean gestational age of the six live births was 36.2 ± 3 wk and the mean birth weight was 2417.5 ± 657 g. The maternal and fetal complications that were observed included, intrauterine growth restriction or small for gestational age (n = 2), preterm delivery (<32 wk) (n = 1), and shortened cervix threatened labor (n = 1). Anemia was accentuated during pregnancy, and intravenous iron and erythropoietin requirements were increased. To maintain normal physiological indices for plasma phosphate, Barua et al augmented dialysate phosphate supplementation regimen as required.

The dialysis prescription that was used comprised of 7 nights of nocturnal for 8 hours at a blood flow and dialysate flow rate 300 to 400 ml/min and 500 to 750 ml/min, respectively. They used either a F80 polysulfone dialyzer (Fresenius Medical Care, Lexington, MA) or the Exceltra 120 dialyzer (Baxter, Chicago, IL). The dialysate composition was as follows: sodium, 137 to 140 mEq/L (mmol/L): potassium, 1.5 to 2 mEq/L (mmol/L); bicarbonate, 35 mEq/L; and calcium 6 to 7 mg/dL (1.5 to 1.75 mmol/L).

Susan Hou from Loyola University in Chicago, in an accompanying editorial (3) in AJKD discusses both papers.

She writes:

“Luders and colleagues provide several important insights. Women who start dialysis after conception need not be on a dialysis regimen of 20 or 48 h/wk. Over 75% of women who start dialysis after conception have a surviving infant, although those who have cared for even 1 woman with a late fetal loss know that 75% is not good enough. We have concentrated on outcomes in women who conceive after starting dialysis because their outcomes have been so poor. There may also be benefit to carefully measuring residual kidney function in women who conceive after starting dialysis. It is clear that the prevention of preeclampsia is urgent in women with kidney disease as it is in all areas of obstetrics”.

Regarding the Barua study, Hou writes:

These unprecedented results reinforce our views that time on dialysis is an important factor in outcomes. Our usual approach is to prescribe 4 hours of dialysis 6 d/wk in an attempt to be sure of reaching 20 h/wk even with access problems and snow days. The schedule is onerous for patients, whose motivation may fade as the pregnancy progresses. In the United States, it is difficult to offer even the most motivated pregnant woman 48 h/wk of dialysis since nocturnal dialysis programs (home or in center) are not yet widely available. The overall success rate of 87% in the current report compares favorably even to the outcomes of pregnancy in transplant recipients, although the mean gestational age of 32.7 weeks is not as good. The success rate of 79% infant survival for pregnancies in women who conceived after starting dialysis is dramatically better than the 50% we reported in 1998”.

What might be the next steps for our patient?

In the United States, where nocturnal dialysis is not easily available, one reasonable approach would be to schedule 4 hours of dialysis 6 days each week (for a total of 24 hours of dialysis) using a high flux polysulfone dialyzer. Adjusting the dialysate to achieve electrolyte concentrations in the patient that parallel the levels observed for that stage of a normal pregnancy is important; however, there is no "normal" value for pregnancy -- it changes as pregnancy progresses.

Generally, however, serum sodium is decreased approximately 5 mEq/L as compared to the non-pregnant state and plasma osmolality decreases by approximately 10 mOsm/Kg H20. Serum potassium level is not altered (although there is total body K retention overall). Pregnancy causes a respiratory alkalosis -- arterial pC02 decreases by approximately 10 mmHg and arterial pH increases slightly to 7.44. The chronic respiratory alkalosis is associated with a decrease in serum bicarbonate to 17 to 20 mEq/L.

Some general adjustments can be made: for example, modifying the HC03 bath to 25 mEq/L (for the normal HC03 in pregnancy of 17-20 mEq/L), and calibrating the dialysate sodium to achieve a serum sodium of 134 mEq/L. No adjustment in the heparin dose is necessary since heparin does not cross the placenta. Very careful monitoring of volume is key, but adjusting this as plasma volume and weight increases, and as pregnancy progresses is also important.

Peritoneal dialysis is another option, but is limited by the volume of exchanges that are tolerable (approximately 1500 cc exchanges) and the potential issues in both the mother and fetus with exposure to high glucose dialysate. Most centers prefer hemodialysis over peritoneal dialysis unless ther are specific reasons that hemodialysis is contraindicated or not preferred.

References

1. Luders C, Castro MC, Titan SM, De Castro I, Elias RM, Abensur H, Romão JE Jr. Obstetric outcome in pregnant women on long-term dialysis: a case series. Am J Kidney Dis. 2010 Jul;56(1):77-85. Epub 2010 Apr 10. PubMed PMID: 20382457.

2. Barua M, Hladunewich M, Keunen J, Pierratos A, McFarlane P, Sood M, Chan CT.Successful pregnancies on nocturnal home hemodialysis. Clin J Am Soc Nephrol. 2008 Mar;3(2):392-6. PubMed PMID: 18308997; PubMed Central PMCID: PMC2390936.

3. Hou S. Pregnancy in women treated with dialysis: lessons from a large series over 20 years. Am J Kidney Dis. 2010 Jul;56(1):5-6. PubMed PMID: 20620681.

A Novel Treatment for Preeclampsia

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. Karumanchi and co-workers in break-through research starting with a landmark paper in JCI in 2003 (1) demonstrated that soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Other key publications from Karumanchi's group are listed at this link.

Very preterm preeclampsia  (<32 weeks) is associated with the greatest risk because the infant mortality rate is 70 times higher than at term. As well, circulating sFlt-1 in very preterm preeclampsia is at a very high level. Delivery of the placenta remains the only effective means to treat preeclampsia. Attempts to remove toxic circulating factors, either through hemodialysis or plasmapheresis, have been unsuccessful in preeclampsia.

Ravi Thadhani and colleagues in their paper in Circulation (2), hypothesized that since circulating sFlt-1 represents <20% of the total body sFlt-1 burden a selective adsorption column would create a concentration gradient and augment its removal.

The paper comprises of a series of experiments: first, they demonstrate that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. Next, 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels are then enrolled in a pilot study in a pilot study to examine whether a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. And, lastly, they perform multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth.

I invited Ravi Thadhani, who has led the clinical discovery and development of sFlt-1, to discuss the study that he published in Circulation. Ravi is Director of Clinical Research in the Renal Unit at the Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. His Harvard Catalyst Profile is available at the following link.

COMMENTARY

Pilot Study of Extracorporeal Removal of Soluble Fms-Like Tyrosine Kinase 1 in Preeclampsia

Preeclampsia is one of the most common medical complications of pregnancy and is associated with significant risk for maternal and fetal morbidity and mortality. Although the pathogenesis of preeclampsia remains unknown, elevated levels of circulating soluble fms-like tyrosine kinase 1 (sFlt-1) may contribute to the pathogenesis of preeclampsia. Therapies targeting circulating sFlt-1 may alleviate the progression of preeclampsia and potentially prolong pregnancy in women presenting with very preterm (gestational age 32 weeks) preeclampsia.

We have been working on therapies targeted against sFlt-1 for nearly a decade, and while the biology is supportive, moving this concept to the clinic to actually treat women with preeclampsia has not been straightforward for obvious reasons. Our challenge was to administer an effective therapy, and importantly ensure safety for both mother and baby. We thought rather than administering a biological agent to neutralize maternal circulating sFlt-1, why not take a "nephrology" approach and remove sFlt-1 using an extracorporeal adsorption column. We have been administering dialysis and pheresis to pregnant women for years, so theoretically this should work. An adsorption column would augment its removal from maternal circulation, and importantly allow us to titrate the dose and immediately terminate the treatment should any adverse consequences become evident. We specifically tested clinically available negatively charged dextran sulfate columns, which would in theory exploit the positive charge of circulating sFlt-1. All along safety was our primary concern.

After a year of ex-vivo work (e.g., to determine which adsorption column could remove sFlt-1 from blood), we prepared for our first-in-human studies in Germany. We chose Germany because both the device and the expertise to use the device were readily available there, and the blood test to screen for elevated sFlt-1 levels in maternal blood (entry criteria) was also easily available there. We purchased insurance, obtained ethics/IRB approval, purchased the needed equipment and columns, and modified the procedure (e.g., citrate > heparin anticoagulation, changed flow rates) so as to accommodate pregnant women. Our initial challenges were many, but the teams we assembled were terrific and motivated.

Our design was to first test this treatment in 5 women with very preterm preeclampsia (presenting <32 weeks of gestation) to obtain initial safety and dose-response information. We showed with a single treatment that we could reduce maternal sFlt-1 levels in a dose-dependent fashion -- longer the duration of treatment, further the reduction of maternal sFlt-1 levels. The most common side effect was a drop in blood pressure, which was observed in the first 15-30 minutes in most women. This reversed with saline in all women. We then asked our DSMB for permission to treat women more than once. With permission, we treated 3 more women with very preterm preeclampsia. With 2-4 extra treatments, we were able to prolong pregnancy for an extra 15, 19, and 23 days. We also showed that each treatment resulted in lowering of urine protein excretion, which was promising. Finally, we did not want to significantly lower blood pressure given the risk for impairing fetal growth, so we titrated our treatments so that only minimal changes in blood pressure were observed. In all women given multiple courses, the treatments were well tolerated and there was evidence of fetal weight gain.

Every extra day and week a preterm fetus remains in utero, the lower the immediate and long-term complications of preterm birth. Importantly, we compared the prolongation of pregnancy with our treatments with contemporaneous controls, but this was not a randomized trial, hence we could not say for sure our treatments extended pregnancy. We are certainly encouraged by these initial results, but we have much to do. We are currently trying to obtain funding for additional studies, including a randomized trial, and in parallel performing in vitro and ex vivo studies to improve the precision and safety of our intervention.  

References

1. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003 Mar;111(5):649-58. PubMed PMID: 12618519; PubMed Central PMCID: PMC151901.

2. Thadhani R, Kisner T, Hagmann H, Bossung V, Noack S, Schaarschmidt W, Jank A, Kribs A, Cornely OA, Kreyssig C, Hemphill L, Rigby AC, Khedkar S, Lindner TH, Mallmann P, Stepan H, Karumanchi SA, Benzing T. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011 Aug 23;124(8):940-50. Epub 2011 Aug 1. PubMed PMID: 21810665.

COMMENTARY

Preeclampsia and Long-term Kidney Outcomes

About 5 years ago, it was unknown if there were any long-term kidney consequences to the mother who develops preeclampsia during pregnancy.  Along came 2 papers, one in 2006 published in JASN (1), and the other in 2008 published in the New England Journal of Medicine (2), that changed our understanding of the consequences of preeclampsia in the mother.

Prof. Bjarne Iversen

I bring up this work for a most important reason. The person behind this research, Professor Bjarne Iversen, died August 5, 2011 in Bergen, Norway reportedly after a full day of his favorite leisure: salmon fishing in the fjords of Norway. Professor Iversen was born March 1942, and was 69 years old. I got to know Bjarne on two visits, the latest being in 2008 (the fuzzy picture of him is taken by me after a memorable dinner in Bergen in 2008). 

I extracted key biographical details from Professor Iversen’s obituary published by the American Physiological Society. Bjarne Iversen received his medical degree in 1968 from the University of Bergen and his PhD in nephrology in 1980. He became a professor in 1988. Professor Iversen ran an active experimental laboratory and mentored over 20 candidates to their PhDs. He was chief of nephrology for several years as well as chief of medicine at Haukeland University Hospital. From 2003 to 2007, he was president of the Norwegian Society of Hypertension. The Norwegian Renal Biopsy Registry was founded on Professor Iversen’s initiative while he was the secretary of the Norwegian Society of Nephrology. He was instrumental in leading, maintaining, and further developing the registry throughout the years. After over 20 years, with records of over 11,000 patients, it is one of the largest registries of renal biopsies in the world.

Professor Iversen’s mastery of using registry data, and linking one registry to another, formed the basis for his epidemiological work on preeclampsia outcomes.

The paper by Iversen and colleagues in JASN in 2006 (1) tested the hypothesis that preeclampsia are associated with later clinical kidney disease in the mother. At the time few studies had investigated this hypothesis. Iversen took advantage of 2 registries. The first, the Medical Birth Registry of Norway, was formed in 1967 of medical data on all childbirths in Norway (total population of 4.5 million inhabitants) that had a gestational age of at least 16 wk. Because notification was compulsory, the registry was remarkable for its completeness. The registry notification form recorded extensive data on maternal disease, complications of delivery, and conditions of the newborn infant.

The Norwegian Kidney Biopsy Registry was founded by Bjarne Iversen himself and comprised of clinical and histopathologic data on virtually all patients with a kidney biopsy in Norway since April 1988. The responsible physicians reported clinical data in a registry notification form. The nephropathologic department at Haukeland University Hospital reviewed the kidney biopsies and reported the histopathologic data. In general, most patients in Norway undergo a kidney biopsy when they have proteinuria >1 g/24 h or a sserum creatinine >150 µmol/L and renal parenchymal disease is suspected.

Iversen and colleagues included a total of 756,420 women in their cohort. After a mean period of 15.9+/-9.4 years, 588 had a kidney biopsy. Women who had preeclampsia and gave birth to offspring with low birth wight (LBW) and short gestation had a substantially increased risk for having a kidney biopsy later in life. Preeclampsia increased the effects of LBW and short gestation. They also concluded that LBW offspring and short gestation was associated with an increased risk for later kidney biopsy in the absence of preeclampsia. This suggested that placental dysfunction without the development of preeclampsia may also be an important risk factor. These findings suggested that preeclampsia and possibly placental dysfunction are associated with irreversible kidney damage

In Iversen’s paper in the New England Journal (2). they linked data from the Medical Birth Registry of Norway, which contained data on all births in Norway since 1967, with data from the Norwegian Renal Registry, which contained data on all patients receiving a diagnosis of end-stage renal disease (ESRD) since 1980. Their objective was to assess the association between preeclampsia in one or more pregnancies and the subsequent development of ESRD. The study population consisted of women who had had a first singleton birth between 1967 and 1991 (they included data from up to three pregnancies). They demonstrated that regardless of whether this was the mother's first or subsequent pregnancy, the risk of preeclampsia was significantly higher if she had preeclampsia.

The Bottom-Line

Professor Bjarne Iversen was a remarkable scientist, who made several notable contributions, of which I have only covered one area. In addition to his important papers on preeclampsia he leaves behind a legacy of having built up one of the largest renal biopsy registry's in the world. The power of combining several registries together is evidenced by his publications. His epidemiologic research demonstrates that there are long-term consequences to preeclampsia, and that following these patients should be seriously considered.

Professor Iversen, it was an honor to know you!

References

1. Vikse BE, Irgens LM, Bostad L, Iversen BM. Adverse perinatal outcome and later kidney biopsy in the mother. J Am Soc Nephrol. 2006 Mar;17(3):837-45. Epub 2006 Jan 18. PubMed PMID: 16421228.

2. Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM. Preeclampsia and the risk of end-stage renal disease. N Engl J Med. 2008 Aug 21;359(8):800-9.PubMed PMID: 18716297.

DIALYSIS QUIZ

A 48 year old male ESRD patient presents to the ED with a K=7.8 mEq/L, HC03 of 22. His EKG shows peaked T waves (see pic). Recommended initial treatment include all of the following EXCEPT:

–A.) Calcium gluconate 10 mls, IV

–B.) Insulin 10 units and 1 amp of 50% dextrose

–C.) Albuterol nebulizer (10-20 mg)

–D.) IV bicarbonate 8.4%, 1 to 2 amps IV

–E.) Emergent dialysis

_______

Answer for Sep 22 Dialysis Quiz: E.) Linezolid. 

Linezolid is a synthetic antibiotic (a member of the oxazolidinone class of drugs) used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics e.g, methicillin-resistant Staphylococcus aureus (MRSA). lLinezolid is also active against most Gram-positive bacteria that cause disease, including streptococci and vancomycin-resistant enterococci (VRE).

JOURNAL CLUB

Should patients receive N-acetyl cysteine to prevent contrast-induced nephropathy?

The use of N-acetyl cysteine (NAC) to prevent contrast-induced nephropathy (CIN) has been a matter for active debate since the original publication by Tepel and co-workers in the New England Journal of Medicine. More than 40 trials and several meta-analyses have been published. As a whole, despite some conflicting results, NAC has been adopted on the most part by many centers around the world, including ours at the Brigham and Women’s Hospital (1). This is particularly so for patients at high-risk for contrast nephropathy. While predictive instruments have been developed to try and identify patients at high risk of contrast nephropathy, most clinicians view the presence of pre-existing renal insufficiency together with diabetes mellitus as the main risk factors, and older age, volume of contrast, vascular disease, multiple myeloma and congestive heart failure as additional risk factors for contrast nephropathy.

This month, in Circulation, Berwanger and colleagues  (2) on behalf of the “ACT investigators” published an important study that might influence whether you continue to use NAC as prophylaxis for CIN.

An editorial by McCullough and colleagues (3) accompanying the published report in Circulation states: "The implications of this adequately powered, well-conducted clinical trial are clear: The short-term use of N-aceytlcysteine for the prevention of CI-AKI in clinical practice should be abandoned".

Should NAC be abandoned based on the results of this study? This is the topic of Journal Club.

The ACT investigators conducted a randomized (concealed) controlled trial of NAC versus placebo in patients at risk for CIN that were undergoing intravascular angiographic procedures. The study was multicenter (46 sites) in Brazil (4). The analyses were performed according to the intention-to-treat principle.

The key enrollment criteria were that subjects had to be undergoing coronary or peripheral intravascular angiography or percutaneous intervention. They also had to have at least one risk factor for CIN: age >70 years, chronic kidney disease (stable Scr >132.6 micromol/L or >1.5 mg/dL), diabetes mellitus, clinical evidence of congestive heart failure, left ventricular ejection fraction <0.45, or hypotension. The investigators excluded patients on dialysis and/or those with ST-segment elevation myocardial infarction undergoing primary angioplasty.

The study intervention was either NAC 1200 mg every 2 hours for 2 doses before and 2 doses after the procedure, or placebo. In all patients, hydration with 0.9% saline, 1 mL/kg/hour, from 6 to 12 hours before and 6 to 12 hours after angiography “was strongly recommended”. However, “changes in the total volume or speed of administration [of the saline] were permitted”.

The primary end-point was contrast induced acute kidney injury defined as a 25% elevation in serum creatinine above baseline between 48 and 96 hours after angiography. There were several secondary end-points including, a composite of death or need for dialysis in 48 to 96 hours and at 30 days; individual components of the composite end-point; cardiovascular deaths; and other adverse events.

The sample size was calculated based on an anticipated incidence of CIN at 48 to 72 hours of approximately 15%. To detect a 30% relative risk reduction with 90% power the investigators calculated a sample size of 2300.

A total of 2308 subjects were enrolled between September 2008 and July 2010. 1172 were allocated to NAC and 1136 to placebo. Looking at the baseline characteristics there appeared to be balance, i.e., randomization worked. Enrolled patients tended to be male (approximately 2/3^rd), older (approximate age 68 yrs), and diabetic (approximately 60%). There were only approximately 15% of patients with a serum creatinine of >1.5 mg (362 subjects in total with a Scr>1.5 mg/dL). In sum, this was essentially a study evaluating the efficacy of NAC in preventing CIN in elderly diabetic males.

Other notable aspects of the trial were that only approximately one-half of the participants had hydration with 0.9% saline at 1 ml/kg/hr for 6 hrs (47.1% in the NAC arm, and 47.5% in the placebo arm). Post-hydration was more common in the two groups: 69.4% had hydration with 0.9% saline in the NAC arm and 69.7% in the placebo arm Bicarbonate 0.9% infusion was also permitted in both groups before and after the procedure and happened in 5 to 6% of patients. We are not provided the volume, infusion rate, or duration of the bicarbonate infusion. We are also not provided post hydration weights or any urine flow rates or urine volumes.

The patients generally received low-osmolar contrast type ≈ 75% each arm and approximately 22% received high osmolar contrast type. The median contrast volume was 100 mls (range of 70-130 mls).

The results for the primary and secondary end-points are listed below:

Outcomes	NAC	Placebo	Relative Risk (95% CI)	P
Primary endpoint	%	%
CIN	12.7	12.7	1.00 (0.81,1.25)	0.97
Secondary endpoints 48-96 h	%	%
Doubling of creatinine	1.1	1.5	0.74 (0.36,1.51)	0.41
Elevation Scr>0.5 mg/dL	3.9	3.8	1.04 (0.69,1.57)	0.85
Elevation Scr>0.3 mg/dL	12.1	11.0	1.10 (0.88,1.39)	0.39

The 30 d results for death or need for dialysis or for death alone, or need for dialysis alone, or cardiovascular death (expressed as hazard ratio with CI and P value obtained by Cox regression) showed no difference between the groups.

To bolster their findings, the authors also updated a prior meta-analysis that they provide in one of the Tables in the online-only Data Supplement. Here they evaluate studies on whether there was adequate allocation concealment or not. In those studies, they claim had inadequate allocation concealment, the pooled relative risk was 0.59 (95% CI, 0.43,0.82). In contrast, they report that in studies where there was adequate concealment the pooled relative risk was 1.01; 95% CI 0.75,1.37). They state that the pooled relative risk for “low-quality studies” was 0.63 (95% CI, 0.47, 0.85) and for studies “meeting all methodological criteria" was 1.05 (95% CI, 0.73,1.53).

The authors conclude: “our trial showed that acetylcysteine did not result in a lower incidence of contrast-induced acute kidney injury or other renal outcomes. On the basis of our results, we do not recommend routine use of acetylcysteine for patients undergoing angiography. These findings have important implications for clinical practice and may prevent unnecessary procedure delays and health expenditures associated with the administration of acetylcysteine”.

Limitations of the Study

1 Generalizability: The investigators observed a lower than anticipated incidence of CIN. This is not surprising since only 15% of the participants had pre-existing renal insufficiency. Parfrey et al in a study in 1989 published in NEJM (5) reported that patients with both pre-existing renal insufficiency and diabetes mellitus were at highest risk CIN. The authors do not state what proportion of subjects had both pre-exisiting renal insufficiency and diabetes. Furthermore, the volume of contrast used was relatively modest – a median volume of 100 mls. In contrast, Marenzi et al (6) used a total volume of contrast medium between ≈260 to 275 mls, and ≈30% received >300 mls of contrast. In summary, the ACT trial is really evaluating whether NAC prevents CIN in patients at low risk of CIN. There needs to be caution in generalizing these findings to patients at high risk of CIN.  

2. Since there were only a total of 362 subjects in total that had a Scr>1.5 mg/dL -- this study is underpowered to detect a significant difference. This conclusion is supported by the rather wide confidence intervals for the relative risk of CIN for either the primary or secondary endpoints.

3. There was imprecision around who received hydration and how much was administered. For example, pre-hydration was only administered in ≈47% of subjects; the remainder received un-stated amounts of hydration, which could have been imbalanced between the two arms of the study. It is also unclear how much 0.9% bicarbonate was administered. The authors state “co interventions other than hydration were at the discretion of the attending physician. Nevertheless, they were well balanced between groups”. However, no weights post-hydration, and no urine flows either during or post-hydration are provided. In this regard, we can’t really be certain if there was balance between the two arms.

4. The definition of CIN and the use of creatinine rather than cystatin add to the limitations. However, if as others have suggested, NAC reduces creatinine secretion, then one would expect a bias towards observing a difference between the two arms rather than the null finding.

Bottom-line

This study does represent the largest randomized trial performed to test whether NAC prevents CIN. Based on this study, NAC is not beneficial in patients at relatively low risk of CIN. However, I would suggest that these results should not be generalized to patients at high risk of CIN: patients with diabetes and CKD with a Scr>1.5 mg/d, especially if they are to receive larger volumes of iodinated contrast.

The study is well designed, well conducted, and nicely presented in Circulation, but the conclusion by McCollough that the “ the short-term use of N-acetylcysteine for the prevention of CI-AKI in clinical practice should be abandoned”, in my opinion at least, is off the mark. Additional studies in high risk patients are needed before we abandon NAC.

References

1. Kakkar R, Sobieszczyk P, Binkert CA, Faxon DP, Mortele KJ, Singh AK. Prevention of intravenous contrast-induced nephropathy in hospital inpatients. Crit Pathw Cardiol. 2008 Mar;7(1):1-4. Review. PubMed PMID: 18458660.

2. ACT Investigators. Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Coronary and Peripheral Vascular Angiography: Main Results From the Randomized Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT). Circulation. 2011 Sep 13;124(11):1250-9. Epub 2011 Aug 22. PubMed PMID: 21859972

3. McCullough PA, Khambatta S, Jazrawi A. Minimizing the renal toxicity of iodinated contrast. Circulation. 2011 Sep 13;124(11):1210-1. PubMed PMID:21911794.

4. ACT Trial Investigators. Rationale, design, and baseline characteristics of the Acetylcystein for Contrast-Induced nephropaThy (ACT) Trial: a pragmatic randomized controlled trial to evaluate the efficacy of acetylcysteine for the prevention of contrast-induced nephropathy. Trials. 2009 Jun 4;10:38. PubMed PMID: 19497091; PubMed Central PMCID: PMC2706243.

5. Parfrey PS, Griffiths SM, Barrett BJ, Paul MD, Genge M, Withers J, Farid N, McManamon PJ. Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N Engl J Med. 1989 Jan 19;320(3):143-9. PubMed PMID: 2643041.

6. Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S, Fabbiocchi F, Montorsi P, Veglia F, Bartorelli AL. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med. 2006 Jun 29;354(26):2773-82. PubMed PMID: 16807414