Friday, March 13, 2015

#NephMadness Tolvaptan Vs Sacubitril in Heart Failure #HeartRegion Abstracts

JAMA. 2007 Mar 28;297(12):1319-31. Epub 2007 Mar 25.

Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.

Konstam MA(1), Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K,
Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy of
Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST)

Author information:
(1)Division of Cardiology, Tufts-New England Medical Center, Boston, Mass, USA.

Comment in
    Curr Cardiol Rep. 2008 May;10(3):166-7.
    JAMA. 2007 Mar 28;297(12):1374-6.
    Curr Heart Fail Rep. 2009 Mar;6(1):3-4.

CONTEXT: Vasopressin mediates fluid retention in heart failure. Tolvaptan, a
vasopressin V2 receptor blocker, shows promise for management of heart failure.
OBJECTIVE: To investigate the effects of tolvaptan initiated in patients
hospitalized with heart failure.
DESIGN, SETTING, AND PARTICIPANTS: The Efficacy of Vasopressin Antagonism in
Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven,
randomized, double-blind, placebo-controlled study. The outcome trial comprised
4133 patients within 2 short-term clinical status studies, who were hospitalized
with heart failure, randomized at 359 North American, South American, and
European sites between October 7, 2003, and February 3, 2006, and followed up
during long-term treatment.
INTERVENTION: Within 48 hours of admission, patients were randomly assigned to
receive oral tolvaptan, 30 mg once per day (n = 2072), or placebo (n = 2061) for
a minimum of 60 days, in addition to standard therapy.
MAIN OUTCOME MEASURES: Dual primary end points were all-cause mortality
(superiority and noninferiority) and cardiovascular death or hospitalization for
heart failure (superiority only). Secondary end points included changes in
dyspnea, body weight, and edema.
RESULTS: During a median follow-up of 9.9 months, 537 patients (25.9%) in the
tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98;
95% confidence interval [CI], 0.87-1.11; P = .68). The upper confidence limit for
the mortality difference was within the prespecified noninferiority margin of
1.25 (P<.001). The composite of cardiovascular death or hospitalization for heart
failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group
patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary end
points of cardiovascular mortality, cardiovascular death or hospitalization, and
worsening heart failure were also not different. Tolvaptan significantly improved
secondary end points of day 1 patient-assessed dyspnea, day 1 body weight, and
day 7 edema. In patients with hyponatremia, serum sodium levels significantly
increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was
not improved at outpatient week 1, but body weight and serum sodium effects
persisted long after discharge. Tolvaptan caused increased thirst and dry mouth,
but frequencies of major adverse events were similar in the 2 groups.
CONCLUSION: Tolvaptan initiated for acute treatment of patients hospitalized with
heart failure had no effect on long-term mortality or heart failure-related
TRIAL REGISTRATION: Identifier: NCT00071331

PMID: 17384437  [PubMed - indexed for MEDLINE]

 Int J Cardiol. 2002 Nov;86(1):1-4.

Omapatrilat--the story of Overture and Octave.

Coats AJ.

Comment in
    Int J Cardiol. 2003 Sep;91(1):113.

At the American College of Cardiology in March two major trials were presented.
The publicity surrounding the two could not have been more different. The LIFE
demonstrated clear superiority of losartan-based therapy over atenolol-based
therapy for the treatment of hypertension. It was published the same week in the
Lancet and received major press coverage all over the world. The OVERTURE
(Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events)
study in contrast received a subdued reception, very little publicity and is yet
to be published. 5770 NYHA class II-IV heart failure patients (LVEFrecent heart failure hospital admission) were randomised and uptitrated to either
10 mg BD of Enalapril or 40 mg once a day Omapatrilat. The primary end-point of
all cause mortality or heart failure related hospitalisation did not differ
significantly: 914/2884 for Enalapril and 914/2886 for Omapatrilat (hazard ratio
0.94, CI's 0.86-1.03, P=0.187). Mortality was also similar: 509 for Enalapril and
477 for Omapatrilat (hazard ratio 0.94, CI's 0.83-1.07, P=0.339). Omapatrilat was
as good as Enalapril but not better. The worrying trend was however, that
angioedema was more common with Omapatrilat; 24 (0.8%) versus 14 cases (0.5%).
The OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril)
study was also presented at this time. 25,267 hypertensives were randomised to
Omapatrilat or enalapril and a difference of approximately 3 mmHg in favour of
Omapatrilat was seen. Significantly more cases of angioedema were seen with
Omapatrilat, 274 (2.17%) compared to 86 (0.68%) with enalapril. Overall death
rates were similar, 0.18% for enalapril and 0.15% for Omapatrilat. All adverse
events were;postID=1531264929101084479 similar, 51.0% for Omapatrilat and 50.4% for enalapril. The rates of
angioedema were much higher in blacks, 5.54% for Ompatrilat and 1.62% for
enalapril and for smokers, 3.93% for Omapatrilat and 0.81% for enalapril. We were
left with a drug that was, for heart failure, not superior to an ACE inhibitor
already off patent, and, as an anti-hypertensive, with an angioedema rate more
than double that of an ACE inhibitor in a large head to head comparison. The
medical community will be watching to make sure these data are published in full
in the medical literature in a timely fashion, in the order of end-points
specified in the protocol and with appropriate emphasis on the logical points of

PMID: 12243845  [PubMed - indexed for MEDLINE]


N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014Aug 30.

Angiotensin-neprilysin inhibition versus enalapril in heart failure.

McMurray JJ(1), Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL,
Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and

Author information:
(1)From the British Heart Foundation (BHF) Cardiovascular Research Centre,
University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); the Department of
Clinical Sciences, University of Texas Southwestern Medical Center, Dallas
(M.P.); the Division of Cardiovascular Medicine, Brigham and Women's Hospital,
Boston (A.S.D., S.D.S.); Novartis Pharmaceuticals, East Hanover, NJ (J.G.,
M.P.L., A.R.R., V.C.S.); Institut de Cardiologie de Montréal, Université de
Montréal, Montreal (J.L.R.); the Department of Molecular and Clinical Medicine,
University of Gothenburg, Gothenburg, Sweden (K.S.); National Heart and Lung
Institute, Imperial College London, London (K.S.); and the Medical University of
South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston

Comment in
    Nat Rev Cardiol. 2014 Nov;11(11):618.
    Perspect Infirm. 2015 Jan-Feb;12(1):61.
    N Engl J Med. 2014 Dec 11;371(24):2336-7.
    N Engl J Med. 2014 Dec 11;371(24):2335-6.
    N Engl J Med. 2014 Dec 11;371(24):2335.
    G Ital Cardiol (Rome). 2014 Dec;15(12):651-5.
    N Engl J Med. 2014 Sep 11;371(11):1062-4.
    N Engl J Med. 2014 Dec 11;371(24):2336.

BACKGROUND: We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with
enalapril in patients who had heart failure with a reduced ejection fraction. In
previous studies, enalapril improved survival in such patients.
METHODS: In this double-blind trial, we randomly assigned 8442 patients with
class II, III, or IV heart failure and an ejection fraction of 40% or less to
receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose
of 10 mg twice daily), in addition to recommended therapy. The primary outcome
was a composite of death from cardiovascular causes or hospitalization for heart
failure, but the trial was designed to detect a difference in the rates of death
from cardiovascular causes.
RESULTS: The trial was stopped early, according to prespecified rules, after a
median follow-up of 27 months, because the boundary for an overwhelming benefit
with LCZ696 had been crossed. At the time of study closure, the primary outcome
had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients
(26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95%
confidence interval [CI], 0.73 to 0.87; P<0 .001="" 711="" a="" br="" of="" patients="" total="">receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio
for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0 .001="" br="" of="" these="">patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular
causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0 .001="" as="" br="" compared="" with="">enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by
21% (P<0 .001="" and="" br="" decreased="" heart="" limitations="" of="" physical="" symptoms="" the="">failure (P=0.001). The LCZ696 group had higher proportions of patients with
hypotension and nonserious angioedema but lower proportions with renal
impairment, hyperkalemia, and cough than the enalapril group.
CONCLUSIONS: LCZ696 was superior to enalapril in reducing the risks of death and
of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF number, NCT01035255.).

PMID: 25176015  [PubMed - indexed for MEDLINE]


Clin Sci (Lond). 1993 Jul;85(1):19-26.

Renal and hormonal effects of chronic inhibition of neutral endopeptidase (EC in normal man.

O'Connell JE(1), Jardine AG, Davies DL, McQueen J, Connell JM.

Author information:
(1)MRC Blood Pressure Unit, Western Infirmary, Glasgow, U.K.

1. Acute pharmacological inhibition of the enzyme neutral endopeptidase (EC, which cleaves the cardiac hormone atrial natriuretic peptide, raises
endogenous levels of the hormone. Short-term administration of inhibitors causes
natriuresis and diuresis in normal and hypertensive subjects; we report here the
effects of an orally active neutral endopeptidase inhibitor (candoxatril, 200 mg)
given twice daily for 10 days to normal salt-replete male subjects (n = 12) in a
placebo-controlled cross-over study. 2. Candoxatril administration caused a
transient natriuresis on day 1 of treatment, but this was not sustained, and
cumulative sodium excretion at the end of the study was not altered by active
therapy [1720 +/- 40 versus 1734 +/- 57 (placebo) mmol; means +/- SEM];
exchangeable body sodium content was similarly unchanged. However, urinary cyclic
GMP excretion was elevated throughout the active treatment phase when compared
with placebo. 3. Although a change in plasma levels of atrial natriuretic peptide
could not be demonstrated, platelet atrial natriuretic peptide binding sites were
reduced by active treatment [23 +/- 3 versus 39 +/- 4 (placebo) fmol/10(9); P <
0.001]. 4. Basal blood pressure and heart rate were not affected by candoxatril
treatment. After 10 days of therapy subjects were given incremental infusions of
angiotensin II (2, 4 and 8 ng min-1 kg-1) followed by phenylephrine. Although
active therapy had not altered basal plasma concentrations of active renin and
angiotensin II, levels of angiotensin II during infusion of the octapeptide were
higher during the active phase.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 8149689  [PubMed - indexed for MEDLINE]


 Nephrol Dial Transplant. 2014 Aug 18. pii: gfu269. [Epub ahead of print]

Neprilysin inhibition in chronic kidney disease.

Judge P(1), Haynes R(1), Landray MJ(1), Baigent C(1).

Author information:
(1)Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield
Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.

Despite current practice, patients with chronic kidney disease (CKD) are at
increased risk of progression to end-stage renal disease and cardiovascular
events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential
to improve outcomes for patients with CKD. NEPi enhances the activity of
natriuretic peptide systems leading to natriuresis, diuresis and inhibition of
the renin-angiotensin system (RAS), which could act as a potentially beneficial
counter-regulatory system in states of RAS activation such as chronic heart
failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting
enzyme inhibitors but were associated with unacceptable rates of angioedema and,
therefore, withdrawn. However, one such agent (omapatrilat) showed promise of
NEP/RAS inhibition in treating CKD in animal models, producing greater reductions
in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with
isolated RAS inhibition. A new class of drug called angiotensin receptor
neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown
substantial benefits in trials in hypertension and HF. In CKD, HF is common due
to a range of mechanisms including hypertension and structural heart disease
(including left ventricular hypertrophy), suggesting that ARNi could benefit
patients with CKD by both retarding the progression of CKD (hence delaying the
need for renal replacement therapy) and reducing the risk of cardiovascular
disease. LCZ696 is now being studied in a CKD population.

© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.

PMID: 25140014  [PubMed - as supplied by publisher]


Diabetologia. 2003 Jul;46(7):961-71. Epub 2003 Jun 28.

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy.

Davis BJ(1), Johnston CI, Burrell LM, Burns WC, Kubota E, Cao Z, Cooper ME, Allen

Author information:
(1)Diabetic Complications Group, Baker Heart Research Institute, P.O. Box 6492,
Melbourne, 8008 Victoria, Australia.

AIMS: Although ACE inhibitors slow progression of diabetic renal disease, the
mortality and morbidity is still high. As other hormonal factors are involved,
inhibition of vasopeptidases could further reduce progression. We studied dual
inhibition of angiotensin converting enzyme and neutral endopeptidase in a model
of progressive diabetic renal injury. The major endpoints were reductions in
systemic blood pressure, albuminuria and renal structural injury.
METHODS: Diabetic spontaneously hypertensive rats were treated with the ACE
inhibitor perindopril ( or the vasopeptidase inhibitor
omapatrilat at doses of 10 (oma10) and 40 (oma40) for 32 weeks.
In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal
structural injury was assessed by measurement of the glomerulosclerotic (GS)
index and tubulointerstitial area (TI). The expression of transforming growth
factor beta, beta-inducible gene-h3 and nephrin were also quantitated.
RESULTS: Despite a similar reduction in blood pressure by perindopril and oma10,
greater attenuation of albuminuria was afforded by oma10, with a complete
amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP
binding and this was associated with less albuminuria and prevention of GS, TI
area and overexpression of TGFbeta and betaig-h3. Diabetes-associated reduction
in nephrin expression was restored by both drugs.
CONCLUSION/INTERPRETATION: These findings suggest that other vasoactive
mechanisms in addition to angiotensin II are important in the prevention of
diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage
over blockade of the RAS alone in the treatment of diabetic renal disease.

PMID: 12838387  [PubMed - indexed for MEDLINE]


Eur J Heart Fail. 2015 Feb 6. doi: 10.1002/ejhf.232. [Epub ahead of print]

Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction.

Voors AA(1), Gori M, Liu LC, Claggett B, Zile MR, Pieske B, McMurray JJ, Packer
M, Shi V, Lefkowitz MP, Solomon SD; for the PARAMOUNT Investigators.

Author information:
(1)Department of Cardiology, University Medical Centre Groningen, University of
Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.

BACKGROUND: Increases in serum creatinine with renin-angiotensin-aldosterone
system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents.
The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves
clinical outcome patients with heart failure with reduced ejection fraction, and
pilot data suggest potential benefit in heart failure with preserved ejection
fraction (HFpEF). The effects of LCZ696 on renal function have not been assessed.
METHODS AND RESULTS: A total of 301 HFpEF patients were randomly assigned to
LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function
[creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary
albumin to creatinine ratio (UACR)] at baseline, 12 weeks, and after 36 weeks of
treatment. Worsening renal function (WRF) was determined as an serum creatinine
increase of >0.3 mg/dL and/or >25% between two time-points. Mean eGFR at baseline
was 65.4 ± 20.4 mL/min per 1.73 m(2) . The eGFR declined less in the LCZ696 group
than in the valsartan group (-1.5 vs. -5.2 mL/min per 1.73 m(2) ; P = 0.002). The
incidence of WRF was lower in the LCZ696 group (12%) than in the valsartan group
(18%) at any time-point, but this difference was not statistically significant (P
= 0.18). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group
(2.4-2.9 mg/mmol), whereas it remained stable in the valsartan group (2.1-2.0
mg/mmol; P for difference between groups = 0.016).
CONCLUSION: In patients with HFpEF, therapy with LCZ696 for 36 weeks was
associated with preservation of eGFR compared with valsartan therapy, but an
increase in UACR.

© 2015 The Authors European Journal of Heart Failure © 2015 European Society of

PMID: 25657064  [PubMed - as supplied by publisher]



Randomized multicentre pilot study of LCZ696 versus irbesartan in patients with chronic kidney disease: UK Heart and Renal Protection (HARP)-III

Portfolio Eligibility
Adopted non-commercial study
ISRCTN 11958993
EudraCT 2013-004205-89
MREC N° 13/EM/0434
UKCRN ID 15842
Research Summary
Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease (ie, need for dialysis or transplantation) and heart disease, despite best available treatment. Current standard treatment includes blocking the renin-angiotensin system with drugs called ACE inhibitors or angiotensin receptor blockers (ARBs). LCZ696 is a new treatment which acts both like an ARB and also blocks an enzyme called neprilysin. Neprilysin breaks down some molecules (natriuretic peptides) which may protect the heart and kidney, so inhibiting neprilysin may be beneficial for patients with CKD. UK HARP-III aims to recruit 360 participants with CKD: half will be randomly allocated to receive LCZ696 while the other half will receive irbesartan. Participants will have a precise measurement of the kidney function at the beginning and end of the study (6 months later), and the change in renal function during the study is the primary outcome of this pilot study. UK HARP-III study clinics will be run by trained research staff in renal units in NHS institutions. Patients eligible to join the study will be aged 18 or above and have CKD. Participants will attend the study clinic about 5 times during the study when they will provide blood and urine samples, have blood pressure and weight measured and answer questions about their health.                             

Wednesday, March 11, 2015

#NephMadness #OncoRegion Nephron Sparing VS Nephrectomy for Kidney Cancer Surgery Abstracts

Urology. 2014 Jan;83(1):111-5. doi: 10.1016/j.urology.2013.08.059. Epub 2013 Oct 11.

Laparoscopic partial nephrectomy for hilar tumors: oncologic and renal functional outcomes.

George AK(1), Herati AS(2), Rais-Bahrami S(2), Waingankar N(2), Kavoussi LR(2).

Author information:
(1)The Arthur Smith Institute for Urology, Hofstra North Shore-LIJ School of
Medicine, New Hyde Park, NY. Electronic address: (2)The
Arthur Smith Institute for Urology, Hofstra North Shore-LIJ School of Medicine,
New Hyde Park, NY.

OBJECTIVE: To present our experience with laparoscopic partial nephrectomy (LPN)
for hilar tumors and evaluate intermediate oncologic and renal functional
MATERIALS AND METHODS: A retrospective review of LPN cases performed in 488
patients was performed. Hilar lesions were defined as renal cortical tumors in
direct physical contact with the renal artery, vein, or both, as identified on
preoperative imaging and confirmed intraoperatively. The clinicopathologic
parameters, perioperative course, complications, and oncologic and 6-month renal
functional outcomes were analyzed.
RESULTS: A total of 488 patients underwent LPN, of which 43 were hilar. The mean
tumor size for hilar and nonhilar tumors was 3.6 cm and 3.1 cm, respectively. The
mean operative time was shorter for hilar as compared with nonhilar tumors (129.1
minutes vs 141.8 minutes). Mean estimated blood loss was greater in LPN for hilar
tumors (311.65 mL vs 298.4 mL). There were no statistically significant
differences noted in any of the perioperative parameters investigated despite a
higher nephrometry complexity score in the hilar group. Change in estimated
glomerular filtration rate at 6 months showed a decrease of 10.9 mL/min and 8.8
mL/min for hilar and nonhilar tumors, respectively (P = NS). There was 1
recurrence detected in the hilar group, with a median follow-up of 41.6 months.
CONCLUSION: In the hands of an experienced laparoscopist, LPN can safely be
performed for hilar tumors, with preservation of perioperative outcomes and
durable renal functional and oncologic outcomes.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID: 24119677  [PubMed - indexed for MEDLINE]

Eur Urol. 2011 Apr;59(4):543-52. doi: 10.1016/j.eururo.2010.12.013. Epub 2010 Dec22.

A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma.

Van Poppel H(1), Da Pozzo L, Albrecht W, Matveev V, Bono A, Borkowski A, Colombel
M, Klotz L, Skinner E, Keane T, Marreaud S, Collette S, Sylvester R.

Author information:
(1)Department of Urology, University Hospital Gasthuisberg, Katholieke
Universiteit Leuven, Leuven, Belgium.

Comment in
    Eur Urol. 2011 Aug;60(2):e9; author reply e10.
    Eur Urol. 2012 Apr;61(4):e37-8.
    Eur Urol. 2012 Sep;62(3):564-5.
    Eur Urol. 2013 Feb;63(2):399-400.
    Eur Urol. 2011 Apr;59(4):553-5.

BACKGROUND: Nephron-sparing surgery (NSS) can safely be performed with slightly
higher complication rates than radical nephrectomy (RN), but proof of oncologic
effectiveness is lacking.
OBJECTIVE: To compare overall survival (OS) and time to progression.
DESIGN, SETTING, AND PARTICIPANTS: From March 1992 to January 2003, when the
study was prematurely closed because of poor accrual, 541 patients with small (≤5
cm), solitary, T1-T2 N0 M0 (Union Internationale Contre le Cancer [UICC] 1978)
tumours suspicious for renal cell carcinoma (RCC) and a normal contralateral
kidney were randomised to NSS or RN in European Organisation for Research and
Treatment of Cancer Genito-Urinary Group (EORTC-GU) noninferiority phase 3 trial
INTERVENTION: Patients were randomised to NSS (n=268) or RN (n=273) together with
limited lymph node dissection (LND).
MEASUREMENTS: Time to event end points was compared with log-rank test results.
RESULTS AND LIMITATIONS: Median follow-up was 9.3 yr. The intention-to-treat
(ITT) analysis showed 10-yr OS rates of 81.1% for RN and 75.7% for NSS. With a
hazard ratio (HR) of 1.50 (95% confidence interval [CI], 1.03-2.16), the test for
noninferiority is not significant (p=0.77), and test for superiority is
significant (p=0.03). In RCC patients and clinically and pathologically eligible
patients, the difference is less pronounced (HR=1.43 and HR=1.34, respectively),
and the superiority test is no longer significant (p=0.07 and p=0.17,
respectively). Only 12 of 117 deaths were the result of renal cancer (four RN and
eight NSS). Twenty-one patients progressed (9 after RN and 12 after NSS). Quality
of life and renal function outcomes have not been addressed.
CONCLUSIONS: Both methods provide excellent oncologic results. In the ITT
population, NSS seems to be significantly less effective than RN in terms of OS.
However, in the targeted population of RCC patients, the trend in favour of RN is
no longer significant. The small number of progressions and deaths from renal
cancer cannot explain any possible OS differences between treatment types.

Copyright © 2010 European Association of Urology. Published by Elsevier B.V. All
rights reserved.

PMID: 21186077  [PubMed - indexed for MEDLINE]

JAMA. 2012 Apr 18;307(15):1629-35. doi: 10.1001/jama.2012.475.

Long-term survival following partial vs radical nephrectomy among older patients with early-stage kidney cancer.

Tan HJ(1), Norton EC, Ye Z, Hafez KS, Gore JL, Miller DC.

Author information:
(1)Dow Division of Health Services Research, Department of Urology, University of
Michigan, Ann Arbor, MI 48109-2800, USA.

Comment in
    Eur Urol. 2012 Aug;62(2):352-3.
    JAMA. 2012 Apr 18;307(15):1641-3.
    Urol Oncol. 2013 Jan;31(1):126-7.
    J Urol. 2012 Nov;188(5):1723-4.

CONTEXT: Although partial nephrectomy is the preferred treatment for many
patients with early-stage kidney cancer, recent clinical trial data, which
demonstrate better survival for patients treated with radical nephrectomy, have
generated new uncertainty regarding the comparative effectiveness of these
treatment options.
OBJECTIVE: To compare long-term survival after partial vs radical nephrectomy
among a population-based patient cohort whose treatment reflects contemporary
surgical practice.
DESIGN, SETTING, AND PATIENTS: We performed a retrospective cohort study of
Medicare beneficiaries with clinical stage T1a kidney cancer treated with partial
or radical nephrectomy from 1992 through 2007. Using an instrumental variable
approach to account for measured and unmeasured differences between treatment
groups, we fit a 2-stage residual inclusion model to estimate the treatment
effect of partial nephrectomy on long-term survival.
MAIN OUTCOME MEASURES: Overall and kidney cancer-specific survival.
RESULTS: Among 7138 Medicare beneficiaries with early-stage kidney cancer, we
identified 1925 patients (27.0%) treated with partial nephrectomy and 5213
patients (73.0%) treated with radical nephrectomy. During a median follow-up of
62 months, 487 (25.3%) and 2164 (41.5%) patients died following partial or
radical nephrectomy, respectively. Kidney cancer was the cause of death for 37
patients (1.9%) treated with partial nephrectomy, and 222 patients (4.3%) treated
with radical nephrectomy. Patients treated with partial nephrectomy had a
significantly lower risk of death (hazard ratio [HR], 0.54; 95% CI, 0.34-0.85).
This corresponded with a predicted survival increase with partial nephrectomy of
5.6 (95% CI, 1.9-9.3), 11.8 (95% CI, 3.9-19.7), and 15.5 (95% CI, 5.0-26.0)
percentage points at 2, 5, and 8 years posttreatment (P < .001). No difference
was noted in kidney cancer-specific survival (HR, 0.82; 95% CI, 0.19-3.49).
CONCLUSION: Among Medicare beneficiaries with early-stage kidney cancer who were
candidates for either surgery, treatment with partial rather than radical
nephrectomy was associated with improved survival.

PMCID: PMC3864575
PMID: 22511691  [PubMed - indexed for MEDLINE]

Eur Urol. 2014 Feb;65(2):372-7. doi: 10.1016/j.eururo.2013.06.044. Epub 2013 Jul 2.

Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904.

Scosyrev E(1), Messing EM(2), Sylvester R(3), Campbell S(4), Van Poppel H(5).

Author information:
(1)Department of Urology, University of Rochester Medical Center, Rochester, NY,
USA. (2)Department of Urology, University of Rochester Medical Center, Rochester,
NY, USA. Electronic address: (3)Department of
Biostatistics, EORTC Headquarters, Brussels, Belgium. (4)Department of Urology,
Cleveland Clinic, Cleveland, OH, USA. (5)Department of Urology, University
Hospital K.U. Leuven, Leuven, Belgium.

Comment in
    J Urol. 2014 Aug;192(2):369-70.
    Eur Urol. 2014 Feb;65(2):378-9; discussion 379-80.

BACKGROUND: In the European Organization for Research and Treatment of Cancer
(EORTC) randomized trial 30904, nephron-sparing surgery (NSS) was associated with
reduced overall survival compared with radical nephrectomy (RN) over a median
follow-up of 9.3 yr (hazard ratio: 1.50; 95% confidence interval [CI],
OBJECTIVE: To examine the impact of NSS relative to RN on kidney function in
EORTC 30904.
DESIGN, SETTING, AND PARTICIPANTS: This phase 3 international randomized trial
was conducted in patients with a small (≤5 cm) renal mass and normal
contralateral kidney who were enrolled from March 1992 to January 2003.
INTERVENTION: Patients were randomized to RN (n=273) or NSS (n=268).
filtration rates (eGFR; milliliters per minute per 1.73 m(2)) were recorded for
259 subjects in the RN arm and 255 subjects in the NSS arm. Percentages of
subjects developing at least moderate renal dysfunction (eGFR <60 advanced="" br="">kidney disease (eGFR <30 br="" calculated="" each="" egfr="" failure="" for="" kidney="" or="" were="">treatment arm based on the lowest recorded follow-up eGFR (intent-to-treat
RESULTS AND LIMITATIONS: With a median follow-up of 6.7 yr, eGFR <60 br="" reached="" was="">by 85.7% with RN and 64.7% with NSS, with a difference of 21.0% (95% CI,
13.8-28.3); eGFR <30 10.0="" 6.3="" a="" and="" br="" by="" nss="" reached="" rn="" was="" with="">difference of 3.7% (95% CI, -1.0 to 8.5); and eGFR <15 1.5="" br="" by="" reached="" was="" with="">RN and 1.6% with NSS, with a difference of -0.1% (95% CI, -2.2 to 2.1). Lack of
longer follow-up for eGFR is a limitation of these analyses.
CONCLUSIONS: Compared with RN, NSS substantially reduced the incidence of at
least moderate renal dysfunction (eGFR <60 although="" available="" br="" follow-up="" with="">the incidence of advanced kidney disease (eGFR <30 br="" in="" relatively="" similar="" the="" was="">two treatment arms, and the incidence of kidney failure (eGFR <15 br="" nearly="" was="">identical. The beneficial impact of NSS on eGFR did not result in improved
survival in this study population.
REGISTRATION: EORTC trial 30904; identifier NCT00002473.

Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All
rights reserved.

PMID: 23850254  [PubMed - indexed for MEDLINE]

#NephMadness #OncoRegion VEGF Inhibitor Toxicity Abstracts

Renal Involvement in Preeclampsia: Similarities to VEGF Ablation Therapy

Janina Müller-Deile and Mario Schiffer

Division of Nephrology and Hypertension, Department of Medicine, IFB-TX Hannover, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany

Received 11 September 2010; Accepted 1 November 2010

Academic Editor: David F. Lewis

Copyright © 2011 Janina Müller-Deile and Mario Schiffer. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Glomerular VEGF expression is critical for the maintenance and function of an intact filtration barrier. Alterations in glomerular VEGF bioavailability result in endothelial as well as in podocyte damage. Renal involvement in preeclampsia includes proteinuria, podocyturia, elevated blood pressure, edema, glomerular capillary endotheliosis, and thrombotic microangiopathy. At least the renal signs, symptoms, and other evidence can sufficiently be explained by reduced VEGF levels. The aim of this paper was to summarize our pathophysiological understanding of the renal involvement of preeclampsia and point out similarities to the renal side effects of VEGF-ablation therapy.

Bevacizumab-Mediated Interference With VEGF Signaling Is Sufficient to Induce a Preeclampsia-Like Syndrome in Nonpregnant Women


Preeclampsia (gestational proteinuric hypertension) complicates 5% to 8% of all pregnancies, and is a major cause of maternal and perinatal morbidity and mortality. It is a multisystem disorder specific to human pregnancy and the puerperium. Although the etiology is unknown, increasing evidence from both animal and human studies suggests that an imbalance in circulating pro-(vascular endothelial growth factor [VEGF], placental growth factor) and anti-angiogenic factors (soluble fms-like tyrosine kinase 1, soluble endoglin) may be important. Bevacizumab (Avastin®; Genentech, South San Francisco, CA), a humanized recombinant monoclonal IgG antibody that binds VEGF, has been shown to inhibit endothelial cell proliferation, suppress angiogenesis, and shrink a variety of solid tumors. We present two cases of bevacizumab toxicity that mimic preeclampsia with a reversible syndrome characterized by acute-onset severe hypertension, proteinuria, central nervous system irritability (headache, photophobia, blurred vision, seizures), abnormal laboratory tests (elevated liver function tests, thrombocytopenia), and evidence of reversible posterior leukoencephalopathy on neuroimaging. In both cases, the clinical and laboratory manifestations returned to normal with discontinuation of bevacizumab therapy and supportive care. Bevacizumab toxicity can mimic preeclampsia in nonpregnant women. These data suggest that interference with VEGF signaling is sufficient to induce a preeclampsia-like syndrome in nonpregnant patients. VEGF signaling therefore appears to play a central role—perhaps the central role—in the pathogenesis of preeclampsia, and provides a potential biomarker for the prediction, prevention, and treatment of this dangerous disorder.
Key words: Bevacizumab, Hypertension, Preeclampsia, Eclampsia, Vascular endothelial growth factor, Reversible posterior leukoencephalopathy syndrome
Anticancer Res. 2007 Sep-Oct;27(5B):3465-70.

Hypertension secondary to anti-angiogenic therapy: experience with bevacizumab.

Pande A(1), Lombardo J, Spangenthal E, Javle M.

Author information:
(1)Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Sts,
Buffalo, NY 14263, USA.

BACKGROUND: Hypertension (HT) is a common complication of anti-angiogenic
therapy. Its incidence, treatment and complications are undefined.
PATIENTS AND METHODS: Retrospective review of patients treated with bevacizumab
(BV) from 2003-5. Common toxicity criteria (CTC) for adverse events version 3.0
were used.
RESULTS: Fifty-five out of the 154 patients treated with BV (35%) experienced HT.
Eleven (20%) developed a new onset HT and 44 (80%) experienced an exacerbation of
pre-existing HT. HT developed after a median of 11 weeks at a median BV dose of
10 mg/kg. HT severity was grade 1 (n =1), grade 2 (n=29) or grade 3 (n=22); 3
experienced hypertensive complications. HT was controlled in 47 (85%); BV was
discontinued in 3. The angiotensin-converting enzyme inhibitor (ACE-I), quinapril
was commonly used and resulted in better HT control than ACE-II, calcium channel
or beta antagonists.
CONCLUSION: HT associated with bevacizumab therapy is a manageable toxicity with
the use of ACE-I.

PMID: 17972502  [PubMed - indexed for MEDLINE]

Am J Kidney Dis. 2007 Feb;49(2):186-93.

Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis.

Zhu X(1), Wu S, Dahut WL, Parikh CR.

Author information:
(1)Division of Nephrology, SUNY at Stony Brook, NY, USA.

BACKGROUND: Angiogenesis inhibitors have emerged as an effective targeted therapy
in the treatment of patients with many cancers. One of the most widely used
angiogenesis inhibitors is bevacizumab, a neutralizing antibody against vascular
endothelial growth factor. The overall risk of proteinuria and hypertension in
patients with cancer on bevacizumab therapy is unclear. We performed a systematic
review and meta-analysis of published clinical trials of bevacizumab to quantify
the risk of proteinuria and hypertension.
METHODS: The databases MEDLINE (OVID, 1966 to June 2006) and Web of Science and
abstracts presented at the American Society of Clinical Oncology annual meetings
from 2004 through 2006 were searched to identify relevant studies. Eligible
studies were randomized controlled trials of patients with cancer treated with
bevacizumab that described the incidence of proteinuria and hypertension.
Relative risk (RR) was calculated by using the fixed-effects model.
RESULTS: A total of 1,850 patients were included in the 7 trials identified from
the literature. Bevacizumab was associated with a significant increased risk of
proteinuria (RR, 1.4 with low-dose bevacizumab; 95% confidence interval [CI], 1.1
to 1.7; RR, 2.2 with high dose; 95% CI, 1.6 to 2.9). Hypertension also was
increased significantly among patients receiving bevacizumab (RR, 3.0 for low
dose; 95% CI, 2.2 to 4.2; RR, 7.5 for high dose; 95% CI, 4.2 to 13.4).
CONCLUSION: There was a significant dose-dependent increase in risk of
proteinuria and hypertension in patients with cancer who received bevacizumab.

PMID: 17261421  [PubMed - indexed for MEDLINE]


#NephMadness #OncoRegion Tyrosine Kinase Inhibitor Toxicity Abstracts

Nephrol Dial Transplant. 2009 Feb;24(2):682-5. doi: 10.1093/ndt/gfn657. Epub 2008 Dec 2.

Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib.

Bollée G(1), Patey N, Cazajous G, Robert C, Goujon JM, Fakhouri F, Bruneval P,
Noël LH, Knebelmann B.

Author information:
(1)APHP, Service de Néphrologie Adulte, Hôpital Necker, Paris, France.

Comment in
    Nephrol Dial Transplant. 2009 Jun;24(6):2002-3.

BACKGROUND: Drugs targeting the VEGF pathway are associated with renal adverse
events, including proteinuria, hypertension and thrombotic microangiopathy (TMA).
Most cases of TMA are reported secondary to bevacizumab. It was shown recently
that sunitinib, a small molecule inhibiting several tyrosine kinase receptors,
including VEGF receptors, can also induce proteinuria, hypertension and
biological features of TMA. Case. A 44-year-old woman with a history of malignant
skin hidradenoma was started on sunitinib for refractory disease. She developed
hypertension after 2 weeks and low-grade proteinuria after 4 weeks. Renal
function remained normal, and biological signs of TMA were absent. A renal biopsy
was performed 6 months later as proteinuria persisted, demonstrating typical
features of TMA. The patient was given irbesartan, and sunitinib was continued
for 3 months after diagnosis. Over this period, blood pressure and renal function
remained stable and proteinuria became undetectable.
CONCLUSION: We report on the first case of histologically documented TMA
secondary to sunitinib and provide detailed description of renal histological
involvement. This suggests that all anti-VEGF drugs may share a common risk for
developing renal adverse events, including TMA. Our case highlights the possible
discrepancy between mild clinical manifestation on one hand and severe TMA
features on renal biopsy on the other hand and pleads for large indication of
renal biopsy in this setting. The renin-angiotensin system blockers may be
considered in patients with mild clinical manifestations and in the absence of
therapeutic alternative to anti-VEGF drugs.

PMID: 19054798  [PubMed - indexed for MEDLINE]

Nephrol Dial Transplant. 2014 Feb;29(2):325-32. doi: 10.1093/ndt/gft465. Epub 2013 Dec 2.

All anti-vascular endothelial growth factor drugs can induce 'pre-eclampsia-like syndrome': a RARe study.

Vigneau C(1), Lorcy N, Dolley-Hitze T, Jouan F, Arlot-Bonnemains Y, Laguerre B,
Verhoest G, Goujon JM, Belaud-Rotureau MA, Rioux-Leclercq N.

Author information:
(1)CHU Rennes, Service de Néphrologie, Rennes, France.

BACKGROUND: Specific therapies that target vascular endothelial growth factor
(VEGF) and its receptors have improved the survival of patients with metastatic
cancers, but can induce side effects. Renal side effects (proteinuria,
hypertension and renal failure) are underestimated.
METHODS: The French RARe (Reins sous traitement Anti-VEGF Registre) study
collects data on patients with cancer who had a renal biopsy because of major
renal side effects during treatment with anti-VEGF drugs.
RESULTS: We collected 22 renal biopsies performed 16.2±10.6 months after the
beginning of treatment; of which 21 had hypertension, mean proteinuria was
2.97±2.00 g/day and mean serum creatinine, 134±117 µmol/L. Thrombotic
microangiopathy (TMA) was observed in 21 biopsy specimens, sometimes associated
with acute tubular necrosis (ATN; n=4). TMA histological lesions were more
important than the biological signs of TMA could suggest. Patients with ATN of
>20% had higher serum creatinine levels than those with only TMA (231 versus 95
µmol/L). Nephrin, podocin and synaptopodin were variably down-regulated in all
renal biopsies. VEGF was down-regulated in all glomeruli.
CONCLUSION: This study underlines the importance of regular clinical and
biological cardiovascular and renal checking during all anti-VEGF therapies for
cancer for early detection of renal dysfunction. Collaboration between
oncologists and nephrologists is essential. In such cases, renal biopsy might
help in appreciating the severity of the renal lesions and after
multidisciplinary discussion whether or not it is safe to continue the treatment.

PMID: 24302609  [PubMed - indexed for MEDLINE]

Am J Geriatr Pharmacother. 2007 Dec;5(4):341-4. doi:

Allergic interstitial nephritis possibly related to sunitinib use.

Khurana A(1).

Author information:
(1)Scott & White Memorial Hospital and Clinic, Texas A&M College of Health
Sciences Center, Temple, Texas 76508, USA.

BACKGROUND: Sunitinib is an oral multitargeted inhibitor indicated for the
treatment of renal cell carcinoma.
OBJECTIVE: This report describes a case of allergic interstitial nephritis
possibly related to this agent.
CASE SUMMARY: A 69-year-old female patient with a history of metastatic renal
cell carcinoma after left radical nephrectomy presented to our nephrology clinic
after completing 2 courses of sunitinib therapy. The patient was noted to have
progressive kidney dysfunction with proteinuria, together with peripheral
eosinophilia and eosinophiluria, which developed during the first of 2 cycles of
sunitinib therapy. Her concomitant medications included atenolol,
triamterene/hydrochlorothiazide, amlodipine, and multivitamin tablets, all of
which she had been receiving at stable doses over the previous 2 years. There
were no other over-the-counter medications involved and other possible causes of
interstitial nephritis were excluded. The proteinuria, eosinophilia, and
eosinophiluria worsened with the second course and resolved after sunitinib
discontinuation, which resulted in initial stabilization followed by slight
improvement in kidney function. The Naranjo Adverse Drug Reaction Probability
Scale score for this event was 7, indicating a probable association of the event
with the drug. With clinical improvement after discontinuation of sunitinib and
the presence of a solitary remaining kidney and thrombocytopenia, renal biopsy
was not performed after discussion with the patient. When challenged with a
related agent, sorafenib, the patient experienced worsening of serum creatinine
and increasing eosinophilia, similar to that noted with sunitinib, suggesting
that this event may be a class effect.
CONCLUSIONS: Nephrologists and oncologists should be aware of allergic
interstitial nephritis as an adverse effect related to this agent. Although there
are no current recommendations for monitoring serum creatinine with sunitinib
therapy, we recommend that serum creatinine and white cell count with
differential be checked within 2 weeks of initiation of therapy with sunitinib to
enable earlier diagnosis of this condition and avoid renal damage.

PMID: 18179992  [PubMed - indexed for MEDLINE]

Nephron Clin Pract. 2011;117(4):c312-9. doi: 10.1159/000319885. Epub 2010 Nov 3.

Nephrotoxicities associated with the use of tyrosine kinase inhibitors: a single-center experience and review of the literature.

Jhaveri KD(1), Flombaum CD, Kroog G, Glezerman IG.

Author information:
(1)Division of Nephrology and Hypertension, Weill Cornell Medical Center, New
York, NY, USA.

BACKGROUND: Sunitinib is an oral multitargeted tyrosine kinase receptor inhibitor
(MTKI) used for the treatment of renal cell carcinoma. These small-molecule
agents inhibit signaling through receptor tyrosine kinases such as vascular
endothelial growth factor receptor, platelet-derived growth factor receptor and
cytokine stem cell factor receptor, among others. Although the development of
these novel molecular-targeted agents represents a substantial advance in the
treatment of metastatic cancer, the spectrum of their adverse effects may be
broader than initially predicted.
METHOD: We performed a retrospective chart review of patients who had received
sunitinib and developed renal insufficiency.
RESULTS: We describe 4 patients with renal cell carcinoma and 1 patient with
transitional cell carcinoma treated with sunitinib who experienced various
degrees of nephrotoxicity including hypertension, proteinuria, thrombotic
microangiopathy, and acute and chronic kidney injury which resolved upon
cessation of MTKI.
CONCLUSIONS: Nephrologists and oncologists should be aware of the potential for
toxic renal effects, and we recommend guidelines for early recognition and
treatment of these conditions in patients receiving MTKI.

Copyright © 2010 S. Karger AG, Basel.

PMID: 21051905  [PubMed - indexed for MEDLINE]

Ann Oncol. 2011 Sep;22(9):2073-9. doi: 10.1093/annonc/mdq715. Epub 2011 Feb 10.

Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients.

Marcolino MS(1), Boersma E, Clementino NC, Macedo AV, Marx-Neto AD, Silva MH, van
Gelder T, Akkerhuis KM, Ribeiro AL.

Author information:
(1)School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte,

BACKGROUND: We analyzed the incidence of acute kidney injury and chronic renal
failure in chronic myeloid leukemia (CML) patients using imatinib and
investigated whether there is a relation between duration of imatinib therapy and
decrease in estimated glomerular filtration rate (GFR).
PATIENTS AND METHODS: One hundred five CML patients on imatinib therapy were
enrolled. Creatinine, urea, uric acid, and potassium measurements from imatinib
treatment onset until the end of follow-up (median 4.5 years) were included in
the analysis. GFR was estimated using the Chronic Kidney Disease Epidemiology
Collaboration equation.
RESULTS: During follow-up, 7% of patients developed acute kidney injury;
creatinine levels returned to baseline in only one of them. According to the
regression equation, the mean baseline value of the estimated GFR was 88.9
ml/min/1.73 m(2). Estimated GFR decreased significantly with imatinib treatment
duration; the mean decrease per year was 2.77 ml/min/1.73 m(2) (P < 0.001); 12%
of patients developed chronic renal failure. Age, hypertension, and a history of
chronic renal failure or interferon usage were not significantly related to the
mean decrease in the estimated GFR over time.
CONCLUSION: The introduction of imatinib therapy in nonclinical trial CML
patients is associated with potentially irreversible acute renal injury, and the
long-term treatment may cause a clinically relevant decrease in the estimated

PMID: 21310760  [PubMed - indexed for MEDLINE]

 Leuk Res. 2009 Feb;33(2):344-7. doi: 10.1016/j.leukres.2008.07.029. Epub 2008 Oct2.

Renal failure and recovery associated with second-generation Bcr-Abl kinase inhibitors in imatinib-resistant chronic myelogenous leukemia.

Holstein SA(1), Stokes JB, Hohl RJ.

Author information:
(1)Division of Hematology, Oncology and Blood & Marrow Transplantation,
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.

Tyrosine kinase inhibitors (TKIs) directed against the Bcr-Abl kinase have
revolutionized the treatment of chronic myelogenous leukemia (CML). Relatively
little is known regarding the effects of these agents on the kidney. Clinically,
there have been a handful of reports associating imatinib with acute renal
failure. Preclinical reports indicate that imatinib inhibits signaling pathways
which may play a role in renal injury. We report the case of a patient with
imatinib-resistant CML who developed renal failure after being placed on
dasatinib. When she later became resistant to dasatinib she was switched to
nilotinib. Shortly thereafter, she became dialysis-independent. Second-generation
Bcr-Abl TKIs may influence renal function based on differential inhibition of
related tyrosine kinases.

PMID: 18835038  [PubMed - indexed for MEDLINE]

N Engl J Med. 2006 May 11;354(19):2006-13.

Altered bone and mineral metabolism in patients receiving imatinib mesylate.

Berman E(1), Nicolaides M, Maki RG, Fleisher M, Chanel S, Scheu K, Wilson BA,
Heller G, Sauter NP.

Author information:
(1)Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
10021, USA.

Comment in
    N Engl J Med. 2006 Aug 10;355(6):627; author reply 628-9.
    N Engl J Med. 2006 Aug 10;355(6):627; author reply 628-9.
    N Engl J Med. 2006 Dec 7;355(23):2494-5.
    N Engl J Med. 2006 Aug 10;355(6):628; author reply 628-9.

BACKGROUND: Imatinib mesylate inhibits several tyrosine kinases, including
BCR-ABL, the C-KIT receptor, and the platelet-derived growth factor receptors
alpha and beta, all of which are associated with disease. We observed that
hypophosphatemia developed in some patients with either chronic myelogenous
leukemia or gastrointestinal stromal tumors who were receiving imatinib.
METHODS: We identified 16 patients who had low serum phosphate levels and 8
patients who had normal serum phosphate levels, all of whom were receiving
imatinib. We performed the following biochemical measurements: whole-blood levels
of ionized calcium, plasma levels of intact parathyroid hormone, and serum levels
of total calcium, phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D,
magnesium, and markers of bone formation (bone alkaline phosphatase and
osteocalcin) and bone resorption (N-telopeptide of collagen cross-links);
urinalysis; and phosphate, calcium, and creatinine levels in "spot" urine
RESULTS: Patients in the low-phosphate group (median serum phosphate level, 2.0
mg per deciliter [0.6 mmol per liter]; normal level, >2.5 mg per deciliter [0.8
mmol per liter]) had elevated parathyroid hormone levels and low-to-normal serum
calcium levels, were younger, and were receiving a higher dose of imatinib than
patients in the normal-phosphate group (median level, 3.2 mg per deciliter [1.0
mmol per liter]). Both groups had high levels of phosphate excreted in the urine
and markedly decreased serum levels of osteocalcin and N-telopeptide of collagen
CONCLUSIONS: Hypophosphatemia, with associated changes in bone and mineral
metabolism, develops in a proportion of patients taking imatinib for either
chronic myelogenous leukemia or gastrointestinal stromal tumors. The drug may
inhibit bone remodeling (formation and resorption), even in patients with normal
serum phosphate levels.

Copyright 2006 Massachusetts Medical Society.

PMID: 16687713  [PubMed - indexed for MEDLINE]

#NephMadness #OncoRegion #Bracket Cancer in Tx Patients Studies Abstracts

JAMA. 2011 Nov 2;306(17):1891-901. doi: 10.1001/jama.2011.1592.
Spectrum of cancer risk among US solid organ transplant recipients.

Engels EA(1), Pfeiffer RM, Fraumeni JF Jr, Kasiske BL, Israni AK, Snyder JJ,
Wolfe RA, Goodrich NP, Bayakly AR, Clarke CA, Copeland G, Finch JL, Fleissner ML,
Goodman MT, Kahn A, Koch L, Lynch CF, Madeleine MM, Pawlish K, Rao C, Williams
MA, Castenson D, Curry M, Parsons R, Fant G, Lin M.

Author information:
(1)National Cancer Institute, 6120 Executive Blvd, EPS 7076, Rockville, MD 20892,

Comment in
    JAMA. 2012 Feb 15;307(7):663; author reply 663-4.

CONTEXT: Solid organ transplant recipients have elevated cancer risk due to
immunosuppression and oncogenic viral infections. Because most prior research has
concerned kidney recipients, large studies that include recipients of differing
organs can inform cancer etiology.
OBJECTIVE: To describe the overall pattern of cancer following solid organ
DESIGN, SETTING, AND PARTICIPANTS: Cohort study using linked data on solid organ
transplant recipients from the US Scientific Registry of Transplant Recipients
(1987-2008) and 13 state and regional cancer registries.
MAIN OUTCOME MEASURES: Standardized incidence ratios (SIRs) and excess absolute
risks (EARs) assessing relative and absolute cancer risk in transplant recipients
compared with the general population.
RESULTS: The registry linkages yielded data on 175,732 solid organ transplants
(58.4% for kidney, 21.6% for liver, 10.0% for heart, and 4.0% for lung). The
overall cancer risk was elevated with 10,656 cases and an incidence of 1375 per
100,000 person-years (SIR, 2.10 [95% CI, 2.06-2.14]; EAR, 719.3 [95% CI,
693.3-745.6] per 100,000 person-years). Risk was increased for 32 different
malignancies, some related to known infections (eg, anal cancer, Kaposi sarcoma)
and others unrelated (eg, melanoma, thyroid and lip cancers). The most common
malignancies with elevated risk were non-Hodgkin lymphoma (n = 1504; incidence:
194.0 per 100,000 person-years; SIR, 7.54 [95% CI, 7.17-7.93]; EAR, 168.3 [95%
CI, 158.6-178.4] per 100,000 person-years) and cancers of the lung (n = 1344;
incidence: 173.4 per 100,000 person-years; SIR, 1.97 [95% CI, 1.86-2.08]; EAR,
85.3 [95% CI, 76.2-94.8] per 100,000 person-years), liver (n = 930; incidence:
120.0 per 100,000 person-years; SIR, 11.56 [95% CI, 10.83-12.33]; EAR, 109.6 [95%
CI, 102.0-117.6] per 100,000 person-years), and kidney (n = 752; incidence: 97.0
per 100,000 person-years; SIR, 4.65 [95% CI, 4.32-4.99]; EAR, 76.1 [95% CI,
69.3-83.3] per 100,000 person-years). Lung cancer risk was most elevated in lung
recipients (SIR, 6.13 [95% CI, 5.18-7.21]) but also increased among other
recipients (kidney: SIR, 1.46 [95% CI, 1.34-1.59]; liver: SIR, 1.95 [95% CI,
1.74-2.19]; and heart: SIR, 2.67 [95% CI, 2.40-2.95]). Liver cancer risk was
elevated only among liver recipients (SIR, 43.83 [95% CI, 40.90-46.91]), who
manifested exceptional risk in the first 6 months (SIR, 508.97 [95% CI,
474.16-545.66]) and a 2-fold excess risk for 10 to 15 years thereafter (SIR, 2.22
[95% CI, 1.57-3.04]). Among kidney recipients, kidney cancer risk was elevated
(SIR, 6.66 [95% CI, 6.12-7.23]) and bimodal in onset time. Kidney cancer risk
also was increased in liver recipients (SIR, 1.80 [95% CI, 1.40-2.29]) and heart
recipients (SIR, 2.90 [95% CI, 2.32-3.59]).
CONCLUSION: Compared with the general population, recipients of a kidney, liver,
heart, or lung transplant have an increased risk for diverse infection-related
and unrelated cancers.

PMCID: PMC3310893
PMID: 22045767  [PubMed - indexed for MEDLINE]

Nat Immunol. 2002 Nov;3(11):991-8.
Cancer immunoediting: from immunosurveillance to tumor escape.

Dunn GP(1), Bruce AT, Ikeda H, Old LJ, Schreiber RD.

Author information:
(1)Department of Pathology and Immunology, Center for Immunology, Washington
University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

Comment in
    Nat Immunol. 2003 Mar;4(3):201.
    Lancet Oncol. 2004 Jul;5(7):397-8.
    Nat Immunol. 2004 Jan;5(1):3-4; author reply 4-5.

The concept that the immune system can recognize and destroy nascent transformed
cells was originally embodied in the cancer immunosurveillance hypothesis of
Burnet and Thomas. This hypothesis was abandoned shortly afterwards because of
the absence of strong experimental evidence supporting the concept. New data,
however, clearly show the existence of cancer immunosurveillance and also
indicate that it may function as a component of a more general process of cancer
immunoediting. This process is responsible for both eliminating tumors and
sculpting the immunogenic phenotypes of tumors that eventually form in
immunocompetent hosts. In this review, we will summarize the historical and
experimental basis of cancer immunoediting and discuss its dual roles in
promoting host protection against cancer and facilitating tumor escape from
immune destruction.

PMID: 12407406  [PubMed - indexed for MEDLINE]

#NephMadness #OncoRegion #Bracket Tx after Cancer Studies Abstracts

 Ann Transplant. 1997;2(4):14-7.

Evaluation of transplant candidates with pre-existing malignancies.

Penn I(1).

Author information:
(1)Department of Surgery, University of Cincinnati Medical Center, USA.

A retrospective study was done of the recurrence rates of 1297 preexisting tumors
in renal transplant recipients. Of 1137 neoplasms that were treated prior to
transplantation, the recurrence rate was 21%, and it was 33% in 99 cancers
treated after transplantation. Fifty-four percent of recurrences in the
pretransplant-treated group occurred among malignancies treated within 2 years of
transplantation, 33% in those treated 2-5 years before transplantation, and 13%
among those treated more than 5 years pretransplantation. Among the 31 neoplasms
in the last group 52% of recurrences occurred within 2 years after
transplantation. Among those cancers treated pretransplantation the highest
recurrence rates occurred with breast carcinomas (23%), symptomatic renal
carcinomas (27%), sarcomas (29%), bladder carcinomas (29%), nonmelanoma skin
cancers (53%) and multiple myeloma (67%). In the tumors treated
posttransplantation 39% of recurrences were from nonmelanoma skin cancers. The
bulk of evidence suggests that immunosuppressive therapy facilitates the growth
of residual cancers. With some exceptions a minimum waiting period of 2 years
between treatment of a neoplasm, with a favorable prognosis, and undertaking
renal transplantation is desirable. A waiting period of approximately 5 years is
desirable for lymphomas, most carcinomas of the breast, prostate or colon, or for
large (> 5 cm) symptomatic renal carcinomas. No waiting period is necessary for
incidentally discovered renal carcinomas, in situ carcinomas, and possibly tiny
focal neoplasms. As it is highly unlikely that most candidates for nonrenal
transplantation can be kept alive for a two year waiting period nonrenal
transplantation can be undertaken in patients who have been treated for major
cancers, provided that the disease appears to have been adequately controlled,
and that the stage of the malignancy does not have a poor prognosis.

PMID: 9869873  [PubMed - indexed for MEDLINE]

 Transplantation. 2013 Aug 15;96(3):297-305. doi: 10.1097/TP.0b013e31829854b7.

Overall and cause-specific mortality in transplant recipients with a pretransplantation cancer history.

Brattström C(1), Granath F, Edgren G, Smedby KE, Wilczek HE.

Author information:
(1)Division of Transplantation Surgery, Department of Clinical Science,
Intervention and Technology, Karolinska Institutet, Karolinska University
Hospital, Stockholm, Sweden.

BACKGROUND: It is unclear to what extent cancer history affects
posttransplantation mortality in solid organ transplant recipients.
METHODS: We identified a Swedish population-based cohort of solid organ
transplant recipients in the National Patient Register 1970 to 2008 and linked it
to the Cancer and Cause-of-Death Register. Overall and cause-specific mortality
was estimated using Cox regression.
RESULTS: Of 10,448 eligible recipients, 416 (4%) had a prior malignancy unrelated
to the indication for transplantation diagnosed 2 months or more before surgery
(median, 5.7 years). Mortality among cancer history recipients was 30% increased
after transplantation, compared with other recipients (adjusted hazard ratio
[HR], 1.3; 95% confidence interval [CI], 1.1-1.5; P<0 .001="" br="" by="" driven="">cancer-specific death with no increase in cardiovascular, infectious, or other
noncancer mortality. An increased rate of death due to cancer history was
primarily observed among nonkidney recipients (adjusted HR(nonkidney), 1.8; 95%
CI, 1.3-2.5; HR(kidney), 1.2; 95% CI, 1.0-1.4). Rates were greatest for patients
with waiting times of 5 years or less but persisted with waiting times more than
10 years among kidney and nonkidney recipients with prior aggressive cancer types
(gastrointestinal, breast, kidney/urothelial, and hematologic malignancies).
CONCLUSION: We conclude that organ transplant recipients with cancer history are
at a moderately increased rate of death after transplantation, driven primarily
by death due to cancer recurrence.

PMID: 23759880  [PubMed - indexed for MEDLINE]

Israel Penn International Transplant Tumor Registry

#NephMadness #OncoRegion #Bracket Amyloidosis Studies Abstracts

Kidney Int. 2012 Jan;81(2):201-6. doi: 10.1038/ki.2011.316. Epub 2011 Sep 7.

Medullary amyloidosis associated with apolipoprotein A-IV deposition.

Sethi S(1), Theis JD, Shiller SM, Nast CC, Harrison D, Rennke HG, Vrana JA, Dogan

Author information:
(1)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester,
Minnesota 55905, USA.

Comment in
    Kidney Int. 2012 Jul;82(1):114; author reply 114.

Amyloidosis is caused by extracellular deposition of proteins in an insoluble
manner within tissues. In hereditary forms of amyloidosis, transthyretin,
fibrinogen A-α, lysozyme, gelsolin, apolipoprotein A-I, and A-II accumulate in
the tissue plaques. Here we describe a 52-year-old man with no family history of
renal disease who presented with increased urinary frequency, gradual loss of
renal function but no significant proteinuria. Renal biopsy found large amounts
of amyloid restricted to the medulla with no involvement of glomeruli or vessels.
Immunohistochemical analysis for transthyretin or serum amyloid A and tests for
an underlying monoclonal gammopathy were negative. Although initially suspected
to be amyloid light chain amyloidosis, laser microdissection and mass
spectrometry showed that the amyloid was composed of large amounts of
apolipoprotein A-IV. This was based on mass spectrometry studies that showed 100,
96, and 73 spectra in three microdissected samples that matched to apolipoprotein
A-IV with 100% probability. DNA analyses detected three sequence variants
representing common polymorphisms of the apolipoprotein A-IV gene. Thus, in this
case, apolipoprotein A-IV deposition and renal involvement appear to be
restricted to the medulla. A high degree of suspicion is required for the
diagnosis of apolipoprotein A-IV amyloidosis as it may be missed if a renal
biopsy consists only of cortex.

PMID: 21900878  [PubMed - indexed for MEDLINE]

Clin J Am Soc Nephrol. 2010 Dec;5(12):2180-7. doi: 10.2215/CJN.02890310. Epub2010 Sep 28.

Mass spectrometry-based proteomic diagnosis of renal immunoglobulin heavy chain

Sethi S(1), Theis JD, Leung N, Dispenzieri A, Nasr SH, Fidler ME, Cornell LD,
Gamez JD, Vrana JA, Dogan A.

Author information:
(1)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
55905, USA.

BACKGROUND AND OBJECTIVES: Amyloidosis is a group of disorders characterized by
accumulation of extracellular deposition of proteins as insoluble aggregates. The
clinical management of amyloidosis is based on identifying the underlying
etiology and accurate typing of the amyloid. Ig heavy chain amyloid involving the
kidney is poorly recognized and often poses a diagnostic dilemma. DESIGN,
SETTING, PARTICIPANTS, & MEASURES: In this study, we describe the use of laser
microdissection (LMD) and mass spectrometry (MS)-based proteomic analysis for the
accurate typing of 14 cases of amyloidosis. We also describe the
clinicopathologic findings of four problematic cases of renal Ig heavy chain
amyloidosis that required LMD/MS proteomic analysis for accurate typing of the
RESULTS: LMD/MS proteomic data of four cases of Ig heavy chain renal amyloidosis
showed Ig heavy chains with or without light chains. The break up of the Ig heavy
chains was as follows: one case showed Igγ1 chain constant region and λ light
chains, one case showed Igα chain constant region and κ light chains variable and
constant regions, whereas two cases showed Igγ3 chain constant region and heavy
chains variable region I and/or III without light chains. We compare the LMD/MS
proteomic data of Ig heavy chain renal amyloid with that of other types of
amyloid, including Ig light chains, serum amyloid A, fibrinogen A-α chain renal
amyloid, and transthyretin amyloid.
CONCLUSIONS: We conclude that LMD/MS is a sensitive and specific tool for
diagnosis and accurate typing of renal amyloidosis, including Ig heavy chain

PMCID: PMC2994078
PMID: 20876678  [PubMed - indexed for MEDLINE]

N Engl J Med. 2002 Jun 6;346(23):1786-91.

Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.

Lachmann HJ(1), Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, Pepys
MB, Hawkins PN.

Author information:
(1)National Amyloidosis Centre, Department of Medicine, Royal Free and University
College Medical School, Royal Free Campus, London, United Kingdom.

Comment in
    N Engl J Med. 2002 Jun 6;346(23):1818-9.
    N Engl J Med. 2002 Oct 10;347(15):1206-7; author reply 1206-7.
    N Engl J Med. 2002 Oct 10;347(15):1206-7; author reply 1206-7.

BACKGROUND: Hereditary, autosomal dominant amyloidosis, caused by mutations in
the genes encoding transthyretin, fibrinogen A alpha-chain, lysozyme, or
apolipoprotein A-I, is thought to be extremely rare and is not routinely included
in the differential diagnosis of systemic amyloidosis unless there is a family
METHODS: We studied 350 patients with systemic amyloidosis, in whom a diagnosis
of the light-chain (AL) type of the disorder had been suggested by clinical and
laboratory findings and by the absence of a family history, to assess whether
they had amyloidogenic mutations.
RESULTS: Amyloidogenic mutations were present in 34 of the 350 patients (9.7
percent), most often in the genes encoding fibrinogen A alpha-chain (18 patients)
and transthyretin (13 patients). In all 34 of these patients, the diagnosis of
hereditary amyloidosis was confirmed by additional investigations. A low-grade
monoclonal gammopathy was detected in 8 of the 34 patients (24 percent).
CONCLUSIONS: A genetic cause should be sought in all patients with amyloidosis
that is not the reactive systemic amyloid A type and in whom confirmation of the
AL type cannot be obtained.

PMID: 12050338  [PubMed - indexed for MEDLINE]

#NephMadness #OncoRegion #Bracket Myeloma Studies Abstracts

#Nephmadness/#OncoNephro #Brackets

 J Am Soc Nephrol. 2012 Nov;23(11):1777-81. doi: 10.1681/ASN.2012040388. Epub 2012Sep 20.

Mechanisms of light chain injury along the tubular nephron.

Sanders PW(1).

Author information:
(1)Division of Nephrology, Department of Medicine, Nephrology Research and
Training Center, University of Alabama at Birmingham, Birmingham, Alabama
35294-0007, USA.

The tubular nephron is responsible for reabsorption and catabolism of filtered
low molecular weight proteins that include Ig free light chains. In the setting
of a plasma cell dyscrasia, significant amounts of free light chains, now
monoclonal proteins, present to the tubular nephron for disposal. The result may
be clinical renal dysfunction in the form of AKI, progressive CKD, and end-stage
kidney disease. Here, I review the mechanisms involved in these processes that
result in tubular injury, including proximal tubulopathy and cast nephropathy.

PMID: 22997259  [PubMed - indexed for MEDLINE]

 J Clin Invest. 2012 May;122(5):1777-85. doi: 10.1172/JCI46490. Epub 2012 Apr 9.

Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent

Ying WZ(1), Allen CE, Curtis LM, Aaron KJ, Sanders PW.

Author information:
(1)Division of Nephrology, Department of Medicine, Nephrology Research and
Training Center, University of Alabama at Birmingham, Birmingham, Alabama
35294-0007, USA.

Comment in
    Nat Rev Nephrol. 2012 Jun;8(6):316.
    J Clin Invest. 2012 May;122(5):1605-8.

A common renal complication of multiple myeloma is "myeloma kidney," a condition
also known as cast nephropathy. The renal lesions (casts) are directly related to
the production of monoclonal immunoglobulin free light chains (FLCs), which
coprecipitate with Tamm-Horsfall glycoprotein (THP) in the lumen of the distal
nephron, obstructing tubular fluid flow. Here, we report that analysis of the
binding interaction between FLCs and THP demonstrates that the secondary
structure and key amino acid residues on the complementarity-determining region 3
(CDR3) of FLCs are critically important determinants of the molecular interaction
with THP. The findings permitted development of a cyclized competitor peptide
that demonstrated strong inhibitory capability in the binding of FLCs to THP in
vitro. When used in a rodent model of cast nephropathy, this cyclized peptide
construct served as an effective inhibitor of intraluminal cast formation and
prevented the functional manifestations of acute kidney injury in vivo. These
experiments provide proof of concept that intraluminal cast formation is
integrally involved in the pathogenesis of acute kidney injury from cast
nephropathy. Further, the data support a clinically relevant approach to the
management of renal failure in the setting of multiple myeloma.

PMCID: PMC3336971
PMID: 22484815  [PubMed - indexed for MEDLINE]

Arch Intern Med. 1990 Apr;150(4):863-9.

Treatment of renal failure associated with multiple myeloma. Plasmapheresis,
hemodialysis, and chemotherapy.

Johnson WJ(1), Kyle RA, Pineda AA, O'Brien PC, Holley KE.

Author information:
(1)Division of Nephrology, Mayo Clinic, Rochester, MN 55905.

The aims of this study were to examine in a prospective, randomized trial the
efficacy of plasmapheresis in preventing irreversible renal failure in patients
with multiple myeloma and to study the renal biopsy tissues from such patients.
Twenty-one patients with active myeloma and progressive renal failure were
randomized to one of two groups: group 1, forced diuresis and chemotherapy (10
patients), and group 2, forced diuresis, chemotherapy, and plasmapheresis (11
patients). Plasmapheresis and chemotherapy lowered the serum myeloma protein
value much more rapidly than chemotherapy alone. Of 5 patients who were oliguric
and undergoing dialysis at presentation, only 3 who were treated by
plasmapheresis recovered. Of 16 polyuric patients, 5 in group 1 and 7 in group 2
showed improvement in renal function. The main factor that determined
irreversibility of renal failure was the severity of myeloma cast formation.

PMID: 2183734  [PubMed - indexed for MEDLINE]

Ann Intern Med. 2005 Dec 6;143(11):777-84.
Plasma exchange when myeloma presents as acute renal failure: a randomized,
controlled trial.

Clark WF(1), Stewart AK, Rock GA, Sternbach M, Sutton DM, Barrett BJ, Heidenheim
AP, Garg AX, Churchill DN; Canadian Apheresis Group.

Author information:
(1)University of Western Ontario, London, Ontario, Canada.

Erratum in
    Ann Intern Med. 2007 Mar 20;146(6):471.

Comment in
    Ann Intern Med. 2005 Dec 6;143(11):835-7.
    Ann Intern Med. 2006 Mar 21;144(6):455; author reply 455.

Summary for patients in
    Ann Intern Med. 2005 Dec 6;143(11):I20.

BACKGROUND: Two small, randomized trials provide conflicting evidence about the
benefits of plasma exchange for patients with acute renal failure at the onset of
multiple myeloma.
OBJECTIVE: To assess the effect of 5 to 7 plasma exchanges on a composite outcome
in patients with acute renal failure at the onset of multiple myeloma.
DESIGN: Randomized, open, controlled trial, stratified by chemotherapy and
dialysis dependence, conducted from 1998 to 2004.
SETTING: Hospital plasma exchange units in 14 Canadian medical centers.
PARTICIPANTS: 104 patients between 18 and 81 years of age with acute renal
failure at the onset of myeloma.
INTERVENTION: Study participants were randomly assigned to conventional therapy
plus 5 to 7 plasma exchanges of 50 mL per kg of body weight of 5% human serum
albumin for 10 days or conventional therapy alone. Ninety-seven participants
completed the 6-month follow-up.
MEASUREMENTS: The primary outcome was a composite measure of death, dialysis
dependence, or glomerular filtration rate less than 0.29 mL x s(-2) x m(-2) (<30 br="">mL/min per 1.73 m2).
RESULTS: At enrollment, the plasma exchange and control groups were similar for
dialysis dependence, chemotherapy, sex, age, hypercalcemia, serum albumin level,
24-hour urine protein level, serum creatinine level, and Durie-Salmon staging.
The primary composite end point occurred in 33 of 57 (57.9%) patients in the
plasma exchange group and in 27 of 39 (69.2%) patients in the control group
(difference between groups, 11.3% [95% CI, -8.3% to 29.1%]; P = 0.36). One third
of patients in each group died.
LIMITATIONS: The study was small, used a composite outcome, and did not use renal
biopsy as an inclusion criterion. Recruiting physicians were blinded to treatment
allocation but not to treatment thereafter.
CONCLUSIONS: In patients with acute renal failure at the onset of multiple
myeloma, there is no conclusive evidence that 5 to 7 plasma exchanges
substantially reduce a composite outcome of death, dialysis dependence, or
glomerular filtration rate less than 0.29 mL.s(-2).m(-2) (<30 1.73="" br="" m2="" min="" ml="" per="">at 6 months.

PMID: 16330788  [PubMed - indexed for MEDLINE]

 N Engl J Med. 2011 Jun 16;364(24):2365-6. doi: 10.1056/NEJMc1101834.

Renal improvement in myeloma with bortezomib plus plasma exchange.

Burnette BL, Leung N, Rajkumar SV.

Comment in
    N Engl J Med. 2011 Sep 15;365(11):1061-2; author reply 1062.
    N Engl J Med. 2011 Sep 15;365(11):1061; author reply 1062.

PMID: 21675906  [PubMed - indexed for MEDLINE]

 J Am Soc Nephrol. 2007 Mar;18(3):886-95. Epub 2007 Jan 17.
Efficient removal of immunoglobulin free light chains by hemodialysis for
multiple myeloma: in vitro and in vivo studies.

Hutchison CA(1), Cockwell P, Reid S, Chandler K, Mead GP, Harrison J, Hattersley
J, Evans ND, Chappell MJ, Cook M, Goehl H, Storr M, Bradwell AR.

Author information:
(1)Department of Renal medicine, Queen Elizabeth Hospital, QEMC, Birmingham, B15

Of patients with newly diagnosed multiple myeloma, approximately 10% have
dialysis-dependent acute renal failure, with cast nephropathy, caused by
monoclonal free light chains (FLC). Of these, 80 to 90% require long-term renal
replacement therapy. Early treatment by plasma exchange reduces serum FLC
concentrations, but randomized, controlled trials have shown no evidence of renal
recovery. This outcome can be explained by the low efficiency of the procedure. A
model of FLC production, distribution, and metabolism in patients with myeloma
indicated that plasma exchange might remove only 25% of the total amount during a
3-wk period. For increasing FLC removal, extended hemodialysis with a
protein-leaking dialyzer was used. In vitro studies indicated that the Gambro HCO
1100 dialyzer was the most efficient of seven tested. Model calculations
suggested that it might remove 90% of FLC during 3 wk. This dialyzer then was
evaluated in eight patients with myeloma and renal failure. Serum FLC reduced by
35 to 70% within 2 hr, but reduction rates slowed as extravascular
re-equilibration occurred. FLC concentrations rebounded on successive days unless
chemotherapy was effective. Five additional patients with acute renal failure
that was caused by cast nephropathy then were treated aggressively, and three
became dialysis independent. A total of 1.7 kg of FLC was removed from one
patient during 6 wk. Extended hemodialysis with the Gambro HCO 1100 dialyzer
allowed continuous, safe removal of FLC in large amounts. Proof of clinical value
now will require larger studies.

PMID: 17229909  [PubMed - indexed for MEDLINE]

Study List:

Study 1:
  Title:                    European Trial of Free Light Chain Removal by Extended Haemodialysis in Cast Nephropathy
  Recruitment:              Recruiting
  Study Results:            No Results Available
  Conditions:               Multiple Myeloma|Cast Nephropathy|Kidney Failure
  Interventions:            Device: FLC removal HD (Gambro HCO 1100)|Procedure: Standard dialysis on a high flux ployflux dialyser

Study 2:
  Title:                    Studies in Patients With Multiple Myeloma and Renal Failure Due to Myeloma Cast Nephropathy
  Recruitment:              Recruiting
  Study Results:            No Results Available
  Conditions:               Chronic Renal Failure With Uremic Nephropathy
  Interventions:            Drug: Cyclophosphamide + Bortezomib + Dexamethasone regimen|Drug: Bortezomib +Dexamethasone regimen|Device: HCO group|Device: conventional high-flux dialyzer