nephrologist Urinary Obstruction Urinary obstruction may occur in patients with prostatic or gynecologic malignancies particularly cervical carcinoma Metastatic disease from other primary sites such as carcinomas of the breast stomach lung colon and pancreas or lymphomas can also cause uri ID: 930413
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Slide1
Kidney & cancers
Dr.Sh.Sajjadieh
nephrologist
Slide2Slide3Urinary Obstruction
Urinary obstruction may occur in patients with prostatic or gynecologic malignancies, particularly cervical carcinoma.
Metastatic disease from other primary sites such as carcinomas of the breast, stomach, lung, colon, and pancreas; or lymphomas can also cause urinary tract obstruction .
Radiation therapy to pelvic tumors may cause fibrosis and subsequent
ureteral
obstruction.
Bladder outlet obstruction is usually due to prostate and cervical cancers and may lead to bilateral
hydronephrosis
and renal failure.
Slide4Urinary Obstruction
Flank pain is the most common symptom.
Persistent UTI, persistent
proteinuria
, or
hematuria
in patients with cancer should raise suspicion of
ureteral
obstruction.
Total
anuria
and/or
anuria
alternating with
polyuria
may occur.
A slow, continuous rise in the serum
creatinine
level necessitates immediate evaluation.
Slide5Urinary Obstruction
Renal ultrasound is the safest and cheapest way to identify
hydronephrosis
.
The function of an obstructed kidney can be evaluated by a nuclear scan.
CT scan can reveal the point of obstruction and identify a retroperitoneal mass or
adenopathy
.
Slide6Urinary Obstruction
Treatment:
Obstruction associated with flank pain, sepsis, or fistula formation is an indication for immediate palliative urinary diversion.
Internal
ureteral
stents can be placed under local anesthesia.
Percutaneous
nephrostomy
offers an alternative approach for drainage.
In the case of bladder outlet obstruction due to malignancy, a
suprapubic
cystostomy
can be used for urinary drainage.
Slide7Metabolic Emergencies
Hypercalcemia
is the most common
paraneoplastic
syndrome.
Syndrome of Inappropriate Secretion of
Antidiuretic
Hormone (SIADH) can also occurs.
Hyponatremia
is a common electrolyte abnormality in cancer patients, and SIADH is the most common cause among patients with cancer.
Lactic acidosis is a rare and potentially fatal metabolic complication of cancer.
Slide8Lactic Acidosis
Normal venous levels of lactate are 0.5–2.2
mmol
/L (4.5–19.8 mg/
dL
).
Lactic acidosis associated with sepsis and circulatory failure is a common
preterminal
event in many malignancies.
Lactic acidosis in the absence of hypoxemia may occur in patients with leukemia, lymphoma, or solid tumors.
Extensive involvement of the liver by tumor is often present.
Slide9Lactic Acidosis
Symptoms of lactic acidosis include
tachypnea
, tachycardia, change of mental status, and
hepatomegaly
.
The serum level of lactic acid may reach 10–20
mmol
/L (90–180 mg/
dL
).
Treatment is aimed at the underlying disease.
The danger from lactic acidosis is from the acidosis, not the lactate
.
Sodium bicarbonate should be added if acidosis is very severe or if hydrogen ion production is very rapid and uncontrolled.
The prognosis is poor.
Slide10Paraneoplastic
glomerulonephritis
Slide11Introduction
Paraneoplastic
glomerulonephritides
are
glomerular lesions
that
are:
not directly related to tumor
burden,invasion
, or
metastasis
but rather are induced by
products from
tumor
cells.
Slide12Introduction
Classic
paraneoplastic
glomerulonephritides
solid tumor-associated membranous nephropathy
Hodgkin lymphoma-associated minimal change disease (MCD)
Slide13Introduction
Other
glomerulonephritides
:
FSGS
membrano
proliferative glomerulonephritis
Iga
nephropathy
RPGN
Slide14Introduction
diagnosis of
paraneoplastic
glomerulonephritis should
be considered
if:
occurs in
the presence of
malignancy
remits after ablation
of the malignancy
recurs in association with the
recurrence of
malignancy
Slide15Introduction
the diagnosis
of
paraneoplastic
glomerulonephritis can be
difficult
due
to:
delayed diagnosis of
malignancy
presence of other
secondary causes of
glomerulonephritis
(
infection,drugs
…)
the rare
occurrence of
certain
paraneoplastic
glomerulo
nephritides after
ablation of a malignancy
Slide16Introduction
Treatment
of
paraneoplastic
glomerulonephritis is
quite different from treatment of
idiopathic glomerulonephritis
Slide17Solid tumors
membranous
nephropathy
is
in general the most
commonly reported
paraneoplastic
glomerulonephritis
M
CD,
membranoproliferative
glomerulonephritis,
RPGN and IgA
nephropathy have been reported less frequently
Slide18Solid tumors
membranous
nephropathy
Marked male preponderance
age over 50
years
full-blown
nephrotic
syndrome
the neoplasm and membranous
nephropathy manifest
themselves within 12 months of
each other.
Slide19Solid tumors
membranous
nephropathy
MN
has been reported in association
with:
Lung cancer
Gastric cancer
Renal cancer
Prostate cancer
Breast cancer
Colon cancer
Slide20Solid tumors
membranous
nephropathy
two
major risk factors separated
para
neoplastic membranous
nephropathy from idiopathic
membranous nephropathy:
age over 65
years
smoking >20
packyears
Slide21Solid tumors
membranous
nephropathy
pathology
The
pathology of membranous nephropathy
is characterized
by
subepithelial
deposits of
immune complex
Tumor
antigens, including
carcinoembryonic
antigen(CEA),
prostate specific
antigen(PSA),
and melanoma
antigens, have
been reported in conjunction with
cancer associated membranous nephropathy
Slide22membranous nephropathy
It is possible that tumor antigens are not sufficient to cause
paraneoplastic
membranous nephropathy and enhanced immune reactions triggered by the cancer itself may be required for the development of membranous nephropathy
Slide23Solid tumors
membranous nephropathy
pathology
IgG1
and igG2 subtypes
are markedly
more prominent in the kidneys of patients
with
paraneoplastic
membranous nephropathy than in
those with
idiopathic membranous
nephropathy (
t-helper
(TH)-
1
cell-related
isotypes
)
Levels
of igG4 are no
different (TH2
cell-related
isotype
)
Slide24Solid tumors
Minimal change
disease
MCD
has been reported in association
with:
Lung
Colon
renal
cancers
Breast
Slide25Solid tumors
Minimal change
disease
ablation
of the tumor frequently
results in
remission of
mCD
therefore:
factors produced
by cancer
cells might contribute to the pathogenesis
of
paraneoplastic
mCD
.
Slide26Solid tumors
Minimal change disease
VEGF
is one potential candidate because of its
ability to
increase glomerular permeability
Slide27Solid tumors
Membranoproliferative
glomerulonephritis
MPGN
has
been reported
in association
with:
Lung
renal
gastric cancers
Colon cancer
Breast cancer
Slide28Solid tumors
Membranoproliferative
glomerulonephritis
In these
patients, tests for hepatitis C virus (
HCV) and
cryoglobulin
were
negative
Therefore:
paraneoplastic
MPGN
is an
immune-complex disease
that is induced by the combination of
tumor antigen formation
and the inability of the host to
effectively clear
antigens
Slide29Solid tumors
Membranoproliferative
glomerulonephritis
Tumor
removal has been shown
to induce
remission of
membranoproliferative
glomerulonephritis in
some
cases
in instances in which this
goal is
not possible, a trial of prednisone treatment to
control
nephrotic
syndrome seems reasonable
Slide30Solid tumors
rapidly progressive
glomerulonephritis
RPGN
has been reported in association
with:
renal cell
carcinoma
Gastric
lung cancers
Prostate cancer
Breast cancer
Colon cancer
Slide31Solid tumors
rapidly progressive
glomerulonephritis
Some reports
demonstrate that
ANCA-associated
vasculitis
can
occur concurrently with cancer, but
cancers are
frequently diagnosed after the initial diagnosis
of
vasculitis
.
Slide32Solid tumors
rapidly progressive
glomerulonephritis
Treatment
in patients in whom
tumor removal
will be performed,
paraneoplastic
RPGN
can
be treated
with steroid and cyclophosphamide
immediately, to
prevent irreversible damage of the kidney
Slide33Solid tumors
IgA nephropathy
IgA nephropathy has been reported associated with:
renal cell
carcinoma
respiratory
tract tumors
Slide34Solid tumors
IgA
nephropathy
tumor
ablation seems
to be the treatment of choice for
para
neoplastic
IgA
nephropathy
, whereas corticosteroid therapy may
promote tumor growth.
Slide35Solid tumors
IgA
nephropathy
Henoch
–
schonlein
purpura
(
HSP) has
also been reported in association
with:
solid
tumors
most commonly lung cancers
Slide36Hematological malignancies
Lymphoid
Myeloid
Thymus
malignancies
Slide37Hematological malignancies
lymphoid
malignancies
Paraneoplastic
glomerulonephritides
are well known
to occur
in association
with CLL
but rarely occur in patients
with ALL
Others:
Hodgkin lymphoma
non-Hodgkin lymphoma
cutaneous t-cell
lymphoma
hairy
cell leukemia
Slide38Hematological malignancies
lymphoid malignancies
MCD
is the most common
paraneoplastic
glomerulonephritis associated
with Hodgkin lymphoma,
followed by FSGS
Slide39Hematological malignancies
lymphoid
malignancies
MPGN and MN
are
more commonly
associated
with:
CLL
, HCL and
non-Hodgkin
lymphoma
IgA
nephropathy has only been reported
in association
with cutaneous t-cell lymphoma
Slide40Hematological malignancies
MCD and
FSGS
MCD
occurs in about 1% of patients with
Hodgkin lymphoma
The
occurrence of
FSGS
is about
one-tenth that
of
MCD
Slide41Hematological malignancies
MCD and
FSGS
a poor response of
MCD to
steroid or
ciclosporin
therapy
seems
to
be indicative
of occult Hodgkin
lymphoma
Slide42Hematological malignancies
MCD and
FSGS
increased cytokine levels, particularly levels of TH2 cytokines and IL-13 could be responsible for inflammatory response
Slide43Hematological malignancies
Membranoproliferative
glomerulonephritis
MPGM
in the setting
of CLL, HCL
and B-cell
non-Hodgkin lymphoma
might be caused by monoclonal
immunoglobulin, which
is secreted by B-cell clones
Slide44Hematological malignancies
Membranoproliferative
glomerulonephritis
In the
past 2 decades,
HCV
infection has been
implicated in
the development of B-cell non-Hodgkin
lymphoma
The
high
incidence of subclinical lymphoma suggests
that type II
mixed
cryoglobulinemia
is a
precancer
condition and
that the expansion of clonal B cells may
eventually progress
to B-cell lymphoma
Slide45Hematological malignancies
Membranoproliferative
glomerulonephritis
the incidence of
nephrotic
syndrome in
patients with CLL
is less than 1%,
with
membrano
proliferative glomerulonephritis being
the most
common pathology
Slide46Hematological malignancies
Membranoproliferative
glomerulonephritis
the response rate of
HCV-associated type II
mixed
cryoglobulinemia
to combined
treatment with
interferon and ribavirin is about 60
%
Patients
who failed
to respond to interferon and ribavirin,
however, responded
well to
rituximab
,
which is used to treat B-cell malignancies
Slide47Hematological malignancies
Membranous
nephropathy
MN
is less common
than MPGN
in relation
to lymphoid
malignancies
(1/8)
Slide48Hematological malignancies
Membranous
nephropathy
Features
atypical of membranous
nephropathy, including:
segmental
mesangial
proliferation
subepithelial
deposits
of
fibrillary
material
monoclonal
IgG
kappa light chain
deposits
have been reported
in disease
associated
with CLL and
non- Hodgkin lymphoma
Slide49Hematological malignancies
Membranous
nephropathy
Paraneoplastic
membranous
nephropathy frequently
responds to
treatment of the underlying malignancy.
Slide50Hematological malignancies
Myeloid
Malignancies
AML like ALL
has been rarely reported
in association
with
glomerulonephritides
.
Slide51Hematological malignancies
Myeloid Malignancies
Among
the
myeloproliferative
neoplasms,
polycythemia
vera
, essential
thrombocythemia
and
primary
myelofibrosis
are associated with
FSGS
and
mesangial
proliferative
glomerulonephritis
Slide52Hematological malignancies
Myeloid
Malignancies
Plasma and urine levels of
platelet derived growth
factor (PDGF) are elevated in
patients with
myeloproliferative
neoplasms and
PDGF has
been shown
to enhance
mesangial
proliferation and
fibrosis.
Slide53Hematological malignancies
Myeloid
Malignancies
Treatment with
myelosuppressive
agents or regular phlebotomies
for
myeloproliferative
neoplasms has achieved
partial remission
of
FSGS
in some cases
Slide54Hematological malignancies
Myeloid
Malignancies
CML
is the most
common
myeloproliferative
neoplasm, but is rarely
associated with glomerulonephritis
CML
may cause or
exacerbate
membranoproliferative
glomerulonephritis
Slide55Thymoma
The prevalence of
paraneoplastic
glomerular diseases in patients
with
thymoma
is about 2%, higher than that for
Hodgkin lymphoma
.
Slide56Thymoma
MCD
is the most common
paraneoplastic
glomerulonephritis
associated with
thymoma
,
followed by:
MN , FSGS , RPGN,
and
lupus nephritis
Slide57Thymoma
Histologically,
thymoma
can be divided
into:
epithelial-predominant
lymphocyte-
predominant
Slide58Thymoma
MN
tends to be associated with
epithelial-predominant
thymoma
Is
always diagnosed with either a newly
diagnosed or
recurrent
thymoma
, and typically
resolves after
tumor
ablation
Thymoma
-associated
membranous nephropathy seems to have a similar
pathogenetic
mechanism to that of solid tumor-associated membranous
nephropathy.
Slide59Thymoma
MCD
tends to be associated
with
lymphocyte-predominant
thymoma
Is
frequently
diagnosed after
tumor removal, and responds relatively
well to
steroid
therapy
Thymoma
-associated MCD could
be associated with persistent t-cell
dysfunction after
thymoma
removal.
Slide60Paraneoplastic
glomerulonephritis treatment by type of malignancy
Malignancy
Treatment
Solid tumors
Tumor ablation, additional immunosuppression for RPGN
Lymphoid malignancies
Ablation of malignancies
Myeloid malignancies
CML
immunosuppression for MCD and RPGN
PV,
ET, PMF
Myelosuppression, phlebotomy
MDS
immunosuppression
CMML
Ablation of malignancies
Thymoma
Epithelial predominant
Tumor ablation
Lymphocyte predominant
immunosuppression
Slide61Tumor
Lysis
Syndrome
Tumor
lysis
syndrome (TLS) is characterized by
hyperuricemia
,
hyperkalemia
,
hyperphosphatemia
, and
hypocalcemia
It is caused by the destruction of a large number of rapidly proliferating
neoplastic
cells.
Acidosis may also develop.
Acute renal failure occurs frequently.
Slide62TLS is most often associated with the treatment of
Burkitt's
lymphoma, acute lymphoblastic leukemia, and other rapidly proliferating lymphomas,
but it also may be seen with chronic
leukemias
and, rarely, with solid tumors.
This syndrome has been seen in patients
withCLL
after treatment with nucleosides like
fludarabine
.
TLS has been observed with administration of
glucocorticoids
, hormonal agents such as
letrozole
and
tamoxifen
, and monoclonal antibodies such as
rituximab
and
gemtuzumab
.
TLS usually occurs during or shortly (1–5 days) after chemotherapy.
Rarely, spontaneous necrosis of malignancies causes TLS.
Slide63Hyperuricemia
may be present at the time of chemotherapy.
Effective treatment kills malignant cells and leads to increased serum uric acid levels from the turnover of nucleic acids.
Owing to the acidic local environment, uric acid can precipitate in the tubules, medulla, and collecting ducts of the kidney, leading to renal failure.
Lactic acidosis and dehydration may contribute to the precipitation of uric acid in the renal tubules.
The finding of uric acid crystals in the urine is strong evidence for uric acid nephropathy.
The ratio of urinary uric acid to urinary
creatinine
is >1 in patients with acute
hyperuricemic
nephropathy and <1 in patients with renal failure due to other causes.
Slide64Hyperphosphatemia
, which can be caused by the release of intracellular phosphate pools by tumor
lysis
, produces a reciprocal depression in serum calcium, which causes severe neuromuscular irritability and
tetany
.
Deposition of calcium phosphate in the kidney and
hyperphosphatemia
may cause renal failure.
Potassium is the principal intracellular
cation
, and massive destruction of malignant cells may lead to
hyperkalemia
.
Hyperkalemia
in patients with renal failure may rapidly become life-threatening by causing ventricular arrhythmias and sudden death.
Slide65The likelihood that TLS will occur in patients with
Burkitt's
lymphoma is related to the tumor burden and renal function.
Hyperuricemia
and high serum levels of lactate
dehydrogenase
(LDH >1500 U/L), both of which correlate with total tumor burden, also correlate with the risk of TLS.
In patients at risk for TLS, pretreatment evaluations should include a CBC, serum chemistry evaluation, and urine analysis.
Slide66High leukocyte and platelet counts may artificially elevate potassium levels ("
pseudohyperkalemia
") due to
lysis
of these cells after the blood is drawn. In these cases, plasma potassium instead of serum potassium should be followed.
In
pseudohyperkalemia
, no electrocardiographic abnormalities are present.
Slide67In patients with abnormal baseline renal function, the kidneys and retroperitoneal area should be evaluated by
sonography
and/or CT to rule out obstructive
uropathy
.
Urine output should be watched closely.
Slide68Treatment
Tumor
Lysis
Syndrome: Treatment
Recognition of risk and prevention are the most important steps in the management of this syndrome .
The standard preventive approach consists of
allopurinol
, urinary
alkalinization
, and aggressive hydration.
Intravenous
allopurinol
may be given in patients who cannot tolerate oral therapy.
In some cases, uric acid levels cannot be lowered sufficiently with the standard preventive approach.
Rasburicase
(recombinant
urate
oxidase
) can be effective in these instances.
Slide69Treatment
Urate
oxidase
is missing from primates and catalyzes the conversion of poorly soluble uric acid to readily soluble
allantoin
.
Rasburicase
acts rapidly, decreasing uric acid levels within hours; however, it may cause hypersensitivity reactions such as
bronchospasm
, hypoxemia, and hypotension.
Rasburicase
should also be administered to high-risk patients for TLS prophylaxis.
Rasburicase
is contraindicated in patients with glucose-6-phosphate
dehydrogenase
deficiency who are unable to break down hydrogen peroxide, an end product of the
urate
oxidase
reaction.
Slide70Despite aggressive prophylaxis, TLS and/or
oliguric
or
anuric
renal failure may occur.
Care should be taken to prevent worsening of symptomatic
hypocalcemia
by induction of alkalosis during bicarbonate infusion.
Administration of sodium bicarbonate may also lead to urinary precipitation of calcium phosphate, which is less soluble at alkaline
pH.
Dialysis is often necessary and should be considered early in the course.
Hemodialysis
is preferred.
Hemofiltration
offers a gradual, continuous method of removing cellular by-products and fluid.
The prognosis is excellent, and renal function recovers after the uric acid level is lowered to 10 mg/
dL
.
Slide71Hemorrhagic Cystitis
Hemorrhagic cystitis can develop in patients receiving
cyclophosphamide
or
ifosfamide
.
Both drugs are metabolized to
acrolein
, which is a strong chemical irritant that is excreted in the urine.
Prolonged contact or high concentrations may lead to bladder irritation and hemorrhage.
Symptoms include gross
hematuria
, frequency,
dysuria
, burning, urgency, incontinence, and
nocturia
.
Slide72Hemorrhagic Cystitis
The best management is prevention. Maintaining a high rate of urine flow minimizes exposure.
In addition, 2-mercaptoethanesulfonate (
mesna
) detoxifies the metabolites and can be
coadministered
with the instigating drugs.
Mesna
usually is given three times on the day of
ifosfamide
administration in doses that are each 20% of the total
ifosfamide
dose.
If hemorrhagic cystitis develops, the maintenance of a high urine flow may be sufficient supportive care.
If conservative management is not effective, irrigation of the bladder with a 0.37–0.74% formalin solution for 10 min stops the bleeding in most cases.
N
-
acetylcysteine
may also be an effective
irrigant
.
Prostaglandin (
carboprost
) can inhibit the process.
In extreme cases, ligation of the
hypogastric
arteries, urinary diversion, or
cystectomy may be necessary.
Slide73Hemorrhagic Cystitis
Hemorrhagic cystitis also occurs in patients who undergo bone marrow transplantation (BMT).
In the BMT setting, early-onset hemorrhagic cystitis is related to drugs in the treatment regimen (e.g.,
cyclophosphamide
), and late-onset hemorrhagic cystitis is usually due to the
polyoma
virus BKV or adenovirus type 11.
BKV load in urine alone or in combination with acute GVHD correlate with development of hemorrhagic cystitis.
Viral causes are usually detected by PCR-based diagnostic tests.
Treatment of viral hemorrhagic cystitis is largely supportive, with reduction in doses of immunosuppressive agents, if possible.
No antiviral therapy is approved, though
cidofovir
is reported to be effective in small series.
Slide74Hemolytic-Uremic Syndrome
Hemolytic-uremic syndrome (HUS) and, less commonly, thrombotic thrombocytopenic
purpura
(TTP) may rarely occur after treatment with
antineoplastic
drugs including
mitomycin
,
cisplatin
,
bleomycin
, and
gemcitabine
.
It occurs most often in patients with gastric, lung, colorectal, pancreatic, and breast carcinoma.
In one series, 35% of patients were without evident cancer at the time this syndrome appeared.
Secondary HUS/TTP has also been reported as a rare but sometimes fatal complication of bone marrow transplantation.
Slide75HUS usually has its onset 4–8 weeks after the last dose of chemotherapy, but it is not rare to detect it several months later.
HUS is characterized by
microangiopathic
hemolytic anemia, thrombocytopenia, and renal failure.
Dyspnea
, weakness, fatigue,
oliguria
, and
purpura
are also common initial symptoms and findings.
Systemic hypertension and pulmonary edema frequently occur.
Severe hypertension, pulmonary edema, and rapid worsening of
hemolysis
and renal function may occur after a blood or blood product transfusion.
Cardiac findings include
atrial
arrhythmias, pericardial friction rub, and pericardial effusion.
Raynaud's
phenomenon is part of the syndrome in patients treated with
bleomycin
.
Slide76Laboratory findings include severe to moderate anemia associated with RBC fragmentation and numerous
schistocytes
on peripheral smear.
Reticulocytosis
, decreased plasma
haptoglobin
, and an LDH level document
hemolysis
.
The serum
bilirubin
level is usually normal or slightly elevated.
The Coombs' test is negative.
The white cell count is usually normal, and thrombocytopenia (<100,000/L) is almost always present.
Most patients have a normal coagulation profile, although some have mild elevations in thrombin time and in levels of FDPs.
The serum
creatinine
level is elevated at presentation and shows a pattern of
subacute
worsening within weeks of the initial
azotemia
.
The urinalysis reveals
hematuria
,
proteinuria
, and granular or hyaline casts; and circulating immune complexes may be present.
Slide77The basic pathologic lesion appears to be deposition of fibrin in the walls of capillaries and arterioles, and these deposits are similar to those seen in HUS due to other causes.
These
microvascular
abnormalities involve mainly the kidneys and rarely occur in other organs.
The pathogenesis of chemotherapy-related HUS is unknown.
Other forms of HUS/TTP are related to a decrease in processing of von
Willebrand
factor by a protease called ADAMTS13.
Slide78The case fatality rate is high; most patients die within a few months.
There is no consensus on the optimal treatment for chemotherapy-induced HUS.
Treatment modalities for HUS/TTP including
immunocomplex
removal (
plasmapheresis
,
immunoadsorption
, or exchange transfusion),
antiplatelet
/anticoagulant therapies, immunosuppressive therapies, and plasma exchange employed varying degrees of success.
Rituximab
is successfully used in patients with chemotherapy-induced HUS as well as in ADAMTS13-deficient TTP.
Slide79Plasma cell
dyscrasia
induced renal failure:
Slide80Chemotherapeutic agents and the kidney
80
Slide81Cisplatin
is the most wildly used chemotherapeutic agent and the most
nephrotoxic
agent.
Used for gastric, bladder, head & neck, NSCLC, SCLC, ovarian CA and lymphoma.
81
Slide82Renal manifestations of cisplatin treatment
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82
condition
incidence
Acute kidney injury
20-30%
Hypomagnesemia
40-100%
Fanconi
-like syndrome
Distal RTA
Hypocalcemia
Renal salt wasting
Renal concentrating defect
Hyperurecemia
Transient proteinuria
Erythropoietin deficiency
Trombotic
microangiopathy
Chronic renal failure
Slide83Cisplatin
is
renally
excreted: more than 50% in the first 24 hours following
cisplatin
administration.
The concentration of platinum achieved in the renal cortex is several-fold greater than that in plasma and other organs.
Renal tubular dysfunction and decreased GFR, can be dose limited.
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83
Slide84Cisplatin
primarily injures the S3 segment of the proximal tubule, causing a decrease in the GFR.
Changes in expression of proximal tubule organic
cation
transporter-2 (OCT2) have been shown to mediate the accumulation of
cisplatin
in proximal tubular epithelial cells, which suggests a key role for OCT2 in the development of
cisplatin
-mediated
nephrotoxicity
.
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84
Slide85Vasoconstriction:
soon after injection
Proinflammatory
effects:
Increases the expression of
proinflammatory
cytokines, such as TNF-alpha, IL-6, IFN-gamma and
caspases
, which promote the differentiation, maturation, and activation of
neutrophils
, T cells, and other components of the cellular inflammatory response.
Increased expression of endothelial cell adhesion molecules and subsequent infiltration of leukocytes and T cells in kidney tissue.
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85
Slide86Effects on the proximal tubule:
PCTs are selectively injured as manifested by both necrosis and apoptosis.
Next: a) reduced expression and function of sodium-dependent glucose and amino acid transporters ; b) reduced expression and function of magnesium and water transporters ; c) metabolism of
cisplatin
to glutathione and
cysteinyl-glycine
conjugates ; d) the generation of reactive oxygen species.
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86
Slide87Risk factors for ARF
Higher doses: > 50mg/body surface area.
Older age
Female
Smoking
Underling kidney disease
Hypoalbuminemia
Previous use of
cisplatin
( or
carboplatin
)
Concomitant use of
nephrotoxic
drugs
Paclitaxel
co-administration
Alcohol ingestion
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87
Slide88When we seen? Within 10 days of
cisplatin
administration.
Usually dose dependent.
It is also
belived
that
cisplatin
administration may lead to
long term reduction of GFR
.
The incidence and severity of renal failure increases with subsequent courses and
can
eventually become irreversible.
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88
Slide8925% of patients have reversible
azotemia
for 1 to 2 weeks after treatment.
A significant minority of patients have a progressive decline in renal function.
Unless the renal failure is advanced, the urine output in patients with
nephrotoxicity
typically remains above 1000
mL
/ day due to the induction of a concentrating defect: Due to damage to the loop of
Henle
.
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89
Slide90Thrombotic microangiopathy
Cisplatin
may be associated with thrombotic
microangiopathy
with features of the HUS or TTP in combination with:
Bleomycin
or
Gemcitabine
.
This disorder presumably reflects direct vascular injury with secondary platelet activation.
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90
Slide91It can develop months after treatment has been discontinued.
The diagnosis of this form of
nephrotoxicity
is suggested by the concurrent presence of a
microangiopathic
hemolytic anemia and thrombocytopenia.
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91
Slide92Hypomagnesemia
In addition to its direct clinical manifestations,
hypomagnesemia
may exacerbate
cisplatin
toxicity.
In normal persons in serum Mg< 1.5mg/
dL
, urine will be nearly Mg-free. If
FEMg
is > 2.5%, some component of Mg wasting in the presence of
hypomagnesemia
.
It frequently complicated by
hypocalcemia
that is probably secondary to diminished PTH release and/or end-organ resistance to parathyroid hormone induced by
hypomagnesemia
.
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92
Slide93Associated
hypocalcemia
is responsive to magnesium repletion and is unresponsive to calcium replacement alone
The more rarely seen
hypokalemia
should be treated by replacement of both potassium and magnesium.
F.
Ries
.
MD, and J.
Klastersky
, MD
Nephrotoxicity
Induced by Cancer Chemotherapy With Special Emphasis on
Cisplatin
Toxicity,
7/28/2016
93
Slide94Fanconi-like syndrome
Increased urinary excretion of glucose and amino acids (such as
alanine
,
valine
,
leucine
,
methionine
) and the presence of lactate and
pyruvate
in the urine.
In addition to being a marker of tubular damage,
glucosuria
may also occur due to
cisplatin
-induced glucose intolerance and hyperglycemia due to abnormal insulin and glucagon responses to a glucose stimulus.
Classic
Fanconi
syndrome has not been reported, although mild tubular dysfunction may persist.
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94
Slide95Diagnostic criteria
Urinary excretion of a proximal tubular injury markers, such as -2
microglobulin
,
N-acetyl--D-glucosaminidase, and 1-acid glycoprotein,
increase after
cisplatin
treatment.
There is little change in urine protein excretion.
Urinalysis typically shows leukocytes, renal tubular epithelial cells, and granular casts.
Anand
AJ,
Bashey
B. Newer insights into
cisplatin
nephrotoxicity
.
Ann
Pharmacother
1993;27:1519–25.
XIN YAO, KESSARIN PANICHPISAL, NEIL KURTZMAN,KENNETH NUGENT.
Cisplatin
Nephrotoxicity
: A Review.
[Am J Med Sci 2007;334(2):115–124.]
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95
Slide967/28/2016
96
Slide97Approaches to Prevention
Excretion and Metabolism:
Hydration: saline:
The administration of intravenous saline to induce a
diuresis
remains the primary approach for preventing
cisplatin
induced
nephrotoxicity
and must be used in all patients treated with
cisplatin
.
Mx
:
Salt also provides a high concentration of chloride ions that prevent the dissociation of the chloride ions from the platinum molecule, thereby reducing the formation of the reactive,
aquated
species of
cisplatin
.
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97
Slide98A solution consisting of 1000
mL
of N.S plus 20
mEq
of
KCl
and 2 grams of Mg sulfate.
Intravenously administration of a minimum of 1000
mL
of this solution over 2-3 hours prior to, and a minimum of 500
mL
over the 2 hours following, the
cisplatin
administration.
This fluid administration should be adequate to establish a urine flow of at least 100
mL
/h for 2 hours prior to, and 2 hours after chemotherapy administration.
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Slide99Manitol
is frequently used to induce
diuresis
, although there is no evidence that this is required.
The addition of
furosemide
is generally not required, unless there is evidence of fluid overload.
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99
Slide100Cisplatin analogs
The less
nephrotoxic
analog,
carboplatin
, has been substituted for
cisplatin
in many chemotherapy regimens.
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100
Slide101Amifostine
An organic
thiophosphate
that may protect against
cisplatin
-induced toxicity by donating a protective
thiol
group, an effect that is highly selective for normal, but not malignant, tissue .
Treatment with
amifostine
prior to
cisplatin
administration decreased
nephrotoxicity
in animal models and preliminary clinical studies.
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101
Slide102On the basis of these results, the 2002 guidelines from the American Society of Clinical Oncology stated that
amifostin
could be considered in patients receiving repeated administrations of
cisplatin
for ovarian or non-small cell lung cancer , a position that was reiterated in the updated 2008 guidelines, with no new data on which to base a change in the recommendation.
7/28/2016
102
Slide103We do
not
use
amofostin
to prevent
cisplatin
-induced
nephrotoxicity
due to:
newer regimens with lower doses of
cisplatin
substitute
carboplatin
,
the significant toxicity (nausea, vomiting, hypotension)
costs associated with the administration of
amifostine
possible interference with the antitumor efficacy of
cisplatin
.
Amifostine
should not be used in settings in which chemotherapy can produce a significant survival advantage or chance of cure.
Upto
date sep 2014
7/28/2016
103
Slide104Other chemopreventive agents
None of the following agents has an established role in patients being treated with
cisplatin
.
Sodium
thiosulfate
:
in patients treated with
intraperitoneal
cisplatin
or
carboplatin
to achieve high local drug levels and relatively low plasma concentrations, that bind covalently with the platinum in blood.
7/28/2016
104
Slide105N-
acetylcystein
:
for primary prophylaxis in preventing platinum
nephrotoxicity
in high-risk patients.
Theophylline
Glycine
Complementary and alternative agents
, such as milk thistle and the
flavonoid
antioxidant,
quercetin
, have shown some protective effects in laboratory models of
cisplatin
-induced
nephrotoxicity
. The clinical utility of these agents remains to be determined
7/28/2016
105
Slide106selenium, vitamin C and E, and
aminoguanidine
, are believed to play a
renoprotective
role.*
Cimetidin
– inhibitor of OCTs- could be used to decrease uptake.
Imatinib
also decrease uptake of drug by inhibiting OCTs.
*
Atasayar
S,
Gürer-Orhan
H,
Orhan
H,
Gürel
B,
Girgin
G,
Özgüne
H. Preventive effect of
aminoguanidine
compared to vitamin E and C on
cisplatin
-induced
nephrotoxicity in rats. Ex Toxicol
Pathol 2009; 61: 23-32.
7/28/2016
106
Slide107Researches
Erythropoietin may lead to different responses against
cisplatin
-induced
nephrotoxicity
in male and female rats.
Estrogen is not
nephron
-protective against CP-induced
nephrotoxicity
. Moreover, it seems that the mechanism may be related to estrogen-induced oxidative stress in the kidney, which may promote the
nephrotoxicity
.
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107
Slide108Vitamin E may prevent CP-induced
nephrotoxicity
in male, but possibly it has not such
nephroprotectant
effect in female.
Co-administration of vitamin C and
losartan
was not more effective than the administration of vitamin C or
losartan
alone.
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108
Slide109losartan
could not improve renal function impaired by toxicity induced by continuous doses of CDDP, and also it worsened the renal failure.
Oral Mg supplementation did not protect the CP induced
nephrotoxicity
in diabetic rats.
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109
Slide110Tratment
Discontinuation of
cisplatin
—
cisplatin
should be discontinued in the presence of AKI, which is an increase in the serum Cr ≥50% percent over baseline levels or a reduction in U/O<0.5
mL
/kg/h for > six hours. Timely discontinuation of
cisplatin
may prevent progressive renal failure.
Hypomagnesemia
— Treatment of
hypomagnesemia
generally consists of magnesium supplementation. High doses may be required since raising the plasma magnesium concentration will increase the degree of urinary magnesium wasting.
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110
Slide111Long-term follow-up of patients exposed to
cisplatin
indicates that renal function either remains stable or improves over time in patients with a GFR >60
mL
/min per 1.73 m
2
at the end of therapy.
Whether such improvement reflects an increase in the number of functioning
nephrons
or hypertrophy of
nephrons
that remained relatively intact is unclear.
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111
Slide112The optimal approach to
cisplatin
therapy in patients with preexisting renal impairment is unknown. Clinical trial protocols often require a serum Cr< 2.0 mg/
dL
or a GFR of ≥60
mL
/min for administration of the full dose of
cisplatin
and exclude patients with more significant renal impairment.
This restriction is probably related more to concerns regarding increased
nonrenal
toxicity (
ototoxicity
, neuropathy) than to an increased risk of acute renal failure.
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112
Slide113The manufacturer recommends that repeat courses of
cisplatin
should not be given unless or until serum
creatinine
is <1.5 mg/
dL
and/or BUN is <25 mg/
dL
.
There are no FDA-approved renal dosing adjustment guidelines. Empiric guidelines have suggested
cisplatin
can be administered to patients with renal impairment with dose reduction, although extensive data supporting such recommendations are lacking.
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113
Slide114One recommendation suggests a 25%dose reduction for a GFR of 46-60
mL
/min and a 50%dose reduction for a GFR of 31-45
mL
/min. Others have recommended
cisplatin
can be administered to patients with even more severe renal impairment.
Although the available data are scant and predominantly comprised of single case reports, combinations containing
cisplatin
have been successfully administered to patients undergoing hemodialysis
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Dr. Moeinzadeh
114
Slide115Carboplatin
Believed that is safer than
cisplatin
.
ARF has been reported with
carboplatin
.
Direct tubular injury seems to be the
Mx
of injury and is dose dependent.
The American journal of medicine: vol1, issue 1, 1991.
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115
Slide116Hypomagnesemia
is a more side effect.
Renal salt wasting is reported.
Renal function has been improved with
prednisolone
1mg/Kg/d for 4 weeks.
Chemotherapy regimens incorporating
carboplatin
have been successfully used in patients undergoing hemodialysis
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116
Slide117Risk factors
Old children
Diabetes mellitus
Hypertension
Concomitant use of
ifosfamide
(more than with
cisplatin
)
Single kidney
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117
Slide118Cyclophosphamide
The main urologic toxicity of
Cyclophosphamide
is hemorrhagic cystitis.
The primary renal effect of
cyclophosphamide
is
hyponatremia
, which is due to an increased effect of ADH, impairing the kidney's ability to excrete water.
Chemotherapy-induced nausea may also play a contributory role, since nausea is a potent stimulus to ADH release.
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118
Slide119Hyponatremia
is usually seen in patients receiving high doses of intravenous
Cyclophosphamide
(
eg
, 30 to 50 mg/kg or 6 g/m
2
in the setting of hematopoietic stem cell transplantation).
Although less common,
hyponatremia
can also occur with oral therapy or with lower intravenous doses (
eg
, 10 to 15 mg/kg) that are given as pulse therapy in autoimmune diseases such as lupus nephritis.
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119
Slide120Hyponatremia
typically occurs acutely and resolves within approximately 24 h after discontinuation of the drug.
Hyponatremia
poses a particular problem for patients undergoing high dose intravenous
Cyclophosphamide
, who are often fluid loaded to prevent hemorrhagic cystitis.
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120
Slide121The combination of increased ADH effect and enhanced water intake can lead to severe, occasionally fatal
hyponatremia
within 24 hours.
This complication can be minimized by using isotonic saline rather than hypotonic solutions to maintain a high urine output. However,
hyponatremia
can worsen even with isotonic saline administration.
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Slide122Other complications
HC
is caused by urinary excretion of
acrolein
, a hepatic metabolite of both
cyclophosphamide
and
ifosfamide
. The incidence of HC is increased with higher individual doses, larger cumulative doses, and the use of
ifosfamide
as opposed to
cyclophosphamide
.
Progressive mucosal changes
can be identified in the bladder mucosa of patients receiving high cumulative doses of
cyclophosphamide
or prolonged treatment for longer than 36 months.
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122
Slide123Ifosfamide
The predominant toxicity on the urinary tract is hemorrhagic cystitis.
Nephrotoxicity
is more likely with
Ifosfamide
than with
cyclophosphamide
.
Ifosfamide
nephrotoxicity
affects the proximal renal tubule and is characterized by one or more of the following signs of acute tubular dysfunction:
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123
Slide124Metabolic acidosis
with a normal anion gap (
hyperchloremic
acidosis) due to type 1 (distal) or type 2 (proximal) renal tubular acidosis
Hypophosphatemia
induced by decreased proximal phosphate
reabsorption
, which can lead to rickets in children
Renal
glucosuria
, aminoaciduria, and a marked increase in beta-2-microglobulin excretion
, all from generalized proximal dysfunction
Polyuria
due to
nephrogenic
DI.
Hypokalemia
, which may be severe, resulting from increased urinary potassium losses
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124
Slide125A persistent decline in GFR over time has been described after as little as one course of
ifosfamide
in adults.
Risk factors for
Ifosfamide
nephrotoxicity
are cumulative dose, age under four to five years, history of
nephrectomy
, renal irradiation and prior or concomitant
cisplatin
therapy.
Usually acute & reversible.
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125
Slide126Therapies of unproven efficacy
Mesna
:
All patients treated with
ifosfamide
in modern chemotherapy regimens also receive
mesna
.
Whether the
coadministration
of
mesna
also reduces renal dysfunction remains unproven.
N-
acetylcysteine
— effective in an animal model for the prevention of
Ifosfamide
nephrotoxicity
. Clinical studies in humans have not been reported.
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126
Slide127Bleomycin
Renal toxicity is not described as a complication of
bleomycin
therapy. However, renal insufficiency is known to alter
bleomycin
elimination, particularly in patients with a GFR below 25 to 35
mL
/min, increasing the likelihood of treatment-related toxicity.
25% dose reduction for patients with GFR 10 to 50mL/min and a 50% reduction for clearance <10
mL
/min
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127
Slide128Anthracyclines and related agents
Epirubicin
and
daunorubicin
, as well as their major metabolites, are excreted mainly through the bile, and to a lesser extent, by urinary excretion.
The FDA-approved labeling recommends
epirubicin
dose adjustment in patients with severe renal impairment (serum
creatinine
>5 mg/
dL
).
A 50 % dose reduction is also recommended for
daunorubicin
in patients with serum
creatinine
>3 mg/
dL
.
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128
Slide129Methotrexate
MTX at doses less than 0.5 to 1.0 g/m
2
is usually not associated with renal toxicity, unless underlying renal dysfunction is present.
In contrast, high-dose intravenous
methotrexate
(1 to 15 g/m
2
) can precipitate in the tubules and induce tubular injury; at particular risk are patients who are volume depleted and those who excrete acidic urine.
Maintenance of adequate urinary output and
alkalinization
will lessen the probability of
methotrexate
precipitation.
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Slide130MTX can also produce a transient decrease in GFR, with complete recovery within 6-8h of discontinuing the drug.
The mechanism responsible for this functional renal impairment involves afferent arteriolar constriction or
mesangial
cell constriction that produces reduced glomerular capillary surface area, diminished glomerular capillary perfusion and pressure.
Methotrexate
……………..SIADH.
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130
Slide131Excretion is decreased in patients who have renal insufficiency, and more significant bone marrow and gastrointestinal toxicity may result.
Patients with
ileal
conduits and those with third space fluid collections (
eg
,
ascites
, pleural effusion) may experience greater MTX toxicity, particularly if their GFR is low.
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131
Slide132Extending
prehydration
beyond 4 hours does not reduce the risk of renal toxicity or delayed MTX clearance after infusions with HDMTX 5-8 g/m
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132
Slide133Gemcitabine
Gemcitabine
is a cell cycle-specific
pyrimidine
antagonist that has been associated with renal failure and
microangiopathic
hemolytic anemia (TTP/HUS).
Prior therapy with
mitomycin
C may be a risk factor for the development of HUS.
Drug discontinuation is recommended if this occurs.
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133
Slide134The US Food and Drug Administration-approved labeling states only that
gemcitabine
should be administered with caution in patients with evidence of significant renal dysfunction.
Retrospective reports suggest that administration of
gemcitabine
is feasible in patients with chronic renal failure on hemodialysis. In these cases, hemodialysis was initiated within 24 hours after each dose of
gemcitabine
. Patients receiving long term hemodialysis may be at higher risk of developing significant
gemcitabine
-related hematological toxicity
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134
Slide135Vincristine
&
Vinblastine
are associated with the SIADH in a small number of treated patients.
135
Slide136VEGF is an endothelial growth factor that promotes endothelial cell proliferation, differentiation and survival.
In the kidney, VEGF receptors are located on
preglomerular
, glomerular and
peritubular
endothelial cells.
VEGF is required for growth and proliferation of glomerular and
peritubular
endothelial cells.
136
Slide137VEGF is essential mediator for glomerular recovery in proliferative GN.
Loss of VEGF is associated with
glomerulosclerosis
&
tubulointerstitial
fibrosis.
VEGF inhibition is believed to suppress
nephrin
affecting integrity of glomerular slit membrane causing proteinuria.
137
Slide138VEGF
ligand
inhibitors :
Bevastizumab
&
A
flibercept
, which bind to and inhibit
ligand
binding to the VEGF receptor (VEGFR), thus preventing activation of the receptor
Antiangiogenic
small molecule tyrosine
kinase
inhibitors (TKIs):
sunitinib
,
sorafenib
,
axitinib
, … which block the intracellular domain of the VEGFR.
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138
Slide139Asymptomatic
albuminuria
, occasionally causing the nephrotic syndrome: 21%(colorectal CA) – 63% (RCC, > 3.5g/d in 6.5% RCC)
Hypertension frequently accompanies proteinuria: 2.7-35.9%.
The most pathology in proteinuria is TMA.
Extrarenal
manifestations are very rare.
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139
Slide140Managemet
is conservative.
HTN: ACEI/ARB and for decreasing proteinuria but may not work.
Proteinuria may respond to drug withdrawal.
But renal function progressively decreases.
7/28/2016
140
Slide141Role of plasma exchange
Bevastizumab
associated TMA that respond to discontinuation of drug, subsequently had relapse when was treated again with
Suitinib
responded to discontinuation of drug and plasma exchange.
One case respond to drug discontinuation, anti HTN drugs and plasma exchange.
Role of plasma exchange should be evaluate more.
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141
Slide142Imatinib
is a small molecule tyrosine
kinase
inhibitor, a key molecular abnormality in CML.
Acute and chronic kidney injury have been rarely described in patients treated with extended duration
Imatinib
.
In one report, the mean decrease per year was 2.77
mL
/min/1.73 m
2
.
Leukemic infiltration into the kidney should always be considered when a patient with CML presents with renal impairment, regardless of the clinical stage, as the renal failure may respond to chemotherapy.
7/28/2016
142
Slide143The FDA-approved manufacturer’s labeling recommends modification of the initial dose for patients with mild to moderate renal dysfunction (
CrCl
<39
mL
/min) because of reduced drug clearance.
Owing to the lack of data, patients with severe dysfunction (GFR<20
mL
/min) should be approached cautiously.
Imatinib
can be safely administered to patients on hemodialysis.
7/28/2016
143
Slide144Bisphosphonates
Bisphosphonate
nephrotoxicity
is dose-dependent and infusion time-dependent, and can be limited by increasing the time interval between doses.
Patterns of
nephrotoxicity
seen with these agents include toxic ATN and collapsing FSGS.
Severe
nephrotoxicity
can often be avoided by strict adherence to guideline for monitoring serum
creatinine
prior to each treatment, withholding therapy in the setting of renal insufficiency, and adjusting doses in the setting of pre-existing chronic kidney disease.
7/28/2016
144
Slide145Currently,
ibandronate
is approved in the US for treatment of PMO and in Europe for treatment of PMO and complications of cancer.
In contrast to
pamidronate
and
zoledronate
,
ibandronate
appears to have a safer renal profile with no evidence of
nephrotoxicity
, even in patients with abnormal baseline kidney function
7/28/2016
145
Slide146Pamidronate
Manufacturer recommends the following guidelines:
Treatment of bone metastases: Use is not recommended in patients with severe renal impairment.
Renal impairment in indications other than bone metastases: Use clinical judgment to determine if benefits outweigh potential risks.
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146
Slide147Multiple myeloma: American Society of Clinical Oncology (ASCO) guidelines (Kyle, 2007):
Severe renal impairment (serum
creatinine
>3 mg/
dL
or
CrCl
<30
mL
/minute) and extensive bone disease: 90 mg over 4-6 hours. However, a reduced initial dose should be considered if renal impairment was pre-existing.
Albuminuria
>500 mg/24 hours (unexplained): Withhold dose until returns to baseline, then recheck every 3-4 weeks; consider reinitiating at a dose not to exceed 90 mg every 4 weeks and with a longer infusion time of at least 4 hours
7/28/2016
147
Slide148Zolendronic acid
Multiple myeloma and bone metastases:
CrCl
>60
mL
/minute: 4 mg (no dosage adjustment necessary)
CrCl
50-60
mL
/minute: Reduce dose to 3.5 mg
CrCl
40-49
mL
/minute: Reduce dose to 3.3 mg
CrCl
30-39
mL
/minute: Reduce dose to 3 mg
CrCl
<30
mL
/minute: Use is not recommended.
Hypercalcemia
of malignancy:
Mild-to-moderate impairment: No dosage adjustment necessary.
Severe impairment (serum
creatinine >4.5 mg/
dL): U.S. labeling: Evaluate risk versus benefit
Canadian labeling: Use is not recommended.
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Slide149Thanks
149