Kidney & cancers Dr.Sh.Sajjadieh - PowerPoint Presentation

Slide1

Kidney & cancers

Dr.Sh.Sajjadieh

nephrologist

Slide2

Slide3

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 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.

Slide4

Urinary 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.

Slide5

Urinary 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

.

Slide6

Urinary 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.

Slide7

Metabolic 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.

Slide8

Lactic 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.

Slide9

Lactic 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.

Slide10

Paraneoplastic

glomerulonephritis

Slide11

Introduction

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.

Slide12

Introduction

Classic

paraneoplastic

glomerulonephritides

solid tumor-associated membranous nephropathy

Hodgkin lymphoma-associated minimal change disease (MCD)

Slide13

Introduction

Other

glomerulonephritides

:

FSGS

membrano

proliferative glomerulonephritis

Iga

nephropathy

RPGN

Slide14

Introduction

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

Slide15

Introduction

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

Slide16

Introduction

Treatment

of

paraneoplastic

glomerulonephritis is

quite different from treatment of

idiopathic glomerulonephritis

Slide17

Solid 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

Slide18

Solid 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.

Slide19

Solid tumors

membranous

nephropathy

MN

has been reported in association

with:

Lung cancer

Gastric cancer

Renal cancer

Prostate cancer

Breast cancer

Colon cancer

Slide20

Solid tumors

membranous

nephropathy

two

major risk factors separated

para

neoplastic membranous

nephropathy from idiopathic

membranous nephropathy:

age over 65

years

smoking >20

packyears

Slide21

Solid 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

Slide22

membranous 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

Slide23

Solid 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

)

Slide24

Solid tumors

Minimal change

disease

MCD

has been reported in association

with:

Lung

Colon

renal

cancers

Breast

Slide25

Solid 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

.

Slide26

Solid tumors

Minimal change disease

VEGF

is one potential candidate because of its

ability to

increase glomerular permeability

Slide27

Solid tumors

Membranoproliferative

glomerulonephritis

MPGN

has

been reported

in association

with:

Lung

renal

gastric cancers

Colon cancer

Breast cancer

Slide28

Solid 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

Slide29

Solid 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

Slide30

Solid tumors

rapidly progressive

glomerulonephritis

RPGN

has been reported in association

with:

renal cell

carcinoma

Gastric

lung cancers

Prostate cancer

Breast cancer

Colon cancer

Slide31

Solid 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

.

Slide32

Solid 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

Slide33

Solid tumors

IgA nephropathy

IgA nephropathy has been reported associated with:

renal cell

carcinoma

respiratory

tract tumors

Slide34

Solid tumors

IgA

nephropathy

tumor

ablation seems

to be the treatment of choice for

para

neoplastic

IgA

nephropathy

, whereas corticosteroid therapy may

promote tumor growth.

Slide35

Solid tumors

IgA

nephropathy

Henoch

–

schonlein

purpura

(

HSP) has

also been reported in association

with:

solid

tumors

most commonly lung cancers

Slide36

Hematological malignancies

Lymphoid

Myeloid

Thymus

malignancies

Slide37

Hematological 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

Slide38

Hematological malignancies

lymphoid malignancies

MCD

is the most common

paraneoplastic

glomerulonephritis associated

with Hodgkin lymphoma,

followed by FSGS

Slide39

Hematological 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

Slide40

Hematological 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

Slide41

Hematological malignancies

MCD and

FSGS

a poor response of

MCD to

steroid or

ciclosporin

therapy

seems

to

be indicative

of occult Hodgkin

lymphoma

Slide42

Hematological malignancies

MCD and

FSGS

increased cytokine levels, particularly levels of TH2 cytokines and IL-13 could be responsible for inflammatory response

Slide43

Hematological 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

Slide44

Hematological 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

Slide45

Hematological 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

Slide46

Hematological 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

Slide47

Hematological malignancies

Membranous

nephropathy

MN

is less common

than MPGN

in relation

to lymphoid

malignancies

(1/8)

Slide48

Hematological 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

Slide49

Hematological malignancies

Membranous

nephropathy

Paraneoplastic

membranous

nephropathy frequently

responds to

treatment of the underlying malignancy.

Slide50

Hematological malignancies

Myeloid

Malignancies

AML like ALL

has been rarely reported

in association

with

glomerulonephritides

.

Slide51

Hematological malignancies

Myeloid Malignancies

Among

the

myeloproliferative

neoplasms,

polycythemia

vera

, essential

thrombocythemia

and

primary

myelofibrosis

are associated with

FSGS

and

mesangial

proliferative

glomerulonephritis

Slide52

Hematological 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.

Slide53

Hematological malignancies

Myeloid

Malignancies

Treatment with

myelosuppressive

agents or regular phlebotomies

for

myeloproliferative

neoplasms has achieved

partial remission

of

FSGS

in some cases

Slide54

Hematological malignancies

Myeloid

Malignancies

CML

is the most

common

myeloproliferative

neoplasm, but is rarely

associated with glomerulonephritis

CML

may cause or

exacerbate

membranoproliferative

glomerulonephritis

Slide55

Thymoma

The prevalence of

paraneoplastic

glomerular diseases in patients

with

thymoma

is about 2%, higher than that for

Hodgkin lymphoma

.

Slide56

Thymoma

MCD

is the most common

paraneoplastic

glomerulonephritis

associated with

thymoma

,

followed by:

MN , FSGS , RPGN,

and

lupus nephritis

Slide57

Thymoma

Histologically,

thymoma

can be divided

into:

epithelial-predominant

lymphocyte-

predominant

Slide58

Thymoma

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.

Slide59

Thymoma

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.

Slide60

Paraneoplastic

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

Slide61

Tumor

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.

Slide62

TLS 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.

Slide63

Hyperuricemia

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.

Slide64

Hyperphosphatemia

, 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.

Slide65

The 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.

Slide66

High 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.

Slide67

In 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.

Slide68

Treatment

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.

Slide69

Treatment

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.

Slide70

Despite 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

.

Slide71

Hemorrhagic 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

.

Slide72

Hemorrhagic 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.

Slide73

Hemorrhagic 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.

Slide74

Hemolytic-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.

Slide75

HUS 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

.

Slide76

Laboratory 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.

Slide77

The 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.

Slide78

The 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.

Slide79

Plasma cell

dyscrasia

induced renal failure:

Slide80

Chemotherapeutic agents and the kidney

80

Slide81

Cisplatin

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

Slide82

Renal manifestations of cisplatin treatment

7/28/2016

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

Slide83

Cisplatin

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.

7/28/2016

83

Slide84

Cisplatin

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

.

7/28/2016

84

Slide85

Vasoconstriction:

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.

7/28/2016

85

Slide86

Effects 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

Slide87

Risk 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

Slide88

When 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

Slide89

25% 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

Slide90

Thrombotic 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

Slide91

It 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

Slide92

Hypomagnesemia

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

.

7/28/2016

92

Slide93

Associated

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

Slide94

Fanconi-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. 

7/28/2016

94

Slide95

Diagnostic 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.]

7/28/2016

95

Slide96

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96

Slide97

Approaches 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

.

7/28/2016

97

Slide98

A 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.

7/28/2016

98

Slide99

Manitol

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

Slide100

Cisplatin analogs

The less

nephrotoxic

analog, 

carboplatin

, has been substituted for

cisplatin

in many chemotherapy regimens.

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100

Slide101

Amifostine

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

Slide102

On 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

Slide103

We 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

Slide104

Other 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

Slide105

N-

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

Slide106

selenium, 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

Slide107

Researches

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

Slide108

Vitamin 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

Slide109

losartan

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

Slide110

Tratment

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

Slide111

 Long-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

Slide112

The 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

Slide113

The 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

Slide114

One 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

7/28/2016

Dr. Moeinzadeh

114

Slide115

Carboplatin

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

Slide116

Hypomagnesemia

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

Slide117

Risk factors

Old children

Diabetes mellitus

Hypertension

Concomitant use of

ifosfamide

(more than with

cisplatin

)

Single kidney

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117

Slide118

Cyclophosphamide

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

Slide119

Hyponatremia

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

Slide120

Hyponatremia

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

Slide121

The 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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121

Slide122

Other 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

Slide123

Ifosfamide

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:

7/28/2016

123

Slide124

Metabolic 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

Slide125

A 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

Slide126

Therapies 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

Slide127

Bleomycin

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

Slide128

Anthracyclines 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

Slide129

Methotrexate

 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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129

Slide130

MTX 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

Slide131

Excretion 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.

7/28/2016

131

Slide132

Extending

prehydration

beyond 4 hours does not reduce the risk of renal toxicity or delayed MTX clearance after infusions with HDMTX 5-8 g/m

7/28/2016

132

Slide133

Gemcitabine

 

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

Slide134

The 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

7/28/2016

134

Slide135

Vincristine

&

Vinblastine

are associated with the SIADH in a small number of treated patients.

135

Slide136

VEGF 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

Slide137

VEGF 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

Slide138

VEGF

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

Slide139

Asymptomatic

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

Slide140

Managemet

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

Slide141

Role 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.

7/28/2016

141

Slide142

Imatinib

 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

Slide143

The 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

Slide144

Bisphosphonates

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

Slide145

Currently,

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

Slide146

Pamidronate

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

Slide147

Multiple 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

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147

Slide148

Zolendronic 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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148

Slide149

Thanks

149