Tossicità renale da terapie a target molecolare

(1)

Tossicità renale da terapie a target

molecolare

Antonello Pani

Struttura Complessa di Nefrologia e Dialisi Azienda Ospedaliera G. Brotzu Cagliari

(2)

Onco‐Nephrology

Nephrologist

Nephrologist OncologistOncologist Kidney

toxicity Kidney toxicity

Chemoterapy induced

Tumor lysis syndrome Target Therapy

Kidney damage Kidney damage

Myeloma Solid tumor

Treatment related

microangiopathies and GN

Stem cell transplant Obstructive uropathies

Severe fluid and electrolite

disturbances

Dosing and timing for

chemotherapy and target therapy

(3)

• Kidney disease either pre existing or developing in the course of the cancer

• New glomerular paraneoplastic disease

• Obstructive Nephropathy

• Tubular interstitial Damage

• Thrombotic microangiopathy

• Radiation Nephropathy

• Tumor invasion of the kidney

• Tumor lysis syndrome

• Multiple Myeloma

• Fluid and electrolyte disorders

• Decision regarding renal replacement therapy

Why is the Nephrologist called?

(4)

(5)

Clinical case (1)

• A 64‐year‐old male patient with metastatic melanoma was

administered combination immunotherapy with nivolumab and ipilimumab. After receiving 2 doses of the combination, the patient developed hypophysis, hypothyroidism, and biopsy‐proven

granulomatous colitis.

• AKI developed with elevation in the serum creatinine from a baseline of 1.5 (0.6‐1.3) mg/dL (132.6 (53‐114) μmol/L) to 4.1 vmg/dL (362.5 μmol/L) in the setting of small bowel obstruction (SBO).

• Urine analysis showed trace proteinuria, 3‐5 red blood cells per high power field (HPF) and 2‐3 white blood cells per HPF.

• Ultrasound imaging ruled out obstructive uropathy.

• AKI persisted after the resolution of SBO. A renal biopsy showed di use active interstitial nephritis with focal, small granulomata, acute tubular injury with active tubulitis, and focal necrosis.

• The patient was treated with prednisone 60 mg/day for 2 weeks with a taper over 4 weeks, and his kidney function returned to baseline

Sathick IJ et Al J Onco‐Nephrol 2017; 1(1): 9‐17

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Acute granulomatous interstitial nephritis after exposure to PD‐1 and CTLA4 Combination therapy

(CTLA‐4 = Cytotoxic T lymphocyte‐associated antigen 4; PD‐1 = programmed cell death protein 1)

(7)

Immune checkpoint inhibitors: antibodies that block the tumor ligand binding to PD‐1 and CTLA‐4 receptors, thus

allowing T cells to function normally and elicit an tumor response

(8)

Immune checkpoint inhibitors:

Prevalent Kidney Damage

• AKI

• Interstitial Nephritis

• Auto Antibodies

disease (Anti‐ds DNA)

• Impaired Treg function (Renal Tubular Injury)

• AIN

• lupus‐like glomerulonephritis and arthritis

• immune‐related adverse effects including AIN in the kidney and lupus‐like syndrome (rare).

• No correlation with dosing from the reported cases.

• Clinicians should monitor for AKI and proteinuria and have a low

threshold to start steroid therapy if there is high clinical suspicion

once other causes of kidney dysfunction have been ruled out.

(9)

AKI diagnosis

< 350 ml in a 70 kg individual

< 210 ml in a 70 kg individual

(10)

Nephrocheck

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Clinical case (2)

• A 62‐year‐old female patient with metastatic breast carcinoma with bone and lung metastases was started on bevacizumab therapy.

• She developed new onset proteinuria and

hypertension requiring more than 2 medications.

• The urine protein/creatinine ratio was >3 despite

adequate blockade of renin angiotension aldosterone system (RAAS).

• The bevacizumab dose was adjusted from 15 mg/kg to 7.5 mg/kg and she was able to continue the therapy along with an hypertensive agents.

• When bevacizumab was discontinued 5 years later, due to progression of breast carcinoma, the hypertension and proteinuria resolved.

(12)

Angiogenesis inhibitors

Rini, Lancet Oncology, 2011

(13)

Angiogenesis inhibitors

• antibodies targeting either VEGF or its receptor

• small molecule tyrosine kinase inhibitors (TKI): affec VEGFR intracellular signaling

(14)

Schematic representation of the nephron and the expression of the targets

• The kidney and lungs have

abundant VEGF expression on the epithelial cells

• In the kidney, VEGF is

expressed on podocytes while the fenestrated glomerular endothelium has an

abundance of VEGFR‐2 and VEGFR‐3 expression

• VEGF also regulates podocyte survival through an autocrine interaction with VEGF‐1 and neuropilin‐1, thus playing an important role in podocyte

homeostasis Kelly RJ, Targ Oncol, 2009

(15)

Angiogenesis inhibitors:

Prevalent Kidney Damage

• Proteinuria

• Hypertension

• podocyte homeostasis

• Endotheliosis

• TMA

• VEGF inhibition, either pharmacologically or in a gene knockout model has been shown to alter glomerular

physiology causing increased permeability and proteinuria.

• Loss of the healthy glomerular fenestration leads to

microvascular injury and TMA

(16)

Collapsing focal segmental

glomerulosclerosis associated with

anti ‐VEGF therapy.

(17)

Clinical Pearls: TMA

• TMA is the predominant renal lesion

• In half of the patients TMA is localized to the kidney with no evidence of systemic

microangiopathic hemolytic anemia.

• With hypertension therapy and withdrawal of the offending drug, renal function usually

remains preserved (in contrast to TMA due to

Gemcitabine)

(18)

Angiogenesis inhibitors:

Prevalent Kidney Damage

• Proteinuria

• Hypertension

• podocyte homeostasis

• Endotheliosis

• TMA VEGF also mediates:

• endothelium‐dependent vasorelaxation,

• upregulation of endothelial nitric oxide synthase (eNOS) expression

• prostacyclin (PG12) release.

These pathways are considered putative mechanisms by

which VEGF inhibition causes hypertension

(19)

Clinical Pearls: Hypertension

• The onset of hypertension during treatment with bevacizumab has been associated with improved outcomes (expression of antitumor effect)

• 1

^st

LINE: RAAS blockade (either ACEi or ARBs) are recommend if renal function is not reduced and risk for hyperkalemia is low

• 2

^nd

LINE:

– Dihydropyridine calcium channel blockers (except nifedipinemay induce VEGF secretion),

– beta blockers,

– alpha blockers

– nitrates

(20)

Imatinib, another “special” Multikinase Inhibitor: renoproctetive effects

• Chronic myelogenous Leukemia

• Antifibrotic activity

• Specific activity in the Kidney

• Potentially attractive therapeutic option for Pts with autoimmune kidney diseases (IMN, SLE, chronic

humoral rejection, Cryo)

• Prevent chronic allograft nephropathy

• Suppress proteinuria, improve renal function, attenuate development glomerulosclerosis and

tubulointerstitial injury, reduced expression of type 1 collagen and TGFbeta in the renal cortex

Ioda M, NDT, 2013

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Clinical case (3)

• A 59‐year‐old male with Erdheim‐Chester disease non‐ Langerhans

histocytosis with rapidly accelerated fibrosarcoma kinase B (BRAF) V600E positive mutation presented with exophthalmos due to an infiltrative

process.

• Computed tomography imaging of abdomen and pelvis showed perirenal infiltration and an atrophic right kidney. His baseline serum creatinine was 1.1 mg/dL (97.2 μmol/L).

• He was started on vemurafenib 960 mg twice a day and was

subsequently referred to the nephrology clinic for new onset AKI.

• Serum creatinine was elevated to 1.9 mg/dL (168 μmol/L) and peaked to 2.4 mg/dL (212.2 μmol/L). He developed a diffuse erythematous papular rash.

• Urinalysis was bland and urine protein/creatinine ratio was 0.04.

• A kidney biopsy was deferred due to a solitary functioning kidney.

• The vemurafenib dose was adjusted from 960 mg twice a day to 480 mg twice a day. Renal function stabilized with the dose reduction, and

creatinine improved to 1.9 mg/dL (168 μmol/L).

• The patient was able to continue therapy with ongoing close follow‐up.

(22)

Vemurafenib

• BRAF mutations commonly involving V600E substitution (glutamic

acid to valine at position 600) result in sustained activation of the

mitogen‐activated protein kinase (MAPK) pathway leading to tumor

cell proliferation.

Access Medicine, Mc Grow Hill 2012

(23)

Vemurafenib

• Vemurafenib and dabrafenib are inhibitors of the mutant BRAF and collectively called BRAF inhibitors and are approved for use in

malignant melanoma.

• BRAF inhibitors may also be used in the treatment of colon cancer, thyroid cancer, and Langerhans cell histiocytosis.

Access Medicine, Mc Grow Hill 2012

(24)

Clinical pearls

• While BRAF is normally expressed in the

glomerulus, reported cases of renal toxicity from BRAF inhibitors have mostly been tubular injury

• Symptoms usually develop 5‐14 days after initiation, and stop the drug led to gradual

improvement in skin lesions and kidney function

• The exact mechanism has not been established

• Close monitoring and withdrawal of therapy is

advised in severe case

(25)

The nephrologist’s workout

1

^st

LEVEL

• SCr, BUN, electrolytes (P and Mg included)

• eGFR or mGFR

• Urinalysis

• Pr/Cr Ratio

2

^nd

LEVEL

• Immunoglobulins

• Autoantibodies (ANA, ENA, anti ds‐DNA, ANCA)

• Electrophoresis

• Free Light Chains K and L

• Urea Clearance, 24h Proteinuria

• BP control

• Urine output evaluation

Renal ultrasound

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Do not forget other causes of cancer‐related kidney injury

Paraneoplastic glomerulonephritis

Prerenal AKI

1) Effective intravascular volume depletion (Vomiting, diarrhea, anemia, sepsis) 2) Sinusoidal obstructive disease

3) Hypercalcemia

Drug-related kidney toxicity Gemcitibine ,Cisplatin, Methotrexate ,Bevacizumab e. Interferon-a, Ifosphamide,

Contrast media

Tumor lysis syndrome

Kidney cell cancer with nephrectomy Myeloma cast nephropathy

Urinary tract obstruction Retroperitoneal fibrosis

(27)

Conclusions

• The majority of targeted therapies are associated with renal toxicity. These renal effects are most often mild in severity

• There is a potential risk of an additional toxic effect on the kidney, from both chemo‐ and targeted therapies

• Renal monitoring is therefore crucial, both during treatment to identify renal alterations at the

earliest, and also before initiation to allow differential analysis of the origin of the renal event

Porta C, Cosmai L, Gallieni M, Pedrazzoli P, Malberti F; Nat Rev Neph, 2015

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Conclusions (2)

• Some targeted therapies may require dosage adjustments to renal function, which makes evaluation of the GFR mandatory before

treatment administration

• Dosage adjustments should be performed according to validated and evidence‐based guidelines

Porta C, Cosmai L, Gallieni M, Pedrazzoli P, Malberti F; Nat Rev Neph, 2015

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FINAL message

A strong collaboration with oncologists is warranted in order to better

understand and manage renal effects of

Targeted Agents

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