Introduction
Vascular endothelial growth factor (VEGF) is a vital factor needed for proper endothelial
cell survival, and it is increasingly recognized as an important part of podocyte
cellular physiology.
1
The disruption of VEGF signaling has been known as a therapeutic target in processes
that involve blood vessel proliferation (angiogenesis), and as such, systemically
the drugs inhibiting VEGF function are used as anti-neoplastic anti-angiogenesis adjunctive
treatments.
2
The systemic effects of VEGF blockade were first realized with findings of severe
hypertensive crisis (due to nitric oxide signaling depletion) and overt proteinuria.
Findings of thrombotic microangiopathy (TMA), increased proteinuria, and multiple
causes of nephrotic syndrome were published by many experts in the burgeoning field
of onco-nephrology.2, 3 It has been notable that agents blocking mammalian target
of rapamycin and the tyrosine kinase pathway (TKI) produce similar renal side effects
as systemic VEGF blockade.
4
Physiologically, preeclampsia demonstrated similar renal effects with soluble fms-like
tyrosine kinase-1–induced depletion of VEGF.
5
Intravitreal use of VEGF antagonists started off label with bevacizumab, and progressed
with use of aflibercept (more potent), and ranibizumab (less potent) agents both given
approval for age-related macular degeneration and diabetic retinopathy by the U.S.
Food and Drug Administration.
6
Intravitreal VEGF blocking agents have been shown to be absorbed,
7
systemic effects, such as hypertension and renal disease, have been reported, including
glomerular disease.6, 8, 9
,
S1–S3 We report a 96-year-old elderly woman who has been on ranibizumab, then bevacizumab,
then aflibercept for progressive age-related macular degeneration since 2007. She
at first had marginal amounts of proteinuria, between 2017 and 2018, the patient developed
high-grade nephrotic-range proteinuria and a faster rate of progression of renal dysfunction.
A renal biopsy disclosed an unexpected finding of collapsing focal and segmental sclerosis
(FSGS), previously reported with systemic VEGF inhibitors and TKI.S4
Case Presentation
Our patient is a 96-year-old White woman with history of nephrolithiasis, colon cancer,
and a wedge resection of the left middle lobe of kidney that had shown both no malignancy
and no evidence of glomerular disease in 2001. She was started on anti-VEGF agents
in 2007 when she was 84 years old. She also had a known history of hypertension and
nephrolithiasis that required removal of the kidney stones via lithotripsy once.
She had a prior history of colon cancer, which was surgically resected in 2001, and
a suspicious renal lesion was biopsied (a small lesion in the left middle lobe of
kidney was resected) and found to have no malignancy. Importantly, the pathology reading
from the kidney showed intact glomeruli without any evidence of systemic sclerosis
or prominent hypertensive changes in her glomeruli. Renal function remained at baseline
after the small resection: serum creatinine was between 1.0 and 1.1 between 2001 and
2007 without much fluctuation. After glaucoma and age-related macular degeneration
were diagnosed in 2007, anti-VEGF therapy was started for severe age-related macular
degeneration of her left eye. Initially, ranibizumab was started at 0.5 mg in the
right eye (OD) given every 2 to 4 weeks depending on the needs with close monitoring.
She underwent extensive numbers of injections in an effort to ameliorate the eyesight
in her right eye and ultimately in both her right and left eyes (OS). She received
19 injections of ranibizumab (Lucentis) 0.5 mg, then had 54 injections of bevacizumab
(Avastin) 1.25 mg, and finally had 75 injections of aflibercept (Eylea) 2 to 4 mg.
No other nephrotoxic agents, including nonsteroidal anti-inflammatory agents or bisphosphonates,S5
were recorded or reported by the patients, and she did not develop diabetes mellitus
type 2 during her treatment course. The patient’s medications include amlodipine,
benazepril, brimonidine/timolol eye drops, cholecalciferol, furosemide, metoprolol,
saliva substitute, simvastatin, spironolactone, and coumadin.
Initially, proteinuria started developing between 2010 and 2012 at 1+ on urinalysis,
that was not present before. A rise in serum creatinine from 1.1–1.3 to 1.4–1.5 was
noted with concomitant proteinuria. Blood pressure did not rise significantly in this
case, but she continued to take her usual antihypertensive regimen. More pronounced
proteinuria was noted in 2017 with a rise in urinalysis proteinuria to 3+. Between
2017 and 2018, urine protein-to-creatinine ratios were quantified at 3.6 to 8.4 g
protein/g creatinine (urine albumin/creatinine ratios of 4–5 g albumin/g creatinine),
which rose to a peak of 19.6 g protein/g creatinine. Her serum creatinine began to
climb to 2 to 3 mg/dl between 2017 and 2018. Figures 1 and 2 demonstrate the progression
of kidney function decline, proteinuria, and the type and doses of VEGF antagonists
being given.
Figure 1
The progression of serum creatinine, urinalysis proteinuria by time (including information
of dose of ranibizumab, bevacizumab, and aflibercept injected between 2007–2017).
Figure 2
The progression of serum creatinine, urinalysis proteinuria, urine protein/creatinine
ratio, and urine albumin/creatinine ratio by time (including information of the dose
of aflibercept injected between 2018–2019).
The patient underwent proteinuria workups that showed a slight elevation in kappa
to lambda ratio of 2.8 to 3.3, but without findings of a monoclonal gammopathy. Her
serological workup was unremarkable otherwise. She ultimately had a native kidney
biopsy in December 2018, and the pathology results showed “collapsing pattern focal
and segmental sclerosis, arterial nephrosclerosis was noted, and mild tubulointerstitial
scarring.” The light microscopy contained 8 glomeruli, 3 of which were completely
sclerotic. Of the remaining glomeruli, several have advanced lesions of segmental
sclerosis and 1 or 2 have very prominent podocyte hypertrophy with numerous intracellular
lipid vacuoles and protein droplets. This podocyte hypertrophy is characteristic of
collapsing glomerulopathy, and no crescents were found. Congo red stain was done and
was negative on light microscopy. Immunofluorescence was not positive for light or
heavy chains of Igs. Electron microscopy was not able to be performed, as the biopsy
showed only fragments of the corticomedullary junction. HIV was checked and found
to be negative due to collapsing FSGS diagnosis. Figure 3 shows native kidney biopsy
details from 2019.
Figure 3
Native kidney biopsy findings in 2019 demonstrating collapsing focal and segmental
sclerosis (hematoxylin and eosin, original magnification ×40 light microscopy).
The patient was White, not African American; this and her advanced age made genetic
causes of FSGS much less likely. This is also in addition to renal tissue without
scarring or FSGS findings in 2001. No viral prodrome or infection with cytomegalovirus,
Epstein-Barr virus, or parvovirus was suspected on clinical grounds and no evidence
was found of these infections serologically.
Serum VEGF-A level was obtained because the patient did not have many of the classic
risk factors for FSGS, and the workup for the initially suspected amyloidosis was
negative. Because a prior renal lobe resection pathology did not show these findings
in 2001, the suspicion of intravitreal injections causing nephrotic-range proteinuria
and FSGS was high. The VEGF-A level was obtained given suspicion of intravitreal anti-VEGF
agent toxicity, and this level was found to be at <31 pg/ml (reference range 31–86
pg/ml), which was below the detection range. Of note, this blood test was obtained
while the patient was still getting aflibercept injections.
At this point, the initial concern for intravitreal VEGF agent absorption and suppression
of endogenous VEGF had a biochemical correlate.4, 6, 7 There was a full discussion
with the patient and she declined to stop the intravitreal injections for fear of
losing her eyesight. A trial of steroids and mycophenolate was initiated without positive
effect on renal function or proteinuria, and she was transitioned to hemodialysis
in February 2019.
Discussion
We discuss a case in which incidental biopsy data were obtained 6 years before the
initiation of intravitreal VEGF blockade showing no hypertensive nephrosclerosis and
no evidence of podocyte disruption or glomerulosclerosis. In the severe age-related
macular degeneration treated in this patient, successively stronger agents were given
at increasing doses to try preserving vision. Proteinuria developed at a low grade,
and renal function declined slowly at first. Between 2017 and 2018 (10 years after
initiating these injections), proteinuria became high grade, and renal function worsened
more quickly. A renal biopsy ultimately showed glomerular disease, which was previously
reported in TKI use and systemic VEGF blockade,S4 but had not been previously seen
in patients with intravitreal VEGF blockade.
6
This case illustrated a novel phenotype of glomerular disease and proteinuria ostensibly
induced and/or worsened by intravitreal VEGF blockade. A prior normal native kidney
biopsy in 2001 and findings of VEGF suppression in 2018 along with the worsening renal
function, proteinuria, and native kidney biopsy-proven collapsing FSGS supported the
role of intravitreal VEGF blockade in the development of this case of nephrotic syndrome.6,
7
,
S2
Despite multiple studies that only showed “no change in renal function and no proteinuria
category (Kidney Disease Improving Global Outcomes A1–A3) with use of these agents,”S6,S7
there is evidence that some patients undergo drastic changes in renal function, hypertension
control, and proteinuria, as reported in Bagheri et al.
S8 It is becoming increasingly clear that like the phenotype seen in preeclampsia,
VEGF depletion can be more disruptive to renal function for certain patients with
environmental and genetic attributes making them more sensitive than others.5, 6 Given
reports of systemic effects and increased mortality seen in population studies, a
large-scale study accounting for proteinuria change as a continuous variable while
monitoring drug and systemic VEGF levels is needed.6, 8, 9
,
S1,S2
Table 1 reviews other published cases of biopsy-confirmed glomerular disease associated
with intravitreal anti-VEGF agent use.
6
,
S2,S9–S13
Table 1
Glomerular disease with intravitreal VEGF blockade
Reference no.
n
Age(s)
Gender
Agent used
Finding
6, S2
1
82
F
Bev, Ran
De novo MCD
S9
2
52, 67
2 M
Bev
MGN, TMA
S10
1
74
M
Bev
MGN
S11
1
77
F
Ran
TMA
S12
1
54
M
Bev
Relapsed MCD
S13
1
16
F
Bev
Relapsed MCD
CC
1
96
F
Bev, Ran, Aflib
Collapsing FSGS
#, number; Aflib, aflibercept; Bev, bevacizumab; CC, current case; F, female; FSGS,
focal and segmental sclerosis; M, male; MCD, minimal change disease; MGN, membranous,
glomerulonephritis, n, number of patients; Ran, ranibizumab; TMA, thrombotic microangiopathy;
VEGF, vascular endothelial growth factor.
The type of lesion seen in this case report is unusual given the molecular biology
of VEGF blockade and TKI blockade. These 2 agents should involve different arms of
the C-Maf–inducing protein (C-MIP) and REL-A (v-rel avian reticuloendotheliosis viral
oncogene homolog A) pathways. Systemic or intravitreal VEGF blockade should increase
Rel-A and induce a proinflammatory signal through the nuclear factor kappa light chain
enhancer of activated B cells, resulting in TMA. TKI agents act by blocking Rel-A
and increase C-Maf–inducing protein (C-MIP), which alters the cell cytoskeleton and
results in minimal change disease or FSGS (MCNS).S14 This was the observation made
in the pioneering work of Izzedine et al. published in Kidney International.S15
The clinical reality involves overlap between TMA and other etiologies of nephrotic
syndrome between VEGF blockers and TKI agents.2, 6
,
S2–S4,S16 Subsequent studies showed cases of minimal change disease or FSGS rather
than TMA with VEGF blockade, and cases of TMA with TKI use.2, 6
,
S2–S4,S15–S16 Later studies compiled several cases of MCNS with intravitreal and systemic
VEGF blockade.2, 6
,
S2,S4 So far, intravitreal VEGF blockade associated with nephrotic syndrome seems
to have more reports of minimal change disease or FSGS than TMA. Although it is important
to mention that some cases link ischemia from TMA with collapsing FSGS,S17 from the
small number of reported cases, we feel it is premature to conjecture why TMA is not
observed more often with intravitreal VEGF blockade. See Table 2 for a summary of
teaching points of this report.2, 6
,
S2,S4
Table 2
Teaching points
1. Systemic VEGF blockade is known to result in hypertension, proteinuria, and renal
injury.
2. Intravitreal anti-VEGF injections have been shown to be absorbed and inhibit systemic
VEGF.
3. Intravitreal anti-VEGF agents can cause TMA and nephrotic syndrome.
4. Patients on intravitreal anti-VEGF therapy should be monitored for proteinuria,
particularly if they have it at baseline.
TMA, thrombotic microangiopathy; VEGF, vascular endothelial growth factor.
Disclosure
All the authors declared no competing interests.