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Pathophysiology of Renal Disease and Progression |
-Particle–Emitting Actinium Daughters
* Molecular Pharmacology and Chemistry Program and Department of Medicine, Memorial Sloan-Kettering Cancer Center, and Department of Pathology and Research Animal Resource Center, Weill Medical College of Cornell University, New York, New York; and || Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Address correspondence to: Dr. David Scheinberg, Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-8635; Fax: 212-717-3068; E-mail: d-scheinberg{at}ski.mskcc.org
Received for publication November 18, 2004. Accepted for publication May 13, 2005.
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Abstract |
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irradiation on the kidneys is well described. However, the mechanisms of radiation nephropathy as a consequence of targeted radionuclide therapies are poorly understood. The functional and morphologic changes were studied chronologically (from 10 to 40 wk) in mouse kidneys after injection with an actinium-225 (225Ac) nanogenerator, a molecular-sized, antibody-targeted, in vivo generator of 
-particle–emitting elements. Renal irradiation from free, radioactive daughters of 225Ac led to time-dependent reduction in renal function manifesting as increase in blood urea nitrogen. The histopathologic changes corresponded with the decline in renal function. Glomerular, tubular, and endothelial cell nuclear pleomorphism and focal tubular cell injury, lysis, and karyorrhexis were observed as early as 10 wk. Progressive thinning of the cortex as a result of widespread tubulolysis, collapsed tubules, glomerular crowding, decrease in glomerular cellularity, interstitial inflammation, and an elevated juxtaglomerular cell count were noted at 20 to 30 wk after treatment. By 35 to 40 wk, regeneration of simplified tubules with tubular atrophy and loss with focal, mild interstitial fibrosis had occurred. A lower juxtaglomerular cell count with focal cytoplasmic vacuolization, suggesting increased degranulation, was also observed in this period. A focal increase in tubular and interstitial cell TGF-
1 expression starting at 20 wk, peaking at 25 wk, and later declining in intensity with mild increase in the extracellular matrix deposition was noticed. These findings suggest that internally delivered -particle irradiation–induced loss of tubular epithelial cells triggers a chain of adaptive changes that result in progressive renal parenchymal damage accompanied by a loss of renal function. These findings are dissimilar to those seen after gamma or beta irradiation of kidneys. |
Introduction |
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-particle–emitting antibodies are Food and Drug Administration approved for the treatment of non-Hodgkin’s lymphoma (2,3). -Particle–emitting radionuclides are particularly advantageous for RIT because particles have high linear energy transfer and short path lengths (50 to 80 µm) (4,5). Therefore, a large amount of energy is deposited over a short distance, which renders particles extremely cytotoxic with a high relative biologic effectiveness (6,7). Little collateral damage to surrounding normal, antigen-negative cells occurs (8).
We and others are investigating actinium-225 (225Ac), an -emitting atomic generator, as a suitable candidate for use in RIT (9). 225Ac has a sufficiently long half-life (10 d) for feasible clinical use, and it decays to stable bismuth-209 via six atoms (Figure 1), yielding a net of four particles (9). The 225Ac-antibody construct acts as a tumor-selective, molecular-sized in vivo atomic generator (targetable nanogenerator) of -particle–emitting elements (9). The nanogenerators are stable in vivo and have been shown to be safe and potent antitumor agents in mouse models of solid prostatic carcinoma, disseminated lymphoma, and intraperitoneal ovarian cancer and in a rat model of meningeal neuroblastoma (9–11). The safety of 225Ac-HuM195 and 225Ac-3F8 at low doses has been demonstrated in primates (11,12). Therefore, these agents possess the potential to treat a variety of tumor types.
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There have been limited reports of radiation nephropathy after the use of radiolabeled antibodies (15). The antibody-radionuclide construct is large and therefore is not filtered via the glomeruli. However, the peculiarities of 225Ac nanogenerators that render them potent cytotoxic agents may also result in potential nephropathy. 225Ac decays via its -emitting daughters francium-221(t1/2 = 5 min), astatine-217 (t1/2 = 32.3 ms), and bismuth-213 (t1/2 = 45.6 min) to stable, nonradioactive Bi-209 (9). The daughters that are generated and retained inside the cancer cell after internalization of the 225Ac-labeled antibody add to its cytotoxic effect. However, the free daughters that are produced in the vasculature from the circulating unbound antibody or the antibody bound to the surface of a target cell could be transported to distant sites via the bloodstream and accumulate in other organs. Bismuth is known to accumulate in the renal cortex (19–21). This has been attributed to the presence of heavy metal binding, metallothionein-like proteins present in the cytoplasm of renal proximal tubular cells. We have also seen a rapid accumulation of francium in mice kidneys after intravenous injection (unpublished observation). Moreover, monkeys that received an injection of escalating doses of the untargeted 225Ac nanogenerator developed a delayed radiation nephropathy (12). Therefore, a possible hurdle to the development of these agents as safe and effective cancer therapeutics is likely to be their nephrotoxicity. Here, we describe chronologically the pathologic and corresponding functional events that occur in the kidneys after 225Ac nanogenerator injection, in an attempt to gain insights into the pathogenesis of radiation nephropathy after radionuclide therapy.
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Materials and Methods |
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Preparation and Quality Control of 225Ac-Labeled Antibodies
HuM195 (humanized IgG1 that recognizes the extracellular domain on CD33) was a gift from Protein Design Labs (Fremont, CA). 225Ac was conjugated to HuM195 antibody and quality controlled, as described previously (22).
Radioimmunoconjugate Administration to Mice
The mice were anesthetized by intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg) and received an injection of 0.35 µCi (720 kBq/kg) of [225Ac]HuM195 via the retro-orbital venous plexus. The specific activity of the radioimmunoconjugate was 0.08 Ci/g.
Clinical and Anatomic Pathology
Urine protein was estimated weekly using Uristix reagent strips (Uristix; Bayer, Elkhart, IN). Mice were killed by carbon dioxide asphyxiation at 10, 20, 25, 30, 35, and 40 wk after injection with 225Ac-HuM195 (three to five per time point), and their blood urea nitrogen (BUN) and serum creatinine were estimated (IDEXX Laboratories, Totowa, NJ). Tissues were fixed in 10% neutral-buffered formalin, processed by routine methods, and embedded in paraffin. Sections (2 to 3 µm) were stained with hematoxylin and eosin, periodic acid-Schiff, and Masson’s trichrome and evaluated with an Olympus BX45 light microscope. Age-matched normal BALB/c mice served as controls for the comparison of gross and microscopic features at each time point.
Immunohistochemistry
Paraffin-embedded kidney sections (2 to 3 µm) were immunostained with polyclonal rabbit anti-human TGF 1 antibody (Promega, Madison, WI; 1:200 dilution), polyclonal rabbit anti-plasminogen activator inhibitor-1 (PAI-1) antibody (Santa Cruz Biotechnology, Santa Cruz, CA; 1:200 dilution), rabbit anticleaved caspase-3 antibody (Cell Signaling Technology, Beverly, MA; 1:50 dilution), and rabbit anti–Wilms’ tumor 1 (WT1) antibody (Santa Cruz; 1:50 dilution), using methods described previously (23–26).
Electron Microscopy
Pieces of renal cortical tissue were fixed in 4% paraformaldehyde, postfixed in 1% osmium tetroxide, and later embedded in Epon. Ultrathin sections (200 to 400 Å) were cut on nickel grids, stained with uranyl acetate and lead citrate, and examined using an electron microscope (Hitachi H-7500, Pleasanton, CA).
Evaluation of Renal Pathologic Damage
The glomeruli were assessed for decrease in size and cellularity. The percentage of glomeruli that showed shrinkage (50% of control size) was evaluated by counting the total number of glomeruli in midcoronal sections of the kidneys (three to four per mouse). The number of juxtaglomerular (JG) cells per glomerular hilus and the extent of glomerular involvement (percentage of glomeruli involved) were calculated. The arterial and arteriolar medial (smooth muscle) cell vacuolization was estimated semiquantitatively on the basis of the percentage of cells involved per vessel cross-section (<25% = +/–; 25 to 50% = 1+; 50 to 75% = 2+; >75% = 3+). The extent of tubular cell vacuolization, tubulolysis, loss of brush border, and tubular atrophy was expressed as the mean percentage of total number of tubules in the kidney sections. The extent of basement membrane thickening in the lysed tubules was examined in trichrome-stained sections. The intensity (1+ or 2+ or 3+) and the extent (percentage of preserved and tubulolytic tubules) of immunoperoxidase staining for TGF-1 and PAI-1 were evaluated. Fifty glomeruli were counted for epithelial cells that showed positive nuclear staining for WT1, and the average number of WT1-positive cells per glomerulus was calculated. The average number of cells that showed positive staining for cleaved caspase-3 per kidney cross-section was also noted.
Estimation of Renal Absorbed Dose
The mean absorbed dose to the kidneys was estimated using a method described previously (12,27). The adult renal cortex-to-total kidney mass ratio (0.69) was used to obtain the renal cortical mass (28). The absorbed dose to the renal cortex was calculated by assuming that the entire measured radioactivity in the kidneys was confined to the renal cortex.
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After 25 wk after injection, the cortical thickness was reduced further by one third compared with that at 20 wk. Increased glomerular crowding and occasional subcapsular glomerulosclerosis (segmental or global) with only a mild compromise in capillary lumina were observed. No glomerular endothelial swelling, mesangiolysis, or inflammatory cell infiltration was seen. As compared with 20 wk (Figure 3D), there was a more widespread cortical tubulolysis (>75%), leaving empty tubular profiles and thickening and wrinkling of basement membranes (Figure 3G). Increased cellular protein resorption droplets were observed in the remaining islands of mildly affected tubules, with focal microcalcification in some simplified or atrophic tubules. There was focal perivascular interstitial inflammation composed primarily of lymphocytes and smaller proportion of plasma cells. Simplification and mild atrophy were seen in >50% of the medullary collecting ducts with diminished peritubular vascular spaces. Other blood vessels showed increased vascular smooth muscle vacuolization and dilation of cortical peritubular capillaries with margination of inflammatory cells.
The renal parenchymal findings at 30 wk were similar to those observed at 25 wk, except for progression in the extent of the tubular cell damage, lysis, and atrophy, with focal evidence of regenerative change in the lining epithelium. The interstitial inflammatory reaction was conspicuously increased with focal tubulitis composed of lymphocytes and plasma cells (Figure 4A). In addition, mild to moderate dilation of the Bowman space was seen in 10 to 30% of the glomeruli.
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The renal pathologic findings at 40 wk demonstrated complete subcapsular cortical atrophy. Occasional narrow or stenotic glomerulotubular neck was recognized. Regenerative changes with attenuated tubules and restoration of the brush border with minimal interstitial fibrosis were noted in approximately 30% of cortical tubules (Figure 4G). Moderate atrophy and tubular loss were also seen in the medulla.
Age-matched control BALB/c mice showed no significant changes at 10, 20, 25, 30, and 35 wk time points (Figure 4, J and K). Mild to moderate glomerular mesangial matrix thickening and mild arteriosclerosis were seen at 40 wk, which is consistent with normal aging process (Figure 4J).
Trichrome Findings
Trichrome-stained sections disclosed progressive basement membrane thickening, wrinkling, and collapse with aggregation of denuded tubular profiles with only minimal or no increase in interstitial fibrosis from 20 to 40 wk after treatment (Figures 3, E and H, and 4, B, E, and H). Progressive increase in JG cell hyperplasia and granularity involving 10 to 20% of glomerular hilar areas was seen. Arteriolar medial cell metaplasia with increased granularity was noted at 20, 25, and 30 wk, which declined to fewer cells and considerable degranulation at 35 to 40 wk.
Immunohistochemical Findings
The immunohistochemical staining for TGF-1 displayed an exclusively tubulointerstitial pattern. Whereas no significant staining was observed in control (untreated) mice (Figure 4L) and those at 10 wk after treatment (Figure 3C), scattered clusters of preserved tubular cells displayed positive (1 to 2+) staining, affecting approximately 25 and 50% of cells at 20 and 25 wk, respectively (Figure 3, F and I). A lower intensity (trace-1+) was seen in <5% of tubular cells at 30, 35, and 40 wk after treatment (Figure 4, C, F, and I). Similarly, there was intense, focal staining for TGF-1 in the interstitial cells at 20 and 25 wk that declined progressively in extent and intensity after 30 wk after injection. However, no significant staining for PAI-1 was observed in the 225Ac nanogenerator–treated or control mice at any time point (data not shown). No significant difference in the number of WT1-positive cells per glomerulus was seen (Figures 5, A B, and C; and 6, A through D) between the untreated control and the radioimmunoconjugate-treated mice at any time point (approximately nine to 12 cells per glomerulus at each time point). The number of cells per kidney cross-section that showed positive perinuclear or cytoplasmic staining for cleaved caspase-3 was mildly increased at 10 wk (approximately three to four cells per kidney cross-section); peaked at 20, 25, and 30 wk (approximately 18 to 20 per-cross section); and was moderately lower at 35 and 40 wk (approximately 10 per cross-section) after 225Ac injection (Figures 5, D, E, and F; and 6, E, F, and G). No staining for cleaved caspase-3 was seen in untreated (negative control) mice (Figure 6H).
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At 35 and 40 wk, there were varying degrees of regeneration of simplified tubular cell lining on preexisting thickened and reduplicated basement membranes (Figure 7, E and F). These cells lacked basolateral membrane infoldings, contained distorted mitochondria, and displayed segmental to circumferential appearance of luminal brush border. Tubules with severe tubulolysis demonstrated no significant restoration of the lining cells.
Summary of Pathologic Findings
In summary, glomerular and tubular cell nuclear hyperchromasia and isolated tubular cell lysis with karyorrhexis were observed as early as 10 wk after injection (Tables 1 and 2). However, the general renal parenchymal architecture was preserved. From 20 to 30 wk after injection, widespread tubulolysis and tubular collapse contributed to progressive thinning of the renal cortex, resulting in glomerular crowding. A relative decrease in glomerular cellularity, variable interstitial inflammation and hyperplasia, and increased granularity of JG cells was noted during this period. By 35 wk, focal regenerative tubular changes began to emerge with epithelial simplification, reactive nuclei, and early recovery of brush border but with only focal minimal increase in interstitial collagen. Thickened and reduplicated tubular basement membranes leaving empty profiles (as a result of tubulolysis) as well as some regenerated, simplified tubules were seen at 40 wk after injection. Areas of tubular regeneration alternated with segmental cortical scarring and moderate medullary atrophy at 40 wk. Microcystic dilation of the glomerular Bowman capsules was seen in the outer cortex. A lower JG cell count with focal cytoplasmic degranulation was also noted at this time point.
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-particle–emitting daughters that are generated in the blood stream from circulating 225Ac nanogenerators can accumulate in and irradiate the kidneys. Although the effective half-lives of many antibodies in humans are usually measured in several days, the 10-d half-life of 225Ac and constant generation of daughters may lead to a more prolonged irradiation of the renal tubules. Therefore, an understanding of the pathogenetic mechanisms of radiation nephropathy, based on systematic renal pathologic examination, is central to the design of interventions to abrogate the potential renal toxicity of 225Ac nanogenerators. Injection of mice with 225Ac nanogenerators led to a progressive decline in renal function, measured as an increase in the BUN. However, the serum creatinine levels remained within normal limits, possibly as a result of loss of muscle mass in 225Ac-treated mice. Pallor of abdominal organs was first seen at 20 wk after injection and increased progressively over time. Renal injury has been shown to reduce the potential for erythropoietin gene expression in interstitial fibroblast-like cells (30). Therefore, the pallor may be due to a reduction in erythropoietin production by the interstitial fibroblasts as a consequence of radiation damage, resulting in a decrease in the hematocrit. However, hematocrit or total red cell count could not be measured in these mice.
Glomerular capillary endothelial and mesangial cells have been shown to play an important role in the pathogenesis of radiation nephropathy, and glomerular injury is considered to be central to the development of radiation nephropathy after external beam irradiation (31,32). Glomerular thrombotic microangiopathy has been reported in patients who were treated with yttrium-90–labeled (a -particle emitter) somatostatin analogue (17). In our mouse model of radiation nephropathy, progressive, severe, and widespread tubular injury (lysis, simplification, and atrophy) is seen in the absence of any specific glomerular pathology or major interstitial fibrosis. This is accompanied by a significant reduction in the renal function. Therefore, it seems that the mechanism of development of radiation nephropathy in this system is different from the processes previously described with external beam radiation (13). The dilation of the Bowman spaces may be secondary to the tubular obstruction by casts or loss of tubules (atubular glomeruli). Because particles have short path lengths (5), the radiation dose is deposited in close vicinity of the sites of daughter accumulation in the nephron (tubules and peritubular endothelial and interstitial cells), and the glomeruli are relatively spared of the radiation dose. Our findings further support the evidence on tubular epithelial cells and interstitial fibroblasts as the targets in the development of radiation nephropathy (33). The more pronounced involvement of cortical tubules as compared with medullary tubules was an expected finding, considering the known affinity of free bismuth for proximal tubular cells.
Radiation-induced renal fibrosis involves complex and dynamic interactions among glomerular, tubular, and interstitial cells (13). Various biologic mediators such as TGF-1, PAI-1, and others have been thought to play a role in this process (13). In vitro irradiation of renal tubular cells resulted in a significant enhancement of TGF-1, PAI-1, and collagen-1 gene expression (34). TGF-1, a profibrogenic cytokine, is considered to be one of the most important mediators in renal fibrosis (35). TGF-1 regulates the transdifferentiation of tubular epithelial cells to -smooth muscle actin–expressing myofibroblasts, a cell type that is believed to be the main source of increased extracellular matrix deposition in renal fibrosis (36). We did not observe a detectable increase in TGF-1 expression until 20 to 25 wk after injection. An increase in TGF-1 expression generally occurs in late phases of radiation nephropathy (24). Moreover, radiation-induced renal pathologic changes appear much later in mice than in other species (13). PAI-1 is the major inhibitor of tissue plasminogen activator in vivo. PAI-1 inhibits matrix degeneration and promotes extracellular matrix deposition and fibrosis via inhibition of plasmin production from plasminogen (37). The source of PAI-1 is glomerular capillary endothelial cells (24), which are relatively spared of the radiation dose in our model of radiation nephropathy. Therefore, in contrast to external beam radiation, PAI-1 does not seem to play a major role in this model of radiation nephropathy.
WT1 is a zinc finger protein that plays a role in transcription as well as posttranscriptional processing of RNA (26). In adult kidneys, WT1 is expressed by the visceral epithelial cells of the glomeruli. The absence of a change in the number of WT1-positive cells between different time points after injection and compared with untreated controls suggests that the observed mild decrease in glomerular cellularity was not a result of visceral epithelial cell loss. It may be due to the loss of parietal epithelial cells, which are more likely to fall in the range of -particle radiation as a result of their anatomic location. The detection of cleaved caspase-3 immunostaining alludes to the role of apoptosis as a mechanism of the observed renal tubular cell death. Caspase-3 is a key effector caspase in the process of apoptosis and is activated via proteolytic cleavage (25). Cleaved caspase-3 immunostaining is detected only transiently in the cells that undergo apoptosis and is lost once the cells have apoptosed.
The renin-angiotensin system has been implicated in the pathogenesis and progression of radiation nephropathy (13,24,38). Angiotensin II (Ang II) is a growth promoter and is thought to cause mitotic cell death of renal epithelial cells by inducing the lethally irradiated cells to divide (39). Ang II has also been shown to trigger the production of profibrogenic mediators such as TGF-1 (40) and PAI-1 (41) in the kidneys. However, Cohen et al. (38) did not observe any increase in plasma renin activity or blood Ang II levels in the first 10 wk after irradiation and suggested that normal activity of the renin-angiotensin system could be detrimental to the irradiated kidney. Capillary endothelial damage from external beam radiation results in a decreased nitric oxide production (42). Therefore, a decreased modulation of the effects of Ang II by nitric oxide may be the reason for enhanced sensitivity of the kidney to the effects of Ang II (43). We have observed hypertrophy and hypergranularity of the JG apparatus cells at 20 and 25 wk after 225Ac injection, which diminished by 30 wk and returned to normal by 35 wk as the JG cells get degranulated, leaving behind vacuolated cells. Because of experimental sample limitations, the plasma renin activity could not be measured in these mice. An increase in the JG cell index at 15 wk after local kidney irradiation in rats was reported previously (44).
On the basis of a mechanism of progressive nephropathy suggested by Remuzzi et al. (45), we propose that radiation-induced nephron loss produces adaptive responses involving increased Ang II production and glomerular-capillary hypertension, which result in enhanced filtration of plasma proteins into the tubular fluid. The reabsorption of filtered proteins by the remaining tubular cells activates intracellular pathways for upregulation of inflammatory and vasoactive genes, the products of which cause varying degrees of interstitial inflammation and fibroblast activation. Because tubular cells are the sites for radioactive daughter accumulation, the radiation-induced loss of TGF-1–expressing tubular and adjoining interstitial cells may account for the reduced extent and intensity of TGF-1 staining and minimal fibrosis than what has been reported previously in studies with external beam irradiation.
In the case of radiation nephropathy after bone marrow transplantation, 10 Gy of total body irradiation with x-rays as a single dose or 14 Gy fractionated over 3 d results in radiation nephropathy (13). In our model, the absorbed dose estimates for the whole kidney and renal cortex are 27.6 and 39 Gy, respectively. The dose estimates are expressed in units of Gy rather than Sv because the exact relative biologic effectiveness value of particles for kidney cells in vivo is not known. The dose of [225Ac]HuM195 used in the experiments (0.35 µCi), on a weight basis, is higher than the planned human dose.
A wide range of preventive pharmacologic strategies is being investigated with an aim of attenuating the radiation-induced renal damage. Because the development of radiation nephropathy is dose dependant (33), a reduction in the radiation dose to the kidneys should be protective. We have shown that chelation of free metal, diuresis, and competitive metal blockade can reduce the accumulation of 225Ac daughter elements and, therefore, the renal radiation dose (27). The use of an enzyme-cleavable linker to link chelated radiometal to the antibody is another potentially useful approach. After the enzymatic cleavage of the linker, the 225Ac-chelate should clear rapidly; therefore, the radiation dose to the kidneys from 225Ac daughter accumulation could be diminished. Pharmacologic modification of the renin-angiotensin-aldosterone system in the intervening period between irradiation and renal failure has been shown to protect against radiation-induced renal damage in a number of animal studies (13). Angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and spironolactone (aldosterone receptor antagonist) ameliorated the functional and morphologic changes in the kidneys after external beam radiation (23,46). Therefore, similar interventions may be useful in reducing the toxicity of internal radio-emitters.
In summary, we show the chronological sequence of morphologic and functional changes in the renal tissue after injection of mice with 225Ac nanogenerators. The observed renal histopathologic changes are different from those reported with external beam irradiation, which reflects the differences in the two models with regard to the pattern and rate of renal radiation dose deposition. An understanding of the pathogenetic mechanisms of -particle–mediated renal toxicity should be useful in designing of interventions for its amelioration.
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Acknowledgments |
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We thank Drs. Eric Cohen and Carlos Flombaum for careful review and valuable comments on the manuscript. We thank Michael Ganger and Steven Bowe for valuable help with electron microscopy and preparation of illustrations, respectively, and Yi-Fang Liu for assistance in immunohistochemistry.
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