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Published ahead of print on July 11, 2007
Clin J Am Soc Nephrol 2: 1014-1023, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.01700407
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Clinical Immunology and Pathology

Spectrum of Renal Pathology in Hematopoietic Cell Transplantation: A Series of 20 Patients and Review of the Literature

Anthony Chang*, Sangeeta Hingorani{dagger}, Jolanta Kowalewska{ddagger}, Mary E.D. Flowers§,||, Tia Aneja||, Kelly D. Smith{ddagger}, Shane M. Meehan*, Roberto F. Nicosia{ddagger}, and Charles E. Alpers{ddagger},§

* Department of Pathology, University of Chicago Medical Center, Chicago, Illinois; and {dagger} Department of Pediatrics, Children's Hospital & Regional Medical Center, Departments of {ddagger} Pathology and § Medicine, University of Washington Medical Center, and || Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

Address correspondence to: Dr. Anthony Chang, University of Chicago Medical Center, Department of Pathology, 5841 S. Maryland Avenue, Room S-628 (MC6101), Chicago, IL 60637. Phone: 773-834-3426; Fax: 773-834-7644; E-mail: anthony.chang{at}uchospitals.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 
Background and Objectives: Hematopoietic cell transplantation is a common treatment option for a variety of hematopoietic malignancies. As a result of the use of total body irradiation and/or chemotherapeutic agents, renal dysfunction often ensues. Many pharmacologic agents, such as cyclosporine and high-intensity conditioning regimens, have been linked with thrombotic microangiopathy. In addition, an association between membranous nephropathy and graft-versus-host disease has been reported in this clinical setting.

Design, Setting, Participants, and Measurements: A study of autologous and allogeneic hematopoietic cell transplantation patients with renal dysfunction was conducted to document the spectrum of renal manifestations. The pathology files at the University of Washington and University of Chicago Medical Centers were reviewed, and 20 patients with a kidney biopsy after hematopoietic cell transplantation were identified. The histologic findings were correlated with relevant clinical information.

Results: A wide spectrum of renal diseases could be classified into four categories: (1) Complications related to hematopoietic cell transplantation (conditioning regimen, immunosuppression, or posttransplantation complications), (2) podocytopathy, (3) membranous nephropathy, or (4) recurrence or persistence of original hematologic disease. Pathologic diagnoses included thrombotic microangiopathy, polyoma virus nephropathy, acute kidney injury/acute tubular necrosis, acute and chronic interstitial nephritis, minimal-change disease, "tip" variant of focal segmental glomerulosclerosis, membranous nephropathy, amyloidosis, and myeloma cast nephropathy. Membranous nephropathy, minimal-change disease, and amyloidosis were common causes of severe proteinuria. Because of the conditioning regimens, posttransplantation complications, and potential nephrotoxic agents used during hematopoietic cell transplantation, it was difficult to attribute the subsequent renal dysfunction to specific factors.

Conclusions: The renal biopsy remains essential for diagnosing the underlying injury that can affect one or more compartments of the kidney in this unique clinical setting.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 
Hematopoietic cell transplantation (HCT) is a common treatment option for a variety of hematopoietic malignancies. Chronic kidney disease occurs in 20 to 60% of HCT patients and has been associated with the use of radiation and/or chemotherapeutic agents, acute and chronic graft-versus-host disease (GVHD), and acute renal failure (1). Many pharmacologic agents, such as cyclosporine and tacrolimus, have been linked to thrombotic microangiopathy (TMA) (2). A range of glomerular injury processes, such as membranous nephropathy (MN) (3–12) and minimal-change disease (MCD) (13–20), have been observed in the setting of HCT, primarily as individual case reports. We conducted a clinicopathologic study of HCT patients with renal dysfunction to document the histopathologic spectrum of renal manifestations that can occur in this unique clinical setting. In addition to the previously described changes, we identified cases with polyoma virus infection, acute kidney injury/acute tubular necrosis, interstitial nephritis, focal segmental glomerulosclerosis (FSGS), and recurrence or persistence of the original hematologic disease.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 Disclosures
 References
 
We reviewed the renal pathology archives at the University of Washington (Seattle, WA) and University of Chicago (Chicago, IL) Medical Centers from 1998 through 2006 and identified 21 biopsies from 20 patients with a clinical history of HCT and renal dysfunction of such severity that a renal biopsy was obtained. Standard procedures were used to process formalin-fixed tissue for light microscopic evaluation. The tissue sections were approximately 2 µm in thickness. Hematoxylin and eosin, periodic acid-Schiff, and Jones methenamine silver stains on three-level sections and a Masson trichrome stain for one-level section were obtained on all specimens. Standard procedures for direct immunofluorescence (IF) microscopy were used in all cases to detect deposition of IgG, IgA, IgM, C3, C1q, fibrinogen, {kappa} and {lambda} light chains, and albumin. The intensity of immunofluorescence staining was semiquantitatively scored on a scale of 0 to 4+, as described previously (21). Standard procedures for electron microscopy (EM) were applied to evaluate renal specimens using a Philips 410LS or CM10 electron microscope. Clinical data were reviewed and extracted from the medical charts. Clinical information obtained during the 2 wk before the renal biopsy included age, type of transplant, date of transplantation, conditioning regimen, medications, GVHD status, weight, BP, presence of edema, serum creatinine and albumin, and urinalysis including 24-h collection for protein when available. Treatment that was instituted after review of the renal biopsy was also obtained when available. The relevant clinical information was correlated with the histopathologic findings. This study was approved by the University of Washington Medical Center, Fred Hutchinson Cancer Research Center, and University of Chicago Medical Center institutional review boards.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 Disclosures
 References
 
Clinical Data
The clinical characteristics of all 20 patients are summarized in Table 1. The median age at presentation was 52 yr (range 37 to 72 yr). Patients presented at an average of 19 mo after transplantation (range 1.5 to 60 mo). Acute elevations in serum creatinine were the primary presentation in nine patients. The remaining 11 patients presented with nephrotic-range proteinuria, seven of whom had severe proteinuria in the range of 11 to 26 g/d. In the 17 patients for whom data were available, the median serum creatinine was 2.5 mg/dl (range 1.1 to 6.0 mg/dl). Serum albumin ranged from 1.5 to 3.9 mg/dl with a median of 2.1 mg/dl, and 75% of patients had edema before their renal biopsy. Half of the patients had GVHD around the time of their renal biopsy. Patients 5 and 16 have been previously reported in detail (22,23). The original hematologic malignancies included multiple myeloma (n = 7), acute myeloid leukemia (n = 5), non-Hodgkin lymphoma (n = 3), amyloidosis (n = 2), Hodgkin lymphoma (n = 1), acute lymphoblastic leukemia (n = 1), and chronic lymphocytic leukemia (n = 1). Six patients underwent autologous HCT, and the remaining patients underwent either an allogeneic or an autologous followed by an allogeneic HCT. Many patients were treated with prednisone ± cyclosporine ± an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Patients 5 and 16 went on to dialysis, and patients 3, 4, and 12 died. Limited clinical follow-up information was available for the remaining patients.


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  		Table 1. Clinical data at presentation and follow-upa

 
Renal Biopsy Findings
TMA.  Glomerular capillary thrombi and mesangiolysis, which are characteristic features of TMA, were present in patients 1, 3, and 4. Focal to diffuse duplication of the glomerular basement membranes (GBM) was seen in all four TMA cases. Patient 1 had small arteries and arterioles that were occluded by eosinophilic thrombotic material (Figure 1A) and prominent hyalinosis in some vessels. One small artery was occluded by lipid-laden macrophages. Adventitial hyaline nodules characteristic of calcineurin inhibitor toxicity were noted in some arteries and arterioles. Many of the proximal tubules demonstrated loss or attenuation of the brush borders. The first renal biopsy of patient 2 had intact glomeruli demonstrating mesangial expansion with a spongiform appearance and focal areas of mesangiolysis. Some of these mesangial areas showed hypercellularity. Most glomerular capillary walls were thickened with focal duplication of the GBM. Intracapillary or arterial thrombi were not identified. A second renal biopsy 3 yr later demonstrated persistent mild mesangial expansion of the glomeruli and focal duplication of the GBM in one glomerulus. Red cell fragments were interposed between the duplicated GBM. The arterioles showed focal subendothelial hyalinosis. Patient 3 had two glomeruli with prominent foam cell infiltration in several capillaries, duplicated basement membranes, and prominence of the adjacent visceral epithelial cells (Figure 1B). This biopsy also showed focal features of polyoma virus infection (Table 2).


Figure 1
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  		Figure 1. (A) Patient 1. Thrombi with red cells and red cell fragments are present within the arterioles, consistent with thrombotic microangiopathy (Jones methenamine silver). Magnification, x200. (B) Patient 3. Duplicated glomerular basement membranes with numerous foam cells (arrow) within the glomerular capillaries and prominence of the visceral epithelial cells are present (Jones methenamine silver). Magnification, x600.

 

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  		Table 2. Summary of renal biopsy findingsa

 
Polyoma Virus Nephropathy.  Patients 3, 5, 6, and 7 initially presented with elevated serum creatinine. The SV40 (Lee Biomolecular Co., San Diego, CA) immunohistochemical stain in patient 3 was positive in only three tubules with focally prominent tubulitis and no histologically identifiable viral cytopathic effect. The predominant finding in this case was TMA and intimal arteriopathy (see previous paragraph). The remaining three cases showed diffuse interstitial inflammation with frequent tubulitis, which was often more prominent in the medulla. Marked nuclear enlargement and intranuclear inclusions were seen in many tubular epithelial cell nuclei (Figure 2A) and focally in parietal epithelial cells, which was confirmed by SV40 immunohistochemical studies. BK virus was detected by PCR in blood and urine samples for all four patients. The additional presence of tubular basement membrane (TBM) deposits was observed by both IF (Figure 2B) and EM in patient 5 (Table 2).


Figure 2
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  		Figure 2. (A) Patient 5. Characteristic "ground-glass" nuclei (arrow) in a few tubular epithelial cells are present in this case of polyoma virus nephropathy (periodic acid-Schiff). Magnification, x400. (B) Patient 5. Tubular basement membrane immune complex deposition is noted by immunofluorescence staining for IgG. Magnification, x400.

 
Acute Kidney Injury/Acute Tubular Necrosis.  Patients 8 and 9 demonstrated severe acute kidney injury characterized by the loss or attenuation of the proximal tubular brush borders (Figure 3). There were no significant glomerular alterations or interstitial inflammation. Patient 8 revealed focal subendothelial hyalinosis of the arterioles, and patient 9 showed mild intimal fibrosis of the arteries. Patients 1, 12, and 15 also had a minor component of acute kidney injury but had other primary histopathologic features (Table 2).


Figure 3
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  		Figure 3. Patient 8. Acute kidney injury characterized by prominent loss and attenuation of the proximal tubular brush borders is shown (Jones methenamine silver). Magnification, x200.

 
Interstitial Nephritis.  Patient 10 had a moderate interstitial mononuclear cell inflammatory infiltrate with a few scattered eosinophils and frequent tubulitis in many well-preserved tubules. One small artery had mucoid intimal change with duplication of the internal elastic lamina, and the other arteries were normal. This patient's medication list included acyclovir, phenytoin, aspirin, citalopram, loratadine, omeprazole, metoprolol, calcitriol, and thalidomide, but the precise cause of interstitial nephritis remains uncertain (Table 2).

Podocytopathy.  Patients 11, 12, and 13 had 38, seven, and nine glomeruli available for evaluation, respectively. Although the possibility of FSGS as a result of sampling could not be entirely excluded, the prominent podocyte injury with extensive foot process effacement (Figure 4) that was observed by EM in all three cases along with the absence of segmentally sclerotic glomeruli was most characteristic of MCD. Patient 11 showed additional findings of prominent fibrocellular intimal expansion with near occlusion of a small artery and focal disruption of the internal elastic lamina. IF microscopy demonstrated granular staining of 10 to 15% of the TBM for IgG and {kappa} and {lambda} light chains in patient 11, which was confirmed by the presence of electron-dense deposits in the TBM. Patient 14 had one glomerulus that revealed foam cells within a few capillaries at the urinary pole, diagnostic of the glomerular "tip" variant of FSGS (Figure 5). EM showed only focal foot process effacement of the podocytes (Table 2).


Figure 4
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  		Figure 4. Patient 11. Electron microscopy shows extensive effacement of the podocyte foot processes, which is consistent with minimal-change disease. Magnification, x2400.

 

Figure 5
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  		Figure 5. Patient 14. Accumulation of foam cells (arrows) within glomerular capillaries at the urinary pole in this mildly ischemic glomerulus is consistent with the "tip" variant of FSGS (periodic acid-Schiff). Magnification, x600.

 
MN.  Patients 15 to 17 demonstrated granular IF staining of the capillary walls for IgG and {kappa} and {lambda} light chains, with focal C3 staining in two cases typical of MN. The glomeruli in patient 15 had no significant alterations, and characteristic subepithelial "spikes" were not present by light microscopy. Patient 16 had glomeruli showing prominent GBM thickening with subepithelial spikes and frequent rarefactions seen with the silver stain (Figure 6). Two glomeruli had segmental sclerosis. EM revealed subepithelial and intramembranous deposits with microspherular substructural organization and extensive podocyte foot process effacement. Patient 17 had intact glomeruli without significant morphologic alterations. Segmental and small subepithelial electron densities were seen by EM. The findings were consistent with an early stage of MN (Table 2).


Figure 6
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  		Figure 6. Patient 15. Prominent thickened glomerular basement membranes with absence of silver staining and possible "spike" formation are present in this case of membranous nephropathy (Jones methenamine silver). Magnification, x600.

 
Recurrence or Persistence of Original Hematologic Disease
Amyloidosis of the AL ({lambda} light chain) subtype was identified in both patients 18 and 19. Significant proteinuria in patient 19 persisted even after HCT. Both biopsies demonstrated significant global glomerulosclerosis, and many glomeruli showed ischemic features and irregular scarring. Amorphous eosinophilic glomerular deposits were predominantly mesangial in location. Some capillary walls and arterioles demonstrated similar eosinophilic material, which was confirmed by Congo red stains to be amyloid. IF staining for both cases demonstrated {lambda} light chain staining only in the glomeruli and vessels for patient 19 and interstitium for patient 18, which did not contain glomeruli in the tissue that was available for IF microscopy. Diffuse interstitial fibrosis and tubular atrophy were present in both biopsies of which patient 18 had aggregates of interstitial foam cells. EM confirmed the presence of randomly arranged, nonbranching fibrils that measured up to 10 nm in thickness. Focal to extensive podocyte foot process effacement was present in these two cases. Patient 20 demonstrated prominent intratubular casts with a fractured appearance and giant cell reaction, consistent with myeloma cast nephropathy. IF microscopy showed confluent staining of the intratubular casts and GBM for {kappa} light chains only, which confirmed the diagnosis of myeloma cast nephropathy and suggested the additional diagnosis of light-chain deposition disease. Small granular electron-dense deposits characteristic of light-chain deposition disease were identified by EM along the TBM but not GBM. There was diffuse interstitial fibrosis and tubular atrophy with focally prominent interstitial inflammation. The small arteries showed moderate intimal fibrosis, and some arterioles demonstrated prominent subendothelial hyalinosis.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 Disclosures
 References
 
Renal dysfunction in HCT patients can be arbitrarily separated into early and late manifestations and has been well reviewed (1,24). The differential diagnosis of early renal dysfunction includes infection, tumor lysis syndrome, sinusoidal obstruction syndrome leading to hepatorenal syndrome, TMA, amphotericin toxicity, and acute kidney injury/acute tubular necrosis (25). Late renal dysfunction is more likely idiopathic or secondary to TMA, nephrotic syndrome, GVHD, and/or calcineurin inhibitor toxicity (1). To date, our study represents the largest series of HCT patients who have acute late renal dysfunction for which the specific pathologic injury has been determined by renal biopsy. Because of the numerous treatment modalities and potential toxic pharmacologic agents during HCT, it is difficult to attribute the various renal lesions identified to a specific factor. Our study demonstrates that renal biopsies of HCT patients often reveal the presence of one or more injuries to different compartments of the kidney. The wide spectrum of renal diseases that was encountered in our series can roughly be classified into four categories: (1) Complications related to the HCT procedure (conditioning regimen, immunosuppression or post-transplant complications), (2) podocytopathy, (3) MN, (4) recurrence or persistence of original hematologic disease.

TMA represents a spectrum of clinical diseases that are characterized by systemic or intrarenal platelet aggregation, thrombocytopenia, and microvascular fragmentation of erythrocytes. Thrombosis can result in ischemia and organ injury. When renal injury is predominant, a diagnosis of hemolytic uremic syndrome (HUS) is usually rendered, whereas the presence of extensive extrarenal manifestations leads to a diagnosis of thrombotic thrombocytopenic purpura (TTP) (26). The pathologic features of TMA include arteriolar and/or glomerular thrombi with subendothelial space widening as detected by electron microscopy. These features of TMA are nonspecific with regard to underlying cause and can be observed in a number of clinical settings, which include but are not limited to TTP, HUS, malignant hypertension, antiphospholipid antibody syndrome, scleroderma, radiation nephropathy, and exposure to various pharmacologic agents. The pathologic finding of TMA in the setting of HCT would correlate with the clinical entity of post-HCT HUS. The pathogenesis of de novo TTP has been attributed to the presence of large multimers of von Willebrand factor as a result of the deficiency or absence of ADAMTS13, but one or more different mechanisms are likely operative in the pathogenesis of post-HCT HUS. This may in part be due to the heterogeneity of the patients with this clinical diagnosis and the difficulty of making a diagnosis in patients early after transplantation. El Seisi et al. (27) conducted the largest analysis of renal pathologic findings in an autopsy study of 26 HCT patients. They found that nearly half of their patients showed TMA, and significant glomerulosclerosis and interstitial fibrosis were often observed despite the relatively young age of the patients. Patients with the clinical entity of post-HCT TMA have a high mortality rate (2), which may explain the large percentage of cases in their autopsy study. Two of four patients with post-HCT TMA in our series also died shortly after development of renal dysfunction.

Of interest, Holmium-166 1,4,7,10-tetraazcyclododecane-1,4,7,10-tetramethylenephosphonate (166Ho-DOTMP) along with melphalan was used to treat the multiple myeloma of patient 2 before HCT. 166Ho-DOTMP is a radiotherapeutic agent that specifically targets bone, which maximizes the delivery of radiation to the marrow of patients with multiple myeloma (28). Given the presence of GBM alterations with focal duplication, the first renal biopsy findings are best classified as a thrombotic microangiopathic injury process, although the initial biopsy did not demonstrate significant subendothelial space widening in one glomerulus that was available for EM. A follow-up biopsy 3 yr later demonstrated focal duplication of the GBM in one glomerulus without overt thrombi in capillaries or arterioles. We observed similar renal biopsy findings in other patients who were treated with 166Ho-DOTMP (29), but it is unclear whether this particular agent or other factors may be contributing to the histopathologic changes in the kidney.

Polyoma virus nephropathy (PVN) is a common complication of immunosuppression that affects up to 8% of renal transplant patients (30). In the nonrenal transplant setting, rare cases of PVN in the native kidney have been described in pancreas, lung, heart, and HCT patients (23,31–34). Our study adds three cases to the medical literature and suggests that PVN may not be such an uncommon manifestation in HCT patients. In our series, patient 11 had MCD and demonstrated TBM immune complex deposition. Although TBM immune complex deposition without glomerular involvement is best described in the setting of systemic lupus erythematosus, Sjögren syndrome, and drug-induced interstitial nephritis (35), this finding recently was described in PVN (36). We speculate that the TBM immune complex deposition in our patient could represent the resolution of a previous polyoma virus infection.

MN is the most common form of immune complex–mediated glomerulonephritis (GN) that has been described in the setting of HCT. More than 40 cases of MN have been reported in the English medical literature (3–12,19,37–46). Reddy et al. (44) and Terrier et al. (46) represent the two largest series with five cases of MN each. Most cases of MN have been associated with acute and/or chronic GVHD. Of note, two of our three cases of MN were associated with GVHD, although we had limited clinical information regarding the GVHD status in one patient. The pathogenic mechanism of idiopathic MN and MN secondary to HCT is largely unknown. Only one antigen, neutral endopeptidase, has been specifically identified in the pathogenesis of MN (47), which we previously demonstrated is not the antigenic target of MN in our HCT patient (22). In addition, IgA nephropathy, membranoproliferative GN, and other unclassified immune complex–mediated GN have been described (45,48–50). The precise relationship of these immune complex–mediated glomerular injuries to HCT, GVHD, or the therapeutic regimens remains unclear.

Non–immune complex–mediated glomerular injuries in HCT patients include MCD, FSGS, and pauci-immune crescentic GN (13–20,42–44,51–53). The finding of FSGS has been reported in non-HCT patients with IFN therapy and high-dosage chemotherapy for chronic myeloid leukemia (54), which provides evidence that high-dosage chemotherapy alone may be sufficient to result in severe podocyte injury. The pathogenesis of MCD remains elusive and has been considered to be a T cell–mediated injury. Although direct podocyte toxicity from the various therapeutic agents could be a contributing factor, most patients present with MCD several months after HCT, frequently when there is a decrease in immunosuppressive medications or acute or chronic GVHD (43). Although MCD has been associated with a variety of hematologic malignancies, particularly Hodgkin lymphoma, two of the three cases in our study were in the setting of multiple myeloma, which has not previously been associated with MCD. Stevenson et al. (19) reported two HCT patients, one of whom had MCD that presented with nephrotic syndrome shortly before the relapse of the underlying hematologic malignancy. The authors suggested that a clinical relapse should be considered in HCT patients without overt evidence of GVHD.

The six patients who underwent autologous HCT had renal dysfunction as a result of TMA, PVN, interstitial nephritis, and amyloidosis. The first three entities could be classified as complications of the therapeutic agents and/or immunosuppression. Although this is based on a small number of patients, neither a podocytopathy nor an immune complex–mediated disease process was encountered in these patients after autologous HCT.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
Disclosures
 References
 
A wide spectrum of renal pathologic findings can be observed in HCT patients. Either severe proteinuria or acute elevations in serum creatinine were common presentations in our study, which can be due to MN, MCD, FSGS, and amyloidosis for the former and TMA, PVN, acute kidney injury, and interstitial nephritis for the latter. Renal biopsies are necessary to establish the underlying cause of renal dysfunction in HCT patients. Once the underlying pathology is known, therapies can be tailored to target the specific disease process and to prevent progression to ESRD.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
References
 
None.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

A.C. and S.H. contributed equally to this work.

Access to UptoDate on-line is available for additional clinical information at http://www.cjasn.org/

Received April 11, 2007. Accepted May 2, 2007.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 

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