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Published ahead of print on March 15, 2006
Clin J Am Soc Nephrol 1: 685-694, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.00380705
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Mini-Reviews

Nephrotic Syndrome after Hematopoietic Cell Transplantation: Do Glomerular Lesions Represent Renal Graft-versus-Host Disease?

Kirsten Brukamp*, Alden M. Doyle*, Roy D. Bloom*, Nancy Bunin{dagger}, John E. Tomaszewski{ddagger}, and Borut Cizman*

* Renal-Electrolyte and Hypertension Division, Department of Medicine, {dagger} Division of Oncology, The Children’s Hospital of Philadelphia, and {ddagger} Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Address correspondence to: Drs. Kirsten Brukamp and Borut Cizman, Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, 700 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104. Phone: 215-573-1830; Fax: 215-898-0189; E-mail: brukampk{at}uphs.upenn.edu, bcizman{at}cceb.med.upenn.edu


   Abstract
Top
 Abstract
Introduction
 Typical Case Reports
 Discussion
 Analysis of the Literature...
 Conclusion
 References
 
Glomerular disease associated with nephrotic syndrome has rarely been recognized as a distinct complication of allogeneic hematopoietic cell transplantation. Case reports in the English and Japanese literature since 1988 have described variable glomerular histology, comprising mainly membranous glomerulonephritis (MGN) in almost two thirds and minimal change disease (MCD) in nearly one quarter of patients. Review of the literature reveals a close temporal relationship between the development of nephrotic syndrome shortly after cessation of immunosuppression and the diagnosis of chronic graft-versus-host disease (GVHD). An association of glomerular disease with simultaneous GVHD was seen in 47% of patients overall. Nephrotic syndrome followed GVHD within 5 months in 60% of the combined MCD and MGN reports. A decrease in immunosuppressive medication use was linked to nephrotic syndrome occurrence within 9 months in 63% of patients with MCD and MGN. MCD occurred earlier after hematopoietic cell transplantation, was diagnosed sooner after medication change, and exhibited a better prognosis in comparison with MGN. Glomerular lesions after hematopoietic cell transplantation may therefore represent the renal manifestation of GVHD. Further studies are warranted to delineate the pathogenesis of this complication.


   Introduction
Top
 Abstract
 Introduction
Typical Case Reports
 Discussion
 Analysis of the Literature...
 Conclusion
 References
 
The emergence of hematopoietic cell transplantation (HCT) for malignant and particularly so-called benign hematopoietic indications has resulted in the increasing recognition of acute and chronic renal failure as a complication. In close temporal proximity to the HCT, well-described conditions such as medication-induced nephrotoxicity, tumor-lysis syndrome, septic-ischemic tubular necrosis, and drug- or virus-induced hemorrhagic cystitis may occur (1). Delayed decline of kidney function is usually caused by radiation nephropathy, calcineurin inhibitor nephrotoxicity as a result of graft-versus-host disease (GVHD) prophylaxis, and hemolytic-uremic syndrome (1). The term bone marrow transplant nephropathy (2,3) has thus far been used to refer to late renal complications after HCT reminiscent of hemolytic-uremic syndrome, attributed to total body irradiation and nephrotoxic therapies. This lesion is characterized by mesangiolysis, mesangial matrix expansion, glomerular capillary widening, endothelial injury and dropout, and subendothelial space widening secondary to deposition of fibrin and newly formed basement membrane (2,3).

GVHD is a serious complication of allogeneic HCT, which can affect skin, eyes, mouth, serous membranes, liver, gastrointestinal and respiratory tracts, and the musculoskeletal, hematopoietic, and immune systems. Acute GVHD (4), affecting up to 80% of patients, usually occurs within days to 2 mo after the transplantation and typically involves the immune system, skin, liver, and gastrointestinal tract. The pathophysiology is complex and consists of cytokine activation of antigen-presenting cells after radiochemotherapy, which leads to T cell proliferation and differentiation into effector cells. These cells secrete cytokines that mediate apoptosis, tissue injury, and a positive inflammatory feedback loop (5). Chronic GVHD (6), by definition, appears >100 d after transplantation. Risk factors for chronic GVHD include history of moderate to severe acute GVHD, older age, extensive skin involvement, and thrombocytopenia.

Despite increasing knowledge about GVHD, nephrotic syndrome (NS) has not been studied extensively, albeit systematically, in this context. Case reports describe various pathologic glomerular changes after HCT. Herein, we report two typical cases followed at our institution, as well as two patients with less frequent features, and we review previous case reports to identify common characteristics among patients.


   Typical Case Reports
Top
 Abstract
 Introduction
 Typical Case Reports
Discussion
 Analysis of the Literature...
 Conclusion
 References
 
A white man (patient 1), born in 1957, underwent an allogeneic peripheral blood progenitor cell transplantation (PBT) after cyclophosphamide and busulfan conditioning therapy from his HLA-identical brother at the Hospital of the University of Pennsylvania (HUP) in September 2001 for first acute myelogenous leukemia (AML M2) relapse. His course was complicated by development of acute skin GVHD despite cyclosporine A (CsA) prophylaxis as well as chronic lung GVHD, consisting of changes reminiscent of bronchiolitis obliterans organizing pneumonia and pleural effusions, in March 2002. The patient was treated with prednisone and CsA, which were tapered and discontinued in February 2003. In July 2003, the patient was found to have new, biopsy-proven chronic GVHD with skin, lung, and pericardial involvement. At the same time, the patient was also noted to have NS, characterized by anasarca, hypoalbuminemia (1.9 mg/dl), proteinuria (22 g/d), hypercholesterolemia (340 mg/dl), and hematuria (5 red blood cells per high-power field on urinalysis). Hepatitis B and C serologies and antinuclear antibody (ANA) titers were within normal limits. The patient began to take prednisone 20 mg/d along with a loop diuretic and an angiotensin II receptor blocker. A kidney biopsy specimen obtained in October 2003 revealed findings of early membranous glomerulonephritis (MGN; Figure 1, A and B). Secondary to steroid resistance, tacrolimus and mycophenolate mofetil were added in November 2003. His edema resolved, and his proteinuria decreased to <0.3 g/d. His creatinine remained relatively stable at 0.9 to 1.2 mg/dl.


Figure 1
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  		Figure 1. Glomerular lesions in patients after hematopoietic cell transplantation. (A and B) Patient 1: Early membranous glomerulonephritis. No definitive basement membrane spikes were present on histology (A), but the electron microscopy (B) showed epimembranous immune complex deposition. The immunofluorescence (not shown) confirmed granular immune deposition for IgG along the capillary loops. In addition, occasional mesangial and subendothelial deposits and rare focal segmental glomerulosclerosis were also noted (not shown). (C and D) Patient 2: Mild mesangial proliferative glomerulopathy. Histology (C) showed very mild mesangial proliferation. Mild interstitial chronicity was also present (not shown). Immunofluorescence (not shown) was negative. Electron microscopy (D) revealed diffuse effacement of the visceral epithelial foot processes, involving approximately 90% of the glomerular capillary loops.

 
A white man (patient 2), born in 1972, received an allogeneic PBT from his HLA-identical brother at HUP in January 2003 after conditioning therapy with cyclophosphamide and fludarabine. His nodular-sclerosing Hodgkin’s lymphoma (HL), stage III B at diagnosis in August 2000, had relapsed despite several cycles of chemotherapy regimens, radiation, and an autologous progenitor cell transplantation in January 2002. After the allogeneic HCT in January 2003, the patient was in complete clinical remission from HL. The patient was admitted to HUP in July 2003 with dyspnea on exertion, foamy urine, facial edema, and a rash on his face and on both arms for 1 wk. His medications had included CsA for GVHD prophylaxis until 1 mo before presentation. He was found to have NS with anasarca, hypoalbuminemia (albumin 1.5 g/dl), microscopic hematuria, and proteinuria of 23.3 g/d, as well as acute renal failure (creatinine 2.4 mg/dl, increased from the previous value of 1.4 mg/dl in the same month). Tests such as hepatitis B and C serologies, complement C3 and C4 levels, ANA, ANCA, serum and urine protein electrophoresis, and antistreptolysin titer were within normal limits, and blood cultures were negative. A kidney biopsy revealed rare mesangial proliferative glomerulonephritis (Figure 1, C and D). A skin punch biopsy of the arm showed new chronic GVHD. The patient responded promptly to diuretic therapy and prednisone treatment, beginning at 1 mg/kg per d. At 4 wk, the forearm skin lesions had disappeared, and only trace lower leg edema was present (creatinine 1.2 mg/dl). Prednisone was tapered, but in April 2004, the patient had a relapse of NS with peripheral edema, nephrotic-range proteinuria, and hypoalbuminemia. His prednisone dose was increased again to 1 mg/kg per d with excellent response, followed by a taper to 10 mg/d in July 2004. In August 2004, a chest computed tomography scan revealed new lymphadenopathy indicating possible recurrence of HL, and the patient is currently receiving chemotherapy. No recurrence of NS or chronic kidney disease (CKD) progression has been noted.


   Discussion
Top
 Abstract
 Introduction
 Typical Case Reports
 Discussion
Analysis of the Literature...
 Conclusion
 References
 
In patient 1, the NS appearance in July 2003 coincided with GVHD involvement of a new organ as well as worsening in previously affected organs after discontinuation of CsA and prednisone in February 2003. This temporal relationship is suggestive of NS’s being a manifestation of GVHD.

The mesangial proliferative glomerulopathy (Figure 1C) seen in patient 2 was characterized by extensive foot process effacement (Figure 1D) and mild interstitial chronicity. This interstitial chronicity precluded the histopathologic diagnosis of classic minimal change disease (MCD). However, nephrotoxic insults surrounding the HCT and the use of CsA as GVHD prophylaxis may have resulted in chronic interstitial atrophy, which led to the patient’s preexisting stable CKD stage 2. The mesangial proliferative glomerulonephritis may then have been the sole acute histologic correlation of NS, thereby constituting an MCD variant. The patient’s responsiveness to glucocorticosteroid therapy thus far supports the latter claim.

The differential diagnosis of NS in a patient with a history of HL includes MCD as a manifestation of lymphoma recurrence (7,8). The association is rare, and the pathophysiology is unknown. A delay of up to 19 mo has been described, in one case report (9), between onset of NS, which spontaneously remitted, and diagnosis of recurrent HL. However, the glomerulopathy typically occurs within 6 mo before a diagnosis of recurrent HL is made. In our case, the patient was in complete remission after HCT for 19 mo, and therefore 13 mo after first development of NS. Although a minimal possibility remains that the NS occurrence was related to the HL relapse, the close proximity between the cessation of CsA prophylaxis and the development of new skin GVHD along with NS 2 to 3 wk later is highly suggestive of a causal association. NS in this patient is more likely a manifestation of GVHD rather than a prodrome of HL recurrence. To our knowledge, this case constitutes the first description of NS after HCT for HL.

In addition to patients 1 and 2, we noted two patients in our institution without clear-cut relationships between the NS presentation and HCT, chronic GVHD, or medication change. Although these cases do not illustrate supposedly typical relationships, their inclusion within the scope of a descriptive analysis is warranted as they demonstrate NS occurrences after HCT. Otherwise, bias would be introduced by overestimation of tight links between NS and potentially inciting events. It is conceivable that some cases do not exhibit possibly typical risk factors before NS presentation despite a connection to HCT, probably dependent on the underlying histologic correlate and its progression pattern. Both additional patients received a diagnosis of focal segmental glomerulosclerosis (FSGS), which may be either a diagnosis that is linked directly to the HCT or a secondary phenomenon after a different glomerular insult.

A white man of Italian ancestry, born in 1956, received a diagnosis of chronic myelogenous leukemia (CML) in March 1993, for which he received an allogeneic bone marrow transplantation (BMT) from his HLA-identical sister in March 1993, followed by acute skin GVHD. He presented with nephrotic-range proteinuria in May 1998 (creatinine 2.0 mg/dl; proteinuria 4.1 g/d; perinuclear ANCA, cytoplasmic ANCA, and complement levels C3 and C4 unremarkable), when his kidneys were borderline small with mildly increased echogenicity. A renal biopsy revealed global glomerulosclerosis in 13 of 15 glomeruli, while one of the two remaining glomeruli had a small segmental area of sclerosis. Electron microscopy showed focal areas of podocyte foot process effacement, and moderate fibrosis and tubular atrophy were seen in the interstitium. Currently, the patient has CKD stage 4, and he may receive a preemptive living-related donor kidney transplantation from his bone marrow donor in the future (10).

A female patient, born in 1979, underwent an allogeneic BMT from her HLA-identical sister for sickle cell ß thalassemia at the Children’s Hospital of Philadelphia in November 1995 after conditioning with cyclophosphamide, busulfan, and antithymocyte globulin, complicated by acute skin GVHD. In November 1997, she developed facial swelling and pedal edema, and laboratory tests were consistent with nephrotic syndrome (creatinine 0.8 mg/dl; proteinuria 3.8 g/d; complement C3 135 mg/dl; ANA and antibodies for hepatitis B and C negative). A renal biopsy in December 1997 showed global sclerosis in two of 20 glomeruli, whereas others had varying degrees of hypercellularity with increased mesangial cells and diffuse foot process effacement. The patient received an intravenous methylprednisolone pulse therapy and oral prednisone thereafter without significant improvement. A second renal biopsy, performed in January 2000 to assess chronicity, prognosis, and future treatment after 2 yr of glucocorticosteroid therapy, was consistent with fully developed FSGS (global sclerosis in seven of 15 glomeruli, variable degrees of segmental sclerosis in the remaining glomeruli, focal visceral epithelial foot process effacement, moderately fibrotic interstitium, and tubular atrophy). Prednisone was then stopped, and the patient’s CKD progressed on an angiotensin-converting enzyme inhibitor. Ultimately, the patient may be a candidate for renal transplantation from her original bone marrow donor (10).


   Analysis of the Literature and Discussion
Top
 Abstract
 Introduction
 Typical Case Reports
 Discussion
 Analysis of the Literature...
Conclusion
 References
 
A literature search was conducted to place individual cases into perspective and to identify global characteristics of NS occurrence after HCT. Case reports were identified by PubMed search (with combinations of terms such as "nephrotic syndrome," "glomerular disease," "hematopoietic cell transplantation," and "graft-versus-host disease") and by following references in the identified articles. Main case features were abstracted, and statistical analysis was performed with SPSS 13.0 (SPSS Inc., Chicago, IL). Time values that were ambiguous in the literature were rounded up to the next month, and concurrent values and those that were <1 mo were considered as 0 and 1 mo, respectively, for statistical purposes, to bias in favor of underestimating an effect. Percentages were calculated under exclusion of cases for which values were not reported, except where otherwise noted, as the number of missing values was usually low. P < 0.05 was considered statistically significant for analysis with the nonparametric Mann-Whitney U test and the nonparametric Spearman {rho} correlation test.

Forty-two previous, well-documented cases (11–43) that link allogeneic HCT and glomerular kidney disease have been published between 1988 and 2005. The pertinent patient characteristics of MGN and MCD cases, which are relevant for the discussion, are summarized in Table 1. Main individual findings of the reviewed 46 cases are listed in complementary Table 2. Other publications (44,45) refer to additional cases, but the details are too scarce to take these patients into account for detailed analysis in this review. In an additional case, NS developed after bone marrow nephropathy was found on renal histology, but the patient did not undergo biopsy again (46). A cohort study (43) of nonmyeloablative HCT listed seven patients with NS, three of whom did not receive a histologic diagnosis and therefore were not included. Two patients with a nephritic pattern as a result of ANCA-associated glomerulonephritis after autologous (47) and allogeneic (48) HCT were also excluded, and two pediatric case reports of membranoproliferative glomerulonephritis after autologous HCT (49) and of glomerular vasculopathy, resembling thrombotic microangiopathy, after cord blood transplantation (50) seemed unrelated as well.


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  		Table 1. Comparative summary of patients with NS and associated MGN and MCD after allogeneic HCTa

 

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  		Table 2. Clinical characteristics of patients with NS and associated glomerular disease after allogeneic HCTa

 
A total of 61% of the patients carry a diagnosis of MGN, and MCD affects 22% of patients. This approximate 3:1 ratio could possibly be due to publication bias, as MGN is favored in most early case reports. Mesangial proliferative glomerulonephritis may be interpreted as an MCD variant (27; our study). Other diagnoses vary and include FSGS that may be secondary to other types of glomerular lesions, mesangial IgA deposition with crescent formation, and diffuse proliferative and crescentic glomerulonephritis that may be superimposed on a different glomerular disease.

Histopathologic findings, both for glomerular disease and for extraglomerular changes, are not straightforward in some studies. For example, in two cases here classified only descriptively as immune complex–mediated glomerulonephritis, the authors reported glomerular subendothelial and subepithelial electron-dense deposits despite negative immunofluorescence, without arriving at a distinct diagnosis (12). FSGS features can accompany and follow a diagnosis of both MGN (17) and MCD (21). Several histopathologic specimens (12,13,25,28–30,32,42) exhibit interstitial infiltrates of variable intensity, consisting of lymphocytes, monocytes, or macrophages. Two studies (30,42) confirm a donor origin of mononuclear interstitial infiltrates. Rare findings include immune complex deposition in the tubular basement membrane along with a diagnosis of MGN (23).

The predominant underlying hematologic diagnosis is CML; acute myeloblastic leukemia and aplastic anemia are other common diagnoses. A shift from BMT toward PBT can be seen in the MGN and MCD groups of renal pathology over time (data not shown), a phenomenon that likely reflects the change of clinical practice in HCT. A comparison between the half of cases published first (11–31) with the more recent half (32–43; our study) reveals a parallel distribution of pathology (13 versus 15 MGN, 5 versus 5 MCD, and 5 versus 3 miscellaneous cases in each group) with a reversal of BMT and PBT frequency (71% BMT in the earlier half and 75% PBT in the later half). This finding suggests a lack of pathophysiologic impact of HCT modality on MGN versus MCD occurrence. It should be noted that a recent meta-analysis (51) has confirmed individual study results that chronic GVHD is more likely after PBT than after BMT, which may be explained by the transfer of a greater T cell dose. The question of whether the continuing relative increase of PBT among HCT leads to a greater probability of NS as a complication is beyond the scope of this review because of the lack of an adequate epidemiologic approach with higher patient numbers.

The vast majority of patients have evidence of acute and chronic GVHD, and chronic GVHD is particularly prevalent in MGN cases (88 versus 50% in MCD). Time from HCT until chronic GVHD onset is identical between the MGN and MCD groups (not significant). The NS presentation is consistently described as obvious, a feature that undermines the probability of lead time bias as a result of early proteinuria detection because of close monitoring after HCT. The presenting creatinine and proteinuria values are the same for MGN and MCD (not significant). ANA titers are mostly reported as negative or low (data not shown), whereas less than one fifth of the cases (14–16,21,32,37,39,40) possess a titer of 1:160 or higher. The average age at NS presentation tends to be lower for MCD as compared with MGN (not significant). It would be speculative to predict that patients who are older at the time of HCT are more prone to MGN than to MCD as a complication, thereby imitating the age distribution of so-called primary glomerulopathies. The typical time period between HCT and NS is shorter for MCD (median 8 versus 14 mo for MGN; P = 0.04). A confounding of overall results by gender (75% male patients for MGN versus 40% for MCD) and occurrence of acute GVHD (78% for MGN versus 40% for MCD) cannot be ruled out completely.

To characterize the occurrence of NS after HCT further, we examined the diverse case reports regarding the time intervals until NS diagnosis after GVHD and after immunosuppression decrease. Overall, chronic GVHD affects single or multiple organs in all groups (data not shown), mostly skin (54%), liver (32%), mucosa (24%), and gastrointestinal tract (17%). In 47% of all patients, a concomitant temporal relationship between GVHD and NS can be observed, as NS appears simultaneously with chronic GVHD. In the 47% with a report of preceding GVHD, a strong correlation between NS temporal distance to HCT and to chronic GVHD is found (P = 0, correlation coefficient 0.804). The potential conclusion that NS appears either simultaneously with GVHD or equally distanced from the HCT and the last GVHD event is difficult to explain pathophysiologically. This phenomenon needs to be reevaluated with larger patient numbers to rule out an effect of disparities in physicians’ attention to GVHD findings at the time of NS and an effect of immunosuppression use as a result of various mechanisms of action and interaction. It may be proposed that the different pathogenesis of MGN and MCD plays a role, because the proportion of concomitant GVHD and NS is higher in MGN and the time period from last GVHD to NS has a tendency of being shorter, although without reaching statistical significance. In the combined MGN and MCD group, 56% within 3 mo and 60% within 5 mo exhibited a pattern of temporal association between most recent chronic GVHD diagnosis and NS occurrence.

The time course between cessation or tapering of immunosuppressive medication and onset of NS suggests the former as a risk factor. For joint consideration of tapering and cessation, this phenomenon can be observed in 58% overall within 9 mo after discontinuation of immunosuppression. The percentages increase to 63% in the combined MGN and MCD group and to even 70% in MCD patients, here within 2 mo only. These proportions were calculated with all cases in the denominator, including those with missing values, and therefore may be falsely low; however, the true effect could also be obscured by recall bias, as case report authors may have overattributed NS occurrence to medication changes retrospectively. NS presents earlier after immunosuppression decrease in the case of MCD (median 1 versus 5 mo for MGN; P = 0.03). In two of our four cases, the temporal relationship to NS is also close for both events, with concomitant diagnosis of chronic GVHD and discontinuation of immunosuppression in <1 and 5 mo before, respectively. Some of the references do not describe details about GVHD examinations or medication changes; therefore, a higher percentage of cases than reported may support the associations outlined above. On the basis of these relationships, the interpretation of glomerular disease as the manifestation of renal GVHD is conceivable. This suggests the possibility that NS may occasionally be the only manifestation of chronic GVHD in an HCT patient.

The seemingly good prognosis has to be weighed against the lack of comparable long-term follow-up time, on which the case report authors often do not comment. Whereas only 27 and 62% of the patients with MGN show complete and partial remission, respectively, almost all (90%) patients with MCD achieve complete remission, which likens the excellent prognosis to idiopathic MCD. Successful treatment options include glucocorticosteroids and CsA. Other agents that have been used in the past for GVHD and glomerular disease, respectively, seem to have therapeutic potential as well, such as cyclophosphamide, tacrolimus, mycophenolate mofetil, and rituximab. A total of 56% of cases can be associated with a dosing change of CsA and 36% of a glucocorticosteroid; however, the relation between the two medications is reversed for treatment, as 51% of patients receive CsA and 87% receive steroids. This discrepancy may be explained by the frequent use of CsA as GVHD prophylaxis for several months after HCT and the comfort with which steroids are used for NS treatment. The significance of the incongruity remains intangible as the question continues to be unsettled whether a steroid-CsA combination for extensive GVHD offers survival benefits over steroids alone or just ameliorates steroid side effects (52–54).

A cohort study (43) identified nonmyeloablative HCT as a risk factor for NS, because seven of 163 consecutive patients from 1997 to 2003 developed this complication as opposed to none of 118 patients after myeloablative HCT, with comparable rates of chronic GVHD during the same period. Because the vast majority (>80%) of all cases reviewed here, aside from the mentioned cohort study, were myeloablative (data not shown) and the preparative regimen was not reported in several of the remaining cases, the cohort study’s authors’ claim that reduced intensity conditioning poses a greater risk for NS than myeloablative preparation can neither be supported nor challenged by this analysis. Follow-up of larger cohorts is mandatory to define potential NS risk factors definitively, such as presence or history of GVHD, immunosuppression change, conditioning regimen, and degree of mixed hematopoietic chimerism. An inquiry to the International Bone Marrow Transplant Registry, which collects data on approximately 40% of allogeneic HCT worldwide, yielded no opportunity to study the association between HCT and NS easily on a large-scale epidemiologic level, because the registry does not routinely collect data regarding specific renal complications.

Regarding further evidence for a link between HCT and glomerular disease, a finding of glomerular sclerosis in 73% of patients at autopsy is suggestive in a study of 26 patients (55). The authors’ hypothesis that acute or chronic GVHD is associated with tubulitis could not be corroborated in this study. This fact underscores the lack of tubulitis in the reviewed biopsy specimens, although one separate case report (56) links tubulitis to GVHD after steroid and CsA withdrawal in the absence of glomerular changes. Japanese HCT recipients were evaluated by questionnaires for renal complications (57), which occurred in 51 of 2136 patients. Although the majority of adverse effects was seen within the first 120 d (36 patients), no case of NS was reported then. However, NS was the most common renal abnormality (eight of 15 patients) after 180 d. An association between chronic GVHD and MGN after HCT was also suggested by the preliminary results of a German study (58) in which all patients with glomerular proteinuria >1 g/d 1 yr after HCT underwent biopsy (19 of 580 patients followed), resulting in a diagnosis of MGN in approximately one third of cases (six patients). Other histologic findings were not reported in the abstract, and only patients with proteinuria of >8 g/d were treated with immunosuppression. Therefore, subjecting all patients to biopsies with a sole indication of non–nephrotic-range proteinuria after HCT does not appear clinically warranted. At this time, it seems prudent to follow patients regularly with urine dipsticks to screen for proteinuria after HCT. Referral to a nephrologist is encouraged to determine indications for a kidney biopsy on the basis of all clinical characteristics of the presentation, including a full urine examination.

Clinical features in chronic GVHD, outside the kidney, are comparable to autoimmune diseases (59), such as systemic lupus erythematosus (SLE) and scleroderma. Mice after allogeneic stem cell injection have been studied as an SLE model in the distant past (60). The histologic spectrum of renal disease after HCT, albeit with preference of MGN and MCD and for the most part without significant ANA titers, is reminiscent of the variety of lupus nephritis manifestations. Production of glomerulotoxic cytokines and development of autoantibodies in chronic GVHD (61) could make this disease a lupus-resembling entity. A sole report (31) of cytokine monitoring after HCT revealed an increased production of IFN-{gamma} and TNF-{alpha} but not IL-4 during the ensuing NS. It remains to be proven that renal lesions of GVHD can mimic most or all of the various pathologic findings of autoimmune diseases in the kidney, such as those found in SLE (62), for example MGN; MCD; mesangial immune deposits; focal, diffuse, segmental, or global glomerular lesions and sclerosis; immune aggregates in the tubular basement membrane and in intrarenal vessels; and true vasculitis.

At this time, the pathogenesis of GVHD-related glomerular disease and NS after HCT remains elusive. The most common diagnoses, MGN, MCD, and FSGS, are typical culprits of nephrotic-range proteinuria with glomerular epithelial cells as their target of injury. The existence of a circulating permeability factor secreted by T cells has been postulated for subsets of both MCD (63) and FSGS (64). MGN is also regarded as a primarily podocyte-linked disease (65,66), because it is associated with subepithelial immune deposits of IgG, C3, and the complement membrane attack complex and because it can be induced by antibodies against antigenic targets on podocytes in the murine model of Heyman nephritis (67). Rare histopathologic correlates seen here affect other glomerular compartments and cell types, such as the mesangial space in IgA nephropathy and the endothelium, mesangium, and infiltrating immune cells in diffuse proliferative and crescentic glomerulonephritis. Possible but diverse immune routes of NS pathogenesis after HCT therefore involve T and B cells and, only locally, monocytes and macrophages. Traditionally, HCT has been used to achieve complete eradication of host immune cells; therefore, it may be hypothesized that donor-derived hematopoietic cells can be the origin of all immune-linked glomerular diseases. Recently, mixed chimerism after HCT has been used for certain conditions, and persisting host B and plasma cells have been thought to increase the risk for NS (43), although their contribution to the proposed GVHD aspect of the disease remains undefined.


   Conclusion
Top
 Abstract
 Introduction
 Typical Case Reports
 Discussion
 Analysis of the Literature...
 Conclusion
References
 
Although chronic GVHD has been found in many organ systems, the effect of GVHD on the kidney has not been recognized widely in the past. The reviewed literature supports the existence of the entity of renal GVHD, specified as glomerular lesions with NS clinically. The case reports are unlikely to have accumulated as a result of publication bias, in favor of occurrence of two unrelated rare events, because of the temporal associations of glomerular alterations with GVHD and medication changes outlined above. This type of renal disease is distinct from progression of nephropathy that develops as a result of injury surrounding the HCT process itself. With the increasing use of HCT for malignant and nonmalignant conditions, both nephrologists and oncologists will more frequently recognize NS as a manifestation of GVHD. The pathophysiology of this association is unclear thus far and warrants further investigation. Specifically, the link of GVHD affecting the kidney to renal manifestations of autoimmune disease such as SLE needs to be elucidated.


   Acknowledgments
 
K.B. is the recipient of a National Kidney Foundation Postdoctoral Research Fellowship from July 2005 to June 2007.

Preliminary results of this study were presented in poster format at the American Society of Nephrology Annual Meeting, Philadelphia, PA, November 8 to 13, 2005.

We would like to thank Masahiko Nagahama, MD, Department of Medicine, Pennsylvania Hospital, Philadelphia, and Taku Kambayashi, MD, PhD, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, for translation of references from the Japanese literature. We thank Cooper Hospital (Camden, NJ) for the opportunity to review pathology data and health information for one case. We wish to thank Marta E. Guttenberg, MD, and Pierre A. Russo, MD, Anatomic Pathology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, for the repeat biopsy review of a case.

We apologize to those authors whose works could not be cited because of publication during the review period and restraints on the number of references.


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


   References
Top
 Abstract
 Introduction
 Typical Case Reports
 Discussion
 Analysis of the Literature...
 Conclusion
 References
 

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