Kidney Biopsy Findings Among Allogenic Hematopoietic Stem Cell Transplant Recipients With Kidney Injury: A Case Series.

Plain Language Summary Kidney diseases are frequent after allogeneic hematopoietic cell transplantation (aHCT), but the etiology is often difficult to define because multiple mechanisms may be involved in this population. This case series of kidney biopsies of patients after allogeneic hematopoietic cell transplantation gives a general idea of the different causative factors encountered in this population. Kidney-isolated thrombotic microangiopathy was frequently found and was usually not suspected clinically before the kidney biopsy. The result of the kidney biopsy was generally not in concordant with what was expected by the clinician, suggesting that kidney biopsies are relevant in this population and should be performed more frequently to help tailor treatment of patients.

Allogeneic hematopoietic cell transplantation (aHCT) is the curative treatment of many hematologic and immune disorders. Although many aHCT complications are commonly recognized by physicians, a less-known but still-frequent complication is kidney disease, with up to 36% of patients developing acute kidney injury (AKI) in the first 100 days after transplantation. 1 Chronic kidney disease (CKD) is also frequent, with ∼44% of patients reported as having new-onset CKD after aHCT. 2 Numerous cases of nephrotic syndrome have also been reported after aHCT, which is believed to represent kidney graft-versus-host disease (GVHD). 3 In addition to the typical causes of AKI and CKD, other causative factor, such as medication toxicity, sinusoidal obstruction syndrome, viral nephropathy, and thrombotic microangiopathy (TMA), can be present in this population. Kidney GVHD is also suspected to exist but has not been described as extensively as for other organs.

Considering the wide array of causative factors causing kidney disease in patients who underwent aHCT, native kidney biopsy (NKB) is generally useful to make an accurate diagnosis. However, even with a high incidence of kidney disease after aHCT, NKB is reported to be performed in only 0.5% to 4.3% of the patients. 4 A dozen of case series have been published on kidney biopsy results in patients with nephrotic syndrome after aHCT, but reports of pathologic findings in patients experiencing AKI or CKD remain scarce in the literature. In this article, we report a case series of 17 patients who underwent a NKB after aHCT from various clinical presentations.

Methods

Patient Selection

Among patients who received aHCT from January 1, 2010, to December 31, 2020, at Maisonneuve-Rosemont Hospital, a tertiary care teaching hospital in Montreal, Canada, all those aged 18 years or older with NKB performed after their aHCT were selected. No time limitation was imposed between aHCT and kidney biopsy. The study was approved by our institution’s research ethics committee (No 2021-2633), in agreement with the tenets of the Declaration of Helsinki.

Data Collection

Data were collected by reviewing medical records and included demographics, kidney disease presentation, comorbidities, medications, details regarding aHCT, and pathologic characteristics of the kidney biopsy. All authors had access to primary clinical trial data.

Proteinuria was quantified using a 24-hour urinary collection; if not available, the urinary protein-creatinine ratio was used. The glomerular filtration rate (GFR) was estimated by applying the Chronic Kidney Disease Epidemiology Collaboration formula. 5 AKI was defined as an increase of serum creatinine concentration of ≥0.3 mg/dL within 48 hours or ≥50% in 7 days. 6 CKD was determined as a GFR of ≤60 mL/min/1.73 m 2 on at least 2 measures covering more than 3 consecutive months. 7 Proteinuria of ≥3.5 g/d and serum albumin concentration of ≤3.5 g/dL were used to characterize nephrotic syndrome.

Treatment outcomes for nephrotic syndrome were categorized as complete remission or partial remission. Complete remission was defined as 24-hour proteinuria of ≤0.5 g/d, serum albumin concentration of ≥3.5 g/dL, and stable GFR. Partial remission was defined as 24-hour proteinuria of ≤2.5 g/d or a reduction of ≥50%, serum albumin concentration of ≥3.0 g/dL, and stable GFR.

Pathology

Standard processing of kidney biopsy specimens for light microscopy, immunofluorescence—IgG, IgA, IgM, C3, C1q, fibrinogen, κ, and λ, and electron microscopy was performed. Additional studies, such as immunofluorescence for C4d in cases of TMA, and immunohistochemistry for PLA2R (M-type phospholipase A2 receptor) in cases of membranous nephropathy (MN), were performed. Immunohistochemistry studies for simian virus 40 (SV40), cytomegalovirus, adenovirus, Epstein-Barr virus, herpes simplex virus (HSV)-1, and HSV-2 were performed when relevant.

Review of Literature

A review of literature was performed to identify all case series published in English or French, which included a minimum of 3 adult patients (≥18 years or older) who underwent NKB after aHCT. On March 25, 2022, the following terms were searched on PubMed and Embase: “hematopoietic cell transplant∗ and (((kidney or renal) and (biops∗ or pathology)) or nephrotic syndrome)”. The following MeSH terms were also added on PubMed: “hematopoietic stem cell transplantation”, “kidney/pathology”, “kidney diseases/pathology” and “kidney glomerulus/pathology.” Autopsy specimens were excluded. The articles in which data were not detailed enough to exclude individual patients who were not fulfilling this review’s criteria (eg, autologous stem cell transplant or children) were also excluded.

Results

Patient Characteristics

Of all 879 patients who received aHCT at Maisonneuve-Rosemont Hospital between January 1, 2010, and December 31, 2020, 17 underwent NKB after transplantation (see Tables 1 and 2 for baseline characteristics). All patients showed normal kidney function before aHCT except patient 6 who showed a baseline serum creatinine concentration of 1.45 mg/dL (estimated GFR of 50 mL/min/1.73 m 2 ). The most frequent indications for aHCT were acute myeloid leukemia (5 patients), chronic lymphocytic leukemia (3 patients), and Hodgkin lymphoma (3 patients). A total of 12 patients received peripheral blood hematopoietic cell transplant, 3 received umbilical cord blood transplant, and 2 received bone marrow transplant. Acute and chronic GVHD was diagnosed before kidney biopsy in 10 patients each. Table 1 Patients Demographics and aHCT Characteristics Patient Age at Biopsy, y Sex aHCT Indication aHCT Type Conditioning Regimen GVHD Prophylaxis (Duration if Not Continued as GVHD Treatment a ) aGVHD (site) cGVHD (Site, Moment of Appearance Before NKB) GVHD Treatments Received GVHD Systemic Treatment at Time of NKB 1 28 F AML PBHCT, unrelated Cyclophosphamide, TBI ATG, MMF, tacrolimus Yes (gastro-intestinal, skin) NA Corticosteroids, MMF, tacrolimus Corticosteroids, tacrolimus 2 40 M MDS PBHCT, unrelated Busulfan, cyclophosphamide Methotrexate, tacrolimus Yes (gastro-intestinal) Yes (gastro-intestinal, 10 m) Corticosteroids, MMF, pentostatin, sirolimus, tacrolimus Corticosteroids, MMF 3 57 M NHL PBHCT, related Cyclophosphamide, TBI Cyclosporine, methotrexate Yes (liver, skin) Yes (eyes, mouth and skin, 63 m; serositis, 43 m; arthritis, 21 m) Bortezomib, corticosteroids, cyclosporine, ECP, imatinib, MMF, rituximab, ruxolitinib, sirolimus, tacrolimus Corticosteroids, MMF, ruxolitinib, tacrolimus 4 59 M AML BMT, unrelated Busulfan, cyclophosphamide Methotrexate, tacrolimus (105 d) No No NA NA 5 24 M HL PBHCT, unrelated Fludarabine, TBI MMF (100 d), tacrolimus No Yes (mouth and skin, 17 m) Corticosteroids, sirolimus, tacrolimus Corticosteroids, sirolimus 6 63 M CLL PBHCT, related Fludarabine, melphalan Cyclosporine (170 d), methotrexate Yes (skin) Yes (eyes and skin, 13 m; mouth, 11 m) Corticosteroids, cyclosporine Corticosteroids 7 62 M AML PBHCT, related Fludarabine, busulfan Cyclosporine, methotrexate Yes (gastro-intestinal) Yes (skin and liver, 4 m) Corticosteroids, cyclosporine Corticosteroids, cyclosporine 8 27 M AML BMT, unrelated Busulfan, cyclophosphamide ATG, methotrexate, tacrolimus (120 d) No No NA NA 9 30 F ALL PBHCT, related Fludarabine, thiotepa, TBI ATG, T-cell depletion Yes (skin) No NA NA 10 51 M CLL PBHCT, unrelated Fludarabine, melphalan ATG, methotrexate, tacrolimus Yes (gastro-intestinal [delayed], skin) Yes (skin, 20 m) Corticosteroids, tacrolimus Corticosteroids, tacrolimus 11 54 M ALL UCBT Cyclophosphamide, fludarabine, thiotepa, TBI Cyclosporine (224 d), MMF (35 d) Yes (gastro-intestinal, liver and skin) No Corticosteroids, cyclosporine, MMF NA 12 45 M NHL UCBT Cyclophosphamide, fludarabine, thiotepa, TBI Cyclosporine, MMF (45 d) No No NA NA 13 33 F HL PBHCT, related Fludarabine, melphalan Cyclosporine, methotrexate, MMF No No NA NA 14 51 F HL UCBT Cyclophosphamide, fludarabine, thiotepa, TBI MMF, tacrolimus Yes (gastro-intestinal) Yes (skin, 2 m) Corticosteroids, sirolimus No 15 65 F CLL PBHCT, related Fludarabine, melphalan Cyclosporine (120 d), methotrexate No Yes (skin gastro-intestinal and liver, 7 m) Corticosteroids, cyclosporine, MMF, sirolimus tacrolimus Corticosteroids, MMF 16 51 F CML PBHCT, related Busulfan, cyclophosphamide ATG, cyclosporine, methotrexate, No Yes (serositis, 2 m) Corticosteroids, tacrolimus Corticosteroids 17 44 F AML PBHCT, related Cyclophosphamide, TBI Cyclosporine, methotrexate Yes (skin) Yes (skin and mouth, 8 m), Corticosteroids, MMF, tacrolimus MMF, tacrolimus Abbreviations: aGVHD, acute graft-versus-host disease; aHCT, allogeneic hematopoietic cell transplantation; GVHD, graft-versus-host disease; cGVHD, chronic graft-versus-host disease; NKB, native kidney biopsy; F, female; AML, acute myeloid leukemia; PBHCT, peripheral blood hematopoietic cell transplant; TBI, total body irradiation; ATG, antithyroglobulin antibodies; MMF, mycophenolate mofetil; NA, not applicable; M, male; MDS, myelodysplastic syndrome; NHL, non-Hodgkin’s lymphoma; ECP, extracorporeal photopheresis; BMT, bone marrow transplant; HL, Hodgkin’s lymphoma; ALL, acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; UCBT, umbilical cord blood transplant. a Methotrexate is usually administered as 3 or 4 doses in the first 2 weeks after aHCT and ATG as a single dose, so no duration of treatment was indicated for these drugs. If no duration is written, the drug was continued as GVHD treatment. Table 2 Kidney Disease Presentation and Pathologic Diagnoses Patient Biopsy Indication Serum Creatinine, mg/dL eGFR, mL/min/1.73 m 2 Proteinuria Hematuria, RBC/HPF Biopsy Timing After aHCT, m Main Pathologic Diagnosis 1 Proteinuria 0.57 >120 2.47 g/d >20 3 TMA and ATI 2 CKD 2.59 28 0.55 g/d – 15 TMA and ATI 3 AKI 1.76 42 0.23 g/d – 68 BK nephropathy, TMA, and immune complex nephropathy 4 NS 0.76 100 3.7 g/d – 5 MCD 5 NS 0.84 >120 30.77 g/d 6-10 24 MN and FSGS 6 CKD 1.71 42 NA 3-5 21 TMA 7 NS 0.86 93 3.85 g/d 6-10 18 MN and TMA 8 NS 0.85 119 6.82 g/d >20 25 MN 9 CKD 2.13 30 76 mg/mmol – 15 TMA 10 AKI 9.76 6 Neg (spot) – 33 AIN 11 CKD 2.47 29 64 mg/mmol – 46 TMA 12 AKI 2.05 38 0.88 g/d >20 1 ATI 13 AKI 1.70 39 0.4 g/d 1-2 3 ATI 14 CKD 1.14 55 343 mg/mmol – 14 TMA 15 AKI on CKD 4.22 10 0.55 g/d 3-5 11 TMA 16 AKI 1.96 29 1.19 g/d – 6 ATI and karyomegalic-like interstitial nephritis 17 Proteinuria 1.86 33 3.14 g/d – 15 MN and TMA Abbreviations: eGFR, estimated glomerular filtration rate; RBC, red blood cells; HPF, high power field; aHCT, allogeneic hematopoietic cell transplantation; TMA, thrombotic microangiopathy ATI, acute tubular injury; CKD, chronic kidney disease; AKI, acute kidney injury; NS, nephrotic syndrome; MCD, minimal change disease; MN, membranous nephropathy; FSGS, focal segmental glomerulosclerosis; AIN, acute interstitial nephritis. Laboratory values are the most recent before biopsy or the ones that mandate biopsy.

Indications for kidney biopsy were diverse: AKI in 6 patients, CKD in 5 patients, nephrotic syndrome in 4 patients, and subnephrotic proteinuria in 2 patients. Pathologic findings are summarized in Table 3 . Features of TMA were found in 10 patients, and 5 patients showed acute tubular injury (ATI). Other diagnoses included MN in 4 patients, and single cases of acute interstitial nephritis (AIN), BK virus nephropathy, focal and segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and karyomegalic-like interstitial nephritis. No significant complication (major bleeding, need for blood transfusion or renal artery embolization, prolongation of hospitalization, or biopsy-related visit to the emergency room) resulted from kidney biopsy. Table 3 Pathologic Findings on Kidney Biopsy Main Light Microscopy Findings # GS TA/IF ATI Arteriolo-sclerosis Routine IF C4d PLA2R 1 TMA; glomerular ischemic changes, and glomerular and arteriolar fibrin thrombi 0/18 Mild Yes Moderate Neg Mesangial (1+) NA 2 TMA; glomerular ischemic changes, mesangiolysis, GBM duplication, arteriolar intimal edema, and lamination 2/28 Moderate Yes Severe Neg Linear GBM (1+) Mesangial (1+) Arteriolar (1+) NA 3 BK virus nephropathy (SV40+), TMA; glomerular ischemic changes, mesangiolysis, GBM duplication, immune complexes GN, and segmental scleroses 12/58 Severe Yes Severe Granular GBM and mesangial IgG (1+), C3 (1+), C1q (2+), κ (1+), λ (1+) Granular GBM (1+) Mesangial (1+) NA 4 Normal gloms and FPE 30% 5/25 Mild No Moderate Neg NA NA 5 MN, stage 2 and FSGS, tip variant 3/50 Mild Yes Mild Granular GBM IgG (3+), C3 (2+), C1q (1+), κ (2+), λ (2+) Granular GBM (1+) Neg 6 TMA; glomerular ischemic changes, mesangiolysis, and GBM duplication 2/22 Moderate Yes Severe Neg Mesangial (1+) Arteriolar (1+) NA 7 MN, stage 2, TMA; ischemic changes, glomerular fibrin thrombi, mesangiolysis, and GBM duplication 0/15 Mild No Mild Granular GBM IgG (3+), C3 (+), κ (2+), λ (3+) Granular GBM (1+) Neg 8 MN, stage 2 and FSGS NOS 0/14 Mild No None Granular GBM IgG (3+), C3 (1+), κ (2+), λ (2+) NA Neg 9 TMA; mesangiolysis, GBM duplication, mesangial expansion and hypercellularity 2/24 Mild No Moderate Neg Mesangial (1+) Arteriolar (1+) NA 10 AIN; moderate interstitial infiltrate, edema, and tubulitis 4/33 Mild Yes Moderate Neg NA NA 11 TMA; mesangiolysis, fragmented RBC, GBM duplication, mesangial expansion and hypercellularity 18/35 Moderate No Moderate Neg Mesangial (1+) Arteriolar (1+) NA 12 ATI 1/11 Mild Yes None Neg NA NA 13 ATI with proximal epithelial cell isometric vacuolizations 0/38 Mild Yes Mild Neg NA NA 14 TMA; mesangiolysis, GBM duplication 1/10 Moderate No Mild Neg Mesangial (1+) NA 15 TMA; mesangiolysis, fragmented RBC, GBM duplication, segmental scleroses, arteriolar intimal edema 3/10 Moderate No Severe Neg Mesangial (1+) Arteriolar (1+) NA 16 ATI with features of karyomegalic-like interstitial nephritis 4/57 Mild Yes Mild Neg NA NA 17 MN, stage 2, TMA; glomerular ischemic changes, mesangiolysis, GBM duplication, and arteriolar fibrin thrombi 1/22 Moderate Yes Mild Granular GBM IgG (3+), κ (1+), λ (2+) Granular GBM (1+) Arteriolar (1+) Neg Abbreviations: GS, global sclerosis; TA/IF, tubular atrophy/interstitial fibrosis; ATI, acute tubular injury; IF, immunofluorescence; TMA, thrombotic microangiopathy; Neg, negative; NA, non-applicable; GBM, glomerular basement membrane; GN, glomerulonephritis; FPE, foot process effacement; MN, membranous nephropathy; FSGS, focal segmental glomerulosclerosis; NOS, not otherwise specified; RBC, red blood cell; AIN, acute interstitial nephritis; Immunofluorescence are described, if positive, on a scale from 1 to 3, 3 being the most intense capture.

Chronic Kidney Disease

Among the 5 patients who underwent biopsy because of CKD [median time between aHCT and kidney biopsy of 15 months (range, 14-46 months)], all showed histologic features suggestive of TMA ( Fig 1 ). Among the patients treated with glucocorticoids or rituximab, none improved their kidney function after treatment. Patient 14 showed a reduction in proteinuria after rituximab, but her serum creatinine concentration remained unchanged. Figure 1 Kidney biopsy findings in patient 9 with thrombotic microangiopathy. (A) On light microscopy, glomeruli show mesangiolysis (white arrows) (periodic acid-Schiff). Original magnification, ×200. (B) At higher magnification, mesangiolysis (asterisks) and duplication of the glomerular basement membrane is present (arrow heads) (Jones silver stain). Original magnification, ×600. (C) On electron microscopy, there is subendothelial space expansion by electron-lucent material (star), with segmental neo-membrane formation (black arrow). Original magnification, ×10,000.

Acute Kidney Injury

Six patients underwent kidney biopsy for AKI, with a median time of 9 months (range, 1-68 months) between their aHCT and kidney biopsy.

The period after aHCT for patient 3 was marked with severe GVHD, unresponsive to multiple therapies, and repeated hospitalizations. More than 5 years after his aHCT, his serum creatinine concentration increased to 2.05 mg/dL. Kidney biopsy showed BK virus nephropathy, TMA, and immune complex nephropathy ( Fig 2 ). The immunosuppressive regimen was reduced. However, the GVHD relapsed and resulted in the patient’s death a few weeks later. Figure 2 Kidney biopsy findings in patient 3 with BK virus nephritis. (A) Light microscopy shows ground glass intranuclear inclusions in tubular epithelial cells (arrows) (periodic acid-Schiff). Original magnification, ×600. (B) Immunohistochemistry study using antibody for simian virus 40 reveals strong nuclear staining in tubular epithelial cells and parietal epithelial cells. Original magnification, ×200.

Patient 10 visited the emergency department ∼3 years after his aHCT because of fatigue and myalgia. A medical history was relevant for nonsteroidal anti-inflammatory drug (NSAID) use the week before. On arrival, his serum creatinine concentration was 9.76 mg/dL, without indication for acute dialysis. On the basis of a presumptive diagnosis of NSAID-induced AIN, glucocorticoids were initiated, and kidney function improved rapidly. A kidney biopsy was performed and confirmed the diagnosis of AIN. In addition, he showed BK viremia with a viral load of 1120 copies/mL, but no viral inclusions were noted on light microscopy and immunohistochemistry study for SV40 showed negative results on kidney biopsy. Glucocorticoids were progressively tapered, and at follow-up 3 months later, the creatinine level reduced to 1.13 mg/dL.

Patient 12 developed AKI and hemorrhagic cystitis with BK and adenovirus viremia and viruria. Considering a persistent fever, he was started on cidofovir and probenecid with intensive intravenous hydration. However, the AKI progressed despite cidofovir treatment. A kidney biopsy demonstrated ATI without viral inclusions (with negative results for SV40 immunohistochemistry). Cidofovir was subsequently stopped, and his serum creatinine level reduced to the baseline value over the next year.

Patient 13 showed a rapid increase in serum creatinine levels 3 months after aHCT, reaching a serum creatinine concentration of 2.17 mg/dL. In the absence of GVHD, calcineurin inhibitor (CNI) was stopped. Given the lack of an obvious AKI etiology, biopsy was requested, which showed ATI with features suggestive of CNI toxicity. Her serum creatinine level subsequently improved but never reached her pretransplantation level, with the last recorded value being 1.35 mg/dL 6 months after AKI (compared with a previous baseline value of 0.79 mg/dL).

Patient 15 developed CKD after aHCT but did not undergo biopsy at that time. Her new baseline creatinine level was ∼1.58 mg/dL. However, 12 months after transplantation, her serum creatinine concentration increased suddenly up to 4.22 mg/dL, with a proteinuria of 0.55 g/d. Moreover, kidney biopsy showed features of TMA. She was treated with glucocorticoids, mycophenolate mofetil (MMF), and eculizumab. She responded partially to this therapy with her last serum creatinine concentration being 2.40 mg/dL.

Patient 16 underwent a peripheral blood–related aHCT to treat chronic myeloid leukemia refractory to tyrosine kinase inhibitors. She received a myeloablative regimen with busulfan and cyclophosphamide. Her clinical course after aHCT was notable for several AKI episodes: the first one in the context of a sinusoidal obstruction syndrome, and another one presumed to be secondary to foscarnet prescribed for human HSV 6 viremia. Given hemorrhagic cystitis with confirmed BK viruria, a treatment of intravesical cidofovir was initiated. A third AKI episode developed concomitantly to intravesical cidofovir therapy with de novo hyperchloremic metabolic acidosis, hypouricemia, and glucosuria without frank hypokalemia or hypophosphatemia. She was diagnosed with tubular acidosis and started on sodium bicarbonate. She was discharged with a serum creatinine concentration of 1.57 mg/dL. Her serum creatinine level continued to increase (up to 1.96 mg/dL), which mandated the kidney biopsy 6 months after her aHCT.

Kidney biopsy consisted of 2 cores of kidney tissue containing 57 glomeruli, of which 5 were globally sclerotic. Glomeruli were unremarkable. Diffuse ATI was observed, with epithelial thinning, loss of brush border, and epithelial sloughing. Tubular epithelial cells showed marked karyomegaly, characterized by hyperchromatic and increased-sized nuclei showing highly irregular nuclear contours ( Fig 3 ). These nuclear changes were found throughout the nephron, predominating in the proximal tubule. No viral inclusions were noted. Interstitial fibrosis was mild, covering <25% of cortical surface, with mild mononuclear interstitial inflammation, interstitial edema, and few tubulitis lesions. There was mild atherosclerosis and arteriolosclerosis. Immunohistochemistry studies for SV40, cytomegalovirus, adenovirus, Epstein-Barr virus, HSV-1, and HSV-2 showed negative results. Routine immunofluorescence also showed negative results. Electronic microscopy showed enlarged tubular epithelial cells nuclei with convoluted nuclear membranes. A diagnosis of ATI with features of karyomegalic-like interstitial nephritis was made. Figure 3 Kidney biopsy findings in patient 16 with acute tubular injury with features of karyomegalic-like interstitial nephritis. (A) Light microscopy shows diffuse acute tubular injury with mild tubular atrophy and interstitial fibrosis (periodic acid-Schiff). Original magnification, ×100. (B) Epithelial thinning, loss of brush border is seen with marked karyomegaly, predominating in proximal tubular epithelial cells (periodic acid-Schiff). Original magnification, ×200. (C) Nuclei are hyperchromatic and increased-sized with highly irregular nuclear contours (arrowhead) (periodic acid-Schiff). Original magnification, ×1,000. (D) Electronic microscopy shows enlarged tubular epithelial cells nuclei with convoluted nuclear membranes. Original magnification, ×5,000.

The patient began a standard-of-care kidney protection therapy with angiotensin-converting enzyme inhibitors. Her serum creatinine level progressively improved, and the angiotensin-converting enzyme inhibitor was ceased because of low blood pressure. Her serum creatinine concentration has remained stable at 1.64 mg/dL on the last follow-up, 22 months after the diagnosis of AKI.

Nephrotic Syndrome and Proteinuria

A total of 4 patients underwent biopsy because of nephrotic syndrome, and 2 reported significant (nonnephrotic) proteinuria; the median time between transplantation and kidney biopsy being of 17 months (range, 3-25 months). Most of them (n=4) was diagnosed with MN ( Fig 4 ), 1 with MCD, and 1 with ATI. Two patients showed concomitant features of TMA. Figure 4 Kidney biopsy findings in patient 8 with membranous nephropathy. (A) On light microscopy, glomerular capillary walls are minimally thickened with subepithelial spikes formation (white arrow) and vacuolated appearance (arrowhead) (Jones silver stain). Original magnification, ×600. (B) Immunofluorescence reveals diffuse granular staining along the glomerular basement membrane for IgG. Original magnification, ×400. (C) On electron microscopy, there are diffuse subepithelial immune-type deposits with diffuse foot process effacement. Original magnification, ×10,000. (D) Immunohistochemistry study for PLA2R is negative. Original magnification, ×400.

Patient 1 did not receive any treatment for her proteinuria because her acute myeloid leukemia relapsed a few weeks after biopsy, and she died 3 months later of neutropenic pneumonia. Of the remaining 5 patients, all but patient 17 were treated with glucocorticoids and CNIs, and patients 4 and 5 also received MMF. Patient 17 was treated with MMF and rituximab and achieved partial remission, with her last 24-hour proteinuria being 0.57 g/d. The remainder of patients reached complete remission. Proteinuria in patient 7 relapsed twice but achieved complete remission with repeated glucocorticoid therapy.

Serum anti-PLA2R antibody was measured in patients 5 and 17 and showed negative results. Immunohistochemistry studies for PLA2R performed on the kidney biopsies with MN showed negative results.

Review of literature

The initial search on PubMed and Embase identified 1,744 articles. Title and abstract of these articles were reviewed, resulting in 49 of them being selected for a more comprehensive analysis. Of these, 9 were excluded because of duplication. Eighteen articles were rejected for not meeting our criteria. Finally, 22 articles were selected. A total of 143 patients were included in this review. A summary of each article is presented in Table 4 . 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 Table 4 Case Series of Kidney Biopsies After aHCT in the Literature Reference Country N aHCT Indication aHCT Type cGVHD Biopsy Indication Biopsy Median Time After aHCT [Max-Min] Pathologic Diagnosis Stevenson et al, 8 (2005) Australia 3 2 AML 1 CML 3 PBHCT 3/3 3 NS 21 [18-24] 2 MN 1 MCD Srinivasan et al, 9 (2005) United States 4 3 Nonhematologic causes 1 AML NA 4/4 4 NS 19 [10-40] 4 MN Colombo et al, 10 (2006) Italy 5 2 AML 2 MDS 1 ALL 4 PBHCT 1 UCBT 5/5 5 NS 17 [13-56] 4 MN 1 MCD Reddy et al, 11 (2006) United States 6 2 MM 2 MDS 1 CLL 1 ET 6 PBHCT 5/6 6 NS NA 5 MN 1 MCD Chang et al, 12 (2007) United States 11 5 AML 4 MM 1 HL 1 NHL NA 10/11 5 AKI 5 NS 1 Proteinuria 12 [1-45] 3 MCD 2 TMA 2 MN 2 PVN 1 ATI 1 FSGS Kemper et al, 13 (2007) Switzerland 3 2 AML 1 ALL 2 BMT 1 PBHCT 3/3 3 NS 20 [14-21] 2 MN 1 MPGN type 1 Terrier et al, 14 (2007) France 5 2 NHL 1 AML 1 CLL 1 MDS NA 5/5 5 NS 21 [14-37] 5 MN Chan et al 15 (2008) China 9 4 CML 2 ALL 1 AML 1 MDS 1 MM NA 7/9 3 NS 3 CKD 3 AKI 34 [1-134] 3 MN 2 TMA 1 IgAN 1 Hypertensive nephrosclerosis 1 ATI 1 MCD Troxell et al, 16 (2008) United States 9 4 AML 2 CML 1 NHL 1 MM 1 N/A 6 PBHCT 2 BMT 1 NA 8/9 NA 30 [9-174] 5 MN 1 FSGS 2 ATI and tubulo-interstitial nephritis 1 TMA and CNI-related toxicity Huang et al, 17 (2012) China 5 2 AML 2 CML 1 ALL NA 5/5 5 NS 19 [10-23] 5 MN Cho et al, 18 (2013) South Korea 15 6 ALL 5 AML 2 CML 1 AA 1 MDS 11 BMT 4 PBHCT 15/15 9 NS 6 Proteinuria 24 [8-144] 12 MN 1 MPGN type 1 1 DN 1 C1q nephropathy Fraile et al, 19 (2013) Spain 6 3 AML 1 CML 1 CLL 1 NHL 6 PBHCT 5/6 6 NS 32 [17-45] 4 MN 1 FSGS 1 LN class III Byrne-Dugan et al, 20 (2014) United States 4 2 AML 1 ALL 1 MDS 4 PBHCT 2/4 NA 20 [15-60] 4 MN Chanswangphuwana et al, 21 (2014) Thailand 3 1 AA 1 CML 1 HL 3 PBHCT 2/3 3 NS 22 [19-24] 2 MN 1 mix of MN, MPGN and LN class III and V Dhakal et al, 22 (2015) United States 9 5 AML 2 CLL 1 MM 1 NHL 9 PBHCT 7/9 9 proteinuria 6 [11-84] 4 MN 2 Tubulitis 2 FSGS 1 MCD Brinkerhoff et al, 23 (2016) United States 8 3 AML 2 MDS 1 AA 1 ALL 1 NHL 4 BMT 2 PBHCT 2 UCBT 8/8 NA 27 [10-252] 3 TMA 2 MCD 1 FSGS 1 FSGS + DN 1 Anti-GBM nephropathy Hiramatsu et al, 24 (2016) Japan 5 3 NHL 1 MDS 1 ALL 5 UCBT 5/5 5 NS 18 [9-40] 4 MN 1 MPGN type 1 Wong et al, 25 2016 Australia 4 2 AML 1 ALL 1 NHL NA 4/4 4 NS 17 [8-36] 3 MN 1 MCD Girsberger et al, 4 (2018) Germany 12 3 MM 2 ALL 2 AA 1 ALL 1 CLL 1 CML 1 HL 1 nonhematologic cause NA 8/12 NA 20 [1-103] 4 TMA 3 MN 2 CNI-related toxicity 1 AIN 1 ATI 1 isolated IFTA Mii et al, 26 (2018) Japan 4 1 AA 1 AML 1 MDS 1 NHL 1 BMT 3 UCBT 2/4 4 CKD 6 [4-36] 4 TMA Lee et al, 27 (2019) United States 8 3 AML 1 CML 1 HLH 1 MDS 1 NHL 5 PBHCT 2 UCBT 1 BMT NA NA NA 5 PVN 3 PVN and TMA 1 PVN and MN Nasr et al, 28 (2021) United States 5 4 AML 1 ALL 3 PBHCT 1 BMT 1 NA 5/5 3 NS 2 NS + AKI 36 [19-41] 2 MN + TMA + ATI + AIN 2 MN + ATI + AIN 1 MN + TMA Abbreviations: AA, aplastic anemia; AKI, acute kidney injury; AIN, acute interstitial nephritis; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; ATI, acute tubular injury; BMT, bone marrow transplant; cGVHD, chronic graft-versus-host disease; CKD, chronic kidney disease; CLL, chronic lymphocytic leukemia; CML, chronic myelocytic leukemia; CNI, calcineurin inhibitor; DN, diabetic nephropathy; ET, essential thrombocytosis; FSGS, focal segmental glomerulosclerosis; HCT, hematopoietic cell transplant; LN, lupus nephritis; HL, Hodgkin lymphoma; HLH, hemophagocytic lymphohistiocytosis; IFTA, interstitial fibrosis with tubular atrophy; IgAN, IgA nephropathy; MCD, minimal change disease; MDS, myelodysplastic syndrome; MM, multiple myeloma; MN, membranous nephropathy; MPGN, membranoproliferative glomerulonephritis; NA, not available; NHL, non-Hodgkin lymphoma; NS, nephrotic syndrome; PBHCT, peripheral blood hematopoietic cell transplant; PVN, polyomavirus nephropathy; TMA, thrombotic microangiopathy; UCBT, umbilical cord blood transplant.

Discussion

We report a group of 17 patients who underwent NKB after aHCT given the presence of CKD, AKI, nephrotic syndrome, or significant subnephrotic proteinuria. Pathologic findings in patients with CKD were notable for TMA in all patients. Patients experiencing AKI showed more heterogeneous presentations on kidney biopsy: 4 presented with ATI and 2 with TMA, whereas AIN and BK virus nephropathy were noted in 1 patient each. All but 1 patient with nephrotic syndrome were diagnosed with MN. We are also reporting, to our knowledge, the first case of karyomegalic-like interstitial nephritis causing AKI after aHCT.

It is of interest to note that TMA was a common diagnosis in our series and was present in all biopsy indication groups. For most patients with TMA, this diagnosis was not suspected by physicians before kidney biopsy. There are no universally accepted clinical criteria for diagnosis of transplant-associated TMA, but Cho et al 29 validated some criteria based on 2 diagnostic guidelines. Young et al 30 proposed in 2021 criteria based on a review of all those published previously. When evaluating the 10 patients with kidney biopsy-proven TMA using these criteria retrospectively ( Table 5 ), none showed the necessary elements for a clinical diagnosis of TMA, mainly because schistocytes were absent, haptoglobin level was normal for all but 2 patients, and no new-onset or significant worsening of hypertension was noted. These results are similar to those described in a previous study showing a mismatch between blood test results and pathologic kidney findings of transplant-associated TMA at autopsy, 31 suggesting that the present criteria are not sensitive enough to detect kidney-isolated TMA. Most patients presented with histologic features of chronic TMA, although 5 cases showed features of acute TMA, such as glomerular and arteriolar fibrin thrombi. It is important to recognize and treat patients with posttransplant TMA early because their mortality rate is significantly higher than those without TMA, even more so in the presence of proteinuria. 32 Of note, total body irradiation (TBI) tended to increase the risk of TMA in previous studies 33 ; this trend seems to be present in our cohort because 6 of the 8 patients who received TBI showed TMA compared with only 4 of the 9 in those who did not receive TBI. CNIs and mTOR inhibitors are also recognized as a cause of TMA. 34 Table 5 Presence of Clinical Criteria for Diagnosis of Transplant-Associated TMA in Patients With NKB-Proven TMA Patients 1 a 2 3 6 7 9 11 14 15 17 ≥2 Schistocytes/HPF No No No No No No No No No No LDH >210 U/L Yes Yes Yes No No Yes No Yes Yes Yes Platelets <50 × 10 9 /L or decrease ≥50% Yes No Yes No No Yes No No Yes No Hemoglobin <13.4 g/dL for men or <11.8 g/dL for women Yes Yes b Yes No No Yes b Yes b Yes b Yes b Yes Haptoglobin <0.14 g/L Yes No No NA NA No No Yes No No Note: Values for increased LDH, and decreased hemoglobin and haptoglobin (>210 U/L) are based on the lower limit of normal established by our laboratory. Abbreviations: TMA, thrombotic microangiopathy; NKB, native kidney biopsy; HPF, high-field power; LDH, lactate dehydrogenase; NA, not available. a Patient 1 relapsed of her leukemia a few weeks after NKB, rendering it difficult to know if these lab values were attributable to TMA or leukemia. b Value never returned to normal after aHCT.

Although no formal criteria have been established for defining kidney GVHD, a growing body of evidence suggests that GVHD might also be associated with intrarenal TMA. 31 Numerous studies found a strong relation between previous GVHD and TMA. 31 , 35 , 36 All our 10 patients with TMA also showed a diagnosis of extrarenal acute or chronic GVHD before kidney biopsy, supporting the fact that TMA may represent a kidney expression of GVHD. Patient 3 also showed features of immune complex nephropathy on his kidney biopsy, which could also be a feature suggesting humoral GVHD. C4d deposition has been described as a possible sign of GVHD in skin and colon biopsies 37 and is used in the Banff classification describing kidney transplant rejection. 38 A few studies showed C4d implication with TMA on kidney biopsy, with 1 pediatric study showing arteriolar C4d deposition in hematopoietic stem cell transplantation (autologous and allogeneic) regardless of GVHD, 39 and 1 on adult patients with arteriolar C4d deposition associated with CD3 + T cells infiltration suggestive of GVHD. 40 In our population, no link can be established between C4d deposition pattern and GVHD. Endothelial cells have been shown to be a target of alloreactive T lymphocytes in patients with chronic GVHD. 41 Because endothelial damage is a key step in the pathophysiology of TMA, this might be a plausible biologic explanation linking GVHD and TMA. All these elements tend to suggest that TMA might be a demonstration of kidney GVHD, although a lot of other elements are also demonstrated to trigger TMA in this population.

BK nephropathy is another common cause of kidney disease after kidney transplantation but seems to be less frequent in the aHCT population, in which it causes mainly hemorrhagic cystitis believed to be triggered by the myeloablative regimen’s side effects on the urothelial endothelium. 42 A high BK viral load in serum and urine with the presence of BK-associated hemorrhagic cystitis can be seen without evidence of associated nephropathy. Cidofovir, an antiviral drug, has shown positive results in polyomavirus-induced diseases in some case reports of aHCT patients, 43 , 44 but no randomized controlled trial has demonstrated a significant benefit. In patients with BK viremia treated with cidofovir, identifying the cause of AKI without a kidney biopsy is challenging because cidofovir may frequently cause severe kidney injury.

One patient with AKI showed evidence of AIN, probably secondary to NSAIDs. No biopsy-proven AIN has been described in the aHCT population to our knowledge. Drug-induced AIN has been described as an immune disease, associated with infiltration of T lymphocytes and macrophages in the kidney in response to drug exposure. 45 In our case, the patient had complete donor chimerism before his AIN episode, meaning that the immune phenomenon must have been of allogeneic nature, therefore reflecting a possible form of drug-induced GVHD.

Brukamp et al 3 showed that 61% of the nephrotic syndrome cases after aHCT were caused by MN whereas MCD was responsible for 22% of the cases. In our 4 patients who presented with nephrotic syndrome, this proportion was respected (3 with MN and 1 with MCD). One other patient showed MN without a complete nephrotic syndrome. Given the current published evidence (based on case reports and series), nephrotic syndrome in the aHCT population seems to represent a manifestation of GVHD; nephrotic syndrome typically emerges in those who had GVHD and is temporally linked to immunosuppressive therapy cessation or dosage reduction. 3 , 20 All our MN biopsies showed negative results for PLA2R. These results are not surprising considering previous data showing that anti-PLA2R antibodies are rarely positive in this population 17 and the recent discovery of protocatherin FAT1 as a possible antigen for MN in patients who underwent aHCT. 46 Although glucocorticoids alone are generally not efficient in primary MN, the response was excellent in our aHCT population (with 3 patients reaching complete remission), supporting the fact that MN might be secondary to GVHD.

Patient 16 seems to be the first described case of karyomegalic-like interstitial nephritis causing AKI in a post-aHCT individual. Karyomegalic interstitial nephritis is a rare genetic disease with progressive CKD and often associated with respiratory symptoms. 47 We identified 2 possible causative factors that may be related to her clinicopathologic presentation: cidofovir toxicity and cyclophosphamide-induced AKI. Two cases of AKI after topical administration of cidofovir have been published 48 but none after intravesical administration. In our case, intravesical cidofovir was given 3 days before serum creatinine level started to increase. A combination of AKI and Fanconi syndrome associated with cidofovir has also been described. 49 However, cidofovir nephropathy is usually characterized by ATI on kidney biopsy. On contrary, many cases of AKI and Fanconi syndrome with ifosfamide, an alkylating agent similar to cyclophosphamide, have been described in the recent literature. 50 , 51 , 52 Pathologic findings found in ifosfamide-induced AKI have been described as karyomegalic-like interstitial nephropathy in 2 case reports. 53 , 54 In our patient, although the chronology of AKI and Fanconi syndrome favors more cidofovir as a potential culprit, the pathologic appearance of the kidney injury compares with those described after the administration of an alkylating agent such as ifosfamide.

A dozen of case series of NKB after aHCT have been published. Most published series describe patients with a specific clinical presentation (mainly nephrotic syndrome) or a specific pathology, rendering it difficult to generalize these findings to the whole population of patients who underwent aHCT. Thus, this present series is one among the few that comprise NKBs performed for diverse indications. This case series also presents the largest number of adult aHCT patients with NKB ever published.

The main limitation of this study is the low number of patients, making it difficult to generalize the results to the entire aHCT population, although with the cases being divided in 3 main clinical presentations (AKI, CKD, and nephrotic syndrome and proteinuria). Moreover, kidney biopsy was performed only in a small sample of patients; when looking at partial data from an ongoing study at our institution, between January 1, 2010, and November 15, 2015, AKI was diagnosed in the first 100 days after aHCT in 78 patients and none of them underwent kidney biopsy at that time. This suggests that kidney biopsy is rarely performed in the first 100 days after aHCT, although AKI is relatively frequent.

In conclusion, we present a case series of 17 patients who underwent NKB after aHCT. The causative factors of kidney impairment after aHCT differ from the general population in our series, with a higher incidence of TMA. It seems reasonable to perform kidney biopsy in all patients who underwent aHCT and present with unexplained AKI not resolving with standard care, new-onset CKD, or significant proteinuria. New criteria for kidney-isolated TMA also seem necessary because the current criteria were unable to predict the pathologic findings, resulting in irreversible CKD in some of our patients. Considering the significant effect of CKD on mortality and quality of life, it is quite important to aggressively investigate patients with kidney disease to avoid complicating the already complex post-aHCT follow-up with a treatable pathology. Nonetheless, whether the benefits of performing kidney biopsy more systematically would outweigh the risks in the aHCT population remains to be demonstrated by further studies.

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Article Information

Authors’ Full Names and Academic Degrees

Guillaume Roy, MD, Ilinca Iordachescu, Virginie Royal, MD, Caroline Lamarche, MD, MSc, Imran Ahmad, MD, MSc, Annie-Claire Nadeau-Fredette, MD, MSc, and Louis-Philippe Laurin, MD, MSc

Authors’ Contributions

Study conception and design : L-PL, CL and IA; data acquisition: GR and II; clinical data analysis/interpretation: GR, II, IA, CL, A-CN-F and L-PL; pathologic data analysis/interpretation: VR; supervision: IA and L-PL. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated, and resolved, including with documentation in the literature if appropriate.

Support

A-CN-F and CL are Fonds de recherche du Québec-Santé Junior 1 Scholars. L-PL is a Fonds de recherche du Québec-Santé Junior 2 Scholar.

Financial Disclosure

The authors declare that they have no relevant financial interests.

Data Sharing

For access to original clinical deidentified data, please contact louis-philippe.laurin@umontreal.ca .

Peer Review

Received October 21, 2022. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form April 1, 2023.

Complete author and article information provided before references.