EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Patients undergoing hematopoietic stem cell transplant have an elevated incidence of acute renal failure. However, the incidence of nephrotic syndrome due to graft-versus-host disease is growing and is independently associated with chronic renal disease after this procedure.

Materials and Methods: We conducted a prospective study to examine the risk of chronic kidney disease in glomerulopathy patients following hematopoietic stem cell transplant with a follow-up of 10 years.

Results: In our follow-up of 14 patients (4 men and 10 women) who were diagnosed with nephrotic syndrome after hematopoietic stem cell transplant, in 10 patients (71%), biopsy showed membranous nephropathy associated with graft-versus-host disease. The remaining 4 patients had focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, or minimal change disease. All patients were treated with angiotensin receptor blockers, cyclosporine (Neoral), and prednisolone. During follow-up, 6 patients (43%) had heavy proteinuria and a rise in serum creatinine, and 1 patient (7%) needed hemodialysis. Eleven patients (79%) achieved complete remission of nephrotic syndrome, 5 (36%) remained hypertensive, and 3 (21%) did not respond to therapy.

Conclusions: The early diagnosis of nephrotic syndrome should be considered after hematopoietic stem cell transplant, and therapeutic outcome measures should be in place in advance. If this is done, we found that patients’ response to treatment can be optimal, and their renal function and overall survival can improve.

Key words : Acute kidney injury, Bone marrow transplant, Chronic kidney disease, Glomerulopathy, Graft-versus-host disease

Hematopoietic stem cell transplant (HSCT) combined with bone marrow transplant has become the mainstay of therapy for treating various hematologic malignancies. In the 1970s, few patients received this therapy, and their 100-day survival rate was only ≤ 50%.¹ Later on, in the mid-1980s, more than 5000 HSCTs were performed each year, and patients’ survival rate increased by as much as 50%.² However, HSCT therapy can cause major complications. The foremost complication is graft-versus-host disease (GVHD), either acute or chronic.³

Although chronic renal GVHD has affected a significant proportion of patients during the past decade, few case reports have been published about nephrotic syndrome following HSCT combined with bone marrow transplant.^4,5 In addition to GVHD, other causative factors for post-HSCT nephrotic syndrome include the type of transplant (bone marrow transplant vs peripheral blood stem cell transplant), conditioning regimen, human leukocyte antigen mismatch, donor–recipient relationship (related vs unrelated), cytomegalovirus antigenemia, and whether or not the patient received cyclosporine as GVHD prophylaxis. The pathologic manifestations of post-HSCT nephrotic syndrome consist mostly of membranous glomerulonephritis, minimal change disease, membranoproliferative glomerulonephritis, and focal segmental glomerulosclerosis. Even so, few data are available about the occurrence of nephrotic syndrome and its outcomes following HSCT.

Materials and Methods

We conducted a prospective study to examine the risk for developing chronic kidney disease in post-HSCT glomerulopathy patients from 2005 to 2015 at a single center for HSCT in Tehran, Iran. We conducted the study in conformity with the ethical guidelines of the 1975 Helsinki Declaration, and the ethics committee of our center approved the study design. Written informed consent was obtained from all patients.

The following criteria were used for detecting nephrotic syndrome after HSCT: 24-hour urine protein levels > 3.5 g, along with percutaneous renal biopsy showing pathologic changes in the glomeruli. Because the total number of HSCT glomerulopathy patients in our sample were few (14), we included all patients (both allograft and autologous stem cell transplant recipients) who met the above criteria for nephrotic syndrome in our follow-up study. The definition of complete remission was a 24-hour urine protein level < 500 mg/day. For chronic kidney disease, the patient’s serum creatinine level had to remain elevated (≥ 3 mg/dL) for > 3 months, and subnephrotic proteinuria was said to be present in patients whose 24-hour urine protein level was < 3000 mg/day.

At the end of the follow-up, 14 patients (4 men and 10 women) had been diagnosed with nephrotic syndrome; of these, 13 patients (93%) underwent allogeneic HSCT and 1 patient (7%) underwent autologous HSCT. In 10 patients (71%), biopsy findings showed membranous nephropathy associated with GVHD (Figure 1). The remaining 4 patients (29%) developed focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, or minimal change disease, and 1 patient (7%) showed calcineurin inhibitor (cyclosporine) toxicity (Table 1).

The symptoms of glomerular involvement occurred after tapering off the immunosuppressive drugs, in particular, after discontinuing 3 months of calcineurin inhibitor therapy posttransplant. We treated all patients with angiotensin receptor blockers (valsartan 80 mg/d or losartan 50 mg/d), cyclosporine (Neoral) (3-5 mg/kg/d in 2 divided doses), and prednisolone (1 mg/kg/d). Only the 1 patient with cyclosporine toxicity had drug dosages decreased. During follow-up, 6 patients (43%) had heavy proteinuria and a rise in serum creatinine, and 1 patient (7%) required hemodialysis. Eleven patients (79%) achieved complete remission of nephrotic syndrome. Two patients (14%) continued to have subnephrotic proteinuria, 5 patients (36%) remained hypertensive (> 160/90 mm Hg), and 3 patients (21%) did not respond to therapy (Table 2).

Hematopoietic stem cell transplant is the most effective therapy for treating a variety of malignant and nonmalignant diseases; however, it confers its own complications,6 the most important of which is GVHD. Acute kidney injury leading to chronic kidney disease following GVHD are important but rare complications that present as glomerular nephropathies. In one study by Luo and colleagues, nephrotic syndrome was found in 9 patients, mainly in the form of membranous glomerulopathy. In our report of 14 patients, the majority (10 [71%]) developed membranous glomerulonephritis, which occurred 100 days following a dose reduction of immunosuppressive drugs after HSCT therapy. Other renal pathologies, such as minimal change disease, are rare. In 2007, such a case was reported by Silva and associates,⁷ and in the present study, 1 patient developed minimal change disease.

Chanswangphuwana and colleagues reported on several HSCT cases developing membranous glomerulopathy as the most common presentation of GVHD.⁸ In this study, we also found that a majority—10 patients (71%)—developed membranous glomerulopathy. Thus, we can conclude that, after HSCT therapy, the most common pathology within nephrotic syndrome is membranous-type glomerulonephritis. It occurs late in the disease course, on average 3 months after transplant, which is coincident with the tapering off of immunosuppressive drugs. In our study, the complication developed 3 to 8 months posttransplant. In a review of the literature, we could not find any follow-up of such patients; however, in this study the results of 10-year follow-up showed that with timely and individually tailored medical therapy, the kidney-injured patients can regain a high level of renal function (> 90 mL/min/1.73 m²). One limitation of this study was that the total number of cases was too low to subject them to a statistical analysis of renal function and overall patient survival.

The early diagnosis of nephrotic syndrome should be considered after HSCT, and therapeutic outcome measures should be set forth in advance. If this is done, then patients’ response to treatment can be optimal, and their renal function and overall survival can be significantly improved.

Volume: 15 Issue: 1 February 2017 - Supplement - 1

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