EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Kidney transplant recipients are more likely to develop posttransplant renal cell carcinoma than the general population. Symptoms of renal cell carcinoma are often nonspecific, such as nausea, vomiting, and weight loss, and tend to occur syndrome caused by the release of peptides and hormones by the cancer itself. However, there have been rare case reports of postoperative paraneoplastic glomerulopathy associated with renal cell carcinoma in kidney transplant recipients. Here, we report the case of a 54-year-old male who presented with subnephrotic range proteinuria with a urine protein-to-creatinine ratio of 1.0 within 1 year after a deceased donor kidney transplant without kidney function decline. The transplant team decided to perform a biopsy of the transplanted kidney, and the ultrasonography before intervention revealed a right-side native renal mass. The result of the kidney biopsy revealed focal segmental glomerulosclerosis. At the same time, computed tomography was done to find the cause of the renal mass, and we found that the right native kidney mass had features highly suspicious for renal cell carcinoma. The urologist subsequently performed a right radical nephrectomy. The pathology diagnosis of the kidney mass was renal cell carcinoma. After the cancer had been eliminated, clinical impro-vement of proteinuria was achieved. Hence, we diagnosed a rare secondary focal segmental glomeru-losclerosis from renal cell carcinoma (paraneoplastic glomerulopathy) about which, to our knowledge, there are no previous reports. To date, there is no consensus recommendation for screening postoperative renal cell carcinoma in organ transplant recipients. The potential postoperative diagnosis of paraneoplastic glomerulopathy-associated renal cell carcinoma in kidney transplant recipients must be recognized.

Key words : Focal segmental glomerulosclerosis, Renal cell carcinoma, Renal transplantation

Postoperative proteinuria occurs in 35% to 45% of kidney transplant patients in the first year after kidney transplant.¹ This condition is associated with a poor prognosis for graft and patient survival after kidney transplant.¹ There are various causes of proteinuria such as residual proteinuria from the native kidney, glomerular disease of the kidney graft, graft rejection, interstitial fibrosis and tubular atrophy of the graft, and side effects from immunosuppressants.¹ A detailed record of patient history and standard physical and laboratory examinations are necessary to determine the possible cause of each presentation.

Primary focal segmental glomerulosclerosis (FSGS) is the most common cause of end-stage renal disease (ESRD) among adults with primary glomerular syndrome.² The diagnosis should be confirmed with a biopsy of kidney tissue. The distinct types of FSGS include primary/idiopathic FSGS, genetic/familial FSGS, drug-induced FSGS, viral-induced FSGS, and adaptive FSGS. The pathologic mechanism of primary FSGS is unknown but appears to be caused by circulating permeability factors that attack the podocytes and result in FSGS lesions.³

Postoperative FSGS in kidney transplant recipients can be attributed to several causes, including recurrent primary disease, de novo FSGS of the graft, drug-associated FSGS from immunosuppressive regimen, or infection-associated FSGS and other secondary FSGS. Therefore, the diagnosis of FSGS should be based on clinical suspicion concomitant with clinicopathology, and a correct diagnosis is crucial to determine the specific and appropriate treatment for each FSGS variant.⁴ However, postoperative FSGS in kidney transplant recipients that presents as paraneoplastic glomerulopathy is rare, and so accurate diagnosis of this disease remains difficult and challenging. Written informed consent was obtained from the patient for publication.

A 54-year-old male Thai patient with ESRD of unknown cause presented with comorbidities of hypertension and dyslipidemia that had been successfully managed for 5 years with a calcium channel blocker and simvastatin. He had been receiving hemodialysis since 2017 and decided to register for a deceased donor kidney transplant 1 year after starting dialysis. A preoperative kidney transplant assessment was performed, and no abnormalities were found. He denied a history of cancer in his family, and he was screened for cancer prior to kidney transplant by esophagogastroduodeno-scopy, colo-noscopy, prostate-specific antigen screening, and abdominal ultrasonography examination. All test results were within the reference ranges.

In September 2020, he received a kidney transplant from a deceased donor. The donor was a 53-year-old Thai male patient with no underlying medical conditions and a preoperative creatinine level of 0.6 mg/dL. The human leukocyte antigen (HLA) typing showed 2 mismatches at HLA-A and HLA-DR. The recipient’s panel reactive antibody screen was 0%, and the crossmatch result was negative. He received an induction regimen with basiliximab and immunosuppressive maintenance therapy with cyclosporine 150 mg twice per day, mycophenolate mofetil 1500 mg once per day, and prednisolone tapered to 5 mg each day. The patient had immediate graft function after the operation and had no postoperative complications. His serum creatinine was stable at 106 μmol/L. Urinalysis found no proteinuria and no cells or casts.

Six months after kidney transplant, the patient had mild bilateral leg edema and complained of progressively foamy urine. Physical examination showed blood pressure of 158/80 mm Hg. His pulse rate was 86 beats/min, and his body temperature was 37.2 °C. The conjunctiva revealed no pale and anicteric sclera. He had no lymphadenopathy. The heart and lungs were otherwise normal. Abdominal examination showed no mass or any tenderness. There was bilateral pitting edema on both legs. Other observations were unremarkable.

The patient’s complete blood count showed hemoglobin of 13.5 g/dL with a white blood cell count of 4.3 × 10³ cells/L and a platelet count of 237 × 10³ platelets/L. Prothrombin and activated prothrombin time were found to be within reference limits during coagulation testing. His serum creatinine was 108 μmol/L with an esti-mated glomerular filtration rate of 74.68 mL/min/1.73 m². The cyclosporine trough level was 97.8 ng/mL. The urinalysis with a urine dipstick test showed proteinuria >2. Light microscopy examination showed no cells or casts. The 24-hour urine protein level was 1.05 g. The liver function test results were within reference ranges, including albumin level (4.1 g/dL). The virology test results for serum cytomegalovirus and serum BK virus were negative.

Our transplant team decided to perform a kidney graft biopsy to find the cause of new-onset proteinuria. Renal ultrasonography was performed and revealed a solid hyperechoic mass-like lesion measuring approximately 2 cm in the right-side native kidney. The findings regarding the kidney graft were unremarkable. A kidney graft biopsy was performed. Light microscopy revealed 22 glomeruli with 6 sites of FSGS (collapsing variant). There was no evidence of glomerulitis or other abnormal features. The tubule and interstitium showed no infiltration of lymphocytes or plasma cells. No microorganisms were found (Figure 1). The immunofluorescence results demonst-rated positive staining for immunoglobulin M (IgM), complement C3c, and complement C1q in the mesan-gium with an intensity of 1+. Staining was negative for IgG, IgA, Ig kappa, and Ig lambda. Additionally, examination by electron microscopy revealed focal foot process effacement of about 10% with podocyte hypertrophy and no immune complex accumulation.

One month later, computed tomography of the abdomen was performed to identify the abnormal lesion first seen on ultrasonography and showed an arterial enhanced mass in the medial cortex of the upper pole of the right kidney of 2.4 × 2.3 cm (Figure 2), which was suspected to be renal cell carcinoma (RCC). The patient immediately underwent right radical nephrectomy. The biopsy of the mass confirmed the diagnosis of clear cell RCC. After tumor removal, clinical remission of proteinuria was achieved as shown by a 24-hour urine protein level of 0.33 g. Kidney graft biopsy was repeated 3 months after surgery and revealed only a single site of FSGS of the cellular variant, with 12 normal glomeruli. The electron microscopy results showed improvement of foot process effacement (<5%).

The pathology and clinical characteristics led to a diagnosis of paraneoplastic glomerulopathy in this patient. The patient had stable kidney graft function, and maintenance immunosuppressive therapy was changed to low-dose tacrolimus and everolimus (mechanistic target of rapamycin inhibitor). At the last follow-up, the patient had a stable serum creatinine level (107 μmol/L) and a 24-hour urine protein level of 0.34 g.

Postoperative FSGS in kidney transplant patients can have various causes. For example, FSGS may be induced by drugs such as anabolic steroids, calcineurin inhibitors, or mechanistic target of rapamycin inhibitors or by viral infections such as parvovirus B19, cytomegalovirus, Epstein-Barr virus, or BK virus. However, most are idiopathic or primary FSGS recurrences, with a reported incidence ranging from 10% to 60%.^2,4,5 The disease mechanism is caused by circulating permeability factor-induced injury and loss of podocytes.⁶ The risk of recurrent disease is FSGS at an early age, which can progress rapidly to end-stage renal failure. White ethnicity, bilateral nephrectomy, and history of previous FSGS in the transplant kidney are factors with the greatest risk.^7,8 The leading cause of graft loss in the first 2 years after organ transplant is FSGS, and it is associated with a 50% incidence of graft loss in the first 5 years after kidney transplant.^2,5,9 Some studies have recommended that treatment be considered when no other cause of secondary FSGS is detected by plasma exchange to eliminate circulating permeability factor, which is more effective when treated within 2 weeks of recurrent idiopathic FSGS in renal transplant patients.^10,11 However, the next challenge is to determine the secondary cause of FSGS.

In our case, the patient’s cause of ESRD was unknown. Therefore, when he developed FSGS, it could not be confirmed as recurrent FSGS. However, the patient’s symptoms were not likely to be recurrent disease because proteinuria in recurrent FSGS typically occurs within 4 weeks after transplant and usually shows more than 3 g/day for urine protein, which is different from our observations in this case.^4,5 Moreover, the histopathology found only 10% of focal foot process effacement. Therefore, secondary FSGS was highly suspected in this case.

Paraneoplastic glomerulopathy is characterized by cancer-causing substances that cause glomerulopathy. The pathophysiology remains unknown, but theories include T-cell abnormality.^12,13 Ronco proposed criteria for the diagnosis of paraneoplastic glomerulopathy including (1) remission of renal disease that occurs after complete surgical removal of the tumor or with medical antineoplastic therapy, (2) relapse of kidney disease accompanied by a relapse in the cancer, and (3) a biologic link between cancer and kidney disease.¹²

Focal segmental glomerulosclerosis is a rare paraneoplastic glomerulopathy that is more strongly associated with hematologic malignancy than with solid tumors. The pathogenesis of the disease remains unknown. Most reports describe the mechanism of origin in patients with hematologic malignancy as being related to the response of the cancer-generated helper T cells and cytokines to podocyte injury.¹³ In solid tumors, there is evidence to suggest an association with levels of vascular endothelial growth factor, fibroblast-derived growth factors, transforming growth factor, and epithelial membrane antigen-induced podocyte injury.¹⁴ In previous reports of patients with sarcomatoid RCC-associated FSGS, elevated levels of the epithelial marker cytokeratin AE1/AE2 and vimentin were found.¹⁵ Treatment of paraneoplastic glomerulopathy focused on cancer treatment includes surgery, chemotherapy, radiation, and targeted therapy.¹³

Our patient was unexpectedly found to have a renal mass during investigation of proteinuria. We extensively worked up the secondary cause of FSGS and found no other suspicious cause except for the renal mass that was confirmed by imaging and pathology as an RCC. Our transplant team hypothesized that FSGS in this case was the manifestation of paraneoplastic glomerulopathy related to his RCC. We therefore discussed the plan of treatment with the patient and decided to remove the tumor by right radical nephrectomy and follow up the proteinuria to determine the response. After tumor removal, his proteinuria achieved remission, which confirmed that we had made the correct diagnosis.

An important consideration is that treatment of cancer with agents such as pamidronate and interferon α can also cause FSGS. Other chemotherapy agents such as mitomycin C, gemcitabine, and agents against vascular endothelial growth factor can cause thrombotic microangiopathy,13 which results in injury of the kidney graft. The physician must consider the benefits and risks to the patient.

Paraneoplastic glomerulopathy after kidney transplant is a rare condition. The diagnosis requires careful consideration because the treatment differs from that for primary glomerular disease. We suggest close follow-up of renal remission after treatment of the primary cancer.

Volume: 20 Issue: 9 September 2022

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