|Year : 2019 | Volume
| Issue : 3 | Page : 732-737
|Acute kidney injury due to sucrose-containing intravenous immunoglobulins
Wasim Siddiqui1, Sadiq Al Lawati1, AM Shaheen Faissal2, Suad Hannawi3, Marwa Al Riyami4, Issa Al Salmi1
1 Department of Renal Medicine, The Royal Hospital, Muscat, Oman
2 Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia
3 Department of Medicine, MOHAP, Dubai, United Arab Emirates
4 Department of Histopathology, Sultan Qaboos University Hospital, Muscat, Oman
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|Date of Submission||27-May-2018|
|Date of Acceptance||11-Jul-2018|
|Date of Web Publication||26-Jun-2019|
| Abstract|| |
Intravenous immunoglobulins (IVIGs) are pooled polyvalent immunoglobulin G antibodies extracted from the human plasma. Stabilizers in IVIG may include sugars, such as sucrose, glucose, or maltose. Sucrose in IVIG preparations may cause acute kidney injury (AKI). We report the case of a renal transplant patient who developed AKI due to sucrose nephropathy following the administration of sucrose-containing IVIG.
|How to cite this article:|
Siddiqui W, Al Lawati S, Shaheen Faissal A M, Hannawi S, Al Riyami M, Al Salmi I. Acute kidney injury due to sucrose-containing intravenous immunoglobulins. Saudi J Kidney Dis Transpl 2019;30:732-7
|How to cite this URL:|
Siddiqui W, Al Lawati S, Shaheen Faissal A M, Hannawi S, Al Riyami M, Al Salmi I. Acute kidney injury due to sucrose-containing intravenous immunoglobulins. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Jul 15];30:732-7. Available from: http://www.sjkdt.org/text.asp?2019/30/3/732/261361
| Introduction|| |
Intravenous immunoglobulins (IVIGs) are pooled polyvalent immunoglobulin G (IgG) antibodies extracted from the human plasma. While the initial indications were mainly immunodeficiency states and some autoimmune diseases, usage of IVIGs has been widened to include several immune-mediated diseases, viral infections, and organ transplant rejection. Stabilizers in IVIG may include sugars, such as sucrose, glucose, or maltose. Sucrose in IVIG prepa-rations may cause acute kidney injury (AKI)., We report the case of a renal transplant patient who developed AKI due to sucrose nephropathy following the administration of sucrose-containing IVIG.
| Case Report|| |
Informed consent was obtained from the patient before reporting the case.
Mr. SN is a 57-year-old Omani male who developed end-stage kidney disease due to an unknown etiology. He underwent dialysis for about a year before having a living unrelated renal transplant. Immunosuppression induction was performed with basiliximab and intravenous methylprednisolone. Maintenance immunosuppression consisted of cyclosporine, mycophenolate mofetil (MMF), and steroids. His serum creatinine (SCr) on the 7th day after transplantation was 104 μmol/L, corresponding to an estimated glomerular filtration rate (eGFR) [by the Modification of Diet in Renal Disease (MDRD) formula] of 68 mL/min/1.73 m2.
Four months after the transplantation, he was referred to our hospital for deterioration of kidney function with eGFR (by the MDRD formula) of 27 mL/min. Cytomegalovirus (CMV) polymerase chain reaction (PCR) was positive (3300 copies/mL). Cyclosporine levels were high (C2: 2937 ng/mL) and hence, cyclos-porine dose was adjusted. Induction therapy with injection ganciclovir for two weeks, followed by a therapeutic dose of oral valganciclovir, was administered for the treatment of CMV infection. Skin examination revealed annular purple patches, suspicious of Kaposi sarcoma, on the upper limbs. Skin biopsy confirmed the diagnosis.
The management of Kaposi sarcoma consisted of conversion from calcineurin inhibitors to mTor inhibitors. MMF was reduced from 750 to 500 mg twice a day. Prednisolone was reduced to 15 mg/day.
Kidney functions showed significant improvement with SCr decreasing to 100 μmol/L and eGFR to 71 mL/min. However, on subsequent follow-up visits few weeks later, blood polyomavirus (BKV) PCR turned out to be positive with 844 mEq/mL.
He was administered sucrose-containing IVIG. It was planned to give total IVIG of 2 g/kg in four daily divided doses. After completion of the second dose, the SCr increased to 370 μmol/L. He was clinically asymptomatic and euvolemic; his vital signs were stable, urine output remained normal, and urinalysis was inactive.
Ultrasound of the transplant kidney was normal with normal resistivity index. IVIG was stopped. He was well hydrated and underwent ultrasound-guided biopsy. Graft biopsy showed acute tubular injury with flattening and vacuolation of tubular epithelial cells. Mitosis indicating tubular regeneration was seen. There was mild focal interstitial inflammation (20%) with mild lymphocytic tubulitis not amounting to graft rejection. Immuno-histochemistry for both C4d and polyoma-virus (BKV) was negative. The features were consistent with sucrose-induced nephropathy [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d.
|Figure 1: (a) Tubules appear dilated with flattening and sloughing of their epithelial lining and contain some proteinaceous material (H and E, ×20). (b) Tubules also show coarse cytoplasmic vacuolation (H and E, ×40). (c) Mitotic figures were seen indicating regenerative activity (black arrow) (H and E, ×40). (d) Glomeruli were unremarkable (PAS, ×20).|
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Subsequent visits showed a decrease in serum BKV-PCR level and eventually unde tected serum level of BKV-PCR at follow-up about a month later.
| Discussion|| |
IVIG therapy was introduced in 1952 to treat patients with immunoglobulin deficiencies and provide passive immunity to patients with chronic lymphocytic leukemia. Since then, because of its immunomodulatory effect, the indication for IVIG has been extended to a wide variety of immune-related disorders, such as idiopathic thrombocytopenic purpura, myasthenia gravis, inflammatory demyelinating neuropathy, systemic lupus erythematous, and glomerulonephritis.,,, The mechanism of action is not completely known and may include several components. In congenital and acquired immunodeficiency states,, IVIG confers a direct anti-infectious effect. In autoimmune diseases, IVIG reduces or modulates immunity by interacting with Fc receptors on phagocytic cells. IVIGs have also an anti-idiotypic activity directed against circulating autoantibodies. These anti-idiotypic antibodies provide a negative feedback signal capable of down regulating the pathogenic immune response.,,
The therapeutic benefit of IVIG has been ascribed to Ρογ receptor blockade, antibody-mediated autoantibody neutralization, inhibittion of complement-mediated damage, modulation of cytokine production, down-regulation of B- or T-cell responses, effects on antigen-presenting cells, and modulation of dendritic cells.,,,,
BKV viremia occurs in 13% and BKV nephropathy (BKVN) occurs in 8% of kidney transplant recipients.,, Viral replication begins early after transplantation and progresses through detectable stages: viruria followed by viremia and then nephropathy., Viruria can be detected by PCR for BKV DNA, reverse transcription-PCR for BKV RNA, urine cytology for BKV inclusion-bearing epithelial cells termed “decoy cells,” or electron microscopy for viral particles.,,
Untreated BKVN can lead to graft loss. The cornerstone of treatment of BKVN is a decrease in maintenance immunosuppression. Various interventions have been pursued, most commonly withdrawal of MMF or tacro-limus,,,,,,, replacement of tacrolimus by cyclosporine, and overall reduction of the immunosuppressive load.,, Simultaneous occurrence of acute rejection and BKVN is a frequent clinical problem. The treatment of acute rejection with pulse steroids has been associated with an increased risk of BKVN., In addition, reduction of immunosuppression to treat BKVN evidently carries a high risk (25%–45%) of acute rejection.,,,,
The use of immunoglobulins may be a valuable treatment option in patients with BKVN and co-existing rejection.,, The choice of IVIG is also of vital importance. Adverse effects associated with IVIG are relatively uncommon, occurring in 1%–13% of infusions.,,,,, Fever, chills, flushing, headache, myalgia, elevated blood pressure, chest pain, and dyspnea are likely related to complement activation by immunoglobulin aggregates.,,,,, To minimize the formation of immunoglobulin aggregates, sugars such as maltose, dextrose, and sucrose are added to IVIG as stabilizing agents.,
Intravenous immunoglobulin preparations nowadays are highly purified and contain around 90% of polyvalent IgG.,,, Stabilizers are used to minimize the formation of immunoglobulin aggregates which can generate adverse events. These include sugars such as sucrose, glucose, and maltose or amino acids such as glycine or proline. After paren-teral infusion, sucrose is exclusively eliminated by the kidney. Because the kidneys do not produce the enzyme disaccharidase, sucrose administered intravenously cannot be metabolized, accumulating in the proximal tubules and causing hyperosmolality, which leads to renal injury.,,, Predisposing risk factors for sucrose nephropathy include pre-existing kidney insufficiency, diabetes mellitus, dehydration, age above 65 years, sepsis, paraprotei-nemia, and concomitant use of nephrotoxic agents.,,,,,,,,,
Sucrose nephropathy is characterized by marked proximal cell swelling, vacuolization, and lumen narrowing and/or occlusion.,, A major element in the pathogenesis of sucrose nephropathy is the absence, in kidney tubular cells, of the enzyme disaccharidase which metabolizes sucrose., Proximal tubules take up filtered sucrose via pinocytosis. The latter accumulates in the cytoplasm, creating an osmotic gradient.,,,,,
Water enters the proximal tubular cells through aquaporines AQP1, leading to cell swelling and subsequent narrowing and occlusion of tubule lumen.,, Some authors have reported that sucrose could produce injury in normal human kidneys at a dose of 6 g/kg body weight given in 1 week.,,,,
The threshold for kidney injury is much lower in patients with kidney dysfunction, with as little sucrose as 1 g/kg being sufficient to cause AKI., When used for immune disorders, the daily dose of IVIG ranges from 0.35 to 2.0 g/kg, corresponding to sucrose load of 0.58 to 3.4 g/kg. Most cases of IVIG- induced AKI have been reported with this treatment regimen.,,,,,
| Conclusion|| |
In this article, we present a case of a living unrelated kidney transplant recipient who developed BKVN and developed impaired kidney function. The patient also had new-onset diabetes mellitus after kidney transplantation but was otherwise in good general health. Treatment included sucrose-containing IVIG. The patient subsequently developed AKI. The outcome was favorable with recovery of filtration rate to the baseline within 21 days without the need for dialysis. We conclude that the administration of sucrose-containing IVIG may lead to AKI. We recommend the use of sucrose-free IVIG whenever possible. In all cases, caution is required when administrating IVIG.
Conflict of interest: None declared.
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Issa Al Salmi
Department of Renal Medicine, The Royal Hospital, PO Box. 1331, Code 111, Muscat
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