The presentation of proteinuria in an adolescent with new-onset diabetes after heart transplantation
Journal
Pediatrics and Neonatology
Journal Volume
60
Journal Issue
1
Pages
114-115
Date Issued
2019
Author(s)
Abstract
A 14-year-old girl presented with new-onset noninsulin-dependent diabetes mellitus for 5 years after a heart transplantation that was performed 7 years ago. The immunosuppressive agents that she received initially were tacrolimus, everolimus, and prednisolone, and she was maintained with cyclosporine and everolimus for the past 5 years. Treatment for her diabetes initially included oral hypoglycemic agents (OHAs), which was then switched to insulin therapy due to OHA-induced gastrointestinal upset. Overt proteinuria [urine protein/urine creatinine ratio (UPCR): 7.2 mg/mg; daily protein loss: 2.2 g] and massive pericardial effusion were detected 7 years after the heart transplantation. Laboratory data revealed normal renal function (creatinine: 0.5 mg/dl, estimated Glomerular Filtration Rate (eGFR) calculated using Schwartz formula: 117 ml/min/1.73 m2), hyperglycemia (HbA1c: 9.0%), and hypoalbuminemia (2.3 g/dl). Immunological profiles analysis of ANA, IgA, IgG, IgM, C3, C4, and ASLO revealed results within the normal limit. The infection profile demonstrated negative results for HBV, HCV, HIV, and CMV infection. Biopsy of the cardiac muscle revealed neither cellular nor humoral rejection. There was also no retinopathy on ophthalmological examination. The differential diagnosis of proteinuria included diabetic nephropathy (DN), idiopathic nephrotic syndrome, and drug-induced nephropathy. Renal biopsy revealed diffuse moderate mesangial hypercellularity with moderate mesangial matrix expansion in the glomeruli (Fig. 1A). Electron microscopy demonstrated partial foot process effacement of podocytes with focally wrinkling changes (Fig. 1B) and irregular thickening of the glomerular capillary wall (400–700 nm) (Fig. 1C). There were trace levels of IgA, IgM, kappa and lambda light chains, linear and trace IgG, and negative C1q and C3c under immunostaining. Therefore, a diagnosis of diabetic glomerulopathy class IIa was established. Due to the reported incidences of everolimus-induced proteinuria,1Kaplan B. Qazi Y. Wellen J.R. Strategies for the management of adverse events associated with mTOR inhibitors.Transplant Rev (Orlando). 2014; 28: 126-133Crossref PubMed Scopus (196) Google Scholar everolimus was replaced with mycophenolate mofetil and low-dose prednisolone (5–10 mg daily). Enalapril maleate (5 mg daily) was prescribed for controlling proteinuria and hypertension. After 1 month of treatment with these medications, the proteinuria decreased to the subnephrotic range (UPCR: 0.38 mg/mg), and the patient was discharged from hospital. The use of calcineurin inhibitors, mammalian target of rapamycin inhibitor (mTORi), and glucocorticoids is a predominant factor that causes the development of new-onset diabetes mellitus after transplantation (NODAT).2Peev V. Reiser J. Alachkar N. Diabetes mellitus in the transplanted kidney.Front Endocrinol (Lausanne). 2014; 5: 141Crossref PubMed Scopus (28) Google Scholar Worsened insulin resistance in puberty and post-transplant cytomegalovirus infection might also have contributed to the poor glucose control2Peev V. Reiser J. Alachkar N. Diabetes mellitus in the transplanted kidney.Front Endocrinol (Lausanne). 2014; 5: 141Crossref PubMed Scopus (28) Google Scholar, 3Sehgal S. Bock M.J. Louks Palac H. Brickman W.J. Gossett J.G. Marino B.S. et al.New-onset diabetes mellitus after heart transplantation in children - incidence and risk factors.Pediatr Transplant. 2016; 20: 963-969Google Scholar and accelerated the development of DN in this patient. Bhalla et al. reported that the duration of the development of DN in the transplanted kidney of patients with pretransplant DM and NODAT is about 5.9 years.2Peev V. Reiser J. Alachkar N. Diabetes mellitus in the transplanted kidney.Front Endocrinol (Lausanne). 2014; 5: 141Crossref PubMed Scopus (28) Google Scholar However, the incidence of DN with macroalbuminuria in less than 5–6 years of diagnosis of diabetes in patients without renal transplantation is rare. In addition, the atypical presentation of macroalbuminuria in patients with preserved renal function and absence of diabetic retinopathy is rare in the early stage of diabetic glomerulopathy. The patient's overt proteinuria may be explained by the nondiabetic finding of partial foot process effacement of podocytes associated with minimal changes of disease or mTORi toxicity.4Schönenberger E. Ehrich J.H. Haller H. Schiffer M. The podocyte as a direct target of immunosuppressive agents.Nephrol Dial Transplant. 2011; 26: 18-24Crossref PubMed Scopus (94) Google Scholar The mechanism underlying the development of mTORi-induced proteinuria remains unknown. Dose-related proteinuria, incidences of nephrotic syndrome, renal histology of podocyte injury, and focal segmental glomerulosclerosis have been reported in the context of mTORi usage.1Kaplan B. Qazi Y. Wellen J.R. Strategies for the management of adverse events associated with mTOR inhibitors.Transplant Rev (Orlando). 2014; 28: 126-133Crossref PubMed Scopus (196) Google Scholar, 4Schönenberger E. Ehrich J.H. Haller H. Schiffer M. The podocyte as a direct target of immunosuppressive agents.Nephrol Dial Transplant. 2011; 26: 18-24Crossref PubMed Scopus (94) Google Scholar In the present case, the podocyte injury involved <50% of the area without glomerulosclerosis. Since diabetic glomerulopathy and mTORi toxicity play important roles in the etiology of glomerular proteinuria, it is difficult to differentiate based on the response to treatment with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).5Letavernier E. Legendre C. mToR inhibitors-induced proteinuria: mechanisms, significance, and management.Transplant Rev (Orlando). 2008; 22: 125-130Crossref PubMed Scopus (98) Google Scholar In our case, mTORi toxicity might have had the majority effect on proteinuria since a marked decreased proteinuria was noted after the withdrawal of mTORi for 1 month (UPCR: from 7.2 mg/mg to 1.02 mg/mg) and was improved in advance under ACEi treatment despite the patient's suboptimal diabetes control during this period. In conclusion, it is difficult to diagnose mTORi-induced proteinuria in post-transplant pediatric patients with DN, and the diagnosis should not be based solely on renal histology. Reversal of proteinuria upon drug withdrawal helps the clinician to clarify the etiology before initiating further therapy. However, proteinuria should be closely monitored for the progression of DN after NODAT. The authors declare no conflict of interest. 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Other Subjects
cyclosporine; enalapril maleate; everolimus; hemoglobin A1c; immunoglobulin A; immunoglobulin G; immunoglobulin M; insulin; mycophenolate mofetil; oral antidiabetic agent; prednisolone; tacrolimus; adolescent; adolescent disease; cardiac muscle; case report; clinical article; diabetes mellitus; drug substitution; drug withdrawal; estimated glomerular filtration rate; female; heart muscle biopsy; heart transplantation; human; hypertension; immunosuppressive treatment; insulin treatment; Letter; low drug dose; proteinuria
Publisher
Elsevier (Singapore) Pte Ltd
Type
letter