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Posttransplantation Normoglycemic Diabetic Nephropathy: The Role of the Allograft Insulin Resistance–A Case Report
Posttransplantation Normoglycemic Diabetic Nephropathy: The Role of the Allograft Insulin ResistanceeA Case Report E.J. Filipponea,*, F. Abubackera, and J.L. Farberb a Division of Nephrology, Department of Medicine, and bDepartment of Pathology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
ABSTRACT Background. The pathogenesis of diabetic nephropathy is incompletely understood. Although the role of hyperglycemia is well-established, the participation of insulin resistance is increasingly appreciated. Podocytes are insulin responsive cells and require normal insulin signaling for sustained viability. Case Report. We have presented a renal transplant recipient with lupus nephritis who received a deceased donor kidney from a patient with diabetes mellitus (DM). The kidney functioned well initially. Within 2 years, however, nephrotic range proteinuria developed, and a biopsy revealed diabetic nephropathy that had clearly evolved in comparison with the implantation biopsy. The recipient was repeatedly normoglycemic with normal glycated hemoglobin and glucose tolerance, and she was found to be quite insulin sensitive on the basis of a low homeostasis model assessment of insulin resistance. Conclusions. We argue that the nephropathy developed in the allograft owing to impaired insulin signaling from intrinsic donor-derived insulin resistance that was exacerbated by low insulin levels in the insulin-sensitive recipient. This case has implications for the most appropriate utilization of kidneys from donors with DM.
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HE SHORTAGE OF DONOR ORGANS for kidney transplantation is well-established. In an effort to increase the pool, less than ideal kidneys are being increasingly utilized, including expanded criteria donors (ECD), donors with primary cardiac death, diabetic donors, and combinations of these categories. In the case of a diabetic donor, registry data indicate a steady increase in their use from 1.5% of deceased donor (DD) kidneys transplanted in the United States in 1994 to 6.4% in 2008 [1]. The vast majority of these kidneys were from otherwise standard criteria donors (SCD), not ECDs. Both single-center studies [2] and analyses of registry data [1,3,4] indicate a reasonably successful outcome for diabetic donors, somewhere in between SCDs and ECDs. Although registry data document an equivalent death-censored graft survival (DCGS) between diabetic and nondiabetic recipients, SCD diabetic donors kidneys are suggested to be offered predominantly to euglycemic recipients with lower risk for development of diabetes mellitus (DM), that is, body mass index of 20e30 kg/m2 [1]. When placed in nondiabetic recipients, kidneys with documented diabetic
nephropathy (DN) have shown histologic regression over time [5]. When type 1 diabetic patients with biopsy-proven DN underwent successful pancreas transplantation, the histologic lesions in their native kidneys markedly regressed over 5e10 years [6]. In distinction to these data, the case is presented of a thin woman with end-stage renal disease secondary to lupus nephritis who received a DD kidney from a patient with a 30-year history of type 1 DM with evidence of insulin resistance (IR). The graft functioned well over 2 years, but because of proteinuria in the nephrotic range, a biopsy was obtained that revealed DN, which was more pronounced than on the implantation biopsy. This progression occurred despite normoglycemia based on fasting glucose, oral glucose tolerance testing, and glycosylated hemoglobin levels. The patient was, however, quite insulin sensitive, and
*Address correspondence to Edward J. Filippone, MD, 2228 South Broad St, Philadelphia, PA 19145. E-mail: kidneys@ comcast.net
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2014.02.028
Transplantation Proceedings, 46, 2381e2385 (2014)
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Fig 1. Kidney biopsy 2 years posttransplantation. (A) Photomicrograph showing mesangial expansion and hypercellularity with hyaline arteriolosclerosis (stain: hematoxylin and eosin; original magnification, 40). (B) Electron micrograph showing thickening of the lamina densa of the glomerular basement membrane with accumulation of basement membrane-like material in the mesangium (original magnification, 2700).
we argue that placing an insulin-resistant diabetic kidney in an insulin-sensitive patient with relatively low insulin levels resulted in progression of the nephropathy through further impairment of insulin signaling at the level of the podocyte.
CASE REPORT A 43-year-old Asian woman with systemic lupus presented in 2003 with nephrotic syndrome. Renal biopsy showed class 3 lupus nephritis, and she was treated with oral prednisone and mycophenolate mofetil (MMF). When serum creatinine levels increased, another biopsy was obtained in 2005 that showed class 4 lupus nephritis. She was treated with monthly IV cyclophosphamide and oral prednisone. Renal function deteriorated, and in 2006 dialysis was initiated. She underwent DD renal transplant on April 28, 2011, from a 35-year-old, obese (body mass index of 31.6 kg/m2), Caucasian male with type 1 DM since age 4, hypertension, hyperlipidemia, and coronary artery disease. Serum creatinine ranged from 1.7 to 2.1 mg/dL with terminal serum creatinine of 1.8 mg/dL. A urinalysis had 2þ protein and 2þ blood. A postimplantation biopsy revealed moderate acute tubular damage, but no evidence of
interstitial fibrosis or glomerulopathy. There was excellent initial graft function. Immunosuppression included thymoglobulin induction, steroids, tacrolimus, and MMF. She was discharged on 20 mg daily of prednisone. This was tapered to 5 mg/d by 90 days and maintained with tacrolimus and MMF. Baseline serum creatinine was 1.2 mg/dL. Spot urine protein/creatinine ratio reached a nadir of 0.3 mg/mg on September 12, 2011. Subsequently, it increased to 2.3 on September 23, 2013, with a serum creatinine of 1.2 mg/dL. Trace hematuria was present on urine dipstick. A transplant biopsy was obtained on May 13, 2013. The biopsy showed evidence of diabetic glomerulosclerosis, class II [7]. By light microscopy, mesangial expansion and hypercellularity in 15 glomeruli total were accompanied by hyaline arteriolosclerosis (Fig 1A). Immunofluorescence microscopy was negative except for trace mesangial immunoglobulin M staining. By electron microscopy, prominent thickening of the lamina densa of the glomerular basement membranes was evident with accumulation in the mesangium of basement membrane-like material (Fig 1B). There were no electron-dense deposits present. Importantly, these alterations were acquired posttransplantation, as shown by an implantation biopsy obtained at the time of transplantation 2 years previously. As shown in Fig 2A, by light
Fig 2. Kidney biopsy obtained at the time of transplantation (implantation). (A) Photomicrograph showing an essentially unremarkable glomerulus. (B) Electron micrograph showing normal thickness of the glomerular basement membrane (original magnification, 2000). Mesangial region is similarly normal.
POSTTRANSPLANTATION NORMOGLYCEMIC DIABETIC NEPHROPATHY microscopy, the glomeruli were unremarkable and hyaline arteriolar sclerosis was not present. Similarly, by electron microscopy (Fig 2B), the glomerular basement membranes were not thickened, and the mesangium was unremarkable. The patient never smoked, and her body mass index is 20.8 kg/m2. Current medications include valsartan, nifedipine, tacrolimus, MMF, famotidine, iron, a multivitamin, and warfarin. Her glycated hemoglobin ranged from 4.9 to 5.6. During the initial 3-month period of steroid taper, 18 fasting or random blood glucoses (BG) were obtained with a mean of 97 mg/dL (range 77e155; 5 of the 18 were >100 mg/dL). Subsequently, another 16 fasting or random BGs had a mean of 85 mg/dL (range, 58e100). An oral glucose tolerance test on May 20, 2013 was normal with a 2-hour BG of 115 mg/dL. On July 30, 2013, fasting BG was 87 mg/dL with insulin 2 mIU/mL. Thus, the homeostasis model assessment of IR was 0.43, a result indicating excellent insulin sensitivity [8].
DISCUSSION
Our patient evidenced normal glucose metabolism based on fasting glucose levels, oral glucose tolerance testing, and glycosylated hemoglobin levels. In fact, she is quite insulin sensitive given the simultaneously low fasting glucose and insulin levels, resulting in a low homeostasis model assessment of IR. Nevertheless, there was progressive posttransplant DN, both clinically with increasing levels of proteinuria and pathologically. This change is neither a de novo nor recurrent process; rather, it is progression of the donor’s inherent disease. The utilization of diabetic donors for kidney transplantation in an effort to meet the organ shortage has been increasing over the last 2 decades. Based on registry data from the United Network for Organ Sharing, the percentage of deceased kidneys from diabetic donors increased from 1.5% in 1994 to 6.4% in 2008 [1]. Both single-center study and registry analyses have confirmed their suitability as a donor source [1e4]. Becker et al [2] reported on 2013 transplants from the University of Wisconsin from 1983 to 2000. Of these, 42 were from patients with either type 1 or 2 DM (25 type 2). These kidneys were associated with increased posttransplant proteinuria when given to nondiabetic recipients, but surprisingly the patient and graft survival for the 17 type 2 diabetic donors given to nondiabetic recipients was the highest, even compared with nondiabetic donor/recipient pairs. Ahmad et al [4] did a propensity score-matched study from the United States Renal Data System database comparing 2302 diabetic donors and nondiabetic DD transplants between 1994 and 2003. No effect on patient survival was noted. The diabetic donors kidneys had a significantly higher risk for graft failure, although the absolute difference was quite small. More recently, Mohan et al [1] utilized the United Network for Organ Sharing database from 1994 to 2008. Both overall and DCGS from diabetic donors SCDs was superior to nondiabetic ECDs, although inferior to nondiabetic SCDs. The authors noted the increasing use of diabetic donors into diabetic recipients, with no difference in DCGS compared with nondiabetic recipients.
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A small case series demonstrated that transplantation of a diabetic kidney into a normoglycemic recipient may result in anatomic regression [5]. Abouna et al [5] transplanted 2 kidneys with histologic DN from the same donor into 2 nondiabetic recipients. In 1 case, complete regression was noted on biopsy at 7 months posttransplant, and a subsequent autopsy confirmed this at 22 months. The second patient also showed regression at 7 months, but subsequently became diabetic with recurrence of the lesion. Fioretto et al [6] followed 8 type 1 diabetic patients with biopsy confirmed nephropathy who received successful pancreas transplants alone (PTA). Significant histologic improvement in the degree of mesangial expansion and glomerular basement membrane thickness was noted by 10 years, although not so after 5 years. In comparison, both large single-center series and registry data of PTAs report a sizeable minority of patients with apparent normoglycemia still progress to end-stage renal disease by 5e10 years [9,10]. For example, Kim et al [9] analyzed the United States Renal Data System database of PTA from 1994 through 2009 and found 10-year probabilities of end-stage renal disease of 22%, 30%, and 52% based on initial estimated glomerular filtration rates (90, 60e89, and <60 mL/min/1.73 m2, respectively). Although potential calcineurin inhibitor toxicity could confound these data, Gruessner et al [10] in a single-center series of PTA found a 5-year rate of end-stage renal disease of 18% in the pre-calcineurin inhibitor era. Our patient’s course supports the concept that factors intrinsic to the kidney are of pathogenic importance in determining susceptibility to development and progression of DN. We suggest that the main factor in the progression of her DN lesion was IR inherent to the transplant itself with impaired insulin signaling being the culprit. The pathophysiology of DN is clearly multifactorial and only incompletely understood. Hyperglycemia is of obvious importance, but the central role of IR is being increasingly recognized [11]. Only a minority of patients with either type 1 or type 2 DM will develop overt DN. Utilizing the gold standard hyperinsulinemiceeuglycemic clamp, those with overt DN in both types of DM are more insulin resistant than those without DN [12e14], because they demonstrate significantly less whole body glucose uptake (25%e50% less). Other evidence for IR in diabetic patients with DN exists as well, such as greater degrees of abdominal obesity [15,16], lipid abnormalities [16], and first-degree relatives demonstrating IR [17]. Furthermore, IR underlies the metabolic syndrome that is strongly associated with kidney disease in the general population [18]. Our patient’s donor had type 1 DM and clear evidence of IR. He was obese, hypertensive, and hyperlipidemic, conditions clearly satisfying criteria for metabolic syndrome. Recent studies have shown that the podocyte plays a crucial role in the pathogenesis of glomerulosclerosis in both types of DM [11]. Abnormalities of podocyte number, density, and/or structure have been demonstrated repeatedly [19e23]. Associated with these findings are significant reductions of the podocyte protein nephrin, an essential
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component of the barrier to filtration of protein that occurs at an early stage of DN [24]. The podocyte is an insulin-responsive cell. In vitro, glucose uptake doubles within 15 minutes upon the translocation of GLUT1 and GLUT 4 to the cell membrane [25]. This response requires a normally functioning actin cytoskeleton [25]. Nephrin is also required, because podocytes with a mutated nephrin gene will not respond [26]. Normal insulin signaling is required to sustain podocyte viability [27]. Insulin receptor ligation results in phosphorylation of protein kinase B (pAkt), a key podocyte survival protein [27,28]. This phosphorylation can be shown to be impaired in the podocytes of various experimental models of DM, including the db/db mouse (type 2 DM) and type 1 diabetic Akita mice [28,29]. Exacerbation of this effect by hyperglycemia in the experimental animal helps to explain what has been demonstrated clinically: Poor glucose control clearly contributes to the genesis of DN together with IR. For example, high glucose exposure in cultured podocytes of Akita mice elevates expression of Src homology-2 domain-containing phosphatase-1, which directly associates with insulin receptor-b and reduces insulin-stimulated pAKT production [29]. In high-fat diet/streptozotocin mice, exposure of podocytes to high glucose levels resulted in reduced nephrin expression and reduced insulinmediated glucose uptake via an enhanced expression of nucleotide-binding oligomerization domain containing 2 [30]. In a model most germane to our patient, Welsh et al [31] generated mice with a specific deletion of the insulin receptor in podocytes alone. These animals with normal extrarenal insulin sensitivity and normoglycemia developed albuminuria by 5 weeks. Subsequently, progressive structural damage developed, including podocyte apoptosis, foot process fusion, a thickened glomerular basement membrane, and glomerulosclerosis. Hence, this case raises questions regarding the optimal use of diabetic donors. Did her lesion progress because an insulinresistant kidney was placed in an insulin-sensitive recipient with low insulin levels, thereby impairing podocyte insulin signaling? Should such kidneys be given to insulin-resistant diabetic recipients with higher insulin levels or to nondiabetic patients with other causes of renal failure? Registry data indicate that DCGS is no different, but it has been recommended that diabetic donors should be directed to more insulin-sensitive recipients (euglycemic and nonobese) [1]. Our case suggests that in some cases this is problematic. REFERENCES [1] Mohan S, Tanriover B, Ali N, Crew RJ, Dube GK, Radhakrishnan J, et al. Availability, utilization and outcomes of deceased diabetic donor kidneys; analysis based on UNOS registry. Am J Transplant 2012;12:2098e105. [2] Becker YT, Leverson GE, D’Alessandro AM, Sollinger HW, Becker BT. Diabetic kidneys can safely expand donor pool. Transplantation 2002;74:141e5. [3] Ojo AO, Leichtman AB, Punch JD, Hanson JA, Dickinson DM, Wolfe RA, et al. Impact of pre-existing donor
FILIPPONE, ABUBACKER, AND FARBER hypertension and diabetes mellitus on cadaveric renal transplant outcomes. Am J Kidney Dis 2000;36:153e9. [4] Ahmad M, Cole AH, Cardella CJ, Cattran DC, Schiff J, Tinckam K, et al. Impact of deceased donor diabetes mellitus on kidney transplant outcomes: a propensity score-matched study. Transplantation 2009;88:251e60. [5] Abouna GM, Adnani MS, Kumar MSA, Samhan SA. Fate of transplanted kidney with diabetic nephropathy. Lancet 1986;1:622. [6] Fioretto P, Steffes MW, Sutherland DER, Goetz FC, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998;339:69e75. [7] Tervaert TWC, Mooyart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, et al. Pathological classification of diabetic nephropathy. J Am Soc Nephrol 2010;21:556e63. [8] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 1985;28:412e9. [9] Kim SJ, Smail N, Paraskevas S, Schiff J, Cantarovich M. Kidney function before pancreas transplant predicts subsequent risk of end-stage renal disease. Transplantation 2013 Nov 6 [Epub ahead of print]. [10] Gruessner RWG, Sutherland DER, Kandaswamy R, Gruessner AC. Over 500 solitary pancreas transplants in nonuremic patients with brittle diabetes mellitus. Transplantation 2008;85: 42e7. [11] De Cosmo S, Menzhaghi C, Prudente S, Trischitta S. Role of insulin resistance in kidney dysfunction: insights into the mechanism and epidemiological evidence. Nephrol Dial Transplant 2013;28:29e36. [12] Yip J, Mattock MB, Morocutti A, Sethi M, Trevisan R, Viberti G. Insulin resistance in insulin-dependent diabetic patients with microalbuminuria. Lancet 1993;342:883e7. [13] Ekstrand A, Groop PH, Gronhagen-Riska C. Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus. Nephrol Dial Transplant 1998;13:3079e83. [14] Parvanova AI, Trevisan R, Lliev LP, Dimitrov BD, Vedovato M, Tiengo A, et al. Insulin resistance and microalbuminuria. Across sectional, case-controlled study of 158 patients with type diabetes and difference degrees of urinary albumin excretion. Diabetes 2006;55:1456e62. [15] de Boer IH, Sibley SD, Kestenbaum B, Sampson JN, Young B, Cleary PA, et al. Central obesity, incident microalbuminuria, and change in creatinine clearance in the epidemiology of diabetes interventions and complications study. J Am Soc Nephrol 2007;18:235e43. [16] Chaturvedi N, Bandinelli S, Mangili R, Penno G, Rottiers RE, Fuller JH. Microalbuminuria in type 1 diabetes: Rates, risk factors and glycemic threshold. Kidney Int 2001;60:219e27. [17] Hadjadj S, Pean F, Gallois Y, Passa P, Aubert R, Weekers L, et al. Different patterns of insulin resistance in relatives of type 1 diabetic patients with retinopathy or nephropathy. Diabetes Care 2004;27:2661e8. [18] Thomas G, Sehgal A, Kashyap SR, Srinivas TR, Kirwan J, Navaneethan S. Metabolic syndrome and kidney disease. Clin J Am Soc Nephrol 2011;6:2364e73. [19] Ellis E, Steffes MW, Chavers B, Mauer SM. Observations of glomerular epithelial cell structure in patients with type 1 diabetes mellitus. Kidney Int 1987;32:736e41. [20] Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M. Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. Diabetes 2007;56:2155e60. [21] White KE, Bilous RW, Marshall SM, El Nahas M, Remuzzi G, Piras G, et al. Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes 2002;51:3083e9. [22] Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, et al. Podocyte loss and progressive glomerular injury in type 2 diabetes. J Clin Invest 1997;99:342e8.
POSTTRANSPLANTATION NORMOGLYCEMIC DIABETIC NEPHROPATHY [23] Vestra MD, Masiero A, Roiter AM, Saller A, Crepaldi G, Fioretto P. Is podocyte injury relevant in diabetic nephropathy? Diabetes 2003;52:1031e5. [24] Doublier S, Salvidio G, Lupia E, Ruotsalainen V, Verzola D, Deferrari G, et al. Nephrin expression is reduced in human diabetic nephropathy. Diabetes 2003;52:1023e30. [25] Coward RJM, Welsh GI, Yang J, Tasman C, Lennon R, Koziell A, et al. The human glomerular Podocyte is a novel target for insulin action. Diabetes 2005;54:3095e102. [26] Coward RJM, Welsh GI, Koziell A, Hussain S, Lennon R, Ni L, et al. Nephrin is critical for the action of insulin on human glomerular podocytes. Diabetes 2007;56:1127e35. [27] Fornoni A. Proteinuria, the podocyte and insulin resistance. N Engl J Med 2010;363:2068e9.
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[28] Tejada T, Catanuto P, Ijaz A, Santoa JV, Xia X, Sanchez P, et al. Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death. Kidney Int 2008;73: 1385e93. [29] Drapeau N, Lizotte F, Denhez B, Guay A, Kennedy CR, Geraldes P. Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes. Am J Physiol Endocrinol Metab 2013;304:E1188e98. [30] Du P, Fan B, Han H, Zhen J, Shang J, Wang X, et al. NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy. Kidney Int 2013;84:265e76. [31] Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezhawa Y, Lennon R, et al. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab 2010;12(4):329e40.
ABSTRACT Background. The pathogenesis of diabetic nephropathy is incompletely understood. Although the role of hyperglycemia is well-established, the participation of insulin resistance is increasingly appreciated. Podocytes are insulin responsive cells and require normal insulin signaling for sustained viability. Case Report. We have presented a renal transplant recipient with lupus nephritis who received a deceased donor kidney from a patient with diabetes mellitus (DM). The kidney functioned well initially. Within 2 years, however, nephrotic range proteinuria developed, and a biopsy revealed diabetic nephropathy that had clearly evolved in comparison with the implantation biopsy. The recipient was repeatedly normoglycemic with normal glycated hemoglobin and glucose tolerance, and she was found to be quite insulin sensitive on the basis of a low homeostasis model assessment of insulin resistance. Conclusions. We argue that the nephropathy developed in the allograft owing to impaired insulin signaling from intrinsic donor-derived insulin resistance that was exacerbated by low insulin levels in the insulin-sensitive recipient. This case has implications for the most appropriate utilization of kidneys from donors with DM.
T
HE SHORTAGE OF DONOR ORGANS for kidney transplantation is well-established. In an effort to increase the pool, less than ideal kidneys are being increasingly utilized, including expanded criteria donors (ECD), donors with primary cardiac death, diabetic donors, and combinations of these categories. In the case of a diabetic donor, registry data indicate a steady increase in their use from 1.5% of deceased donor (DD) kidneys transplanted in the United States in 1994 to 6.4% in 2008 [1]. The vast majority of these kidneys were from otherwise standard criteria donors (SCD), not ECDs. Both single-center studies [2] and analyses of registry data [1,3,4] indicate a reasonably successful outcome for diabetic donors, somewhere in between SCDs and ECDs. Although registry data document an equivalent death-censored graft survival (DCGS) between diabetic and nondiabetic recipients, SCD diabetic donors kidneys are suggested to be offered predominantly to euglycemic recipients with lower risk for development of diabetes mellitus (DM), that is, body mass index of 20e30 kg/m2 [1]. When placed in nondiabetic recipients, kidneys with documented diabetic
nephropathy (DN) have shown histologic regression over time [5]. When type 1 diabetic patients with biopsy-proven DN underwent successful pancreas transplantation, the histologic lesions in their native kidneys markedly regressed over 5e10 years [6]. In distinction to these data, the case is presented of a thin woman with end-stage renal disease secondary to lupus nephritis who received a DD kidney from a patient with a 30-year history of type 1 DM with evidence of insulin resistance (IR). The graft functioned well over 2 years, but because of proteinuria in the nephrotic range, a biopsy was obtained that revealed DN, which was more pronounced than on the implantation biopsy. This progression occurred despite normoglycemia based on fasting glucose, oral glucose tolerance testing, and glycosylated hemoglobin levels. The patient was, however, quite insulin sensitive, and
*Address correspondence to Edward J. Filippone, MD, 2228 South Broad St, Philadelphia, PA 19145. E-mail: kidneys@ comcast.net
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2014.02.028
Transplantation Proceedings, 46, 2381e2385 (2014)
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Fig 1. Kidney biopsy 2 years posttransplantation. (A) Photomicrograph showing mesangial expansion and hypercellularity with hyaline arteriolosclerosis (stain: hematoxylin and eosin; original magnification, 40). (B) Electron micrograph showing thickening of the lamina densa of the glomerular basement membrane with accumulation of basement membrane-like material in the mesangium (original magnification, 2700).
we argue that placing an insulin-resistant diabetic kidney in an insulin-sensitive patient with relatively low insulin levels resulted in progression of the nephropathy through further impairment of insulin signaling at the level of the podocyte.
CASE REPORT A 43-year-old Asian woman with systemic lupus presented in 2003 with nephrotic syndrome. Renal biopsy showed class 3 lupus nephritis, and she was treated with oral prednisone and mycophenolate mofetil (MMF). When serum creatinine levels increased, another biopsy was obtained in 2005 that showed class 4 lupus nephritis. She was treated with monthly IV cyclophosphamide and oral prednisone. Renal function deteriorated, and in 2006 dialysis was initiated. She underwent DD renal transplant on April 28, 2011, from a 35-year-old, obese (body mass index of 31.6 kg/m2), Caucasian male with type 1 DM since age 4, hypertension, hyperlipidemia, and coronary artery disease. Serum creatinine ranged from 1.7 to 2.1 mg/dL with terminal serum creatinine of 1.8 mg/dL. A urinalysis had 2þ protein and 2þ blood. A postimplantation biopsy revealed moderate acute tubular damage, but no evidence of
interstitial fibrosis or glomerulopathy. There was excellent initial graft function. Immunosuppression included thymoglobulin induction, steroids, tacrolimus, and MMF. She was discharged on 20 mg daily of prednisone. This was tapered to 5 mg/d by 90 days and maintained with tacrolimus and MMF. Baseline serum creatinine was 1.2 mg/dL. Spot urine protein/creatinine ratio reached a nadir of 0.3 mg/mg on September 12, 2011. Subsequently, it increased to 2.3 on September 23, 2013, with a serum creatinine of 1.2 mg/dL. Trace hematuria was present on urine dipstick. A transplant biopsy was obtained on May 13, 2013. The biopsy showed evidence of diabetic glomerulosclerosis, class II [7]. By light microscopy, mesangial expansion and hypercellularity in 15 glomeruli total were accompanied by hyaline arteriolosclerosis (Fig 1A). Immunofluorescence microscopy was negative except for trace mesangial immunoglobulin M staining. By electron microscopy, prominent thickening of the lamina densa of the glomerular basement membranes was evident with accumulation in the mesangium of basement membrane-like material (Fig 1B). There were no electron-dense deposits present. Importantly, these alterations were acquired posttransplantation, as shown by an implantation biopsy obtained at the time of transplantation 2 years previously. As shown in Fig 2A, by light
Fig 2. Kidney biopsy obtained at the time of transplantation (implantation). (A) Photomicrograph showing an essentially unremarkable glomerulus. (B) Electron micrograph showing normal thickness of the glomerular basement membrane (original magnification, 2000). Mesangial region is similarly normal.
POSTTRANSPLANTATION NORMOGLYCEMIC DIABETIC NEPHROPATHY microscopy, the glomeruli were unremarkable and hyaline arteriolar sclerosis was not present. Similarly, by electron microscopy (Fig 2B), the glomerular basement membranes were not thickened, and the mesangium was unremarkable. The patient never smoked, and her body mass index is 20.8 kg/m2. Current medications include valsartan, nifedipine, tacrolimus, MMF, famotidine, iron, a multivitamin, and warfarin. Her glycated hemoglobin ranged from 4.9 to 5.6. During the initial 3-month period of steroid taper, 18 fasting or random blood glucoses (BG) were obtained with a mean of 97 mg/dL (range 77e155; 5 of the 18 were >100 mg/dL). Subsequently, another 16 fasting or random BGs had a mean of 85 mg/dL (range, 58e100). An oral glucose tolerance test on May 20, 2013 was normal with a 2-hour BG of 115 mg/dL. On July 30, 2013, fasting BG was 87 mg/dL with insulin 2 mIU/mL. Thus, the homeostasis model assessment of IR was 0.43, a result indicating excellent insulin sensitivity [8].
DISCUSSION
Our patient evidenced normal glucose metabolism based on fasting glucose levels, oral glucose tolerance testing, and glycosylated hemoglobin levels. In fact, she is quite insulin sensitive given the simultaneously low fasting glucose and insulin levels, resulting in a low homeostasis model assessment of IR. Nevertheless, there was progressive posttransplant DN, both clinically with increasing levels of proteinuria and pathologically. This change is neither a de novo nor recurrent process; rather, it is progression of the donor’s inherent disease. The utilization of diabetic donors for kidney transplantation in an effort to meet the organ shortage has been increasing over the last 2 decades. Based on registry data from the United Network for Organ Sharing, the percentage of deceased kidneys from diabetic donors increased from 1.5% in 1994 to 6.4% in 2008 [1]. Both single-center study and registry analyses have confirmed their suitability as a donor source [1e4]. Becker et al [2] reported on 2013 transplants from the University of Wisconsin from 1983 to 2000. Of these, 42 were from patients with either type 1 or 2 DM (25 type 2). These kidneys were associated with increased posttransplant proteinuria when given to nondiabetic recipients, but surprisingly the patient and graft survival for the 17 type 2 diabetic donors given to nondiabetic recipients was the highest, even compared with nondiabetic donor/recipient pairs. Ahmad et al [4] did a propensity score-matched study from the United States Renal Data System database comparing 2302 diabetic donors and nondiabetic DD transplants between 1994 and 2003. No effect on patient survival was noted. The diabetic donors kidneys had a significantly higher risk for graft failure, although the absolute difference was quite small. More recently, Mohan et al [1] utilized the United Network for Organ Sharing database from 1994 to 2008. Both overall and DCGS from diabetic donors SCDs was superior to nondiabetic ECDs, although inferior to nondiabetic SCDs. The authors noted the increasing use of diabetic donors into diabetic recipients, with no difference in DCGS compared with nondiabetic recipients.
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A small case series demonstrated that transplantation of a diabetic kidney into a normoglycemic recipient may result in anatomic regression [5]. Abouna et al [5] transplanted 2 kidneys with histologic DN from the same donor into 2 nondiabetic recipients. In 1 case, complete regression was noted on biopsy at 7 months posttransplant, and a subsequent autopsy confirmed this at 22 months. The second patient also showed regression at 7 months, but subsequently became diabetic with recurrence of the lesion. Fioretto et al [6] followed 8 type 1 diabetic patients with biopsy confirmed nephropathy who received successful pancreas transplants alone (PTA). Significant histologic improvement in the degree of mesangial expansion and glomerular basement membrane thickness was noted by 10 years, although not so after 5 years. In comparison, both large single-center series and registry data of PTAs report a sizeable minority of patients with apparent normoglycemia still progress to end-stage renal disease by 5e10 years [9,10]. For example, Kim et al [9] analyzed the United States Renal Data System database of PTA from 1994 through 2009 and found 10-year probabilities of end-stage renal disease of 22%, 30%, and 52% based on initial estimated glomerular filtration rates (90, 60e89, and <60 mL/min/1.73 m2, respectively). Although potential calcineurin inhibitor toxicity could confound these data, Gruessner et al [10] in a single-center series of PTA found a 5-year rate of end-stage renal disease of 18% in the pre-calcineurin inhibitor era. Our patient’s course supports the concept that factors intrinsic to the kidney are of pathogenic importance in determining susceptibility to development and progression of DN. We suggest that the main factor in the progression of her DN lesion was IR inherent to the transplant itself with impaired insulin signaling being the culprit. The pathophysiology of DN is clearly multifactorial and only incompletely understood. Hyperglycemia is of obvious importance, but the central role of IR is being increasingly recognized [11]. Only a minority of patients with either type 1 or type 2 DM will develop overt DN. Utilizing the gold standard hyperinsulinemiceeuglycemic clamp, those with overt DN in both types of DM are more insulin resistant than those without DN [12e14], because they demonstrate significantly less whole body glucose uptake (25%e50% less). Other evidence for IR in diabetic patients with DN exists as well, such as greater degrees of abdominal obesity [15,16], lipid abnormalities [16], and first-degree relatives demonstrating IR [17]. Furthermore, IR underlies the metabolic syndrome that is strongly associated with kidney disease in the general population [18]. Our patient’s donor had type 1 DM and clear evidence of IR. He was obese, hypertensive, and hyperlipidemic, conditions clearly satisfying criteria for metabolic syndrome. Recent studies have shown that the podocyte plays a crucial role in the pathogenesis of glomerulosclerosis in both types of DM [11]. Abnormalities of podocyte number, density, and/or structure have been demonstrated repeatedly [19e23]. Associated with these findings are significant reductions of the podocyte protein nephrin, an essential
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component of the barrier to filtration of protein that occurs at an early stage of DN [24]. The podocyte is an insulin-responsive cell. In vitro, glucose uptake doubles within 15 minutes upon the translocation of GLUT1 and GLUT 4 to the cell membrane [25]. This response requires a normally functioning actin cytoskeleton [25]. Nephrin is also required, because podocytes with a mutated nephrin gene will not respond [26]. Normal insulin signaling is required to sustain podocyte viability [27]. Insulin receptor ligation results in phosphorylation of protein kinase B (pAkt), a key podocyte survival protein [27,28]. This phosphorylation can be shown to be impaired in the podocytes of various experimental models of DM, including the db/db mouse (type 2 DM) and type 1 diabetic Akita mice [28,29]. Exacerbation of this effect by hyperglycemia in the experimental animal helps to explain what has been demonstrated clinically: Poor glucose control clearly contributes to the genesis of DN together with IR. For example, high glucose exposure in cultured podocytes of Akita mice elevates expression of Src homology-2 domain-containing phosphatase-1, which directly associates with insulin receptor-b and reduces insulin-stimulated pAKT production [29]. In high-fat diet/streptozotocin mice, exposure of podocytes to high glucose levels resulted in reduced nephrin expression and reduced insulinmediated glucose uptake via an enhanced expression of nucleotide-binding oligomerization domain containing 2 [30]. In a model most germane to our patient, Welsh et al [31] generated mice with a specific deletion of the insulin receptor in podocytes alone. These animals with normal extrarenal insulin sensitivity and normoglycemia developed albuminuria by 5 weeks. Subsequently, progressive structural damage developed, including podocyte apoptosis, foot process fusion, a thickened glomerular basement membrane, and glomerulosclerosis. Hence, this case raises questions regarding the optimal use of diabetic donors. Did her lesion progress because an insulinresistant kidney was placed in an insulin-sensitive recipient with low insulin levels, thereby impairing podocyte insulin signaling? Should such kidneys be given to insulin-resistant diabetic recipients with higher insulin levels or to nondiabetic patients with other causes of renal failure? Registry data indicate that DCGS is no different, but it has been recommended that diabetic donors should be directed to more insulin-sensitive recipients (euglycemic and nonobese) [1]. Our case suggests that in some cases this is problematic. REFERENCES [1] Mohan S, Tanriover B, Ali N, Crew RJ, Dube GK, Radhakrishnan J, et al. Availability, utilization and outcomes of deceased diabetic donor kidneys; analysis based on UNOS registry. Am J Transplant 2012;12:2098e105. [2] Becker YT, Leverson GE, D’Alessandro AM, Sollinger HW, Becker BT. Diabetic kidneys can safely expand donor pool. Transplantation 2002;74:141e5. [3] Ojo AO, Leichtman AB, Punch JD, Hanson JA, Dickinson DM, Wolfe RA, et al. Impact of pre-existing donor
FILIPPONE, ABUBACKER, AND FARBER hypertension and diabetes mellitus on cadaveric renal transplant outcomes. Am J Kidney Dis 2000;36:153e9. [4] Ahmad M, Cole AH, Cardella CJ, Cattran DC, Schiff J, Tinckam K, et al. Impact of deceased donor diabetes mellitus on kidney transplant outcomes: a propensity score-matched study. Transplantation 2009;88:251e60. [5] Abouna GM, Adnani MS, Kumar MSA, Samhan SA. Fate of transplanted kidney with diabetic nephropathy. Lancet 1986;1:622. [6] Fioretto P, Steffes MW, Sutherland DER, Goetz FC, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998;339:69e75. [7] Tervaert TWC, Mooyart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, et al. Pathological classification of diabetic nephropathy. J Am Soc Nephrol 2010;21:556e63. [8] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 1985;28:412e9. [9] Kim SJ, Smail N, Paraskevas S, Schiff J, Cantarovich M. Kidney function before pancreas transplant predicts subsequent risk of end-stage renal disease. Transplantation 2013 Nov 6 [Epub ahead of print]. [10] Gruessner RWG, Sutherland DER, Kandaswamy R, Gruessner AC. Over 500 solitary pancreas transplants in nonuremic patients with brittle diabetes mellitus. Transplantation 2008;85: 42e7. [11] De Cosmo S, Menzhaghi C, Prudente S, Trischitta S. Role of insulin resistance in kidney dysfunction: insights into the mechanism and epidemiological evidence. Nephrol Dial Transplant 2013;28:29e36. [12] Yip J, Mattock MB, Morocutti A, Sethi M, Trevisan R, Viberti G. Insulin resistance in insulin-dependent diabetic patients with microalbuminuria. Lancet 1993;342:883e7. [13] Ekstrand A, Groop PH, Gronhagen-Riska C. Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus. Nephrol Dial Transplant 1998;13:3079e83. [14] Parvanova AI, Trevisan R, Lliev LP, Dimitrov BD, Vedovato M, Tiengo A, et al. Insulin resistance and microalbuminuria. Across sectional, case-controlled study of 158 patients with type diabetes and difference degrees of urinary albumin excretion. Diabetes 2006;55:1456e62. [15] de Boer IH, Sibley SD, Kestenbaum B, Sampson JN, Young B, Cleary PA, et al. Central obesity, incident microalbuminuria, and change in creatinine clearance in the epidemiology of diabetes interventions and complications study. J Am Soc Nephrol 2007;18:235e43. [16] Chaturvedi N, Bandinelli S, Mangili R, Penno G, Rottiers RE, Fuller JH. Microalbuminuria in type 1 diabetes: Rates, risk factors and glycemic threshold. Kidney Int 2001;60:219e27. [17] Hadjadj S, Pean F, Gallois Y, Passa P, Aubert R, Weekers L, et al. Different patterns of insulin resistance in relatives of type 1 diabetic patients with retinopathy or nephropathy. Diabetes Care 2004;27:2661e8. [18] Thomas G, Sehgal A, Kashyap SR, Srinivas TR, Kirwan J, Navaneethan S. Metabolic syndrome and kidney disease. Clin J Am Soc Nephrol 2011;6:2364e73. [19] Ellis E, Steffes MW, Chavers B, Mauer SM. Observations of glomerular epithelial cell structure in patients with type 1 diabetes mellitus. Kidney Int 1987;32:736e41. [20] Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M. Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. Diabetes 2007;56:2155e60. [21] White KE, Bilous RW, Marshall SM, El Nahas M, Remuzzi G, Piras G, et al. Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes 2002;51:3083e9. [22] Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, et al. Podocyte loss and progressive glomerular injury in type 2 diabetes. J Clin Invest 1997;99:342e8.
POSTTRANSPLANTATION NORMOGLYCEMIC DIABETIC NEPHROPATHY [23] Vestra MD, Masiero A, Roiter AM, Saller A, Crepaldi G, Fioretto P. Is podocyte injury relevant in diabetic nephropathy? Diabetes 2003;52:1031e5. [24] Doublier S, Salvidio G, Lupia E, Ruotsalainen V, Verzola D, Deferrari G, et al. Nephrin expression is reduced in human diabetic nephropathy. Diabetes 2003;52:1023e30. [25] Coward RJM, Welsh GI, Yang J, Tasman C, Lennon R, Koziell A, et al. The human glomerular Podocyte is a novel target for insulin action. Diabetes 2005;54:3095e102. [26] Coward RJM, Welsh GI, Koziell A, Hussain S, Lennon R, Ni L, et al. Nephrin is critical for the action of insulin on human glomerular podocytes. Diabetes 2007;56:1127e35. [27] Fornoni A. Proteinuria, the podocyte and insulin resistance. N Engl J Med 2010;363:2068e9.
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[28] Tejada T, Catanuto P, Ijaz A, Santoa JV, Xia X, Sanchez P, et al. Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death. Kidney Int 2008;73: 1385e93. [29] Drapeau N, Lizotte F, Denhez B, Guay A, Kennedy CR, Geraldes P. Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes. Am J Physiol Endocrinol Metab 2013;304:E1188e98. [30] Du P, Fan B, Han H, Zhen J, Shang J, Wang X, et al. NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy. Kidney Int 2013;84:265e76. [31] Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezhawa Y, Lennon R, et al. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab 2010;12(4):329e40.