Diabetic nephropathy is one of the main long-term diabetic microangiopathies that can complicate type 1 and 2 and other secondary forms of diabetes mellitus, including posttransplant diabetes mellitus. Posttransplant diabetes mellitus was initially reported in the 1960s, with case reports of recurrent and de novo diabetic nephropathy after kidney transplant reported in the early 2000s, mostly as a result of same-risk and precipitating factors of diabetic nephropathy as in native kidneys. The disease may appear early in view of the hyperfiltration risk of being a single grafted kidney. Here, we discuss risk factors, early serologic and genetic biomarkers for early detection, and strategies to avoid and delay the progression of diabetic nephropathy after posttransplant diabetes mellitus. In this overview of published literatures, we searched PubMed and MEDLINE for all articles published in English language between January 1994 and July 2018. Included studies reported on the prevalence, incidence, or determinants of post-transplant diabetes among renal transplant recipients and studies reporting diabetic nephropathy in their cohorts. Our review showed that avoidance or good control of posttransplant diabetes is the cornerstone in management of posttransplant diabetes mellitus and hence diabetic nephropathy. Control and avoidance can be commenced in the preparatory stage before transplant using validated genetic markers that can predict posttransplant diabetes mellitus. The use of well-matched donors with tailored immunosuppression (using less diabetogenic agents and possibly steroid-free regimens) and lifestyle modifications are the best preventative strategies. Tight glycemic control, early introduction of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and possibly conversion to less diabetogenic regimens can help to delay progression of diabetic nephropathy.
Key words : End-stage kidney disease, Immunosuppression, Kidney transplantation, New-onset diabetes after transplant
Diabetes mellitus is the most common cause of end-stage kidney disease (ESKD) in most parts of the world; however, transplant in these patients is less common than in patients with glomerulonephritis because of a higher prevalence and severity of cardiovascular comorbidities. Recurrence of diabetic nephropathy (DN) has been shown to occur in about 25% of recipients at an average follow-up of 6 years, with some patients diagnosed within 3 years of transplant.1 Histologic and clinical features are similar to those of native kidney DN. Posttransplant diabetes mellitus (PTDM) is associated with increased mortality and morbidity; patients also have higher rates of cardiovascular disease and infection, which are the leading causes of death in renal transplant recipients. Posttransplant diabetes mellitus has been reported to cause nephropathy in the graft in a similar proportion of patients, which most often manifests within 5 years of transplant.2 Diabetic nephropathy is increasingly recognized as an important cause of ESKD in renal allograft recipients. In their case series, Salifu and colleagues described development of end-stage graft failure due to DN (2 with recurrent DN and 1 with de novo DN); these patients developed ESGK 11, 12, and 14 years after transplant. All of these cases had native kidney disease of adult polycystic kidney disease before transplant.3
In this study, we reviewed the pathogenesis, stages, and diagnosis of DN after transplant, its epidemiology, clinical implications of PTDM, and new strategies for prevention and management of DN.
Pathophysiology of diabetic nephropathy
The pathophysiologic mechanisms leading to DN are multifactorial. As shown in Figure 1, hyperglycemia-induced metabolic and hemodynamic pathways are proven to be mediators of kidney disease. Hyperglycemia causes the formation of Amadori products (the altered proteins) and advanced glycation end products, which are the molecular players in the phases of DN. Moreover, activation of electron transport chain induced by hyperglycemia can result in an increase in reactive oxygen species (ROS) formation, which may be the initiating event in the development of complications in diabetes. Hemodynamic changes, hypertrophy, extracellular matrix accumulation, growth factor/cytokine induc-tion, ROS formation, podocyte damage, proteinuria, and interstitial inflammation are steps in the devel-opment of DN. High glucose, advanced glycation end products, and ROS act in harmony to induce growth factors and cytokines through signal transduction pathways involving protein kinase C, mitogen-activated protein kinases, and the trans-cription factor nuclear factor κB. Transforming growth factor-β causes hypertrophy of the renal cells and accumulation of extracellular matrix.4 Activation of the renin-angiotensin system with the subsequent formation of angiotensin II is involved in almost all steps in development of DN.5
Renal inflammation also plays a significant role in DN progression. The previously mentioned changes lead to interstitial infiltration by inflammatory cells, mainly macrophages and lymphocytes, chemoat-tracted by cytokines released by injured renal cells. The released proinflammatory cells and cytokines (such as tumor necrosis factor-alpha, interferon-gamma, and interleukin 1) can stimulate oxidative stress through activation of nicotinamide adenine dinucleotide phosphate hydrogen oxidase subunits.6,7 Massive proteinuria is associated with intense protein reabsorption activity of proximal tubular cells, which is followed by the formation of proteinaceous casts at distal points that cause tubular dilatation and obstruction.8 Tubular basement membrane integrity becomes jeopardized, with proteins transported from the urinary space to the interstitium triggering an inflammatory reaction.9,10
Familial or perhaps even genetic factors also play a role. Certain ethnic groups, particularly African Americans, persons of Hispanic origin, and American Indians, may be particularly disposed to renal disease as a complication of diabetes. Some evidence has accrued for a polymorphism in the gene for angiotensin-converting enzyme (ACE) in either predisposing to nephropathy or accelerating its course. However, definitive genetic markers have yet to be identified. More recently, the role of epigenetic modification in the pathogenesis of DN has been highlighted.11
Stages and diagnosis of diabetic nephropathy
The pathologic findings of DN after renal transplant are similar to those of typical DN in native kidneys, with thickening of the glomerular basement mem-brane and the tubular basement membrane as the first signs of DN followed by mesangial matrix expansion. Table 1 summarizes stages of DN and their clinical correlation. The extracellular matrix forms nodular mesangial changes, which gradually compress glomerular capillaries and lead to end-stage glomerular sclerosis, associated hyalinosis of afferent and efferent arterioles, and tubulointerstitial-related chronic changes.12 Diabetic nephropathy in the transplanted kidney is frequently associated with vascular and tubulointerstitial changes due to allograft rejection, viral infection, or calcineurin inhibitor (CNI) nephrotoxicity, which may help to distinguish it from DN in the native kidney.
Although widespread data on DN in the native kidney are available, data on DN after renal transplant are scarce. There have been no studies confirming that similar mechanisms in DN are involved as those in the native kidney. However, Fiorina and associates13 described the role of podocyte B7-1 in podocyte injury resulting from hyperglycemia, which in turn leads to upregulated B7-1. This upregulation was shown to be mediated by activation of the 110-kDa catalytic PI3Kα subunit. Addition of CTLA4 immunoglobulin, such as abatacept, also prevented cytoskeleton disruption and adhesion in podocytes that were exposed to hyperglycemia in vitro.13 Belatacept, a CTLA4 immunoglobulin with higher affinity to B7-1, has been approved as a maintenance immunosup-pressive therapy in renal transplant. Therefore, it will be of great interest to evaluate the effects of belatacept in preventing the development of DN after kidney transplant. The potential exists for utilization of mammalian target of rapamycin (mTOR) inhibitors in the prevention of DN development as patients with DN show significant activation of podocytes with mTOR.14
The circulating soluble urokinase plasminogen activator receptor (suPAR) has been shown to play a dynamic role in patients with DN.15 Increased suPAR serum levels cause podocyte apoptosis through its link with acid sphingomyelinase-like phosphodiesterase 3b on podocytes. In addition, suPAR was shown to be a predictor of proteinuria in patients with DM.16 Therefore, suPAR can be a novel approach to treat DN in native and perhaps in transplanted kidneys.
Posttransplant diabetes mellitus
Posttransplant diabetes mellitus is the occurrence of diabetes in previously nondiabetic individuals after organ transplant. Incidence rates of PTDM vary by organ transplanted and posttransplant interval. The estimated incidence rates at 12 months posttransplant are 10% to 74% for kidney transplants.17 International consensus guidelines on PTDM were published in 2003, which recommended that PTDM be diagnosed based on American Diabetes Association (ADA) criteria for type 2 diabetes mellitus.18,19 Post-transplant diabetes mellitus may be diagnosed at any time after transplant by any of the following: symptoms of diabetes (including polyuria, polydipsia, and unexplained weight loss), random plasma glucose ≥ 200 mg/dL (11.1 mmol/L), fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L, with fasting defined as no caloric intake for at least 8 hours), and 2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test. This test should be performed as described by the World Health Organization (WHO), using a glucose load con-taining the equivalent of 75 g anhydrous glucose dissolved in water. An abnormal result of fasting blood glucose obtained on routine screening should be confirmed on another day.18
Pretransplant assessment should include screening for risk factors for PTDM and for history of gestational diabetes. All patients should be screened with fasting plasma glucose test for evidence of metabolic syndrome and for other cardiovascular risk factors. All patients, whether or not preidentified as having increased risk, should have fasting blood glucose measured weekly during the first 4 weeks post-transplant, then at 3 and 6 months posttransplant, and then yearly. Hemoglobin A1c (HbA1c) levels can be checked 3 months posttransplant, particularly if it is difficult to obtain fasting plasma glucose levels. Among patients who have HbA1c levels greater than 6%, we recommend home blood sugar monitoring and assessment of levels every quarter. We do not recommend additional therapy beyond diet and exercise until the HbA1c is greater than 7%. Home blood sugar monitoring should be performed in those with perioperative hyperglycemia, particularly in patients with blood sugar levels ≥ 200 mg/dL or those who require insulin administration, since such patients are at higher risk for PTDM. Initially, blood glucose should be checked 4 times/day (before each meal and before bed). However, monitoring 2-hour postprandial blood glucose levels may be a better indicator of diabetes and its control. Glycated hemoglobin (HbA1c) analyses should not be used before 3 months posttransplant, as the test may not be valid until new hemoglobin has been synthesized and glycated for the appropriate period in the diabetogenic posttransplant setting. These guidelines are per standard WHO and ADA criteria for diagnosis of diabetes mellitus and impaired glucose tolerance.20
Prediabetes includes impaired fasting glucose and/or impaired glucose tolerance and is diagnosed by fasting plasma glucose of between 100 and 125 mg/dL (5.6 and 6.9 mmol/L) or a 2-hour plasma glucose of between 140 and 199 mg/dL (7.8 and 11.0 mmol/L) during an oral glucose tolerance test, in accordance with ADA guidelines. Of note, the normal range of fasting plasma glucose differs according to ADA and WHO criteria; an abnormal fasting glucose is defined as ≥ 100 mg/dL (5.6 mmol/L) by the ADA and ≥ 110 mg/dl (6.1 mmol/L) by WHO. Among transplant recipients, the lower threshold advocated by the ADA is more sensitive in identifying patients at risk for PTDM.21
The 2-hour oral glucose tolerance test is more sensitive than the fasting blood glucose for detecting prediabetes. In addition, the oral glucose tolerance test is more or less impractical and associated with expense, and the results generally do not alter transplant candidacy or posttransplant management. Thus, we do not recommend that it be used for screening or management before or after transplant.22
The pathophysiology of PTDM has been shown to be similar to that of type 2 diabetes mellitus22 but can be complicated by both transplant-specific and nontransplant-related risk factors. The high incidence of de novo hyperglycemia immediately after transplant is high, which may be due to exposure of pancreatic β-cells to several stress factors, including the surgical procedure, weight gain due to physical inactivity immediately after surgery (insulin sensitivity), high doses of corticosteroids, and initiation of CNIs.23 Because PTDM is a serious complication in patients after renal transplant, identification of risk factors could help to prevent the condition.
Risk factors for PTDM could be divided into 2 groups: nonmodifiable factors (age, ethnic and genetic background, family history of type 2 diabetes mellitus, polycystic kidney disease, and previous impaired glucose tolerance) and modifiable factors (obesity, viral infection, including hepatitis C virus [HCV] and cytomegalovirus [CMV], immunosup-pressive drugs, HLA mismatch, donor sex, and genetic susceptibility). These factors are important determinants of both incidence and severity of DN . The likelihood of developing DN is markedly increased in patients who have a sibling with diabetes or a parent with DN; these observations have been made for both type 1 and type 2 diabetes mellitus.24,25 Moreover, pharmacogenetic susceptibility to tacro-limus, confirmed by the role of KCNQ1 gene variants, has been shown to increase the risk of developing PTDM among tacrolimus-treated patients.26
Risk factors of posttransplant diabetes mellitus
Age increases the risk for developing PTDM by 1.5-fold for every 10-year increase in age.27 African American and Hispanic patients have a higher risk for development of PTDM because of their genetic polymorphisms; these polymorphisms lead to more common disease prevalence than in individuals with white ethnicity.28 A family history of diabetes increases the risk of PTDM up to 7 times.29,30 HLA mismatching has been shown to be associated with increased risk of PTDM, although HLA phenotype is not considered to be a reliable risk factor for PTDM.22 Autosomal dominant or recessive polycystic kidney disease has also been linked to PTDM. A logical mechanism for this association is not yet available.31,32
Patients who are obese (that is, with body mass index over 30 kg/m2) have a relative risk of PTDM of 1.73 (95% confidence interval, 1.57-1.90; P < .0001),33 and obesity, along with age, is considered as one of the strongest risk factors. Risk of PTDM increases linearly for every 1 kg above 45 kg.34 Proteinuria within 3 to 6 months after transplant is a strong risk factor for PTDM. Low-grade (< 1 g/day) and very low-grade (< 0.3 g/day) proteinuria are independent risk factors for PTDM.35
With regard to HCV infection, a 2005 meta-analysis of 10 studies that included 2502 patients found that anti-HCV-positive patients were nearly 4 times more likely to have PTDM than uninfected individuals.36 Hepatitis C virus elicited an apoptosis-like death of pancreatic beta cells through an endoplasmic reticulum stress-involved, caspase 3-dependent pathway.37 With regard to CMV infection, a 2014 meta-analysis that included 1389 kidney transplant patients found that CMV infection was a risk factor for increased incidence of PTDM. The study added that prophylaxis against CMV infection after kidney transplant was strongly recommended. Several mechanisms have been suggested to explain the impact of CMV on diminishing insulin secretion, such as beta-cell damage directly by CMV and apoptosis or by infiltrative leukocytes or by induction of proinflammatory cytokines.38
Glucocorticoids are well known to induce hyperglycemia by increasing glucose resistance, reducing insulin secretion, and inducing beta-cell apoptosis; glucocorticoids have been shown to reduce the expression of glucose transporter 2 and glucokinase.39 A large retrospective study that included more than 25 000 transplant recipients from 2004 to 2006 demonstrated that steroid-free immuno-suppression was associated with a significantly reduced likelihood of developing PTDM compared with steroid-containing regimens. The cumulative incidence rates of PTDM within 3 years post-transplant were 12.3% and 17.7% in steroid-free and steroid-containing regimens, respectively.40 Calcineurin inhibitors, both cyclosporine and tacrolimus, increased the risk of PTDM.41 These inhibitors induce PTDM by decreasing insulin secretion, with direct toxic effects on pancreatic beta cells. The DIRECT study showed that the incidence of PTDM at 6 months after transplant was significantly lower in cyclosporine-treated patients than in tacrolimus-treated patients.42 Voclosporin is a novel CNI being developed for organ trans-plantation. The PROMISE study showed that incidence rates of PTDM with voclosporin were 1.6%, 5.7%, and 17.7% (at low, medium, and high concentrations, respectively) compared with a rate of 16.4% with tacrolimus.43 Sirolimus, a diabetogenic agent, when given in combination with CNIs (cyclosporine or tacrolimus), resulted in the highest incidence of PTDM.44 Other immunosuppressive agents, including azathioprine and mycophenolate mofetil (MMF), were not diabetogenic. The com-binations of tacrolimus plus MMF or cyclosporine plus MMF have been shown to be associated with lower rates of PTDM compared with tacrolimus plus azathioprine.45
Role of new biomarkers in predicting and assessing the course of posttransplant diabetes mellitus Vattam and associates46 reported that the insulin-like growth factor 2 ApaI G allele could be used as a biomarker for identifying individuals at high risk of developing new-onset diabetes mellitus, especially in patients after renal transplant for appropriate management of immunosuppression, which could thus prevent the development of PTDM. Heldal and associates47 reported a strong association between PTDM and inflammatory biomarkers, including soluble tumor necrosis factor type 1 (P = .027), pentraxin 3 (P = .019), macrophage migration inhibitory factor (P = .024), and endothelial protein C receptor (P = .001). These associations suggested that these markers could be targets for future studies on pathogenesis and possibly treatment of PTDM.48 Tarnowski and associates49 suggested that the presence of some genetic variants with other inde-pendent risk factors of PTDM should be considered as a contraindication for strongly diabetogenic im-munosuppressive regimens. There is a need for large genome-wide association studies to identify the genetic risk factors associated with PTDM devel-opment. Vattam and colleagues50 reported that TCF7L2 and SLC30A8 polymorphisms could be used as biomarkers to identify individuals at high risk of developing PTDM, especially among Asian Indian populations.
Microalbuminuria has been recognized as the earliest marker of DN in clinical practice; however, a large proportion of renal impairment occurs in a nonalbuminuric state or before the onset of microalbuminuria.51,52 Some patients have normal renal function as represented by serum creatinine without microalbuminuria, despite advanced DN on renal biopsy, whereas others may develop pro-gressive renal dysfunction before diagnosis of microalbuminuria. Other biomarkers of glomerular damage (eg, transferrin, nephrin, podocalyxin), oxidative stress, inflammation (eg, tumor necrosis factor-alpha-α), profibrotic cytokines (eg, trans-forming growth factor-b), advanced glycation end products, vascular dysfunction (eg, von Willebrand factor and vascular cell adhesion protein 1), tubular biomarkers (eg, megalin, cubilin, neutrophil gela-tinase-associated lipocalin), activation of the intrarenal renin-angiotensin system, urinary micro-RNA, urinary proteomics, urinary peptidome, and exosomes are still under evaluation for the diagnosis and prediction of progression of DN.53
Intensive glycemic control was clearly associated with reduction in the incidence of micro- and macroalbuminuria, decline in glomerular filtration rate, and development of ESKD. This benefit could be observed even after proteinuria had developed.54
Fioretto and colleagues confirmed the dis-appearance of diabetic lesions after pancreas transplant55; similarly, the ADVANCE trial showed that there was no significant increased risk for development of albuminuria, doubling of serum creatinine level, need for renal replacement therapy, or death due to kidney disease in patients with HbA1c of ~6.5%.56
Wada and associates57 suggested urinary nephrin-to-creatinine ratio as a reliable marker for predicting the effectiveness of treatment. However, it will need validation regarding its efficacy, especially among children or adolescents with DN. Together, these studies suggest that measuring renal protective mediators such as ACE-2 along with urine levels of urinary liver-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, and urinary kidney injury molecule-1 might provide prognostic information in DN.
Role of diabetes education, monitoring, and reversibility of early diabetic
Optimizing glucose and blood pressure control has been shown to prevent DN in both type 1 and type 2 diabetes mellitus.58 Clinical trials have shown that the risk of developing microalbuminuria and neph-ropathy can be remarkably diminished with intensive glucose control in patients with diabetes.59 A reduction in DN can also be attributed to nonpharmacologic interventions and lifestyle modifications, including regular exercise, weight reduction, and smoking cessation.60 Interventions to reverse a sedentary lifestyle and promote weight loss have been shown to improve glucose control and may prevent the onset of type 2 diabetes mellitus itself.61
Diabetes education, in which patients with diabetes are informed about their disease, is of vital importance.62 It enables individuals to take respon-sibility regarding their health,63 with self-care constituting about 98% of diabetes care. To control their disease and prevent complications of diabetes, patients with diabetes need to adopt self-care activities, such as adopting an appropriate diet, performing regular physical activities, controlling blood glucose, appropriately using oral anti-diabetics, having awareness of the effects and possible side effects of insulin treatment, and avoiding alcohol and tobacco products, and need to comply with life-long medication.64
In studies with patients with type 2 diabetes, it was determined that disease-oriented education had a positive effect on self-care activities of patients.30-33 Other studies displayed decreased lipid levels and arterial blood pressure values in patients who were given education by diabetes nurse educators and monitored for approximately 3 months to 1 year.65,66 This approach can also control cardiovascular risk factors and improve related morbidities.
Management of posttransplant diabetes mellitus
Pretransplant screening of all patients should be carried out with fasting plasma glucose in addition to evidence of metabolic syndrome and other cardiovascular risk factors. Patients should also be counseled regarding their risk of PTDM and lifestyle modifications to decrease this risk. Individuals at high risk should be referred to a dietitian.67,68
Regarding posttransplant management, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines have suggested screening for PTDM with fasting blood glucose, oral glucose tolerance, and/or HbA1c tests weekly during the first 4 weeks after transplant, then at 3, 6, and 9 months posttransplant, and then yearly. Screening for PTDM should also be performed after starting treatment with glucocorticoids, sirolimus, or CNIs.69 Immunosuppressive protocols should be indivi-dualized according to risk of PTDM, but the potential benefit of altering an immunosuppressive regimen must be weighed against the risk of allograft rejection. Glucocorticoid doses should be decreased as soon as possible, but complete withdrawal is recommended only in patients with low immunologic risk and no history of acute rejection episodes.18 Reduction of prednisolone dose to 5 mg/day at 1 year has been associated with a decrease in glucose intolerance from 55% to 34%.70 If lifestyle modifications alone are insufficient to control hyperglycemia, pharma-cotherapy targeting glucose metabolism should be initiated. The choice between insulin and oral hypoglycemic agents depend on the severity, timing, and expected duration of hyperglycemia.71
Prevention and management of diabetic nephropathy
Lifestyle modifications in combination with less diabetogenic immunosuppressants could con-ceivably decrease the incidence of PTDM. If the incidence of PTDM could be reduced, patients, providers, private insurers, and federal programs such as Medicare and Medicaid may all benefit. Successful lifestyle interventions might ultimately improve quality of life, morbidity, and mortality for transplant recipients and lengthen the life span of the transplanted kidney. Moreover, the cost of caring for patients with kidney transplants might also be reduced.72 Prompt intervention is needed after development of early hyperglycemia, as it is a strong predictor for PTDM. When PTDM develops, monitoring and control of blood glucose profile, lipid profile, microalbuminuria, diabetic complications, and comorbid conditions are recommended. Immuno-suppressive regimen modification should also be considered, as suggested by KDIGO guidelines, to reverse or to improve diabetes after the risk of rejection and the potential for adverse effects are weighed. Strategies for modifying immuno-suppressive agents include dose reduction, discontinuation, and selection of CNIs, antimetabolite agents, mTOR inhibitors, belatacept, and corticosteroids. Lifestyle modifications and conventional approaches, similar to those suggested for type 2 diabetes mellitus, are also recommended in PTDM management.73
In patients who develop DN with overt micro- and macroalbuminuria, strict glycemic control and use of angiotensin inhibitors and statins are strongly recommended. In transplant patients, in accordance with measures extrapolated from the general population, the benefit of decreasing immunosup-pression with respect to prevention and treatment of new-onset diabetes mellitus posttransplant should be carefully weighed against the risk of infuriating graft rejection. Switching from one class of immunosuppressive medication to another should be individualized, since the more diabetogenic transplant medications may have other advantages to the longevity of the allograft compared with their competitors.28 The single best evidence-based treatment for DN is therapy with a RAS-blocking medication.74
Avoidance or good control of posttransplant diabetes is the cornerstone of management of PTDM and therefore DN. These measures may be commenced in the preparatory stage before transplant using validated genetic markers that can predict PTDM. The use of well-matched donors and tailoring of immunosuppression (using less diabetogenic agents and possibly steroid-free regimens) and lifestyle modification are the best preventive strategies. Tight glycemic control, early introduction of ACE inhibitors or angiotensin II receptor blockers, and possibly conversion to less diabetogenic regimens can help to delay progression of DN.
Volume : 17
Issue : 2
Pages : 138 - 146
DOI : 10.6002/ect.2018.0157
From the 1Department of Dialysis and Transplantation, Urology Nephrology Center,
Mansoura University, Mansoura, Egypt; the 2Public Health Nursing, Faculty of
Nursing, Mansoura University, Mansoura, Egypt; and the 3Nephrology Department,
Hamed Al-Essa Organ Transplant Center, Ibn Sina Hospital, Sabah area, Kuwait
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Ayman Maher Nagib, Urology and Nephrology Center, Mansoura University, El-Gomhoria Street, PO Box 35516, Mansoura, Egypt
Phone: +96 56 0354 347
Figure 1. Pathways Involved in the Development of Diabetic Nephropathy
Table 1. Stages of Diabetes and Their Clinical Correlations