Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Renal Protection in Diabetes: Role of Glycemic Control
Paola Fioretto*,
Marino Bruseghin*,
Ilaria Berto*,
Pietro Gallina*,
Enzo Manzato* and
Michele Mussap
Departments of * Medical and Surgical Sciences and Laboratory Medicine, University of Padova Medical School, Padova, Italy
Address correspondence to: Dr. Paola Fioretto, Department of Medical and Surgical Sciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy. Phone: +39-049-8211879; Fax: +39-049-8212151; E-mail: paola.fioretto{at}unipd.it
Diabetes is the most common cause of ESRD in Western countries.This article describes the impact of glycemic control in thevarious stages of the disease and considers the impact of tightglycemic control on the development and progression of diabeticnephropathy (DN). The Diabetes Control and Complications Trialand the United Kingdom Prospective Diabetic Study have demonstratedin type 1 and type 2 diabetes that intensive glycemic controlsignificantly reduces the risk for development of microalbuminuria.Although observational studies suggest an impact of glycemiaalso on the progression of DN, fewer data are available on theimpact of improved metabolic control in secondary prevention.The long-term follow-up of the patients who participated inthe Diabetes Control and Complications Trial (Epidemiology ofDiabetes Interventions and Complications Study) demonstrateda sustained effect of previous tight glycemic control on bothdevelopment and progression of DN. Finally, long-term normoglycemia,achieved by pancreas transplantation, is able not only to preventthe development of early diabetic glomerulopathy in kidney transplantrecipients but also to halt progression and induce regressionof the established diabetic renal lesions in nonuremic patients.Taken together, these studies strongly demonstrate that improvementin glucose control is the most important therapeutic approachin primary prevention. Tight glycemic control also is importantin slowing progression of DN, and if blood glucose is normalized,then regression of DN can be achieved. Therefore, a target ofglycated hemoglobin levels <7% should be recommended in allpatients with diabetes.
Diabetic nephropathy (DN) is the single most common cause ofESRD in the United States, accounting for >50% of new casesof renal failure (1). Patients who have diabetes and reach ESRDhave high cardiovascular risk and poor prognosis (1,2). Therefore,early identification of diabetic patients who are at high nephropathyrisk and initiation of nephroprotective treatment are mandatoryto prevent the progression and, possibly, the development ofDN. In this article, we briefly review the impact of glycemiccontrol in the development, progression, and regression of DNand the crucial role of intensive glucose control to achieveeffective nephroprotection.
Epidemiologic studies have demonstrated that DN risk is higherin patients with poor metabolic control (2–5). Althoughit is clear that genetic factors modulate DN risk and that somepatients escape this complication despite decades of poor glycemiccontrol (2–5), it is also clear that hyperglycemia isa necessary precondition for DN lesions and renal functionaldisturbances to develop. Indeed, the two major early glomerularlesions, glomerular basement membrane (GBM) thickening and mesangialexpansion, are not present at diagnosis of diabetes but arefound 2 to 5 yr after onset of hyperglycemia (2).
Additional support for the concept that hyperglycemia is necessaryfor the development of diabetic glomerulopathy is provided bystudies in identical twins who are discordant for type 1 diabetes.In these families, the kidneys of the nondiabetic members ofthe twin pairs were structurally normal, and in each instance,GBM and mesangial measures were greater in the twin who haddiabetes in the pair (6). Furthermore, normal kidneys from nondiabeticdonors that are transplanted into patients with diabetes developall of the lesions of DN (7,8).
Finally, patients who had type 1 diabetes and were randomlyassigned to receive maximized glycemic control in the first5 yr after kidney transplantation did not develop mesangialmatrix expansion, whereas this occurred in patients who wererandomly assigned to receive standard glycemic control (9).This study, along with the very large multicenter Diabetes Controland Complications Trial (DCCT), which documented that patientswho were randomly assigned to strict control had lower incidencesof microalbuminuria and proteinuria after 7 to 8 yr of follow-up(10), proves the role of glycemia as a risk factor for nephropathyin type 1 diabetes. Similar trends were seen for the preventionof microalbuminuria and proteinuria in the large United KingdomProspective Diabetes Study (UKPDS) in patients with type 2 diabetes(11). Perhaps most striking is the dramatic reversal of establishedDN lesions in the native kidneys of patients with type 1 diabetesand long-term normoglycemia after successful pancreas transplantation(12). Therefore, strategies that aim to improve or normalizethe metabolic abnormalities of diabetes could prevent, arrest,or reverse the pathologic influences of diabetes on the kidney.
The DCCT and the UKPDS have demonstrated in type 1 and type2 diabetes, that intensive glycemic control significantly reducesthe risk for development of microalbuminuria (10,11). In theDCCT, the initially normoalbuminuric patients who were allocatedto strict glycemic control had a relative risk reduction ofdevelopment of microalbuminuria of 34% and of proteinuria of44% compared with those in the conventional group over 6.5 yr(10). During the DCCT, mean glycated hemoglobin (HbA1c) levelswere approximately 7.0 and 9.1% in the intensively and conventionallytreated groups, respectively. It is interesting that the benefitsof prolonged tight glycemic control persisted also when patientswere no longer in intensified glycemic control (13). Indeed,the Epidemiology of Diabetes Interventions and Complications(EDIC) Study (long-term follow-up of the DCCT patients afterthe end of the study) (13) demonstrated that patients who wereon strict glycemic control during the DCCT developed significantlyless microalbuminuria than patients who were on conventionaltreatment after 8 yr from the end of DCCT, with an adjustedrisk reduction of 49%, although at similar levels of glycemiccontrol.
In the UKPDS (11), a difference in HbA1c of 0.9% was associatedwith a reduction in the relative risk for development of microalbuminuriaor proteinuria of 30% in the intensively treated group at 9to 12 yr. Similarly, intensive glucose control reduced the riskfor development of microalbuminuria by 62% in a very small numberof Japanese patients during 6 yr of follow-up (14). Althoughit has been proposed that there is threshold of HbA1c belowwhich DN risk is very low (15), data from the DCCT (16), theUKPDS (17), and the European Diabetes (EURODIAB) study (18)demonstrate that the lower the HbA1c values, the lower the riskfor development of nephropathy, with no evidence for a thresholdeffect. Finally, intensive insulin treatment prevented the developmentof early glomerulopathy lesions, as elegantly shown in patientswho had type 1 diabetes and were randomly assigned to receivemaximized glycemic control in the first 5 yr after kidney transplantation,whereas diabetic glomerular lesions developed in patients whowere randomly assigned to receive standard glycemic control(9).
In summary, it now is well established that tight metaboliccontrol is effective in achieving nephroprotection in both type1 and type 2 diabetes and that the lower the HbA1c value obtained,the lower the risk for development of microalbuminuria. No othertherapeutic intervention so far has been shown to be as effectiveas improved metabolic control in the primary prevention of DNin humans.
Pancreas Transplantation and Primary Prevention
Pancreas transplantation (PT) offers a unique opportunity toevaluate the effects of prolonged normoglycemia, without exposingthe patients to the risks of severe hypoglycemia; therefore,it has been possible to test the capability of long-term normoglycemiain preventing, halting, and reversing DN. PT most commonly isperformed in uremic patients with type 1 diabetes at the timeof renal transplantation (simultaneous pancreas-kidney [SPK]transplantation) or, less frequently, shortly after kidney transplant(PAK). SPK offers the opportunity to test the ability of PTto prevent the development of diabetic glomerular lesions, becausethe renal graft has never been exposed to hyperglycemia. Inrecipients of SPK (two patients) and PAK (six patients) Bohmanet al. (19) first demonstrated that the development of diabeticglomerulopathy was prevented. Glomerular structural parametersstill were in the normal range 2 to 8 yr after PT. More recently(20), the same group reported data on a larger cohort of 20SPK patients who were followed for 1 to 6.5 yr compared witha group of 34 kidney transplant recipients with diabetes, confirmingthe previous observation.
In addition to the early work of Bohman et al. (19), only onestudy to date has been performed in PAK patients (21). In thisstudy, PT was performed shortly (1 to 7 yr) after kidney transplantation.Baseline renal biopsies were performed before successful PTand 4 yr later and were compared with those that were obtainedat similar times from kidney transplant recipients with diabetes.Mesangial expansion was lower in the recipients of PAK thanin the recipients of kidney alone; in contrast, GBM width wasnot different in the two groups. PAK patients had smaller glomeruli,suggesting that the glomerular enlargement induced by diabetesis reversible. Therefore, PT, performed simultaneously or withina few years after kidney transplant, can prevent or halt progressionof diabetic glomerulopathy lesions (19–21).
The impact of glycemic control on progression from microalbuminuriato overt nephropathy is less clear (22). In a small study of26 microalbuminuric patients with type 1 diabetes, during 10yr of follow-up, progression to overt nephropathy was associatedwith poor metabolic control (23). The Steno I study (24) demonstratedthat 2 yr of strict metabolic control by intensified insulintreatment was effective in reducing progression to overt nephropathyin microalbuminuric patients with type 1 diabetes. In the DCCT,there was no difference in the number of patients who progressedfrom microalbuminuria to overt nephropathy between the intensivelyand conventionally treated patients (25); it should be keptin mind, however, that at the end of the DCCT, only 10 of the73 originally microalbuminuric patients had progressed to proteinuria(25). The beneficial effects of tight glycemic control, in contrast,clearly emerged during the subsequent 8 yr (EDIC Study); indeed,despite no difference in metabolic control between groups, patientswho were treated intensively during DCCT had a risk reductionto progress to proteinuria of 84% compared with conventionallytreated patients (13). These findings suggest that previousintensive treatment with near normoglycemia during DCCT hadan extended benefit in slowing progression of DN. The UKPDS(11) did not report data on the impact of intensive glucosecontrol on the progression from microalbuminuria to overt nephropathy;however, during the 15 yr of the study, there was a beneficialeffect on both development of proteinuria and doubling of serumcreatinine (11). The Kumamoto study, in a small number of microalbuminuricpatients with type 2 diabetes, reported a significant reductionin progression to proteinuria in patients who were on an intensiveinsulin regimen (26). The effects of improved metabolic controlon glomerular structure have been tested by sequential kidneybiopsies in a small group of patients with type 1 diabetes andmicroalbuminuria (27). In this study, nine patients receivedintensive insulin therapy and nine received conventional treatment.At the end of follow-up (24 to 36 mo), diabetic glomerulopathylesions progressed less in the intensively treated group thanin the conventionally treated group (27).
In patients with overt nephropathy, observational studies havedemonstrated the influence of metabolic control on the lossof renal function in both type 1 and type 2 diabetes (22,28,29).However, the influence of glycemic control on the rate of progressionof DN is not supported by large and long-term intervention studies.
Pancreas Transplantation and Secondary Prevention
In patients with diabetes, the possibility to halt or reverseDN lesions can be addressed adequately by studying the recipientsof PT alone (PTA). We studied 13 PTA recipients and found that,despite 5 yr of normoglycemia, there was no amelioration orreversal of the established DN lesions (30).
Of the original cohort of 13 PTA recipients, eight were availablefor studies after 10 yr of normoglycemia (12). The data on renalfunction in these patients are complex to interpret, given theeffects of cyclosporine on GFR and albuminuria. As far as renalstructure is concerned, there was no beneficial effect on glomerularstructure at 5 yr after PTA; in contrast, we observed obviousreversal of diabetic glomerulopathy lesions in all eight patients,with glomerular and tubular morphometric parameters returningto the normal range in several instances. GBM and tubular basementmembrane width, unchanged at 5 yr, decreased at 10 yr of follow-up.The values at 10 yr fell into the normal range in several patientsand in the remaining patients were approaching normal. Mesangialfractional volume and mesangial matrix fractional volume increasedfrom baseline to 5 yr but were lower at 10 yr than at baselineor 5 yr. Light microscopic observations revealed a remarkableremodeling of glomerular architecture in these patients, includingthe total disappearance of Kimmelstiel-Wilson nodular lesionsand reopening of glomerular capillaries that previously werecompressed by mesangial expansion. Therefore, this study providesclear evidence that diabetic glomerular and tubular lesionsare reversible in humans (12).
The reasons for the long delay in reversal of DN lesions areunknown. It can be hypothesized that renal cells have developed"memory" for the diabetic state (31) or that extracellular matrix(ECM) molecules are heavily glycosylated and therefore moreresistant to proteolysis until replaced by less glycosylatedmolecules (32). Nevertheless, the long time necessary for thesediabetic lesions to disappear is consistent with their slowdevelopment. In fact, diabetic renal lesions develop and progressfrom onset of diabetes during at least 1 decade before theycan cause any functional abnormality (2). Regardless of themechanisms involved, at some point after PTA, ECM removal beginsto exceed ECM production. This is abnormal because, normally,renal ECM production and removal remain in near perfect balanceduring adult life. If normal balance had been reestablished,then the renal lesions would have remained stable, but thiswas not the case. In simplest terms, glomerular and tubularcells can "sense" that their ECM environment is abnormal andcan alter their behavior toward ECM removal and architecturalremodeling. Therefore, these studies indicate that diabeticrenal lesions are not only preventable but also reversible.Despite these encouraging results, however, PT cannot be considereda primary treatment for DN. It is possible, however, that thisview will change in the near future with the development ofnonnephrotoxic immunosuppressive agents and with better outcomesof islet transplantation.
In summary, glycemic control significantly influences the rateof progression from microalbuminuria to proteinuria and fromovert nephropathy to ESRD. Although large and long-term randomizedtrials on the effect of improved metabolic control on progressionof DN are lacking, results from PT recipients and the EDIC studysupport the concept that very prolonged periods of extremelygood metabolic control are necessary to have a positive impacton progression or even obtain regression of DN. Therefore, accordingto current guidelines (33), a target of HbA1c level of <7%is recommended in all patients with diabetes to preserve theirkidney function.
US Renal Data System: Annual Data Report 2005. Available: http://www.usrds.org/adr.htm. Accessed February 23, 2006
Parving H-H, Mauer M, Ritz E: Diabetic nephropathy. In:
Brenner and Rector’s the Kidney, 7th Ed., edited by Brenner BM, Philadelphia, WB Saunders, 2004
, pp 1777
–1818
Pirart J: Diabetes mellitus and its degenerative complications: A prospective study of 4,400 patients observed between 1947 and 1973.
Diabetes Metab 3
: 173
–182, 1977
Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR: The changing natural history of nephropathy in type I diabetes.
Am J Med 78
: 785
–794, 1985[CrossRef][Medline]
The EURODIAB IDDM Complications Study Group: Microvascular and acute complications in insulin dependent diabetes mellitus: The EURODIAB IDDM Complications Study.
Diabetologia 37
: 278
–285, 1994[Medline]
Steffes MW, Sutherland DER, Goetz FC, Rich SS, Mauer SM: Studies of kidney and muscle biopsy specimens from identical twins discordant for type I diabetes mellitus.
N Engl J Med 312
: 1282
–1287, 1985[Abstract]
Mauer SM, Goetz FC, McHugh LE, Sutherland DE, Barbosa J, Najarian JS, Steffes MW: Long-term study of normal kidneys transplanted into patients with type I diabetes.
Diabetes 38
: 516
–523, 1989[Abstract]
Mauer SM, Steffes MW, Connett J, Najarian JS, Sutherland DE, Barbosa J: The development of lesions in the glomerular basement membrane and mesangium after transplantation of normal kidneys into diabetic patients.
Diabetes 32
: 948
–952, 1983[Abstract]
Barbosa J, Steffes MW, Sutherland DER, Connett JE, Rao KV, Mauer SM: The effect of glycemic control on early diabetic renal lesions. A 5-year randomized controlled clinical trial of insulin-dependent diabetic kidney transplant recipients.
JAMA 272
: 600
–606, 1994[Abstract]
Diabetes Complications and Control Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin dependent diabetes mellitus.
N Engl J Med 329
: 977
–986, 1993[Abstract/Free Full Text]
UKPDS Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes.
Lancet 352
: 837
–853, 1998[CrossRef][Medline]
Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M: Reversal of lesions of diabetic nephropathy after pancreas transplantation.
N Engl J Med 339
: 69
–75, 1998[Abstract/Free Full Text]
Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) study.
JAMA 290
: 2159
–2167, 2003[Abstract/Free Full Text]
Ohkubo Y, Kishikawa H, Araki E: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with noninsulin dependent diabetes: A randomized prospective 6-year study.
Diab Res Clin Pract 28
: 103
–117, 1995[CrossRef][Medline]
Krolewski AS, Laffel LMB, Krolewski M, Quinn M, Warram JH: Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus.
N Engl J Med 332
: 1251
–1255, 1995[Abstract/Free Full Text]
The Diabetes Control and Complications Study Group: The absence of a glycemic threshold for the development of long-term complications: The perspective of the Diabetes Control and Complications Trial.
Diabetes 45
: 1289
–1298, 1996[Abstract]
Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study.
BMJ 321
: 405
–412, 2000[Abstract/Free Full Text]
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 60
: 219
–227, 2001[CrossRef][Medline]
Wilczek HE, Jaremko G, Tyden G, Groth CG: Pancreatic graft protects a simultaneously transplanted kidney from developing diabetic nephropathy: A 1 to 6 year follow-up study.
Transplant Proc 1
: 1314
–1315, 1993
Bilous RW, Mauer SM, Sutherland DER, Najarian JS, Goetz FC, Steffes MW: The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes.
N Engl J Med 32
: 80
–85, 1989
Rossing P, Hougaard P, Parving HH: Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: A 10-year prospective observational study.
Diabetes Care 25
: 859
–864, 2002[Abstract/Free Full Text]
Bojestig M, Arnqvist HJ, Karlberg BE, Ludgvisson J: Glycemic control and prognosis in type 1 diabetic patients with microalbuminuria.
Diabetes Care 19
: 313
–317, 1996[Abstract]
Felt-Rasmussen B, Mathiesen ER, Deckert T: Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes.
Lancet 2
: 1300
–1304, 1986[CrossRef][Medline]
The Diabetes Control and Complications Trial Research Group: Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial.
Kidney Int 47
: 1703
–1720, 1995[Medline]
Shichiri M, Kishikawa H, Ohkubo Y, Wake N: Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients.
Diabetes Care 23[Suppl 2]
: B21
–B29, 2000
Bangstad HJ, Osterby R, Dahl-Jorgensen K, Berg KJ, Hartmann A, Hanssen KF: Improvement of blood glucose control in IDDM patients retards progression of morphologic changes in early diabetic nephropathy.
Diabetologia 37
: 483
–490, 1994[CrossRef][Medline]
Rossing K, Christensen PK, Hovind P, Tarnow L, Rossing P, Parving HH: Progression of nephropathy in type 2 diabetic patients.
Kidney Int 66
: 1596
–1605, 2004[CrossRef][Medline]
Fioretto P, Mauer SM, Bilous RW, Goetz FC, Sutherland DER, Steffes MW: Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys.
Lancet 342
: 1193
–1196, 1993[CrossRef][Medline]
Roys S, Sala R, Cagliero E, Lorenzi M: Overexpression of fibronectin induced by diabetes or high glucose: Phenomenon with a memory.
Proc Natl Acad Sci U S A 87
: 404
–408, 1990[Abstract/Free Full Text]
Brownlee M, Cerami A, Vlassara H: Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications.
N Engl J Med 318
: 1315
–1322, 1988[Medline]
Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, Steffes MW; American Diabetes Association: Nephropathy in diabetes.
Diabetes Care 27[Suppl]
: S79
–S83, 2004
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Abstract
Introduction
