Clinical and cellular markers of diabetic nephropathy
2003; Elsevier BV; Volume: 63; Issue: 6 Linguagem: Inglês
10.1046/j.1523-1755.2003.00053.x
ISSN1523-1755
Autores Tópico(s)Birth, Development, and Health
ResumoA 21-year-old white woman was referred for evaluation of microalbuminuria. She stated that at the age of 11 a diagnosis of diabetes was made because of polyuria and polydipsia, and she was begun on a regimen of insulin. Two months later, she was hospitalized with an episode of diabetic ketoacidosis. Review of her medical records revealed no further episodes of ketoacidosis. During her adolescence, compliance with insulin therapy was problematic despite frequent counseling and adjustment of her insulin dose. On one evaluation at the age of 18, her blood glucose was 200 mg/dL, and her plasma electrolytes, blood urea nitrogen (BUN), and serum creatinine were in the normal range. Her blood pressure while seated was 122/70 mm Hg, and her heart rate was 86 beats/min. A urinalysis was normal with a negative dipstick for protein; a 24-hour urine collection revealed a creatinine clearance of 125 mL/min, and a urine albumin excretion (UAE) rate of 20 mg/24 hours (normal, 0–30 mg/24 hours) Figure 1. Over the following years, her glycemic control was poor, as revealed by glycosylated hemoglobin (HbA1c) ranging between 9% and 11%. When she was 20 years old, her pediatrician found that the urine albumin excretion had increased to 200 mg/24 hours and referred the patient to us for nephrologic evaluation. Therapy with an angiotensin-converting enzyme (ACE) inhibitor was considered by her pediatrician but not initiated at that time because the patient was reluctant to start this treatment in the event that she became pregnant. When the patient was evaluated in our office at the age of 21, we did not elicit a family history of renal disease. Her social history was negative for tobacco, alcohol, and recreational drug use. Her medications included insulin, 10–15 units of NPH and 20–25 units of regular insulin in the morning and 8 units of NPH insulin and 10–15 units of regular insulin before dinner. Her blood pressure was 121/68 mm Hg in the seated position and 120/68 mm Hg in the standing position. Her heart rate was 70 beats/min and 75 beats/min in the seated and standing positions, respectively. Her fundi showed mild proliferative changes. No hemorrhages were seen. Her abdomen was soft, and no masses were felt. Her pulses in the lower extremities were 2+ bilaterally. At that time the BUN and serum creatinine were 15 mg/dL and 1.1 mg/dL, respectively. Her blood glucose was 160 mg/dL and HbA1c was 9.9%. Her serum electrolytes were: sodium, 138 mmol/L; potassium, 4.1 mmol/L; calcium, 8.5 mg/dL (2.2 mmol/L); and chloride, 103 mmol/L. Total cholesterol was 190 mg/dL; fasting triglycerides, 140 mg/dL. Dipstick urinalysis was negative for protein; a 24-hour urine collection indicated a glomerular filtration rate (GFR) (creatinine clearance) of 115 mL/min, and an albumin excretion rate of 250 mg/24 hours Figure 1. A 24-hour ambulatory blood pressure monitoring was done at this time Figure 2. Mean systolic and diastolic blood pressures were 122 mm Hg and 70 mm Hg, respectively. Mean systolic and diastolic blood pressures during the sleep period were 121 mm Hg and 69 mm Hg, respectively. Mean systolic and diastolic blood pressures during daily activities were 123 mm Hg and 71 mm Hg, respectively. At that time, renoprotective therapy with an ACE inhibitor, captopril at a dose of 25 mg orally twice daily, was initiated. She also was referred to the Endocrinology Clinic to optimize her glycemic control. Dr. Daniel Batlle (Chief, Division of Nephrology; and Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA): Diabetic nephropathy is a microvascular complication of both type 1 and type 2 diabetes, which is associated with end-stage renal disease (ESRD) and premature death from cardiovascular disease1.Borch-Johnsen K. Andersen P.K. Deckert T. The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus.Diabetologia. 1985; 28: 590-596Crossref PubMed Scopus (518) Google Scholar,2.Parving H.-H. Nephrology Forum: Diabetic nephropathy: Prevention and treatment.Kidney Int. 2001; 60: 2041-2055Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar. The development of clinical nephropathy is insidious, and macroalbuminuria [urinary albumin excretion rate>300 mg/24 hours], the hallmark of the condition, is preceded by a phase of microalbuminuria (UAE 30–300 mg/24 hours), which usually lasts 5 to 10 years. As albuminuria worsens and blood pressure increases, there is a relentless decline in GFR and progression to ESRD2.Parving H.-H. Nephrology Forum: Diabetic nephropathy: Prevention and treatment.Kidney Int. 2001; 60: 2041-2055Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar. Tight metabolic control can reduce the incidence of nephropathy3.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. 1995; 47: 1703-1720Abstract Full Text PDF PubMed Scopus (701) Google Scholar, but hyperglycemia alone is not sufficient for the development of nephropathy. This is apparent from the finding that nephropathy develops in some patients with type 1 diabetes despite good glycemic control and that a substantial proportion of patients with poor control escape diabetic nephropathy4.Borch-Johnsen K. Norgaard K. Hommel E. et al.Is diabetic nephropathy an inherited complication?.Kidney Int. 1992; 41: 719-722Abstract Full Text PDF PubMed Scopus (290) Google Scholar, 5.Krolewski A.S. Canessa M. Warran J.H. et al.Predisposition to hypertension and susceptibility to renal disease in insulin-dependent mellitus.N Engl J Med. 1998; 318: 140-145Crossref Scopus (614) Google Scholar, 6.Seaquist E.R. Goetz F.C. Rich S. Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.N Engl J Med. 1989; 320: 1161-1165Crossref PubMed Scopus (881) Google Scholar, 7.Quinn M. Angelico M.C. Warran J.H. Krolewski A.L. Familial factors determine the development of diabetic nephropathy in patients with IDDM.Diabetology. 1996; 39: 940-945Crossref PubMed Scopus (400) Google Scholar, 8.Diabetes Control and Complications Trial Research Group Clustering of long term complications in families with diabetes in the Diabetes Control and Complications Trials.Diabetes. 1997; 46: 1829-1839Crossref PubMed Google Scholar, 9.Fioretto P. Steffes M.W. Barbosa J. et al.Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs.Diabetes. 1999; 48: 865-869Crossref PubMed Scopus (64) Google Scholar, 10.Earle K. Walker J. Hill C. Viberti G. Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy.N Engl J Med. 1992; 326: 673-677Crossref PubMed Scopus (195) Google Scholar. Overall, only about one-third of type 1 diabetes patients develop nephropathy, and the risk of nephropathy appears, at least in part, to be genetically determined4.Borch-Johnsen K. Norgaard K. Hommel E. et al.Is diabetic nephropathy an inherited complication?.Kidney Int. 1992; 41: 719-722Abstract Full Text PDF PubMed Scopus (290) Google Scholar, 5.Krolewski A.S. Canessa M. Warran J.H. et al.Predisposition to hypertension and susceptibility to renal disease in insulin-dependent mellitus.N Engl J Med. 1998; 318: 140-145Crossref Scopus (614) Google Scholar, 6.Seaquist E.R. Goetz F.C. Rich S. Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.N Engl J Med. 1989; 320: 1161-1165Crossref PubMed Scopus (881) Google Scholar, 7.Quinn M. Angelico M.C. Warran J.H. Krolewski A.L. Familial factors determine the development of diabetic nephropathy in patients with IDDM.Diabetology. 1996; 39: 940-945Crossref PubMed Scopus (400) Google Scholar, 8.Diabetes Control and Complications Trial Research Group Clustering of long term complications in families with diabetes in the Diabetes Control and Complications Trials.Diabetes. 1997; 46: 1829-1839Crossref PubMed Google Scholar, 9.Fioretto P. Steffes M.W. Barbosa J. et al.Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs.Diabetes. 1999; 48: 865-869Crossref PubMed Scopus (64) Google Scholar, 10.Earle K. Walker J. Hill C. Viberti G. Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy.N Engl J Med. 1992; 326: 673-677Crossref PubMed Scopus (195) Google Scholar, 11.Bain S.C. Chowdhury T.A. Genetics of diabetic nephropathy and MA.J R Soc Med. 2000; 93: 62-66PubMed Google Scholar. Strong evidence for genetic factors in nephropathy came from studies of families with type 1 diabetes6.Seaquist E.R. Goetz F.C. Rich S. Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.N Engl J Med. 1989; 320: 1161-1165Crossref PubMed Scopus (881) Google Scholar, 7.Quinn M. Angelico M.C. Warran J.H. Krolewski A.L. Familial factors determine the development of diabetic nephropathy in patients with IDDM.Diabetology. 1996; 39: 940-945Crossref PubMed Scopus (400) Google Scholar, 8.Diabetes Control and Complications Trial Research Group Clustering of long term complications in families with diabetes in the Diabetes Control and Complications Trials.Diabetes. 1997; 46: 1829-1839Crossref PubMed Google Scholar, 9.Fioretto P. Steffes M.W. Barbosa J. et al.Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs.Diabetes. 1999; 48: 865-869Crossref PubMed Scopus (64) Google Scholar. In families with two or more siblings with type 1 diabetes, when one sibling has developed nephropathy, the other has a fourfold risk of nephropathy compared with a sibling of a patient without nephropathy4.Borch-Johnsen K. Norgaard K. Hommel E. et al.Is diabetic nephropathy an inherited complication?.Kidney Int. 1992; 41: 719-722Abstract Full Text PDF PubMed Scopus (290) Google Scholar,6.Seaquist E.R. Goetz F.C. Rich S. Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.N Engl J Med. 1989; 320: 1161-1165Crossref PubMed Scopus (881) Google Scholar. In a larger study7.Quinn M. Angelico M.C. Warran J.H. Krolewski A.L. Familial factors determine the development of diabetic nephropathy in patients with IDDM.Diabetology. 1996; 39: 940-945Crossref PubMed Scopus (400) Google Scholar, if the proband had nephropathy, the cumulative risk of nephropathy to diabetic siblings was 71.5%, and the risk fell to 25.4% when the proband did not have nephropathy2.Parving H.-H. Nephrology Forum: Diabetic nephropathy: Prevention and treatment.Kidney Int. 2001; 60: 2041-2055Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar. A recent analysis of the Diabetes Control and Complications Trial (DCCT) cohort has confirmed these findings8.Diabetes Control and Complications Trial Research Group Clustering of long term complications in families with diabetes in the Diabetes Control and Complications Trials.Diabetes. 1997; 46: 1829-1839Crossref PubMed Google Scholar. Other factors have been suggested as determinants of risk for diabetic nephropathy, including a family history of hypertension5.Krolewski A.S. Canessa M. Warran J.H. et al.Predisposition to hypertension and susceptibility to renal disease in insulin-dependent mellitus.N Engl J Med. 1998; 318: 140-145Crossref Scopus (614) Google Scholar,12.Viberti G.C. Keen H. Wiseman M.J. Raised arterial pressure in parents of proteinuric insulin-dependent diabetics.Br J Med. 2000; 93: 62-66Google Scholar. Parents of patients with type 1 diabetes who develop nephropathy have higher arterial blood pressures than do parents of patients who have no nephropathy13.Brazilay J. Warram J.H. Bak M. et al.Predisposition to hypertension: Risk factors for nephropathy and hypertension in IDDM.Kidney Int. 1992; 41: 723-730Abstract Full Text PDF PubMed Scopus (120) Google Scholar. Moreover, parents of type 1 diabetic patients with nephropathy seem to have an increased incidence of cardiovascular disease as compared with parents of type 1 diabetic patients with normal albumin excretion10.Earle K. Walker J. Hill C. Viberti G. Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy.N Engl J Med. 1992; 326: 673-677Crossref PubMed Scopus (195) Google Scholar. Albuminuria, cardiovascular disease, and hypertension might be linked by an inherited predisposition to insulin resistance. Patients with nephropathy are more insulin-resistant than are non-nephropathic patients14.Yip J. Mattock M.B. Morocutti A. et al.Insulin resistance in insulin-dependent diabetic patients with MA.Lancet. 1993; 342: 883-887Abstract PubMed Scopus (226) Google Scholar. Insulin resistance also has been noted in parents of type 1 diabetic patients with proteinuria14.Yip J. Mattock M.B. Morocutti A. et al.Insulin resistance in insulin-dependent diabetic patients with MA.Lancet. 1993; 342: 883-887Abstract PubMed Scopus (226) Google Scholar. These clinical markers of increased risk for diabetic nephropathy are useful in themselves, but we also need genetic markers to define people at risk for nephropathy when the diagnosis of diabetes is made. Identification at an early age would not only allow for more intensive follow-up of such patients, but also would provide insight for the design of therapeutic approaches based on the particular genetic marker11.Bain S.C. Chowdhury T.A. Genetics of diabetic nephropathy and MA.J R Soc Med. 2000; 93: 62-66PubMed Google Scholar. Genes encoding the various components of the renin-angiotensin-aldosterone system seem logical candidates for a genetic marker of susceptibility to nephropathy and its associated cardiovascular disease. No significant genetic marker of diabetic nephropathy has been conclusively identified among the components of the renin-angiotensin system or other potential candidates such as the aldose reductase gene and the apolipoprotein E gene11.Bain S.C. Chowdhury T.A. Genetics of diabetic nephropathy and MA.J R Soc Med. 2000; 93: 62-66PubMed Google Scholar. Recent studies, however, suggest that certain polymorphisms of the ACE gene might identify type 1 diabetic patients in whom diabetic nephropathy progresses at a faster rate (DD genotype) and those who are responsive to renoprotective intervention using ACE inhibitors. These findings were discussed by Dr. Hans-Henrich Parving in a recent Forum2.Parving H.-H. Nephrology Forum: Diabetic nephropathy: Prevention and treatment.Kidney Int. 2001; 60: 2041-2055Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, and I will not review them here. A marker is not necessarily based on the genotype (that is, an alteration of DNA), but it can be based on phenotypic features, clinical or biochemical, that predict with reasonable sensitivity and specificity the susceptibility to diabetic nephropathy before it becomes clinically evident15.Mogyorosi A. Ziyadeh F.N. Update on pathogenesis, markers and management of diabetic nephropathy.Curr Opin Nephrol Hypertens. 1996; 5: 243-253Crossref PubMed Scopus (27) Google Scholar. Table 1 lists markers of diabetic nephropathy classified as clinical, cellular, or genetic. In this classification, the term marker is used loosely, in that it implies a predictive value for the development of nephropathy. In this context, the best available predictor of diabetic nephropathy to date is microalbuminuria. By the time it develops, however, many patients have already advanced renal structural changes on renal biopsy16.Chavers B.M. Bilous R.W. Ellis E.N. et al.Glomerular lesions and urinary albumin excretion in type 1 diabetic patients without overt proteinuria.N Engl J Med. 1989; 320: 966-970Crossref PubMed Scopus (256) Google Scholar, 17.Fioretto P. Steffes M.W. Mauer S.M. Glomerular structure in nonproteinuric insulin-dependent diabetic patients with various levels of albuminuria.Diabetes. 1994; 43: 1358-1364Crossref PubMed Scopus (241) Google Scholar, 18.Bangstad H.J. Osterby R. Dahl-Jorgensen K. et al.Early glomerulopathy is present in young, type 1 (insulin-dependent) diabetic patients with MA.Diabetologia. 1993; 36: 523-529Crossref PubMed Scopus (92) Google Scholar. This suggests that rather than being a predictor of diabetic nephropathy, microalbuminuria is a marker of established nephropathy. As part of my discussion of the patient presented here, I will try to distinguish between a marker and a predictor of nephropathy. Later we will look at the potential role of cellular markers of diabetic nephropathy, such as overactivity of the Na+/H+ antiporter and phenotypic features of altered cell growth.Table 1Markers of diabetic nephropathy in type 1 diabetesClinicalCellular phenotypesGenetic markers (potential)MicroalbuminuriaIncreased erythrocyte Na+/Li+ countertransportAngiotensin-converting enzymeFamily history of nephropathyNa+/H+ antiporter overactivityAngiotensinogenFamily history of HTN and/or insulin resistanceAltered cell growthAngiotensin II, type 1 receptorIncreased GFRCell cycle regulatory proteins (decreased p16?)Aldolase reductaseNocturnal HTN (non-dipping status)Apolipoprotein E Open table in a new tab When today's patient with type 1 diabetes was evaluated at the age of 21, she had developed microalbuminuria Figure 1. Her GFR, estimated by the creatinine clearance, was in the normal range, as is usually the case in microalbuminuric patients with type 1 diabetes. Her blood pressure was likewise in the normal range, which also is usual for type 1 diabetics with microalbuminuria19.Lurbe A. Redon J. Pascual J.M. et al.Altered blood pressure during sleep in normotensive subjects with type 1 diabetes.Hypertension. 1993; 21: 227-235Crossref PubMed Scopus (141) Google Scholar,20.Parving H-H. Rossing P. Tarnow L. et al.Circadian rhythm of arterial pressure and albuminuria in diabetic nephropathy.Kidney Int. 1996; 50: 579-589Abstract Full Text PDF Google Scholar. This finding is in sharp contrast with patients with type 2 diabetes, in whom blood pressure is always elevated by the time microalbuminuria is documented21.Parving H-H. Lehnert H. Brochner-Mortensen J. et al.The irbesartan in patients with type 2 diabetes and MA study group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2845) Google Scholar. In fact, type 2 diabetics are usually overtly hypertensive (that is, systolic blood pressure>145 mm Hg) when the diagnosis of diabetes is made. With this background in mind, I would like to address two main issues: the likelihood of progression to overt proteinuria from microalbuminuria, and whether microalbuminuria could have been predicted in this patient when she was first seen years ago by her pediatrician. Until recently, if we had asked whether the microalbuminuria would have progressed to overt proteinuria, the answer would have been a resounding "yes." That is, it was only a matter of time before she progressed from microalbuminuria to overt proteinuria, as depicted in the typical course of nephropathy in type 1 diabetics Figure 1. Indeed, initial retrospective studies in type 1 diabetics reported in the 1980s that the risk for progression from microalbuminuria to proteinuria over a period of 6 to 14 years was as high as 80%22.Parving H-H. Oxenbol B. Svendsen P.A. et al.Early detection of patients at risk of developing diabetic nephropathy: A longitudinal study of urinary albumin excretion.Acta Endocrinol (Copenh). 1982; 100: 550-555PubMed Google Scholar, 23.Viberti G.C. Hill R.D. Jarret R.J. et al.Microalbuminuria as a predictor of a clinical nephropathy in insulin-dependent diabetes mellitus.Lancet. 1982; 1: 1430-1432Abstract PubMed Scopus (1402) Google Scholar, 24.Mogensen C.E. Christensen C.K. Predicting diabetes in insulin-dependent patients.N Engl J Med. 1984; 311: 89-93Crossref PubMed Scopus (1369) Google Scholar. Such a high predictive value led to the broad acceptance of microalbuminuria as a predictor of diabetic nephropathy. This view, however, is no longer acceptable. Caramori, Fioretto, and Mauer25.Caramori M.L. Fioretto P. Mauer M. The need for early predictors of diabetic nephropathy risk: Is albumin excretion rate sufficient?.Diabetes. 2000; 49: 1399-1408Crossref PubMed Scopus (351) Google Scholar have convincingly argued that microalbuminuria is likely a marker rather than a predictor of renal structural changes. This argument is based on the finding that in some patients with microalbuminuria, renal lesions are already quite advanced11.Bain S.C. Chowdhury T.A. Genetics of diabetic nephropathy and MA.J R Soc Med. 2000; 93: 62-66PubMed Google Scholar, 12.Viberti G.C. Keen H. Wiseman M.J. Raised arterial pressure in parents of proteinuric insulin-dependent diabetics.Br J Med. 2000; 93: 62-66Google Scholar, 13.Brazilay J. Warram J.H. Bak M. et al.Predisposition to hypertension: Risk factors for nephropathy and hypertension in IDDM.Kidney Int. 1992; 41: 723-730Abstract Full Text PDF PubMed Scopus (120) Google Scholar. I know of no prospective data regarding rates of progression based on results of renal biopsy. For individuals with advanced renal lesions, microalbuminuria is not a predictor, but simply a sign of established nephropathy. In others with only mild lesions on renal biopsy, microalbuminuria might not be a predictor of nephropathy. On the other hand, regardless of findings on renal biopsy, microalbuminuria would be a powerful predictor of nephropathy if most patients were to progress to overt proteinuria as initially reported. However, more recent studies have clearly shown that the percentage of microalbuminuric patients progressing to proteinuria over more than 10 years is only 30% to 45%25.Caramori M.L. Fioretto P. Mauer M. The need for early predictors of diabetic nephropathy risk: Is albumin excretion rate sufficient?.Diabetes. 2000; 49: 1399-1408Crossref PubMed Scopus (351) Google Scholar, 26.Forsblom C.M. Groop P-H. Ekstrand A. Groop L.C. Predictive value of MA in patients with insulin-dependent diabetes of long duration.Br Med J. 1992; 305: 1051-1053Crossref PubMed Scopus (128) Google Scholar, 27.Rundberg S. Persson B. Dahlquist G. Increased glomerular filtration rate as a predictor of diabetic nephropathy: an 8 year prospective study.Kidney Int. 1992; 41: 822-828Abstract Full Text PDF PubMed Scopus (292) Google Scholar. Of the remaining patients in these more recent studies, 30% became normoalbuminuric, and the rest remained microalbuminuric25.Caramori M.L. Fioretto P. Mauer M. The need for early predictors of diabetic nephropathy risk: Is albumin excretion rate sufficient?.Diabetes. 2000; 49: 1399-1408Crossref PubMed Scopus (351) Google Scholar. It should be noted that interpretation of the data should take into account disease duration, as most diabetic patients destined to develop proteinuria will do so within 20 years. Duration of diabetes is often shorter in subjects with microalbuminuria progressing to proteinuria (17 ± 8 years) than in those remaining with microalbuminuria (22 ± 9 years, P < 0.005)25.Caramori M.L. Fioretto P. Mauer M. The need for early predictors of diabetic nephropathy risk: Is albumin excretion rate sufficient?.Diabetes. 2000; 49: 1399-1408Crossref PubMed Scopus (351) Google Scholar. In today's 21-year-old patient, diabetes was diagnosed at the age of 11 and microalbuminuria at the age of 20. Accordingly, it is too early to predict, based on the criteria of microalbuminuria and disease duration, whether she will progress to proteinuria. If she remains microalbuminuric for another 10 years, her risk for progression to proteinuria from that point on (that is, after about 20 years of disease duration) is increasingly low. With a disease duration of less than 15 years, the rate of progression from microalbuminuria to proteinuria over the next 5 to 10 years has been estimated to be as much as 45%25.Caramori M.L. Fioretto P. Mauer M. The need for early predictors of diabetic nephropathy risk: Is albumin excretion rate sufficient?.Diabetes. 2000; 49: 1399-1408Crossref PubMed Scopus (351) Google Scholar. This risk is still below the risk of nephropathy (about 80%) estimated from earlier studies. The impact of therapy with an ACE inhibitor and/or improved glycemic control on progression from microalbuminuria to proteinuria also needs to be considered. The DCCT demonstrated a positive effect of improved glycemic control on preventing microalbuminuria, but not on the progression from microalbuminuria to proteinuria3.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. 1995; 47: 1703-1720Abstract Full Text PDF PubMed Scopus (701) Google Scholar. Therapy with ACE inhibitors, by contrast, retards the progression from microalbuminuria to proteinuria (see28.The ACE Inhibitors in Diabetic Nephropathy Trialist Group Should all type 1 diabetic microalbuminuric patients receive ACE inhibitors? A meta-regression analysis.Ann Intern Med. 2001; 134: 370-379Crossref PubMed Scopus (371) Google Scholar for review). As documented by a meta-regression analysis, ACE inhibitors reduce the progression from microalbuminuria to overt proteinuria by 62% compared to placebo28.The ACE Inhibitors in Diabetic Nephropathy Trialist Group Should all type 1 diabetic microalbuminuric patients receive ACE inhibitors? A meta-regression analysis.Ann Intern Med. 2001; 134: 370-379Crossref PubMed Scopus (371) Google Scholar. Importantly, the impact of ACE inhibitors on preventing progression from microalbuminuria to overt nephropathy lasts for many years and is associated with preservation of GFR29.Mathiesen E.R. Hommel E. Hansen H.P. et al.Randomized controlled trial of long term efficacy of captopril and preservation of kidney function in normotensive patients with insulin dependent diabetes and MA.Br Med J. 1999; 319: 24-25Crossref PubMed Google Scholar. Other predictors of progression from microalbuminuria to proteinuria that should be considered include a family history of diabetes, an abnormal lipid profile, and smoking2.Parving H.-H. Nephrology Forum: Diabetic nephropathy: Prevention and treatment.Kidney Int. 2001; 60: 2041-2055Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, none of which was present in our patient. Based on the foregoing considerations, I conclude that while our patient is clearly at risk for progressing to overt nephropathy, her risk is less than 50%, far below the 80% estimated from earlier studies. Indeed, persistent microalbuminuria does not predict clinical proteinuria with more than 50% accuracy25.Caramori M.L. Fioretto P. Mauer M. The need for early predictors of diabetic nephropathy risk: Is albumin excretion rate sufficient?.Diabetes. 2000; 49: 1399-1408Crossref PubMed Scopus (351) Google Scholar. Clearly we need additional markers or predictors of diabetic nephropathy. Moreover, with appropriate therapy, which includes optimization of glycemic control and the use of an ACE inhibitor or perhaps an angiotensin receptor antagonist, the risk of progression to overt proteinuria in our patient could be further reduced. Both interventions seem in order, and it is quite conceivable that they have an additive or even a synergistic effect. I will now address the second issue, namely, whether we could have predicted that this patient was going to develop microalbuminuria when she was normoalbuminuric. At present, there is no simple way to predict the development of microalbuminuria among type 1 diabetics. Only about 25% to 30% of patients with type 1 diabetes develop overt nephropathy, so one could infer that, in general, the risk for developing microalbuminuria cannot be much higher than that. This assumes that the development of proteinuria (macroalbuminuria) is always preceded by a microalbuminuric phase that is always progressive, but this might not be the case. Forsblom et al26.Forsblom C.M. Groop P-H. Ekstrand A. Groop L.C. Predictive value of MA in patients with insulin-dependent diabetes of long duration.Br Med J. 1992; 305: 1051-1053Crossref PubMed Scopus (128) Google Scholar found that about 7% of normoalbuminuric patients progressed to proteinuria and 14% to microalbuminuria over 10 years of follow-up. Thus, progression took place in 21% of the patients when one adds both groups. In a different study, Mathiesen et al29.Mathiesen E.R. Hommel E. Hansen H.P. et al.Randomized controlled trial of long term efficacy of captopril and preservation of kidney function in normotensive patients with insulin dependent diabetes and MA.Br Med J. 1999; 319: 24-25Crossref PubMed Google Scholar found a somewhat lower progression rate of microalbuminuria (10%) over a mean observation also of 10 years. Based on this and the review of other studies, Caramori, Fioretto, and Mauer25.Caramori M.L. Fioretto P. Mauer M. The need for early predictors of diabetic nephropathy risk: Is albumin excretion rate sufficient?.Diabetes. 2000; 49: 1399-1408Crossref PubMed Scopus (351) Google Scholar estimated that 5% of normoalbuminuric patients with at least 7 years of type 1 diabetes will progress to proteinuria over the following 5 to 10 years, whereas 17% will progress from normoalbuminuria to microalbuminuria. In a recent study, we found that in adolescents and young adults with type 1 diabetes, progression from normoalbuminuria to microalbuminuria over a follow-up of approximately 5 years occurred in 18%30.Lurbe E. Redon J. Kesani A. et al.Increase in nocturnal blood pressure and progression to micr
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