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NIDDM
AJH
1997;10:202S–207S
Pathogenesis and Course of Renal Disease in IDDM/NIDDM Differences and Similarities Eberhard Ritz, Christine Keller, Kristian Bergis, and Krzysztof Strojek
In the past the opinion prevailed that renal prognosis was less adverse in non–insulindependent diabetes mellitus (NIDDM) as compared with insulin-dependent diabetes mellitus (IDDM). This notion has to be revised in the light of recent evidence, based on epidemiologic data of NIDDM patients reaching endstage renal failure and a comparison of the cumulative prevalence of proteinuria and renal failure, respectively, in NIDDM as compared with IDDM. It has also been established that initial renal hemodynamic changes are quite comparable
in NIDDM and in IDDM. It follows that past complacency about the renal sequelae of NIDDM is no longer justified and that preventive measures to interfere with the development of diabetic nephropathy are similarly important in NIDDM and IDDM. Am J Hypertens 1997;10:202S–207S © 1997 American Journal of Hypertension, Ltd.
I
renal failure,2 in contrast with 30% to 40% in IDDM. We feel, however, that this reflects a biostatistical artifact: the risk of endstage renal failure competes with the risk of cardiovascular death. Because of the high rate of cardiovascular death in elderly persons with NIDDM, few with NIDDM used to live long enough to experience endstage renal failure. As described in detail elsewhere,3 this situation has changed dramatically. Table 1 compares the incidence of endstage renal failure in Lombardia,4 in southwest Germany,5 and for the US among white citizens.6 It is obvious that in Germany the incidence of endstage renal failure (ESRF) in diabetic patients has approached the figures reported from the US, at least in white persons. In contrast, in northern Italy, the incidence is still only one fifth of what is observed in Germany. There was no difference concerning IDDM reaching ESRF; the difference between northern Italy and southwest Germany was entirely accounted for by the high incidence of ESRF in patients with NIDDM. This trend has continued. In 1990 the proportion of diabetics among
n the not too distant past, it was thought that non–insulin-dependent diabetes mellitus (NIDDM) carried a benign renal prognosis, in contrast to insulin-dependent diabetes mellitus (IDDM). In 1982 Fabre et al1 reported the experience of the Geneva clinic with 510 patients with NIDDM. They found that only 43 patients had a reduction of glomerular filtration rate (GFR) (corrected for age) and only one patient progressed to endstage renal failure but this patient suffered from superimposed glomerulonephritis. It is known that in the distant past only ;5% of patients with NIDDM went into endstage
From the Department Internal Medicine, University of Heidelberg, Heidelberg, (ER, CK); FIDAM Forschungsinstitut der Diabetes-Akademie Bad Mergentheim, Bad Mergentheim, Germany (KB); and Silesian Medical Academy, Sabrze, Poland (KS). Address correspondence and reprint requests to Professor Dr. med. Eberhard Ritz, FRCP (Lond. and Edinb.), FACP, Department of Internal Medicine, Bergheimer Straße 58, D-69115 Heidelberg, Germany.
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Non–insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, renal disease, proteinuria.
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TABLE 1. INCIDENCE OF TERMINAL RENAL FAILURE Total (pat/mio/year)
Diabetic Pattern (pat/mio/year)
Type I (pat/mio/year)
Type II (pat/mio/year)
Type II (%)
102 125 150
10 52 46
5 5 *
5 47 *
50 90 *
Lombardy Lower Neckar region USA (white) * Not specified.
patients admitted for ESRF to Heidelberg University was 36%; in 1991, 44%; 1994, 52%; and in 1995, no less than 95%.7 In 1995, 90% of the patients had NIDDM. It is obvious that in Europe a continuous increase of the number of NIDDM patients reaching ESRF is currently observed. Obviously the question arises as to whether all those with NIDDM reaching ESRF actually develop ESRF as a consequence of Kimmelstiel Wilson’s disease. In two independent studies, we found that more than 20% of NIDDM patients had some other type of primary chronic renal disease, for example, reflux nephropathy, glomerulonephritis, polycystic kidney disease, analgesic nephropathy, etc. This has also been found by others.10 This percentage appears to be more than can be accounted for by chance, and raises the question as to whether superimposition of NIDDM upon primary chronic renal disease accelerates the rate of progression.3 One characteristic feature of NIDDM is the frequent occurence of ischemic nephropathy from atherosclerotic renal artery stenosis, cholesterol embolism, or the combination of the two. A further nonclassical mode of progression to endstage renal failure is irreversible acute renal failure occuring in the context of septicemia or administration of contrast media.3 THE RENAL LESION IN NIDDM In principle the same histological lesions are found in NIDDM and in IDDM,11 that is, nodular or diffuse glomerulosclerosis, ie, Kimmelstiel Wilson’s disease.
Nevertheless the lesions in NIDDM are more varied,12 with a particularly high prevalence of nonspecific and ischemic lesions.12 This is also confirmed by our own observations (Mall, Amann, Ritz, in preparation). In the past it had been stated that glomerulonephritis is found in a high proportion of NIDDM patients who present with proteinuria.13,14 Studies of our own15 failed to show an excess prevalence of glomerulonephritis in elderly NIDDM patients who had come to autopsy. This observation is in good agreement with preliminary findings of others.16 RENAL HEMODYNAMICS IN INCIPIENT NIDDM Renal vasodilation and hyperfiltration are well known features of incipient IDDM, but it has remained somewhat controversial as to whether the same is true in NIDDM. Scandinavian investigators17 found an average GFR of 106 mL/min/1.73 m2, that is, within the normal range, at the time of diagnosis of NIDDM; GFR decreased to some extent after treatment. In contrast (Table 2) we found glomerular hyperfiltration irrespective of age in a considerable proportion of newly diagnosed NIDDM.3,18 This is in line with other studies19,20 in white patients and in Pima Indians.21 These observations show that in NIDDM and IDDM renal functional changes are comparable from early on. In view of this observation, the relative similarity of the clinical evolution of diabetic nephropathy is less surprising.
TABLE 2. RENAL HEMODYNAMICS IN PATIENTS WITH NEWLY DIAGNOSED NIDDM
GFR (mL/min/1.73 m2) ERPF (mL/min/1.73 m2) PVR (mm Hg/L 3 min)
Normal (Range)*
Diabetic Patients (n 5 16)
Obese Controls (n 5 8)
115 (92–145) 510 (320–610) 152 (148–170)
133 (95–165)† 517 (315–700) 141 (135–151)
118 (95–139) 526 (503–604) 139 (129–143)
GFR, glomerular filtration rate; ERPF, effective renal plasma flow; RVR, renovascular resistance. * Values in 31 healthy nonobese volunteers examined in this laboratory with the same technique. † Significant difference between diabetic patients and obese control (P 5 .01). Adapted from Nowack et al.19
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TABLE 3. CARDIOVASCULAR EVENTS IN FIRST DEGREE RELATIVES AND GLYCEMIC CONTROL AS PREDICTORS OF MICROALBUMINURIA IN NEWLY DIAGNOSED NIDDM Events
Prevalence of Microalbuminuria
No CV events in relatives and HbA1 , 8% (n 5 12) Either CV events in relatives or HbA1 . 8% (n 5 52) CV events in relatives and HbA1 . 8% (n 5 21)
0/12 5 0% 1/52 5 1.9%* 10/21 5 48%*
* Difference between risk groups P , 4.1 3 1027. Adapted from Keller et al.18
GENETICS IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY Observations of familial clustering of diabetic nephropathy in families provided persuasive indirect evidence of genetic predisposition to diabetic nephropathy in IDDM,22 although confounding effects of shared environment cannot be completely excluded. Familial clustering of diabetic nephropathy was also found in Pima Indians with NIDDM.23 For genetic studies, NIDDM is certainly problematic because of its obvious molecular heterogeneity.3 Nevertheless, familial aggregation of hypertension and cardiovascular accidents among first-degree relatives, as observed in IDDM,24 has recently also be noted in NIDDM.18 As shown in Table 3, both cardiovascular events in first-degree relatives and poor glycemic control were related to the prevalence of microalbuminuria, and the prevalence was particularly pronounced when the two conditions were simultaneously present, suggesting interaction between the two risk factors. TABLE 4. AMBULATORY BLOOD PRESSURE IN OFFSPRING ACCORDING TO PRESENCE OF NIDDM AND DIABETIC NEPHROPATHY OF PARENTS 24 h BP Patients/Parents Offspring of control parents (n 5 30) Offspring of NIDDM parents Without nephropathy (n 5 30) With nephropathy (n 5 26)
Systolic
Diastolic
114 6 8.5
71.6 6 6.4
117 6 12.9
74
6 8.6
125 6 16.9*
76
6 9.2
* Difference versus offspring of controls 1 offspring of nonnephropathic parents, P , .01; difference versus offspring of controls, P , .05. Adapted from Strojek et al.25
As shown in a preliminary recent observation,25 we found higher albumin excretion rates and higher ambulatory blood pressures (Table 4) in offspring of NIDDM patients with diabetic nephropathy compared with offspring of NIDDM without diabetic nephropathy. Higher albuminuria in such offspring has also been observed by Gruden et al.26 These observations would be consistent with the notion that separate genes, independent of the ones predisposing to NIDDM, code for the risk for developing progressive renal lesions. In animal experiments using a positional cloning approach, such genes predisposing to progressive renal damage have recently been identified.27 It had been reported that in IDDM the D/I polymorphism of the angiotensin converting enzyme (ACE) gene was related to the risk of diabetic nephropathy.28 This could not be confirmed in two large studies, which included also patients with NIDDM.29,30 More recent evidence,31 however, is compatible with the notion of more rapid progression in IDDM patients who are homozygous for the D allele of the polymorphism in intron 16 of the ACE gene.31 No information is available concerning patients with NIDDM. Furthermore, in two separate studies, polymorphisms of the angiotensinogen gene were not shown to be related to the risk of diabetic nephropathy.32,33 Nevertheless, the search for genetic determinants of diabetic nephropathy using a molecular genetic approach continues to be one of the most promising current frontiers of research in this field. COMPARISON OF THE NATURAL HISTORY OF DIABETIC NEPHROPATHY IN IDDM AND NIDDM Some decades ago, cumulative renal mortality by 75 years of age was only 5% in NIDDM patients,2 and the proportion of NIDDM patients dying from renal disease was reported35,36 to be as small as 1.6% to 2%. The relative risk of renal death compared with that in the general population was increased only twofold.37 More recently, however, Perneger38 found that in NIDDM the odds ratio for development of ESRF was as high as 7.0. In Pima Indians with NIDDM, Nelson et al39 found an incidence of ESRF that was comparable to that reported for IDDM by the Joslin Clinic. In a population based survey, Humphrey et al10 found that the cumulative incidence of renal failure was similar in NIDDM and IDDM. This is in agreement with our own observations,40 where we found similar cumulative risk of developing proteinuria at any given duration of diabetes in NIDDM and IDDM, respectively. In addition, a similar cumulative risk for the development of renal failure was found in the two types of diabetes once patients had developed proteinuria. One item that is puzzling, and for which we do not
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FIGURE 1. Decrease of measured endogenous creatinine clearance in patients with diabetic nephropathy: comparison of patients with IDDM and NIDDM. (Adapted from Biesenbach et al.41).
have an explanation, is the curious fact that in IDDM, once microalbuminuria has appeared, the kidney is uniquely sensitive to even minor increments in blood pressure within the normotensive range. In contrast, the majority of patients with NIDDM are hypertensive even prior to the onset of diabetes mellitus. Yet, progression as judged from the time intervals to onset of proteinuria, to onset of renal failure, and to onset of ESRF, are almost superimposible in IDDM and NIDDM.40 How this paradox can be resolved is currently unknown. As far as progression of established diabetic nephropathy is concerned, the data of Biesenbach et al41 clearly established that the rate of loss of endogenous creatinine clearance was superimposible in NIDDM and IDDM (Figure 1).
aware of the true renal risk of NIDDM. Intense efforts must be made to improve the currently abysmal quality of medical care of NIDDM prior to the onset of diabetic nephropathy and particularly prior to the onset of ESRF.3 An integrated part in this effort will be education of patients to improve self-control and compliance. Nevertheless we feel justified in concluding on an optimistic note. We are convinced that, at least in principle, diabetic nephropathy is a preventable condition. This consideration justifies the emotional appeal of Hansen42: ‘‘No more deaths from diabetic nephropathy by the year 2005.’’ REFERENCES 1.
Fabre J, Balant LP, Dayer PG, et al: The kidney in maturity onset diabetes mellitus: a clinical study of 510 patients. Kidney Int 1982;21:730 –738.
2.
Marble A, Krall LP, Bradley RF, et al: Joslin’s Diabetes Mellitus, ed 11. Lea & Febiger, Philadelphia, 1985.
3.
Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J Kidney Dis 1996;27:167–194.
4.
Marcelli D, Spotti D, Conte F, et al: Prognosis of diabetic patients on dialysis: analysis of Lombardy Registry data. Nephrol Dial Transplant 1995;10:1895–1901.
CONCLUSIONS It emerges from the above that, with respect to the renal risk, NIDDM must be taken every bit as seriously as IDDM. This necessitates changes in our intervention strategies7 with respect to glycemic control, blood pressure control, and general medical management are concerned.7 Thorough educational initiatives are required to make nonnephrological colleagues
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5.
Lippert J, Ritz E, Schwarzbeck A, Schneider P: The rising tide of endstage renal failure from diabetic nephropathy type II—an epidemiological analysis. Nephrol Dial Transplant 1995;10:462– 467.
6.
Excerpts from United States Renal Data System 1990. Annual report. IV. The demographics of ESRD. Am J Kidney Dis 1990;16:28 –33.
7.
tering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989;320:1161–1165. 23.
Pettitt DJ, Saad MF, Bennett PH, et al: Familial predisposition to renal disease in two generation of Pima Indians with type 2 (non–insulin-dependent) diabetes mellitus. Diabetologia 1990;33:438 – 443.
Ritz E, Lippert J, Keller CH: Rapider Anstieg der Zahl niereninsuffizienter Typ II Diabetiker—nicht nur ein Problem der Nephrologen (Leitartikel). Dtsch Med Wschr (in press).
24.
Earle K, Walker J, Hill C, Viberti GC: Familial clustering of cardiovascular disease in patients with insulindependent diabetes and nephropathy. N Engl J Med 1992;326:673– 677.
8.
Koch M, Thomas B, Tscho¨pe W, Ritz E: Diabetes mellitus accounts for an ever-increasing proportion of the patients admitted for renal replacement therapy. Nephrol Dial Transplant 1989;4:399.
25.
Strojek K, Grzeszczak W, Morawin E, et al: Clinical manifestation of hereditary predisposition to type II diabetes and nephropathy. Nephrol Dial Transplant 1996;11:A119.
9.
Koch M, Thomas B, Tschoepe W, Ritz E: Survival and predictors of death in dialysed diabetic patients. Diabetologia 1993;36:1113–1117.
26.
10.
Humphrey LL, Ballard DJ, Frohnert PP, et al: Chronic renal failure in non-insulin-dependent diabetes mellitus. A population-based study in Rochester, Minnesota. Ann Intern Med 1989;111:788 –796.
Gruden G, Cavallo-Perin P, Olivetti C, et al: Albumin excretion rate levels in non-diabetic offspring of NIDDM patients with and without nephropathy. Diabetologia 1995;38:1218.
27.
Brown DM, Provoost AP, Daly MJ, et al: Renal disease susceptibility and hypertension are under independent genetic control in the fawn hooded rat. Nature Genetics 1996;12:44 –51.
28.
Marre M, Bernadet P, Gallois Y, et al: Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes 1994;43:384 –388.
11.
Ditscherlein G: Nierenvera¨nderungen bei Diabetikern. Gustav Fischer Verlag, Jena, Germany, 1969.
12.
Gambara V, Mecca G, Remuzzi G, Bertani T: Heterogenous nature of renal lesions in type II diabetes. J Am Soc Nephrol 1993;3:1458 –1466.
13.
Amoah E, Glickman JL, Malchoff CD, et al: Clinical identification of non-diabetic renal disease in diabetic patients with type I and type II disease presenting with renal dysfunction. Am J Nephrol 1988;8:204 –211.
29.
Schmidt S, Scho¨ne N, Ritz E, and Diabetic Nephropathy Study Group: Association of ACE gene polymorphism and diabetic nephropathy. Kidney Int 1995;47: 1176 –1181.
14.
Parving HH, Gall MA, Skott P, et al: Prevalence and causes of albuminuria in non–insulin-dependent diabetic patients. Kidney Int 1992;41:758 –762.
30.
15.
Waldherr R, Ilkenhans C, Ritz H: How frequent is glomerulonephritis in diabetes mellitus type II? Clin Nephrol 1992;37:271–273.
Tarnow L, Cambien F, Rossing P, et al: Lack of relationship between an insertion/deletion polymorphism in the angiotensin I-converting enzyme gene and diabetic nephropathy in IDDM patients. Diabetes 1995;44: 489 – 494.
31.
16.
Pinel N, Fadel B, Bilous RW, et al: Renal biopsies in 30 micro- and macroalbuminuric non-insulin-dependent (type 2) (NIDDM) patients: heterogeneity of renal lesions (abst). Eighth Meeting of the European Diabetic Nephropathy Study Group Heidelberg, Germany, May 1995.
Jacobsen P, Tarnow L, Rossing P: The insertion/deletion (I/D) polymorphism in the angiotensin I convertng enzyme (ACE) gene predicts the progression of diabetic nephropathy during ACE inhibition (ACEI) in insulin-dependent diabetic (IDDM) patients (abst). J Am Soc Nephrol 1995;6:450.
32.
Tarnow L, Cambien F, Rossing P, et al: Angiotensinogen gene polymorphism in IDDM patients with diabetic nephropathy. Diabetes 1996;45:367–369.
33.
Schmidt S, Geißel R, Bergis KH, et al, and the Diabetic Nephropathy Study Group: Angiotensinoten gene M235T polymorphism is not associated with diabetic nephropathy. Nephrol Dial Transplant (in press).
17.
Schmitz A, Hansen HH, Christensen T: Kidney function in newly diagnosed type 2 (non-insulin-dependent) diabetic patients, before and during treatment. Diabetologia 1989;32:434 – 439.
18.
Keller CK, Bergis KH, Fliser D, Ritz E: Renal findings in patients with short term type 2 diabetes. J Am Soc Nephrol (in press).
34.
19.
Nowack R, Raum E, Blum W, Ritz E: Renal hemodynamics in recent onset type II diabetes. Am J Kidney Dis 1992;20:342–347.
Schmidt S, Ritz E: The role of angiotensin I converting enzyme gene polymorphism in renal disease (invited review). Current Opinion (in press).
35.
20.
Vora JP, Dolben J, Dean JD, et al: Renal hemodynamics in newly presenting non-insulin dependent diabetes mellitus. Kidney Int 1992;41:829 – 835.
Palumbo PJ, Elveback LR, Chu CP, et al: Diabetes mellitus: Incidence, prevalence, survivorship, and causes of death in Rochester, Minnesota, 1945–1970. Diabetes 1976;25:566 –573.
21.
Silveiro SP, Friedman R, Gross JL: Glomerular hyperfiltration in NIDDM patients without overt proteinuria. Diabetes Care 1993;16:115–119.
36.
Ochi JW, Melton LJ, Palmubo PJ, Chu CP: A population-based study of diabetes mortality. Diabetes Care 1985;8:224 –229.
22.
Seaquist ER, Goetz FC, Rich S, Barbosa J: Familial clus-
37.
Geiss LS, Herman WH, Teutsch SM: Diabetes and renal
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mortality in the United States. Am J Public Health 1985;75:1325–1326. 38.
39.
40.
Perneger TV, Brancati FL, Whelton PK, Klag MJ: Endstage renal disease attributable to diabetes mellitus. Ann Intern Med 1994;121:912–918. Nelson RG, Newman JM, Knowler WC, et al: Incidence of endstage renal disease in type 2 (non-insulin-dependent) diabetes mellitus in Pima Indians. Diabetologia 1988;31:730 –736. Hasslacher C, Ritz E, Wahl P, Michael C: Similar
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risks of nephropathy in patinets with type I or type II diabetes mellitus. Nephrol Dial Nephrol 1989;4:859 – 863. 41.
Biesenbach G, Janko O, Zazgornik J: Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus. Nephrol Dial Transplant 1994;9: 1097–1102.
42.
Hanssen KF: How tight must blood glucose control be to prevent diabetic nephropathy? Nephrol Dial Transplant 1994;9:226 –227.
1997;10:202S–207S
Pathogenesis and Course of Renal Disease in IDDM/NIDDM Differences and Similarities Eberhard Ritz, Christine Keller, Kristian Bergis, and Krzysztof Strojek
In the past the opinion prevailed that renal prognosis was less adverse in non–insulindependent diabetes mellitus (NIDDM) as compared with insulin-dependent diabetes mellitus (IDDM). This notion has to be revised in the light of recent evidence, based on epidemiologic data of NIDDM patients reaching endstage renal failure and a comparison of the cumulative prevalence of proteinuria and renal failure, respectively, in NIDDM as compared with IDDM. It has also been established that initial renal hemodynamic changes are quite comparable
in NIDDM and in IDDM. It follows that past complacency about the renal sequelae of NIDDM is no longer justified and that preventive measures to interfere with the development of diabetic nephropathy are similarly important in NIDDM and IDDM. Am J Hypertens 1997;10:202S–207S © 1997 American Journal of Hypertension, Ltd.
I
renal failure,2 in contrast with 30% to 40% in IDDM. We feel, however, that this reflects a biostatistical artifact: the risk of endstage renal failure competes with the risk of cardiovascular death. Because of the high rate of cardiovascular death in elderly persons with NIDDM, few with NIDDM used to live long enough to experience endstage renal failure. As described in detail elsewhere,3 this situation has changed dramatically. Table 1 compares the incidence of endstage renal failure in Lombardia,4 in southwest Germany,5 and for the US among white citizens.6 It is obvious that in Germany the incidence of endstage renal failure (ESRF) in diabetic patients has approached the figures reported from the US, at least in white persons. In contrast, in northern Italy, the incidence is still only one fifth of what is observed in Germany. There was no difference concerning IDDM reaching ESRF; the difference between northern Italy and southwest Germany was entirely accounted for by the high incidence of ESRF in patients with NIDDM. This trend has continued. In 1990 the proportion of diabetics among
n the not too distant past, it was thought that non–insulin-dependent diabetes mellitus (NIDDM) carried a benign renal prognosis, in contrast to insulin-dependent diabetes mellitus (IDDM). In 1982 Fabre et al1 reported the experience of the Geneva clinic with 510 patients with NIDDM. They found that only 43 patients had a reduction of glomerular filtration rate (GFR) (corrected for age) and only one patient progressed to endstage renal failure but this patient suffered from superimposed glomerulonephritis. It is known that in the distant past only ;5% of patients with NIDDM went into endstage
From the Department Internal Medicine, University of Heidelberg, Heidelberg, (ER, CK); FIDAM Forschungsinstitut der Diabetes-Akademie Bad Mergentheim, Bad Mergentheim, Germany (KB); and Silesian Medical Academy, Sabrze, Poland (KS). Address correspondence and reprint requests to Professor Dr. med. Eberhard Ritz, FRCP (Lond. and Edinb.), FACP, Department of Internal Medicine, Bergheimer Straße 58, D-69115 Heidelberg, Germany.
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Non–insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, renal disease, proteinuria.
0895-7061/97/$17.00 PII S0895-7061(97)00154-4
AJH–SEPTEMBER 1997–VOL. 10, NO. 9, PART 2
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TABLE 1. INCIDENCE OF TERMINAL RENAL FAILURE Total (pat/mio/year)
Diabetic Pattern (pat/mio/year)
Type I (pat/mio/year)
Type II (pat/mio/year)
Type II (%)
102 125 150
10 52 46
5 5 *
5 47 *
50 90 *
Lombardy Lower Neckar region USA (white) * Not specified.
patients admitted for ESRF to Heidelberg University was 36%; in 1991, 44%; 1994, 52%; and in 1995, no less than 95%.7 In 1995, 90% of the patients had NIDDM. It is obvious that in Europe a continuous increase of the number of NIDDM patients reaching ESRF is currently observed. Obviously the question arises as to whether all those with NIDDM reaching ESRF actually develop ESRF as a consequence of Kimmelstiel Wilson’s disease. In two independent studies, we found that more than 20% of NIDDM patients had some other type of primary chronic renal disease, for example, reflux nephropathy, glomerulonephritis, polycystic kidney disease, analgesic nephropathy, etc. This has also been found by others.10 This percentage appears to be more than can be accounted for by chance, and raises the question as to whether superimposition of NIDDM upon primary chronic renal disease accelerates the rate of progression.3 One characteristic feature of NIDDM is the frequent occurence of ischemic nephropathy from atherosclerotic renal artery stenosis, cholesterol embolism, or the combination of the two. A further nonclassical mode of progression to endstage renal failure is irreversible acute renal failure occuring in the context of septicemia or administration of contrast media.3 THE RENAL LESION IN NIDDM In principle the same histological lesions are found in NIDDM and in IDDM,11 that is, nodular or diffuse glomerulosclerosis, ie, Kimmelstiel Wilson’s disease.
Nevertheless the lesions in NIDDM are more varied,12 with a particularly high prevalence of nonspecific and ischemic lesions.12 This is also confirmed by our own observations (Mall, Amann, Ritz, in preparation). In the past it had been stated that glomerulonephritis is found in a high proportion of NIDDM patients who present with proteinuria.13,14 Studies of our own15 failed to show an excess prevalence of glomerulonephritis in elderly NIDDM patients who had come to autopsy. This observation is in good agreement with preliminary findings of others.16 RENAL HEMODYNAMICS IN INCIPIENT NIDDM Renal vasodilation and hyperfiltration are well known features of incipient IDDM, but it has remained somewhat controversial as to whether the same is true in NIDDM. Scandinavian investigators17 found an average GFR of 106 mL/min/1.73 m2, that is, within the normal range, at the time of diagnosis of NIDDM; GFR decreased to some extent after treatment. In contrast (Table 2) we found glomerular hyperfiltration irrespective of age in a considerable proportion of newly diagnosed NIDDM.3,18 This is in line with other studies19,20 in white patients and in Pima Indians.21 These observations show that in NIDDM and IDDM renal functional changes are comparable from early on. In view of this observation, the relative similarity of the clinical evolution of diabetic nephropathy is less surprising.
TABLE 2. RENAL HEMODYNAMICS IN PATIENTS WITH NEWLY DIAGNOSED NIDDM
GFR (mL/min/1.73 m2) ERPF (mL/min/1.73 m2) PVR (mm Hg/L 3 min)
Normal (Range)*
Diabetic Patients (n 5 16)
Obese Controls (n 5 8)
115 (92–145) 510 (320–610) 152 (148–170)
133 (95–165)† 517 (315–700) 141 (135–151)
118 (95–139) 526 (503–604) 139 (129–143)
GFR, glomerular filtration rate; ERPF, effective renal plasma flow; RVR, renovascular resistance. * Values in 31 healthy nonobese volunteers examined in this laboratory with the same technique. † Significant difference between diabetic patients and obese control (P 5 .01). Adapted from Nowack et al.19
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TABLE 3. CARDIOVASCULAR EVENTS IN FIRST DEGREE RELATIVES AND GLYCEMIC CONTROL AS PREDICTORS OF MICROALBUMINURIA IN NEWLY DIAGNOSED NIDDM Events
Prevalence of Microalbuminuria
No CV events in relatives and HbA1 , 8% (n 5 12) Either CV events in relatives or HbA1 . 8% (n 5 52) CV events in relatives and HbA1 . 8% (n 5 21)
0/12 5 0% 1/52 5 1.9%* 10/21 5 48%*
* Difference between risk groups P , 4.1 3 1027. Adapted from Keller et al.18
GENETICS IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY Observations of familial clustering of diabetic nephropathy in families provided persuasive indirect evidence of genetic predisposition to diabetic nephropathy in IDDM,22 although confounding effects of shared environment cannot be completely excluded. Familial clustering of diabetic nephropathy was also found in Pima Indians with NIDDM.23 For genetic studies, NIDDM is certainly problematic because of its obvious molecular heterogeneity.3 Nevertheless, familial aggregation of hypertension and cardiovascular accidents among first-degree relatives, as observed in IDDM,24 has recently also be noted in NIDDM.18 As shown in Table 3, both cardiovascular events in first-degree relatives and poor glycemic control were related to the prevalence of microalbuminuria, and the prevalence was particularly pronounced when the two conditions were simultaneously present, suggesting interaction between the two risk factors. TABLE 4. AMBULATORY BLOOD PRESSURE IN OFFSPRING ACCORDING TO PRESENCE OF NIDDM AND DIABETIC NEPHROPATHY OF PARENTS 24 h BP Patients/Parents Offspring of control parents (n 5 30) Offspring of NIDDM parents Without nephropathy (n 5 30) With nephropathy (n 5 26)
Systolic
Diastolic
114 6 8.5
71.6 6 6.4
117 6 12.9
74
6 8.6
125 6 16.9*
76
6 9.2
* Difference versus offspring of controls 1 offspring of nonnephropathic parents, P , .01; difference versus offspring of controls, P , .05. Adapted from Strojek et al.25
As shown in a preliminary recent observation,25 we found higher albumin excretion rates and higher ambulatory blood pressures (Table 4) in offspring of NIDDM patients with diabetic nephropathy compared with offspring of NIDDM without diabetic nephropathy. Higher albuminuria in such offspring has also been observed by Gruden et al.26 These observations would be consistent with the notion that separate genes, independent of the ones predisposing to NIDDM, code for the risk for developing progressive renal lesions. In animal experiments using a positional cloning approach, such genes predisposing to progressive renal damage have recently been identified.27 It had been reported that in IDDM the D/I polymorphism of the angiotensin converting enzyme (ACE) gene was related to the risk of diabetic nephropathy.28 This could not be confirmed in two large studies, which included also patients with NIDDM.29,30 More recent evidence,31 however, is compatible with the notion of more rapid progression in IDDM patients who are homozygous for the D allele of the polymorphism in intron 16 of the ACE gene.31 No information is available concerning patients with NIDDM. Furthermore, in two separate studies, polymorphisms of the angiotensinogen gene were not shown to be related to the risk of diabetic nephropathy.32,33 Nevertheless, the search for genetic determinants of diabetic nephropathy using a molecular genetic approach continues to be one of the most promising current frontiers of research in this field. COMPARISON OF THE NATURAL HISTORY OF DIABETIC NEPHROPATHY IN IDDM AND NIDDM Some decades ago, cumulative renal mortality by 75 years of age was only 5% in NIDDM patients,2 and the proportion of NIDDM patients dying from renal disease was reported35,36 to be as small as 1.6% to 2%. The relative risk of renal death compared with that in the general population was increased only twofold.37 More recently, however, Perneger38 found that in NIDDM the odds ratio for development of ESRF was as high as 7.0. In Pima Indians with NIDDM, Nelson et al39 found an incidence of ESRF that was comparable to that reported for IDDM by the Joslin Clinic. In a population based survey, Humphrey et al10 found that the cumulative incidence of renal failure was similar in NIDDM and IDDM. This is in agreement with our own observations,40 where we found similar cumulative risk of developing proteinuria at any given duration of diabetes in NIDDM and IDDM, respectively. In addition, a similar cumulative risk for the development of renal failure was found in the two types of diabetes once patients had developed proteinuria. One item that is puzzling, and for which we do not
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FIGURE 1. Decrease of measured endogenous creatinine clearance in patients with diabetic nephropathy: comparison of patients with IDDM and NIDDM. (Adapted from Biesenbach et al.41).
have an explanation, is the curious fact that in IDDM, once microalbuminuria has appeared, the kidney is uniquely sensitive to even minor increments in blood pressure within the normotensive range. In contrast, the majority of patients with NIDDM are hypertensive even prior to the onset of diabetes mellitus. Yet, progression as judged from the time intervals to onset of proteinuria, to onset of renal failure, and to onset of ESRF, are almost superimposible in IDDM and NIDDM.40 How this paradox can be resolved is currently unknown. As far as progression of established diabetic nephropathy is concerned, the data of Biesenbach et al41 clearly established that the rate of loss of endogenous creatinine clearance was superimposible in NIDDM and IDDM (Figure 1).
aware of the true renal risk of NIDDM. Intense efforts must be made to improve the currently abysmal quality of medical care of NIDDM prior to the onset of diabetic nephropathy and particularly prior to the onset of ESRF.3 An integrated part in this effort will be education of patients to improve self-control and compliance. Nevertheless we feel justified in concluding on an optimistic note. We are convinced that, at least in principle, diabetic nephropathy is a preventable condition. This consideration justifies the emotional appeal of Hansen42: ‘‘No more deaths from diabetic nephropathy by the year 2005.’’ REFERENCES 1.
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