Renal disease in type 2 diabetes

Nephrol Dial Transplant (2001) 16 wSuppl 5x: 11±18

Renal disease in type 2 diabetes Eberhard Ritz1 and Der-Cherng Tarng2 1

Ruperto Carola University Heidelberg, Germany and 2National Yang-Ming University, Taipei Veterans General Hospital, Taiwan

After a plenary lecture on the occasion of the eighth meeting of the South East Asian Society of Nephrology, Taipei, 26±30 March 2000. Abstract The prevalence of type 2 diabetes is rising in all Westernized societies. Presumably as a consequence of diminishing cardiovascular mortality, end-stage renal failure (ESRF) in patients with diabetes (mostly type 2) as a co-morbid condition has risen dramatically in the past decade. This constellation has become the single most common cause of ESRF in most countries. Such an epidemiological trend is particularly regrettable, since in uraemic diabetic patients, medical rehabilitation and survival are remarkably poor. Recent studies indicate that an interplay between genetic predisposition and factors, some of them susceptible to intervention, such as hyperglycaemia, blood pressure, smoking, age, gender and ethnicity, predispose to the development and progression of nephropathy. It has also become clear that trace albuminuria (`microalbuminuria') provides unique opportunities to recognize incipient renal involvement early on, although it is less speci®c in type 2 as compared with type 1 diabetes. Factors that promote progression include hypertension, proteinuria, smoking, glycaemic control and, less certainly, dietary protein intake and hyperlipidaemia. Cumulating evidence indicates that early intervention delays progression of nephropathy. The most important strategies to combat the medical catastrophe of increasing numbers of diabetic patients with ESRF include: (i) prevention of diabetes (mainly type 2); (ii) glycaemic control to prevent onset of renal involvement; and (iii) meticulous antihypertensive treatment to avoid progression of nephropathy. Keywords: diabetic glomerulopathy; dialysis; endstage renal failure; hypertension; microalbuminuria; proteinuria

Correspondence and offprint requests to: Professor Dr E. Ritz, Department Internal Medicine, Bergheimer Straûe 58, D-69115 Heidelberg, Germany. #

Introduction Type 2 diabetes has been known since antiquity. Presumably, the oldest description was provided in the Sanskrit literature, i.e. a polidipsic polyuric syndrome associated with the passage of `honey urine' (Madhumeha), attracting ants and insects. It deserves comment, however, that according to G.J. Tee w1x, in 750 A.D. the Chinese physician Li HsuÈan had also referred to the sweet taste of the urine of polyuric patients, quoting the work of Chen ChuÈan (deceased 643). Recognition of a polyuric polidipsic syndrome per se goes even further back, since the great Chinese physician Tschang Tug King (200 A.D.) referred to a disease characterized by excessive thirst w2x. The recognition of proteinuria as a complication of diabetes dates back to Contugno, who ®rst described proteinuria in patients with diabetes by necessity type 2 w3x. There are numerous references to `Bright's disease' in patients with diabetes in the medical literature of the 19th century. To quote one report of Griesinger w4x `Renal involvement complicates diabetes in a decisive fashion . . . If glucosuria disappears in a diabetic patient with heavy proteinuria, M. Bright (today we would say renal failure) will take its known fatal course with generalized hydrops etc. . . .'. The existence of histological lesions in the kidneys of patients with type 2 diabetes had also been known for a long time w5,6x, but their speci®city had been questioned until the seminal report of Kimmelstiel and Wilson w7x in 1938 dispelled any doubt about the speci®city of glomerulosclerosis. It is of interest that some of their patients unquestionably had type 2 diabetes. Early reports suggested that renal failure was an infrequent outcome in type 2, compared with type 1, diabetes. This opinion was based on the observation that a much smaller proportion of type 2 than type 1 diabetic patients developed uraemia. Furthermore, in longitudinal studies it had been stated that the rate of loss of glomerular ®ltration (GFR) in patients with

2001 European Renal Association±European Dialysis and Transplant Association

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type 2 diabetes did not exceed the rate anticipated due to advancing age w8x. Recently, however, the number of patients with type 2 diabetes as a co-morbid condition who develop end-stage renal failure (ESRF) and require renal replacement therapy has increased dramatically w9x. There has been growing consensus that renal failure in the type 2 diabetic patient is largely, if not completely, a preventable condition. Based on this consideration we welcome the invitation to provide an update on pathophysiology, evaluation and therapy in this condition.

E. Ritz and D-C. Tarng

diabetic patients, but it is possible that this low prevalence is an underestimate because of the small sample size, the short follow-up and the diagnostic criteria used. In this analysis, age, diabetes duration, insulin treatment and presence of hypertension as well as hypertriglyceridaemia and poor glucose control were predictive of the risk to develop proteinuria. In the study of Chen et al. w16x, the rate of death was 5.8% per 3 years in type 2 diabetic patients. Adjusted for age, the risk of death was 2.2-fold higher compared with the background population. For 11.4% of the diabetic subjects who succumbed, nephropathy was given as the cause of death.

Epidemiology of type 2 diabetes In Germany it has been estimated that the point prevalence of type 2 diabetes in the adult population is 6% depending on age; the point prevalence rises to 20% at age 80 years. The same is also seen in most developed countries. The prevalence of type 2 diabetes is generally rising, but at a particularly rapid pace in the developing world. The 1998 World Health Organization (WHO) report estimated that by the year 2025 the absolute prevalence of patients with type 2 diabetes will be 300 million throughout the world.

Epidemiology of diabetes and its complications in Taiwan Against this background it is not without interest to brie¯y summarize the information available from Taiwan. In a survey in Taipei, the prevalence of type 2 diabetes for adults aged )40 years was 5.1% in 1970 and 7.1% in 1979 w10x. Using the WHO diagnostic criteria, three subsequent surveys were performed in Taiwan that showed prevalence rates of 5.3, 12.4 and 6.5%, respectively w11±13x. The last two studies were performed in Pu-Li Town and the region of Kenmen. In the latter analysis, Chou et al. w13x noted that the ratio of known to undiagnosed diabetics, i.e. diabetes detected during the study, was 1 : 2, i.e. 2% and 4.5%, respectively. The reasons that were offered to explain the high prevalence of diabetes were increasing af¯uence and increased life expectancy, in agreement with what has been discussed in the Western world w14x. It is of interest to compare these prevalence rates with reports from various Chinese communities outside of Taiwan, e.g. 1.3% for adults )20 years of age in Shanghei, 1.8% in Hawai, 4.7% in Malaysia and 1.6% in Singapore, whilst in Americans of Chinese extraction the diabetes mortality rate was shown to be even higher than in the general American population w15x. The rate of microvascular and macrovascular complications in the Chinese population is also of interest. High prevalence rates of retinopathy were reported by Tai et al. w10x and by Chang et al. w11x. In the study of Tai et al. w10x, the prevalence of proteinuria, i.e. stix-positive urine, was 12.1% in type 2

Epidemiology of ESRF in type 2 diabetic patients in Taiwan The 1997 National Dialysis Surveillance, comprising the data from 292 haemodialysis (HD) and 33 continuous ambulatory peritoneal dialysis (CAPD) facilities, reported that as of the end of 1996, 18 705 patients received dialysis therapy in Taiwan, 94% of whom had HD and 6% CAPD w17x. This corresponds to a prevalence of 869 patients per million population (pmp). The annual incidence had increased between 1987 and 1996 from 92 to 249 pmp. The most common cause of ESRF was glomerulonephritis (38.0%), followed closely by diabetic nephropathy (21.5%). The proportion of diabetic patients has risen from 21.2% in 1987±1988 to 26.6% in 1996, whilst the proportion of patients with glomerular disease decreased from 39.2 to 35.3% during the same period. Comparison of the incidence of uraemic patients with diabetes as a co-morbid condition in Taiwan and some other countries illustrates that Taiwan is a country with a very high incidence indeed (Table 1). In contrast to the common statement that cardiovascular death is relatively infrequent in the Asian population w18x, cardiovascular diseases were the most common cause of death in the Taiwan dialysis population (29.5%). Nevertheless, the cumulative 1, 3, 5 and 7 year survival rates were astonishingly high, i.e. 90.5, 70.9, 58.0 and 48.2%, respectively. These ®gures are in stark contrast to the mortality ®gures reported from the USA, i.e. 23.2% at 1 year in 1996 (USRDS report 1999). In the absence of multivariate analysis to account for confounding factors, such global ®gures may, however, to some extent be misleading.

Epidemiology of ESRF of type 2 diabetic patients in the Western world Against this background, recent international comparisons of this issue are of interest. ESRF in type 2 diabetes has been characterized as a medical catastrophe of worldwide dimensions w19x. From Table 1 it is obvious that the incidence of ESRF in diabetic patients has increased dramatically in the past decade.

Renal disease in type 2 diabetes

13

The increase started ®rst in the USA and Eastern Asia, but later occurred in European countries as well. In many countries, ESRF in patients with diabetes as a co-morbid condition has become the most frequent cause of ESRF. It is true that type 2 diabetes and ESRF are both frequent conditions in elderly populations. Consequently, coincidental diabetes may well occur in patients with non-diabetic primary renal disease. In several analyses, 20±30% of type 2 diabetic patients with ESRF were shown to suffer from primary chronic renal diseases such as polycystic kidney disease, analgesic nephropathy, glomerulonephritis, etc. As shown in Table 2, a wide spectrum of renal conditions may be found in patients with type 2 diabetes. Based on ultrasonographic examinations w14x and recently also on renal biopsy ®ndings w20x, up to 20% of type 2 diabetic patients were shown to have ischaemic nephropathy, secondary to atherosclerotic disease of the abdominal aorta with renal artery stenosis or cholesterol microembolism. It is important, however, that in contrast to previous opinion w8x, the risk to develop proteinuria or renal failure is similar for patients with type 1 or type 2 diabetes (Figure 1). As discussed in more detail elsewhere w19x, we believe that the major reason for the apparent increase in the number of patients with type 2 diabetes and ESRF is the progressive diminution of cardiac mortality in these patients that has recently been observed. In the University Hospital of Heidelberg: 5 year mortality for proteinuric type 2 diabetic patients has decreased from 65 to 25% in the decade between 1975 and 1985 w14x. Viewed in this perspective, ESRF in type 2

diabetes is a disease of medical progress w21x, since nowadays such patients survive long enough to experience advanced nephropathy and ESRF. The high incidence of ESRF in patients with type 2 diabetes is particularly regrettable, since medical rehabilitation, quality of life and survival are consistently worse in diabetic compared with non-diabetic dialysed patients (Table 3). Reporting on mortality and medical rehabilitation would be incomplete, however, without mentioning the immense human suffering that is hidden behind these dry ®gures. Co-morbidity, particularly cardiovascular morbidity, is frighteningly high. In Western countries, up to 40% of type 2 diabetic patients suffer from coronary heart disease and up to 20% require amputation. Further handicaps are blindness and the sequelae of autonomic polyneuropathy. Against this background it requires no further justi®cation that all efforts must be made to prevent this deplorable condition.

Renal lesions and clinical presentation The kidney of a diabetic patient is characterized by thickening of the basal membrane, but basal

Table 1. Incidence of ESRF in patients with diabetes Country

United States Japan Australia Norway Germany (Southwest) Italy (Lombardia)

No. of cases per million population per year 1984

1994

19.2 23.4 4.0 6.5 ±

107.0 66.0 14.0 15.4 (11.1) 52.0 (47.0)

6.5 (2.9)

13.0 (7.0)

Figures in parentheses are the number of cases with type 2 diabetes. Data from Ritz et al. w19x. Table 2. Causes of ESRF in patients with type 2 diabetes Classical Kimmelstiel Wilson glomerulosclerosis Other primary renal diseases Re¯ux nephropathy Polycystic renal disease Glomerulonephritis Bilateral renal artery stenosis Cholesterol embolism `Benign' nephrosclerosis Ischaemic nephropathy Irreversible acute renal failure (X-ray contrast, septicaemia)

Fig. 1. Cumulative prevalence of persistent proteinuria among patients with type 1 or type 2 diabetes according to the duration of diabetes (A) and cumulative prevalence of renal failure among patients with type 1 or type 2 diabetes, and according to the duration of proteinuria (B) w53x.

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membrane thickness is not correlated to the risk of developing renal failure. Studies by Mauer et al. w22x showed that mesangial expansion is the morphological lesion that is most closely related to the evolution of the GFR. The very ®rst morphological lesion is the reduction of the number of podocytes w23x. With advancing nephropathy, either classical nodular lesions, ®rst described by Kimmelstiel Wilson w5x, or more diffuse lesions are seen. De®nite renal lesions are seen in all type 1 diabetic patients who have elevated albumin excretion rates, i.e. in the microalbuminuric range or higher. In contrast, the renal morphology is less uniform in microalbuminuric type 2 diabetic patients. Fioretto et al. w24x noted that only one-third of microalbuminuric type 2 diabetic patients had Kimmelstiel Wilson's lesions. One-third had non-speci®c lesions and one-third had normal kidneys by light microscopy.

Evolution of diabetic nephropathy There are few renal diseases that follow such a predictable evolution as is found in diabetic nephropathy. A modi®ed scheme after Mogensen is shown in Table 4. At least in type 1 diabetic patients (this is less well documented in type 2 diabetes), an initial stage of glomerular hyper®ltration is followed by a stage of clinical latency. The ®rst clinical sign of renal involvement is the appearance of microalbuminuria, Table 3. Comparison of actuarial 5 year survival of non-diabetic and diabetic patients on dialysis treatment Country

No diabetes

Diabetes

Australia Japan Taiwan Hong Kong Lombardy (Italy) Catalonia (Spain) Germany United States

60 64u73 65 70 61 65 ± 35

42u27* 50u40 37 20 28 30 38u5 21

Values are expressed as percentage of surviving patients. *Reported as type 1utype 2 diabetes.

i.e. albumin excretion rates that cannot be discovered by routine measurements of proteinuria, but are detectable by speci®c assays sensitive enough to detect very low albumin concentrations. In parallel with albumin excretion, blood pressure rises usually within the range of normotensive values. When macroalbuminuria, i.e. an excretion rate of )300 mguday, has supervened, patients usually develop clinically manifest hypertension. In the course of few years they will then progress to ESRF. The stage of microalbuminuria provides a unique window of opportunity, since by appropriate interventions, particularly administration of ACE inhibitors w25x, further progression can be delayed or even halted at a stage when the GFR has not yet decreased. Although appropriate long-term studies are currently not available, it appears that such early intervention is much more ef®cacious than intervention in later stages of diabetic nephropathy. It is obvious, however, that lowering blood pressure alone is not suf®cient and that concerted multi-model intervention is necessary w26x.

Pathogenesis of diabetic nephropathy The onset of diabetic nephropathy is determined both by genetic and non-genetic factors. One important argument for strong genetic determination is the observation of familial clustering of nephropathy both in type 1 w27x and type 2 w28x diabetes. In a study of our group we found that cardiovascular accidents and hypertension in ®rst degree relatives were the single most powerful predictors of early microalbuminuria in patients with recent onset of type 2 diabetes. There is apparently a strong interaction between the genetic risk, i.e. a family history of cardiovascular accidents in ®rst degree relatives, and glycaemic control w29x (Table 5). Today, taking the family history is, and in the future presumably monitoring of genes determining the renal risks presumably will be, of importance in targeting preventive measures to those individuals at the greatest renal risk. Several genes have been implicated as determinants of the risk of nephropathy, but so far no genetic test has been suf®ciently sensitive and speci®c to gain

Table 4. The stages of diabetic nephropathyÐtypical ®ndings Stage

Glomerular ®ltration

Albuminuria

Blood pressure

Time course (years after diagnosis)

Renal hyperfunction Clinical latency Microalbuminuria (incipient nephropathy) Macroalbuminuria or persisting proteinuria (clinically manifest nephropathy) Renal failure

Elevated High normal Within the normal range Decreasing

-20 mgumin -20 mgumin 20±200 mgumin (30±300 mguday) 200 mgumin (300 mguday)

Normal

At diagnosis

Diminished

Massive

Rising within or above normal range Increased

5 15 10 15

Increased

15 30


15

acceptance by clinicians. A polymorphism in the ACE gene apparently explains a certain proportion of the variance according to a prospective study in type 1 diabetic patients (Marre, personal communication). There are numerous reports from Asia concerning the positive association between the D allele of the ACE gene polymorphism and risk of onset or progression of nephropathy, but reports from Europe or USA have been consistently negative w30x. Another predictor is an elevated sodium-lithium counter transport, which is a phenotypically stable abnormality in patients with diabetic nephropathy and is found even in skin ®broblast cultures w31x. Hyperglycaemia has been documented as an extremely important risk factor for the onset of microalbuminuria both in type 1 w32x and type 2 diabetes w33,34x. There is no risk threshold, i.e. the renal risk increases progressively with higher HbA1c values. In the patient with type 1 diabetes, the presence of hypertension usually indicates the presence of renal disease. In contrast, in type 2 diabetes, hypertension very frequently precedes the onset of type 2 diabetes by years or decades, since hypertension is one facet of the so-called metabolic syndrome, which is a condition predisposing to, and occurring before, the onset of type 2 diabetes. Studies in Pima Indians showed that hypertension prior to the onset of diabetes (prediabetic hypertension) was a strong predictor of the risk of developing proteinuria once diabetes mellitus had set in w35x. Whether treatment of hypertension prior to the onset of diabetes or of proteinuria attenuates the risk to develop diabetic nephropathy has not been clari®ed. Another strong determinant of the risk of nephropathy is smoking w36x. According to Sawicki et al. w37x, cessation of smoking markedly reduces the renal risk.

Table 5. Interaction between genetic risk (family history of cardiovascular accidents in ®rst degree relatives) and glycaemic control Group

Prevalence of microalbuminuria

No family history and HbA1 -8% (ns12) Either family history or HbA1 )8% (ns52) Family history and HbA1 )8% (ns21)

0u12 (0%) 1u51 (2%) 10u21 (48%)*

*Difference between risk groups P-0.0001 (after Keller et al. w29x).

Accordingly, diabetic patients should be encouraged to stop smoking.

Management of the patient with diabetic nephropathy It is said that even today diabetic nephropathy, or even diabetes per se, is frequently diagnosed only in late stages of the disease. In a recent study of 173 diabetic patients (16 with type 1, 157 type 2 diabetes) admitted to German renal units, we found that the patients were referred to the nephrologist with an average creatinine clearance of 29 mlumin, with a known duration of diabetes (in the type 2 diabetic patients) of 0±44 years and with a median systolic and diastolic blood pressure of 170 mmHg (120±260) and 90 mmHg (60±180), respectively. Thirty-two of the 173 patients received no antihypertensive medication. Median LDL cholesterol was 176 mgudl (67±307), but only 15% had received lipid-lowering treatment. This observation illustrates that non-specialists neglect nephropathy as a complication of diabetes. It is a strong argument for early diagnosis and involvement of the nephrologist in the treatment of the patient with diabetic nephropathy. The key step to recognizing incipient renal involvement is monitoring the rate of urinary albumin excretion (UAE). The upper limit of normal UAE is de®ned as 30 mgu24 h (20 mgumin). Microalbuminuria is de®ned as an albumin excretion rate between 20 and 200 mgumin (or 30±300 mgu24 h). The potential presence of confounding factors that may limit the speci®city of albuminuria has to be excluded, e.g. uncontrolled hypertension, urinary tract infection, heart failure or acute conditions such as uncontrolled hyperglycaemia, fever or excessive physical exercise. Because of the considerable day-to-day variability (coef®cient of variation 30%), at least two out of three determinations must be positive on separate occasions. A single demonstration of elevated UAE is not diagnostic. Table 6 summarizes the measures that should be taken to prevent progression of overt nephropathy. These comprise: . adequate glycaemic control; . lowering of blood pressure with the speci®c aim to reduce proteinuria, since proteinuria is strongly correlated to progression of renal failure and

Table 6. Measures to prevent progression of overt nephropathy Achieve glycaemic control (HbA1c close to 7%); avoid hypoglycaemia. Maintain blood pressure in the mid-normal range (125u75 mmHg), preferably with the use of ACE inhibitors (possibly also angiotensin II receptor blockers). Reduce the level of proteinuria (therapeutic goal is a protein excretion rate of -1 guday) Stop smoking Restrict dietary protein intake to ;0.8 gukg body weightuday (preferentially by reducing the intake of animal proteins), except among patients with preterminal renal failure.

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since proteinuria has recently been shown to be a `nephrotoxin' w39x; . cessation of smoking; and possibly (although this is less well documented); . restriction of dietary protein intake. Of particular importance is the selection of an adequately low target blood pressure. In type 2 diabetic patients, the UKPDS study w40x showed that tight control of blood pressure compared with less tight blood control had a dramatic effect on outcome. Even though this is no longer considered adequate according to today's concepts, a target blood pressure of -150u85 mmHg had been adopted for `tight BP control' when the study was planned more than a decade ago. Nevertheless, the modest 10 mmHg difference in systolic blood pressure between `tight' and `less tight' blood pressure control was associated with an impressive 30% reduction of the rate of death (Table 7). Based on these and other observations, a number of authorities consider blood pressure -130u85 mmHg w41,42x optimal for the diabetic patient and the National Kidney Foundation recommends even lower pressures, i.e. 125u75 mmHg in patients with proteinuric renal disease w43x. A particular bone of contention is the selection of the appropriate antihypertensive agent. Based on the observation that reduction of proteinuria is the single most important predictor of success in halting progression of diabetic disease w44x, it has been recommended that for antihypertensive treatment one should start by using an ACE inhibitor w25x. ACE inhibitors were superior to placebo in patients with advanced diabetic nephropathy and type 1 diabetes w45x and the same has been shown in type 2 diabetic patients, at least in the early stages of the disease w46,47x. Whether this is also true for advanced diabetic nephropathy in type 2 diabetes is currently under study in two large, multicentre, international trials, which are designed to study the effect of Irbesartan and Losartan on progression of advanced nephropathy. So far, no controlled evidence for a bene®cial effect of angiotensin receptor blockers is available, but given the evidence for a role of angiotensin in progression w48x, the use of these drugs appears to be rational. There is much less evidence concerning calcium channel blockers w49x. In the study by Bakris et al. w50x,

non-dihydropyridine calcium channel blockers reduced proteinuria and attenuated progression better than beta-blockers. There are also good arguments for combining calcium channel blockers and ACE inhibitors w51x. There has been great concern about potential cardiovascular side effects of calcium channel blockers in diabetic patients. Estacio et al. w52x found a higher rate of myocardial infarction in diabetic patients on calcium channel blockers compared with patients on ACE inhibitors. This ®nding does presumably not indicate an excess cardiovascular risk with calcium channel blockers, but rather inferiority to ACE inhibitors in the prevention of cardiovascular events. This interpretation is supported by the observation in the SystEur study that with respect to the reduction of cardiovascular events, diabetic patients derived proportionally even more bene®t from treatment with calcium channel blockers than did non-diabetic patients w53x. When the diabetic patient has reached the stage of renal failure, heushe usually suffers from a multitude of medical problems caused by diabetic microvascular and macrovascular complications. These are summarized in Table 8. Because of such co-morbidity, the diabetic patients seen by the nephrologist are on average more severely ill than the average patient seen by the diabetologist. It is for this reason that Table 8. Common associated problems in type 2 diabetes patients with diabetic nephropathy Microvascular complications Retinopathy (non-proliferative, proliferative) Polyneuropathy, including autonomic polyneuropathy Cystopathy (detrusor paresis) Gastroparesis Diarrheauconstipation Impotence Diabetic foot (neuropathic) Macrovascular (atherosclerotic) complications Coronary heart disease (Ischaemic) cerebrovascular disease Arterio-occlusive disease (lower extremities; diabetic foot (ischaemic) Ischaemic nephropathy (renal artery stenosis, cholesterol microembolism) Other Hypertensiveunon-hypertensive cardiomyopathy

Table 7. Effects of tight and less tight control of blood pressure among 1148 patients with type 2 diabetes* Variable

Tight blood pressure control (ns758)

Less tight blood pressure control (ns390)

Target blood pressure (mmHg) Achieved blood pressure (mmHg)

-150u85 144u82

-180u50 154u87

Reduction in the risk of endpoints in the tight control group as compared with the less tight control group (%; 95% con®dence interval) Death 32 ( 51 to 6) Diabetes-related endpoints 24 ( 38 to 8) Stroke 44 ( 65 to 11) Microvascular endpoints 37 ( 56 to 11) *Data were obtained from the UK Prospective Diabetes Study, which lasted 8.4 years w40x.


optimal management of these multi-morbid patients requires an effective interdisciplinary approach.

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