Review Early Diabetic Nephropathy: Assessment and ... - Diabetes Care

Review

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arly Diabetic Nephropathy: Assessment and Potential Therapeutic Interventions JULIO ROSENSTOCK, MD AND PHILIP RASKIN, MD

End-stage renal failure secondary to diabetes has increasingly become a health and socioeconomic issue. Diabetic nephropathy is the major cause of death in type I insulin-dependent diabetic patients and accounts for —25% of all patients beginning hemodialysis in the United States. Once diabetic nephropathy is well established, attempts to modify the relentless downward progression of the disease have been essentially unsuccessful. We focus on the early structural and functional changes that occur as a consequence of diabetic renal disease and examine the evidence for microalbuminuria as an early marker and predictor for future overt diabetic nephropathy. The rationale for different therapeutic interventions to alter the course of early diabetic nephropathy are discussed, DIABETES CARE 1986; 9:529-45.

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nd-stage renal failure secondary to diabetes mellitus has become an important health and socioeconomic issue in the United States. Diabetic nephropathy is the major cause of renal failure in twenty-five percent of all patients beginning therapy for end-stage renal disease in this country.1 By the end of this decade, the cost of care for the uremic diabetic patient is estimated to approach $2 billion a year.2 Once diabetic renal disease is well established, attempts to modify the relentless progression of the disease have been essentially unsuccessful. Apparently, when diabetic nephropathy reaches a certain level of severity, the process becomes self-perpetuating. Improved glycemic control has not been shown to have obvious beneficial effects.3 Treatment of hypertension has retarded the progression of the kidney disease, however.4"6 Considerable interest has emerged with recent reports that have characterized a much earlier stage of diabetic nephropathy. A growing body of evidence suggests that a persistent elevation of urinary albumin excretion in diabetic patients without clinical proteinuria predicts future development of overt diabetic nephropathy.7 This review addresses the issue of diabetic nephropathy from the different and much more promising perspective of early identification and early intervention. We discuss the rationale for different therapeutic approaches on the progression of early diabetic nephropathy. OVERT DIABETIC NEPHROPATHY

Magnitude of the nephropathy problem in diabetes mellitus.

Diabetic nephropathy is the major cause of death in pa-

tients with type I diabetes mellitus.8 Deckert et al.9 reported that of 306 diabetic patients whose illness was diagnosed before age 31 yr and analyzed after at least 40 yr of diabetes, proteinuria was present in 38% and uremia in 22% of the patients. In 31% of the deceased patients, uremia was the cause of death. The excess mortality in patients exhibiting persistent proteinuria with 50% of the deaths. Important information has emerged from the elegant epidemiological studies carried out at Steno Memorial Hospital. These workers have been able to analyze ~ 2 3 % of all IDDM patients diagnosed in Denmark between 1923 and 1953. n In 1303 patients, who were followed until death or for at least 25 yr after the onset of diabetes, they were able to obtain sufficient information on proteinuria. Diabetic nephropathy, defined by persistent proteinuria (protein excretion >0.5 g/ 24 h in at least four consecutive 24-h samples), was found in 41% of the patients. Fifty-seven percent did not develop persistent proteinuria during the follow-up period. The max-

DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986

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EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN

imal prevalence of nephropathy in relation to duration of diabetes was 21% after 20-25 yr of diabetes. It declined (probably by a process of self-selection) to —10% in patients who had suffered from diabetes for >40 yr. The cumulative incidence data from the study indicate that ~45% of all IDDM patients will develop nephropathy after 40 yr of the disease. Patients with nephropathy had a much poorer survival rate than those without proteinuria. After 40 yr of diabetes, only 10% of the patients who developed nephropathy were alive, whereas >70% of patients who did not develop nephropathy survived. Uremia was the cause of death in 66% of the patients with nephropathy. Mortality was ~49% in patients with persistent proteinuria for ^ 7 yr." Diagnosis of overt diabetic nephropathy. There are clear struc-

tural and functional abnormalities in the kidney in IDDM patients. The hallmark for the classic clinical diagnosis of diabetic nephropathy is the appearance of persistent dipstickpositive proteinuria that usually represents a urinary protein excretion >0.5 g/24 h . n Arterial blood pressure then usually begins to rise, and the glomerular filtration rate (GFR) starts its apparent inexorable decline with the subsequent progressive elevation of serum creatinine levels.13 The advanced pathologic lesions of diabetic nephropathy are highly specific and separate chronic renal failure due to diabetes from other causes of end-stage renal disease. Glomerular basement membrane (GBM) thickening and mesangial expansion, as well as afferent and efferent arterial hyalinosis, are commonly seen. In addition, there is an increased renal linear extracellularmembrane staining for albumin and immunoglobulin G (IgG) that are quite specific for diabetic nephropathy.14 GBM thickening and expansion of the glomerular mesangium, primarily due to the enlargement of the mesangial matrix, is a constant finding in most patients with diabetic nephropathy.15 It seems that initially the pattern is of a progressive GBM thickening, and then most of the basement membrane-like material eventually accumulates in the mesangial region.16 The end result of the basement membrane accumulation within an individual glomerulus is glomerular occlusion. This event occurs after ~15 yr of diabetes, and it may be related to mesangial expansion encroaching on the subendothelial space, eventually compromising the glomerular capillary lumen and blood flow.H The number of occluded glomeruli appears to increase as the duration of diabetes increases. In autopsy studies of patients with long-standing IDDM, Gunderson and Osterby17 found a relationship between the number of glomeruli with capillary occlusions and both duration of the disease and degree of renal failure. However, an intriguing dissociation occurs when structural and morphological changes in the kidney are related to renal function in IDDM patients. Whereas 30-40% of all IDDM patients will develop overt clinical diabetic nephropathy, 6070% of patients never develop clinical renal disease, despite histological evidence of glomerulosclerosis in nearly all IDDM patients after only a few years of the disease.18 To elucidate the relationship between clinical diabetic renal disease and renal pathology, the Steno group studied autopsy

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material from 34 long-term IDDM patients. Half of these patients had no clinical evidence of nephropathy, and the other 17 matched patients had severe clinical nephropathy. 19>2° Patients who had clinical renal disease had significantly more interstitial tissue and glomerular mesangium expansion and less open glomerular capillaries than the diabetic subjects without clinical nephropathy. However, severe glomerulosclerosis was also seen in patients without clinical evidence of nephropathy. Serum creatinine levels were best correlated with the mesangial area, and a significant negative correlation existed between the relative areas of open capillaries and amount of mesangium present. Remarkable mesangial expansion was seen in most of the patients with clinical renal disease, but it was also present in several diabetic subjects who did not have clinical nephropathy. The area of open capillaries appeared to be a good light-microscopic indicator of clinical nephropathy. Mauer et al.21 have reported elegant studies of renal biopsies from 45 patients with IDDM. These specimens were examined by semiquantitative light-microscopic and quantitative electron-microscopic stereologic morphometry. These patients had IDDM for 2.5-29 yr, but only 16 patients had clinical evidence of nephropathy. The renal biopsies were performed as part of their evaluation as potential pancreastransplant recipients. Surprisingly, no relationship was found between either GBM thickening or mesangial expansion and the duration of the diabetes. A relatively weak but statistically significant relationship was found between the thickness of the GBM and the expansion of the mesangium, suggesting a different production and turnover rate for GBM and mesangial matrix constituents. The total mesangium volume had a strong inverse correlation with the capillary-filtration surface area. Finally, there was no significant relationship between creatinine clearance and GBM thickness. The mesangial expansion had a strong inverse correlation with creatinine clearance, however. This meticulous study demonstrates that clinical diabetic nephropathy does not become manifest until renal lesions become far advanced. Patients with the earliest findings of overt clinical nephropathy uniformly had severe glomerular lesions. It was hypothesized that progressive mesangial expansion could ultimately contribute to glomerular functional deterioration by restriction of the glomerular capillary vasculature and the surface area available for filtration. Natural course of diabetic nephropathy. Once clinical pro-

teinuria develops in diabetic patients, glomerular function progressively and relentlessly declines. The mean duration of diabetes at onset of proteinuria and the subsequent clinical course was reported in a retrospective study by the Joslin Clinic (Table I). 22 Similar results were found by the Steno Memorial Hospital in 157 IDDM patients with diabetic nephropathy.23 Persistent proteinuria appeared after an average of 19 yr, and death ensued 5-6 yr later. The rate of deterioration of glomerular function in diabetic nephropathy varies considerably among patients. However, the decline is linear over time and is characteristic for the individual patient.24'25 Once the serum creatinine concentration rises above 2 mg/dl, the progression of the renal failure



TABLE 1 Duration of diabetes and degree of renal dysfunction at various stages of nephropathy Renal failure

Duration of diabetes (yr) Blood urea nitrogen level (mg/100 ml) Creatinine level (mg/100 ml)

Onset of proteinuria (N = 112)

Early (N = 70)

(N = 62)

Death (N = 61)

17.3 ± 6.0 18.2 ± 6.0 1.2 ± 0.3

19.4 ± 5.4 41.2 ± 13.5 2.8 ± 0.9

21.6 ± 6.3 98.5 ± 45.5 8.5 ± 3.9

22.1 ± 6.4 151.0 ± 53.6 12.4 ± 6.4

Late

From Kussman et al. 22

in each patient is constant and predictable. The relationship between the inverse of the serum creatinine concentration and time in months is used to show this straight-line correlation (Fig. 1). Prospective studies in IDDM patients with clinical proteinuria have also shown that the decline in GFR has a striking linear relationship with time.26'27 Mogensen26 found that GFR fell at a rate of 0.9 ml • min" 1 • mo" 1 during 34 mo of observation. Recently, Viberti et al.27 reported a similar linear decline in GFR. In this study the rate of fall of the GFR ranged between 0.63 and 2.4 ml • min" 1 -mo" 1 with a mean of 1.2 ml • min" 1 • mo" 1 . Furthermore, a positive correlation was found between the rate of change of GFR and the reciprocal of the serum creatinine level. When the reciprocal of the plasma 32-microglobulin concentration was used, there was an even stronger correlation with GFR. The plasma fi2microglobulin concentration rises to levels above normal as the GFR falls below 80 ml • min" 1 • 1.73 m" 2 . This is in clear contrast with the plasma creatinine concentration, which is still within the normal range at a similar level of glomerular filtration.28 Although Parving et al.29 found a similar strong correlation between the reciprocal of the plasma (32-microglobulin concentration and the rate of decline of GFR, the cutoff point when the serum p2-microglobulin concentration exceeded the upper limit of normal was at a GFR of 0.5 g/24 h, of which 50% is albumin.36 The glomerular origin of the microalbuminuria found in IDDM patients is supported by the concommitant finding of a normal excretion of 32'microglobulin, a sensitive indicator of tubular reabsorptive capacity.37 In January 1985, researchers from the three major diabetes centers in Denmark met at "The Gentofte Convention on Microalbuminuria and Incipient Diabetic Nephropathy. "38 A consensus was reached to define microalbuminuria as an UAER >20 (xg/min but ^200 (xg/min (Table 3). The diagnosis of early or incipient diabetic nephropathy is made only when microalbuminuria is found in two of three urine samples collected within 6 mo. Note that collections of sequential urine samples are required. Diabetic subjects with and without microalbuminuria can have a daily variation in albumin excretion as high as 47%.39 The reason for this high coefficient of variation among multiple samples remains largely unknown, but several factors such as incomplete urine collections, physical activity, and differences in metabolic control might influence the AER. Before a patient is categorized as having microalbuminuria, other causes of transient or reversible elevation of albumin excretion must be excluded. Such transient or reversible causes include poor diabetic control, urinary tract infection, physical exercise, essential hypertension, cardiac insufficiency, and water loading.

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At diagnosis, Mogensen found slight elevations of AER that promptly reverted to normal with insulin therapy.40 Even short periods of poor glycemic control would elevate the AER, as shown by Parving et al. ,41 when insulin therapy was deliberately withdrawn in type I diabetic patients. It has been estimated that with conventional diabetes management ~ 3 0 45% of dipstick-negative IDDM patients will be found to have an elevated AER.42 The prevalence of real and persistent microalbuminuria, however, remains to be established. Enthusiastic attention was initially given to exercise-induced albuminuria in an attempt to establish a provocative test that might identify an even earlier stage of diabetic nephropathy.43"47 Under conventional glycemic control, diabetic patients with normal resting AER show marked albuminuric response to physical exercise compared with matched nondiabetic controls. In most studies, patients with microalbuminuria responded with an even greater potentiation of AER. However, exercise-induced albuminuria may have no predictive value and adds no additional information to that obtained with timed urine collections (under basal conditions) that measure AER.48 The AER can be transiently increased by an acute increase in urine flow during water loading (as with GFR studies). The peak albumin excretion is reached 30—60 min after water loading and then falls by 90 min to remain constant thereafter with a steady state of water diuresis.49 Predictive value of microalbuminuria. Substantial evidence

is available to suggest that an elevation of UAE without clinical proteinuria, strongly predicts a later progression of diabetic renal disease.50"55 Table 4 summarizes the long-term longitudinal studies that have examined the predictive value of microalbuminuria. Parving et al.50 were probably the first to attempt to identify patients at high risk of developing diabetic nephropathy. After 6 yr, 5 of the 8 patients with an elevated AER (mean 115 ± 24 mg/24 h) had subsequently developed persistent overt proteinuria, elevated serum creatinine, and raised blood pressure. One patient developed intermittent proteinuria. In contrast, only 2 of 15 patients with normal AER developed proteinuria. Viberti et al.51 reported a cohort study of 63 insulin-treated diabetic subjects screened in 1966—1967 and reassessed 14 yr later. Persistent dipstick-positive proteinuria developed in 7 of the 8 patients (88%) with an overnight AER >30 |xg/min and in only 2 of the remaining 55 (4%) TABLE 3 Early diabetic nephropathy Albumin excretion rates Normoalbuminuria (dipstick-negative) 300 mg/24 h) Diagnosis Persistent microalbuminaria levels found in at least two of three urine samples collected within 6 mo From Mogensen.38



TABLE 4 Predictive value of microalbuminuria Type of diabetes

No. of patients

Initial age (yr)

Parving et al.50

Age 16-40 yr Onset >31 yr Duration 10-25 yr

25

29

Viberti et al.51

Insulin treated Age 56147 Wiseman et al.147 divided 28 IDDM patients into a low-microalbuminuria (12-29 |xg/ min) and a high-microalbuminuria group (>30 (xg/min). A significant correlation was found between AER and blood pressure; the latter was significantly higher in the high-microalbuminuria group. An association between AER and essential hypertension was previously reported.148 Antihypertensive therapy has been shown to reduce AER.149 The reason for this mild elevation in blood pressure associated with microalbuminuria is unclear. Microalbuminuria may indicate renal dysfunction and mesangial expansion sufficient to raise the blood pressure. Alternatively, the conventionally accepted normal blood pressure level may be too high for a diabetic subject and may account for the increased albumin excretion. Of interest is the study by Christiansen and Mogensen150 that demonstrates the effect of early antihypertensive therapy in six microalbuminuric diabetic patients with minimally elevated blood pressure levels. Treatment with 100 mg metoprolol twice daily for a mean of 2.6 yr reduced blood pressure from 135 ± 8/93 ± 9 to 124 ± 6/84 ± 3 mmHg and the mean blood pressure from 107 ± 7 to 97 ± 3 mmHg. AER decreased from 131 ± 2 to 56 ± 3 |xg/min. GFR was elevated and remained so despite treatment. It is tempting to speculate that the initiation of antihypertensive treatment at an early stage of microalbuminuria may prove to have a more effective long-term beneficial impact on the progression of diabetic nephropathy than when

treatment is started in the overt stage of diabetic nephropathy. The 1984 report of the "Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure"151 defines the diagnosis of hypertension in adults as confirmed when the average of two or more diastolic blood pressures on at least two subsequent visits is ^90 mmHg or when the average of multiple systolic blood pressures on two or more subsequent visits is consistently >140 mmHg. It is also stated: "The benefits of drug therapy seem to outweigh any known risks from such therapy for those with a diastolic blood pressure persistently elevated above 95 mmHg and for those with a lesser elevation who are at high risk, i.e., patients with target organ damage, diabetes mellitus, or other major risk factors for coronary heart disease." The presence of diabetes mellitus and the coexistence of microalbuminuria as a marker of initial and progressive target organ damage may justify an aggressive approach to treat blood pressure, perhaps in the levels of > 140/85, in an attempt to stop or retard the progression of the renal disease. It remains an open question whether conventional levels of hypertension are set too high for potentially reversible diabetic nephropathy or whether some lower level of blood pressure should be chosen to initiate antihypertensive treatment in patients with diabetes.152 Well-designed controlled studies are needed to show whether antihypertensive treatment given for minimal hypertension has any impact on the course of diabetic nephropathy and also on the morbidity and mortality associated with other cardiovascular conditions.153 Low-protein diets. Dietary intervention with low-protein diets has long been recommended in patients with chronic renal failure.154 Several studies have shown that protein-restricted diets slow the progressive decline of renal function and prolong life in patients with moderate to severe renal disease. 154~157 The rationale for this dietary approach is based on early experimental evidence that high-protein diets accelerate the glomerular lesions in intact and uninephrectomized rabbits or rats.158-161 Conversely, low-protein diets appear to retard the progression of nephrotoxic serum nephritis in rats.162 Graded reductions in dietary protein intake have been shown to induce stepwise increases in the life span of rats subjected to extensive renal ablation.163 Protein restriction is clearly effective in preventing the hyperfiltration and renal


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pathologic changes occurring in the remnant glomeruli of rats with reduced renal mass. A reduction of dietary protein content from 24 to 6% in rats after the ablation of 90% of their renal mass blunts the hemodynamic changes and prevents the development of glomerular lesions and proteinuria. 10° Brenner and colleagues,164165 and Jamison166 have reconciled the hyperfiltration model of the "remnant kidney" with the chronic effects of excess protein intake on the progression of renal disease. This theory proposes that an increase in protein intake causes renal vasodilation and glomerular hyperperfusion. The elevated transcapillary flux of ultrafiltrate eventually disrupts the glomerular permselectivity and causes albuminuria with subsequent mesangial expansion. As discussed above, the same model of glomerular hyperfiltration has been proposed by those authors to explain the genesis of diabetic nephropathy.98102 Note the report by Neugarten et al.167 that streptozocin diabetic rats fed with high protein diets (50%) have an acceleration of the diabetic nephropathy as evidenced by greater mesangial expansion and GBM thickening as well as higher proteinuria than diabetic rats fed with 20% protein chow. To date there is only one clinical study available assessing the effect of low-protein diets on an homogenous population of patients with advanced diabetic nephropathy.168 Preliminary data suggests that dietary protein restriction significantly reduces proteinuria, but more prolonged observation is needed to determine whether the course of diabetic nephropathy is indeed retarded. No studies are available on the potential beneficial effect of low-protein diets on microalbuminuria in patients with early diabetic nephropathy. Short- and longterm prospective and controlled studies are required to explore this attractive "noninvasive" intervention. Aldose reductase inhibitors. Much experimental evidence reviewed by Cogan et al.169 and in unpublished data of Raskin and Rosenstock suggests that the enhanced polyol pathway activity may provide a common biochemical vinculum in the pathogenesis of late diabetic complications. The intracellular accumulation of sorbitol and fructose occurs as a consequence of the increased activity of aldose reductase, the rate-limiting and key enzyme in this pathway. An osmotic effect was originally thought to be the main pathogenic mechanism that results from the increased polyol concentration in tissues.170 Recently, more attention has been given to the concomitant reduction of tissue-myoinositol levels seen in diabetes.171 Acute reversible nerve-conduction abnormalities found in experimental diabetes are apparently due to a myoinositol-related defect in Na + -K ATP+-ase activity.172 Administration of an aldose-reductase inhibitor ameliorated the diabetes-related changes in nerve sorbitol and myoinositol and improved nerve-conduction velocities in rats173 and humans174 with an apparent beneficial effect in painful diabetic neuropathy.175-176 In addition, experimental evidence has also shown that aldose-reductase inhibitors prevent cataract formation169 and, more importantly, prevent galactoseinduced retinopathy with striking reduction in retinal capillary basement membrane thickness.177 The presence of aldose-reductase activity has been clearly 540

documented in retina, lens, Schwann's cell, aorta, and also in glomerular tissue.169 Beyer-Mears et al.178 measured polyols in glomeruli isolated from control and streptozocin-diabetic rats and assessed whether changes in diabetic glomeruli could be prevented by oral treatment with the aldose-reductase inhibitor drug, sorbinil. Compared with controls, the polyol content of glomeruli isolated from diabetic rats was increased 10-fold and 4-fold at 6 and 9 wk, respectively, after induction of diabetes. It was unchanged in glomeruli from rats treated with sorbinil. In contrast, glomeruli myoinositol content was reduced in diabetic animals, and this fall was completely prevented by the drug. Note that the glomerular accumulation of protein in diabetic rats was also prevented with aldosereductase inhibition, suggesting a role for this pathway in the genesis of diabetic nephropathy. Treatment of streptozocindiabetic rats with sorbinil reduces proteinuria and restores the urine electrophoresis pattern towards normal.179 To date no human studies have been reported on the potential beneficial effects of aldose-reductase inhibitors on either overt proteinuria or on the microalbuminuria of early diabetic nephropathy. CONCLUSION

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he problem of diabetic nephropathy is so great that the classic passive spectator approach can no longer be justified. Although the natural history of early diabetic nephropathy remains to be further elucidated, microalbuminuria seems to be a reliable early marker of self-perpetuating, slowly progressive diabetic kidney disease. The last annual report of the National Diabetes Advisory Board2 has acknowledged that "elevated urinary albumin excretion predicts with a high degree of accuracy the ultimate development of overt clinical diabetic nephropathy." Moreover, one of their recommendations is: "Further tests must be designed to unmask early glomerular injury so the treatment of hyperglycemia and hypertension can be instituted at an optimum time." In accordance with the spirit of that recommendation and the evidence presented, we suggest the following protocol: I) Type I patients with >5 yr duration of IDDM need to have UAER (overnight collections) assessed regularly (every 12 mo). NIDDM diabetics may have overnight UAER measured every 2 yr. 2) If AER is elevated, a series of three determinations over 3-6 mo is required to define persistent microalbuminuria. 3) If microalbuminuria is found, efforts should be directed toward improving glycemic control and early intervention to maintain normal blood pressure. Long-term prospective studies are required to evaluate the role of glycemic and blood pressure control as well as the potential role of low-protein diets and aldose reductase inhibitors on the progression of early diabetic nephropathy. ACKNOWLEDGMENTS: We appreciate the invaluable help of Suzanne Strowig, RN, MSN; Susan Mullen, RN; Laura Schnurr, RN; and Susan Cercone, RDMS. We thank Rueben Dickter, Lisa Gagliano, Katie Hammon, Arthur Ojirika, and Kevin



Sullivan for technical assistance and Betty Newton and Charlene Davis-Williams for assistance in preparing the manuscript. From the Department of Internal Medicine, The University of Texas Health Science Center, Dallas, Texas. Address reprint requests to Julio Rosenstock, MD, Department of Medicine, University of Texas Health Science Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235. REFERENCES 1

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