Between hyperfiltration and impairment: Demystifying early renal functional changes in diabetic nephropathy

diabetes research and clinical practice 82s (2008) s46–s53

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/diabres

Between hyperfiltration and impairment: Demystifying early renal functional changes in diabetic nephropathy Elizabeth T. Rosolowsky a,b, Monika A. Niewczas a,c,e, Linda H. Ficociello a, Bruce A. Perkins d, James H. Warram a, Andrzej S. Krolewski a,c,* a

Research Division, Joslin Diabetes Center, Boston, MA, United States Division of Endocrinology at Children’s Hospital Boston, Boston, MA, United States c Department of Medicine at Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States d Division of Endocrinology and Metabolism, University of Toronto, Toronto, Canada e Department of Immunology, Transplant Medicine and Internal Diseases, Warsaw Medical University, Warsaw, Poland b

article info Published on line 11 October 2008 Keywords: Type 1 Diabetes Microalbuminuria Early renal function decline Cystatin C

abstract Renal functional changes in diabetic nephropathy conventionally have been linked to progression of urinary albumin excretion. This paradigm was based on historic evidence noting that hyperfiltration occurred in the setting of normoalbuminuria and microalbuminuria and that loss of renal function began in the context of proteinuria. More contemporaneous research findings, using serum cystatin-C-based estimates of glomerular filtration rate (cC-GFR), have challenged this paradigm. Rather, the process of renal function loss appears to begin prior to the onset of proteinuria. In the 2nd Joslin Kidney Study on the Natural History of Microalbuminuria, over one-third of type 1 diabetes (T1DM) patients with microalbuminuria at the time of enrollment already had evidence of mild (cC-GFR < 90) or moderate (cC-GFR < 60 ml/min) renal function impairment. Understanding the mechanisms underlying this phenomenon of early renal function impairment may allow for interventions directed at altering or retarding early renal function decline. To date, serum uric acid and components of the TNFa pathway appear to be involved. # 2008 Elsevier Ireland Ltd. All rights reserved.

1. Historical predictive markers of diabetic nephropathy: microalbuminuria and hyperfiltration Diabetic nephropathy is a microvascular complication characterized by the presence of proteinuria, hypertension, and loss of renal function and historically affected 45% of T1DM patients [1,2]. After 35 years duration, one-third of patients with T1DM would progress to end-stage renal disease [3]. Diabetes continues to be the primary cause of chronic renal failure in the United States [4]. The historically poor prognosis of T1DM patients with diabetic nephropathy was in part due to the limited methods

with which clinicians could detect and follow chronic renal insufficiency. Measurement of renal function was primarily performed in research settings, and clinicians instead relied on proxies of renal function. One popular method for screening for renal disease among diabetes patients was the use of Albustix, but the test did not register positive until a minimum concentration of protein representative of an excretion rate of 75 mcg/min had accumulated [5]. In the early 1960s, the development of a radioimmunoassay technique enabled the quantification of minute amounts of urinary albumin, termed microalbuminuria [6]. Several publications subsequently demonstrated that microalbuminuria in the range of 15–70 mcg/min could predict future diabetic

* Corresponding author at: Section on Genetics & Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, United States. E-mail address: [email protected] (A.S. Krolewski). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.09.018

diabetes research and clinical practice 82s (2008) s46–s53

nephropathy [7–9]. One prospective study showed that 80% of T1DM patients with an average baseline albumin excretion rate (AER) of 50 mcg/min developed proteinuria 10 years later, while none with a baseline AER of 5 mcg/min progressed to proteinuria [9]. The convening of a consensus panel resulted in the establishment of arbitrary and convenient thresholds of normoalbuminuria, microalbuminuria, and proteinuria: 20, >20 but 200, and >200 mcg/min, respectively [10]. By the time these results were published, it was well-known that alterations in renal function occur at the time of diagnosis of T1DM. Glomerular filtration rate (GFR) and plasma renal flow were found to be supranormal in young T1DM patients compared to non-diabetes controls [11]. Many investigators then tested the potential for these early changes in renal function to set the stage for overt diabetic nephropathy. Elevated GFR was an independent predictor of future microalbuminuria and macroalbuminuria [12]. Specifically, GFR >140 ml/min/1.73 m2 was strongly predictive of the occurrence of microalbuminuria, and data supported a threshold AER of 200 mcg/min before GFR began to decline [9,13]. Glomerular hyperfiltration was attributed to abnormalities in glomerular and pre-glomerular vessels and/or hyper-resorptive proximal tubules that occurred in the setting of hyperglycemia and insulin deficiency [14–16]. It was hypothesized that alterations in the glomerular microcirculation would lead to single nephron injury; remnant nephrons would compensate with increases in pressures and flows; and a self-perpetuating cycle of renal injury would be established [17]. Although the poor performance of hyperfiltration as a predictor of overt nephropathy was reported by some investigators [18,19], the pairing of glomerular hyperfiltration and normoalbuminuria in short duration diabetes followed by the pairing of diminished renal function and proteinuria later quite naturally led to the supposition that declining renal function and increasing albumin excretion are coupled. Mogensen and colleagues have best articulated this model. Under this paradigm, renal function is normal or elevated when the appearance of microalbuminuria marks the onset of diabetic nephropathy. Urinary albumin excretion increases to overt nephropathy and causes renal function to decline as it progresses to proteinuria [5,20]. Several important consequences have stemmed from this conventional paradigm. First, because renal function parallels the degree of albuminuria, the latter has become an accepted proxy of the former. Next, this paradigm emphasizes prevention of microalbuminuria because once microalbuminuria is established, progression to proteinuria and renal failure will inexorably take place. Last, prevention and reduction of microalbuminuria have served and continue to serve as the primary endpoints towards which clinical interventions have been directed [21–23].

2. Challenges to the conventional paradigm of diabetic nephropathy The work that propelled the current model of diabetic nephropathy focused on early hyperfiltration and late renal function loss, with the assumption that normal renal function is maintained in the stages of normoalbuminuria and micro-

S47

albuminuria. However, there has to-date been a paucity of data detailing how GFR declines from the normal levels centered at 120 to significantly impaired levels less than 60 ml/min. At least two reasons may explain the dearth of research: (1) the assumption that microalbuminuria would eventually progress to overt nephropathy focused research energy into understanding the mechanisms of and treatments for microalbuminuria and (2) the lack of accurate, convenient methods of estimating GFR when it is within or near the normal range precluded large, prospective studies from being conducted. To address these two issues, it is important to recognize that regression of microalbuminuria occurs more commonly than progression to proteinuria and that a method currently exists that permits the estimation of normal or near-normal GFR.

2.1. Regression of microalbuminuria is more common than progression to proteinuria Several seminal publications have perturbed the conventional paradigm of diabetic nephropathy. They counter the assertion that the majority of T1DM patients with microalbuminuria progress to proteinuria. For instance, the percentage of patients progressing from microalbuminuria to proteinuria has been modified to 30%, much lower than previous estimates [7–9]. Furthermore, not only is progression to proteinuria not as common as historically reported, but regression of microalbuminuria is more likely than progression. In the 1st Joslin Kidney Study on the Natural History of Microalbuminuria in Type 1 Diabetes, of 386 T1DM patients with microalbuminuria with an average diabetes duration of 18 years at baseline, only 19% progressed to proteinuria while 60% exhibited regression during the 6-year follow-up period [24]. This finding has been reproduced in another large study of T1DM patients [25]. There is also a wide range of underlying diabetic glomerular lesions among long-standing T1DM patients. Many microalbuminuric patients have only mild diabetic renal injury, while some normoalbuminuric patients have wellestablished lesions, consistent with those once believed to develop only at the time of proteinuria [26,27]. Together, these studies provide evidence that renal function and albuminuria status are not completely coupled, suggesting that separate mechanisms might account for loss of renal function and development of albuminuria. Conversely, urinary albumin excretion and renal function decline may represent two phenotypes of diabetes-related renal disease with the same underlying etiology.

2.2.

Cystatin-C-based estimates of GFR

The ideal marker for measuring GFR would be metabolically inactive, freely filtered by the kidney, and neither reabsorbed nor secreted during intrarenal transit. The exogenous marker inulin possesses these properties, and iothalamate is almost as ideal and has the added benefit of subcutaneous delivery. While inulin and iothalamate are the gold-standard methods for measuring GFR, they have limited clinical application because of their cumbersome protocols and are generally reserved for the research setting. Instead, estimating equations of GFR have been derived using an endogenous marker,

S48

diabetes research and clinical practice 82s (2008) s46–s53

serum creatinine. While convenient, they are problematic because they are influenced by gender, muscle mass, and age; are most accurate in the range of chronic kidney insufficiency; and suffer from non-standardization of the Jaffe assay that is used to measure serum creatinine [28]. Serum cystatin-C is an endogenous, non-glycosylated basic protease inhibitor that has many features of an ideal marker of renal function. Also, its production is reportedly unaffected by age, gender, or body mass and correlates better than creatinine with measured GFR when renal function is normal [29–31]. Estimations of GFR using cystatin-C have taken various forms, including the reciprocal of cystatin-C and regression-derived conversion equations. The value of using serum cystatin-C estimations of GFR (cC-GFR) was highlighted in a longitudinal study of type 2 diabetes Pima Indians who were followed over 4 years with annual measurements of cystatin-C and creatinine. The baseline measured GFR (using iothalamate clearance) was 153  27, and final GFR was 136  42 ml/min. The reciprocal of cystatin-C was best correlated with measured GFR, more than the MDRD, the reciprocal of creatinine, or the Cockcroft-Gault formulas [32]. These results subsequently have been replicated in type 1 and 2 diabetes patients, though the regression equation developed in those studies produces estimates that are slightly lower than those obtained using the inverse of cystatin-C [33,34].

3. Early renal function decline occurs prior to the onset of proteinuria The reliability and accuracy of serum cystatin-C-based estimates of GFR have made feasible large-scale prospective studies directed at monitoring patterns of renal function change prior to the development of proteinuria. In addition, where previous nephropathy studies were limited to small study groups, the ease of measuring serum cystatin-C has permitted larger cohorts to be assembled. For the 1st Joslin Kidney Study on the Natural History of Microalbuminuria in Type 1 Diabetes, Perkins et al. assembled a cohort of 568 patients whom they followed over 8–12 years with serial measurements of serum cystatin C and AER [35]. Fig. 1 depicts eight patients participating in the follow-up study. None were proteinuric at baseline. Serial measurements of cystatin-C were obtained periodically over the follow-up period, and the reciprocal of cystatin-C was used to estimate GFR. Slopes were derived from linear regression of serial estimates of GFR for each individual, and renal function decline was defined as a slope more negative than 3.3% per annum according to a threshold determined from the Baltimore Aging Study, adjusted for the age of the 1st Joslin Kidney Study cohort [36]. The four participants in panel A had a range of slopes from 1 to +0.5% per year, so they did not manifest renal function loss. However, the range of slopes was 3.4 to 17.3% per year among the four participants depicted in panel B, so they experienced renal function loss. The starting cC-GFR for all eight participants was more than 100 ml/min. Furthermore, it is clear that the slopes are straight lines leading from normal to impaired renal function. This unrelenting loss of renal function occurring prior to the development of proteinuria has

Fig. 1 – Demonstration of progressive early renal function decline. Panels A and B show serial measurements of cCGFR in eight type 1 diabetes patients followed over 8–12 years in the 1st Joslin Kidney Study. None of the patients were proteinuric. Patients were deemed to have early renal function decline if the slope of loss of renal function was more than S3.3% per year. The progressive pattern of early renal function decline is evident in panel B. cC-GFR, cystatin-C-based glomerular filtration rate (the reciprocal of cystatin-C). Adapted from Perkins et al. [37].

engendered the concept of progressive early renal function decline. Fig. 2 summarizes the results of the follow-up analyses from the 1st Joslin Kidney Study. Starting with an average baseline cC-GFR of 155  22 ml/min, 9% of the normoalbuminuric group (4% among low-normoalbuminuric and 13% among high-normoalbuminuric patients) had progressive early renal function decline. Among the microalbuminuric group, whose average baseline cC-GFR was 143  26 ml/min, 31% experienced progressive ERFD according to the criteria derived from the Baltimore Aging Study. The onset of renal function decline in relation to urinary albumin excretion has also been studied in a subcohort of patients from the 1st Joslin Kidney Study. Seventy-nine patients who developed microalbuminuria between 1992 and 1996 were followed for 10–14 years with serial measurements of AER, serum cystatin-C, and serum creatinine through 2006. Renal function was initially normal for all patients (MDRD-GFR 80– 150 ml/min); but by the completion of follow-up, 6 (8%) progressed to ESRD, 18 (23%) developed Chronic Kidney Disease Stage (CKD) 3 or 4, and 55 (69%) retained normal or mildly impaired renal function. Change in AER during follow-up strongly tracked with CKD staging by the end of the study: Twothirds of patients who progressed from microalbuminuria to proteinuria experienced severe decline in renal function (MDRD-GFR < 60), compared to one-third of those with stable microalbuminuria and one-tenth of those with regression to normoalbuminuria. This decline was progressive and appeared to have been launched at the onset of microalbuminuria, 5–10 years prior to the onset of proteinuria [37]. Fig. 3 depicts the concept of progressive early renal function decline in a T1DM patient from the 1st Joslin Kidney Study, showing changes in estimated GFR (reciprocal of

diabetes research and clinical practice 82s (2008) s46–s53

Fig. 2 – The percentage of patients in the 1st Joslin Kidney Study with early renal function decline according to microalbuminuria status. Early renal function decline was defined as a loss of cC-GFR over 3.3% per year in the absence of proteinuria. ERFD was present in 9% of patients with normoalbuminuria (baseline GFR 155 W 21 ml/min) and 31% with microalbuminuria (143 W 26 ml/min). cCGFR, cystatin-C-based glomerular filtration rate (the reciprocal of cystatin-C); (*) patients with stable renal function; () patients with early renal function decline; (D) patients who required renal replacement therapy by the end of follow-up. Adapted from Perkins et al. [37].

cystatin-C) and AER during the follow-up period. This patient had normal renal function at the beginning of the study, but renal function decline began with progression of AER into the microalbuminuric range. Loss of renal function became more severe as microalbuminuria evolved into proteinuria. This early renal function decline can be adequately represented by a linear slope showing its progressive pattern from normal to moderate impairment.

4. Determinants of early renal function decline That the trajectory for renal function decline is initiated prior to the establishment of proteinuria has important implications for clinical interventions and research agendas. It spotlights the importance of understanding mechanisms that underlie early renal function decline. Towards this goal, the 2nd Joslin Kidney Study on the Natural History of Microalbuminuria in Type 1 Diabetes seeks to identify clinical and biochemical factors that are associated with early renal function decline. The cohort consists of 675 T1DM patients with normoalbuminuria or microalbuminuria who fulfilled inclusion and exclusion criteria. Clinical histories and anthropometric and biochemical measurements have been taken from all at baseline, and followup data are being collected. Details regarding methods can be found in a recently published article [38].

S49

Fig. 3 – Demonstration of progressive early renal function decline. This type 1 diabetes patient from the 1st Joslin Kidney Study had normal renal function that began to decline as urinary albumin excretion encroached upon the microalbuminuric range. The rate of renal function loss was approximately S6.5% per year. This early renal function loss was progressive and accelerated as microalbuminuria evolved into proteinuria. This patient developed Chronic Kidney Stage 3 after 10 years of followup. AER (D), albumin excretion rate; cC-GFR (), cystatin-Cbased glomerular filtration rate (the reciprocal of cystatinC). Adapted from Perkins et al. [37].

4.1.

Serum uric acid

Chief among baseline exposure variables was serum uric acid, the main byproduct of purine metabolism, that has received renewed attention for its presence in late renal disease. Serum uric acid is associated with impaired renal function among diabetes and non-diabetes persons and has been predictive of renal failure among patients attending a community health screening [39–41]. The primary outcome in these studies was either albuminuria or renal insufficiency (as approximated by creatinine-based GFR <60 ml/min), and serum uric acid levels were in the hyperuricemic range (>6.5 mg/dl for women and >7.0 mg/dl for men) [42]. In contrast, the 2nd Joslin Kidney Study consists of T1DM patients who primarily had normal renal function at the time of enrollment (Table 1). The majority had cC-GFR greater than 90 ml/min, though 10% of normoalbuminuric patients and 36% of microalbuminuric patients had baseline cC-GFR less than 90 ml/min. The mean cC-GFR among normoalbuminuric and microalbuminuric patients was 119 and 99 ml/min, respectively. Cystatin-C-based GFR was estimated using the equation cC-GFR = [86.7(cystatin-C) 1 4.2], developed and validated among individuals with diabetes by MacIsaac et al. [33]. Among this cohort of T1DM patients with relatively normal or only mildly impaired renal function, reduction in cC-GFR was independently associated with higher serum uric acid concentration, higher AER, older age, and use of antihypertensive medications (Table 2). Furthermore, uric acid levels were not in the hyperuricemic range; rather, highnormal levels were observed to relate to variation in cC-GFR. We also found an additive effect between serum uric acid and AER, such that lower cC-GFR values were associated with higher tertiles of serum uric acid that were simultaneously present in higher tertiles of AER.

S50

diabetes research and clinical practice 82s (2008) s46–s53

Table 1 – Baseline characteristics of participants in the 2nd Joslin Kidney Study according to microalbuminuria statusa Characteristic

NA (n = 364)

MA (n = 311)

AER (mcg/min) Diabetes duration (years) Systolic BP (mmHg) Diastolic BP (mmHg) Use of ACEi or ARB (%) Use of other anti-hypertensive agentsc (%) HbA1c (%)

15.0 (11.4, 21.5) 20.2 (9.4) 119.4 (12.9) 71.8 (8.0) 30 12 8.2 (1.2)

70.8 (45.8, 132.5) 23.4 (9.6) 124.7 (13.8) 73.7 (8.2) 76 22 8.5 (1.5)

cC-GFR (ml/min)d cC-GFR category (%) 130 90–129 60–89 <60

118.8 (24.1)

98.7 (27.3)

30 61 9 1

10 54 28 8

p-Value b

<0.0001 <0.0001 0.004 <0.0001 0.0004 0.03 <0.0001 <0.0001

Adapted from Rosolowsky et al. [38]. Data presented as median (25th, 75th interquartile range) or mean (standard deviation). NA, Normoalbuminuria; MA, microalbuminuria; AER, albumin excretion rate; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HbA1c, hemoglobin A1c; cCGFR, cystatin-C-based glomerular filtration rate. b AER differs by design. c Other anti-hypertensive agents include a- and b-blockers and calcium-channel antagonists. d cC-GFR was estimated using the equation [86.7(cystatin-C) 1 4.2] [33]. a

Table 2 – Unadjusted and adjusted mean cC-GFR according to tertiles of serum uric acid, TNFR1, AER, and age and categories of medication usea Unadjusted Adjusted p-Valuec cCGFR cCGFRb Serum uric acid tertiles 4.0 mg/dl 4.1–5.2 mg/dl 5.3 mg/dl

122.9 110.4 93.3

117.0 109.0 101.6

Reference 0.0001 <0.0001

TNFR1 tertiles 1244 1245–1578 1579

124.1 112.9 91.0

118.2 111.8 97.6

Reference 0.0024 <0.0001

AER tertiles 18.3 mg/min 18.4–46.8 mg/min 46.9 mg/min

122.0 111.7 94.5

116.9 109.4 101.2

Reference 0.0004 <0.0001

Age tertiles 33 years 34–44 years 45 years

118.1 110.9 101.0

112.6 111.3 103.6

Reference 0.55 <0.0001

Medication use None ACEI or ARB only Diuretic Other anti-hypertensive

118.9 104.3 89.6 97.2

110.4 109.9 103.1 105.2

Reference 0.82 0.04 0.14

4.2.

Adapted from Rosolowsky et al. [38]. cC-GFR, cystatin-C-based glomerular filtration rate; TNFR-1, tumor necrosis factor alpha receptor 1; AER, albumin excretion rate; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; other anti-hypertensive medications include a- and b-blockers and calcium channel antagonists. cC-GFR was estimated using the equation [86.7(cystatin-C) 1 4.2] [33]. b Gender, BMI, HbA1c were sequentially added to but excluded from the final model because they were neither confounders (change in estimate of >10%) nor had statistically important independent effects on cC-GFR. Model r2 = 39%. c Tertile or category compared to reference in adjusted models. a

That serum uric acid has an independent effect on normal or mildly impaired cC-GFR suggests that the mechanisms underlying microalbuminuria and early renal function loss may be distinct from one another. How serum uric acid might incite early renal injury is not completely understood, but hypotheses include (1) inhibition of endothelial nitric oxide production and direct damage to vascular endothelium, (2) production of pro-oxidants, and (3) upregulation of the renin–angiotensin–aldosterone system [43–45]. Another speculation is that serum uric acid activates the complement system, triggering a host of inflammatory reactions that damage the renal vasculature and interstitium [46].

Inflammatory cytokines

In a separate manuscript, the relationships between variation in cC-GFR and serum and urinary concentrations of markers of inflammation and apoptosis were reported (Niewczas, in press [47]). The speculation that cytokines would be present in the setting of early renal function decline was motivated by prior publications demonstrating that chronic inflammation and apoptosis may be involved in the pathogenesis of diabetic nephropathy [48,49]. Tumor-necrosis-factor-alpha (TNFa) and Fas pathways have been implicated, yet previous studies have focused on their associations with microalbuminuria or proteinuria, not renal function. Soluble markers of the TNFa pathway (TNFa, sTNFR1, and sTNFR2), its downstream effectors (sICAM-1, sVCAM-1, IL8/ CXCL8, MCP1, and IP10/CXCL10), the Fas pathway (sFAS and sFasL), CRP, and IL6 were measured from baseline samples. Six markers – TNFa, sTNFR1, sTNFR2, sFas, sICAM-1, and sIP10 – were negatively correlated with cC-GFR, but only the TNF receptors and sFas continued to have independent effects on variation in renal function after multivariate adjustment. In addition, AER and age also had independent effects, but the magnitude of their effect on cC-GFR was much less that that of TNFR-1.

diabetes research and clinical practice 82s (2008) s46–s53

The strong associations between markers of the TNF and Fas pathways and cC-GFR are novel in that they were demonstrated in the context of normoalbuminuria or microalbuminuria when renal function was relatively normal. When the effects of sTNFR1 and sFas on cC-GFR were examined in conjunction with levels of serum uric acid, sTNFR1 and serum uric acid levels, but no longer sFAS, continued to show independent associations with variation in renal function (Table 2) (sTNFR1 and sTNFR2 were highly correlated, so only sTNFR1 was modeled). The exact nature of the roles that either serum uric acid or the TNFa pathway play in the setting of early reductions in renal function has yet to be elucidated. Though TNFa itself was not independently associated with cC-GFR in Niewczas et al.’s study, it is recognized that TNFa has a short half-life in serum and that TNF receptors serve as a repository for TNFa. Serum uric acid and sTNFR1 may be merely standing in as markers for other unmeasured, etiologic factors, but their associations with variation in non-impaired renal function imply that they are in the causal pathway of diabetic nephropathy. Both are capable of inducing glomerular vascoconstriction and increasing permeability of blood vessels to other cytokines [48,50]. Conversely, several studies have demonstrated tubulointerstitial apoptosis in streptozocin-induced diabetic mice and human diabetic kidneys, and activation of the TNFa pathway has been implicated in apoptosis [51,52]. In addition, in a murine model, rats rendered mildly hyperuricemic developed renal disease, characterized by glomerular sclerosis and interstitial fibrosis [53]. Inflammatory pathways such as Cox-2 were also upregulated. Whether or not serum uric acid and TNFa cause early renal function decline, and if they do, whether they act through parallel or separate mechanisms must be further investigated in prospective studies.

S51

It is not enough simply to identify markers and risk factors of early renal function decline; further research should be conducted to unearth modifiable causes. Modification of serum uric acid holds promise, since drugs such as allopurinol or probenacid can reduce uric acid synthesis or enhance its urinary excretion, respectively. Certainly in advanced-stage renal disease, a randomized control trial has already demonstrated that allopurinol (serum uric acid 9.8 decreased to 5.9 mg/dl) can reduce the progression of chronic renal insufficiency (estimated GFR < 60 ml/min) to end-stage renal disease after 1 year of treatment (4/25 intervention group vs. 12/26 controls) [54]. Developing insight into the etiologic factors responsible for early renal function decline would permit the identification of T1DM patients most susceptible to progressive renal function loss and curtail progression before it becomes clinically significant.

Acknowledgments This research is supported by the National Institutes of Health grant DK41526. ETR is supported by the Agency for Healthcare Research and Quality T32, Child Health Services Research Training Program, grant HS00063. MAN is supported by the American Diabetes Association mentor-based fellowship 703-MN-28. BAP is a Canadian Diabetes Association Scholar and is supported by the Banting and Best Diabetes Center.

Conflict of interest There are no conflicts of interest.

references

5.

Conclusion

In summary, among some individuals with T1DM, renal function can begin to decline in the presence of or prior to the establishment of microalbuminuria. Once it begins, the pattern of decline is progressive, and clinically meaningful renal impairment may already be present. In contrast, persons with low-normoalbuminuria infrequently demonstrate progressive early renal function decline. Therefore, monitoring renal function with serial measurements of serum cystatin-C may be an important adjunct to screening for microalbuminuria in identifying patients susceptible to experiencing progressive early renal function decline. Knowledge of the etiology of progressive early renal function decline remains elusive. Most experts presently concur that hyperfiltration in itself is not a reliable predictive marker of which patients will or will not progress to advancedstage renal impairment. However, the return of renal function from supranormal to normal ranges may signal the onset of progressive early renal function loss. Therefore, rather than identifying markers or risk factors related to hyperfiltration per se, investigators can more effectively expend their resources on identifying markers or risk factors linked to its fall into normal and then impaired ranges.

[1] A. Andersen, J. Christiansen, J. Andersen, S. Kreiner, T. Deckert, Diabetic nephropathy in type I (insulin-dependent) diabetes: an epidemiological study, Diabetologia 25 (1983) 496–501. [2] A. Krolewski, J. Warram, A. Christlieb, E. Busick, C. Kahn, The changing natural history of nephropathy in type 1 diabetes, Am. J. Med. 78 (1989) 785–794. [3] M. Krolewski, P. Eggers, J. Warram, Magnitude of end-stage renal disease in IDDM: a 35 year follow-up study, Kidney Int. 50 (1996) 2041–2046. [4] U.S. Renal Data System, USRDS 2007 Annual Data Report. Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2007. [5] C. Mogensen, Renal function changes in diabetes, Diabetes 25 (1976) 872–879. [6] H. Keen, C. Chlouverakis, An immunoassay method for urinary albumin at low concentrations, Lancet 2 (1963) 913–916. [7] G. Viberti, R. Hill, R. Jarrett, Argyropoulos, U. Mahmud, H. Keen, Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus, Lancet 1 (1982) 1430–1432. [8] H. Parving, B. Oxenboll, P. Svendsen, J. Christiansen, A. Andersen, Early detection of patients at risk of developing

S52

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16] [17]

[18]

[19]

[20] [21]

[22]

[23]

[24]

[25]

[26]

[27]

diabetes research and clinical practice 82s (2008) s46–s53

diabetic nephropathy. A longitudinal study of urinary albumin excretion, Acta Endocrinol. 100 (1982) 550–555. C. Mogensen, C. Christensen, Predicting diabetic nephropathy in insulin-dependent patients, N. Engl. J. Med. 311 (1984) 89–93. C. Mogensen, A. Chachati, C. Christensen, C. Close, T. Deckert, E. Hommel, et al., Microalbuminuria: an early marker of renal involvement in diabetes, Uremia Invest. 9 (1985–1986) 85–95. J. Christiansen, J. Gammelgaard, M. Frandsen, H. Parving, Increased kidney size, glomerular filtration rate and renal plasma flow in short-term insulin-dependent diabetics, Diabetologia 20 (1981) 451–456. S. Rudberg, B. Persson, G. Dahlquist, Increased glomerular filtration rate as a predictor of diabetic nephropathy—an 8year prospective study, Kidney Int. 41 (1992) 822–828. K. Hansen, M. Mau Pedersen, C. Christensen, A. Schmitz, C. Mogensen, J. Christensen, Normoalbuminuria ensures no reduction of renal function in type 1 (insulin-dependent) diabetic patients, J. Intern. Med. 232 (1992) 161–167. T. Hostetter, J. Troy, B. Brenner, Glomerular hemodynamics in experimental diabetes mellitus, Kidney Int. 19 (1981) 410–415. V. Vallon, R. Blantz, S. Thomson, Glomerular hyperfiltration and the salt paradox in early type 1 diabetes mellitus: a tubulo-centric view, J. Am. Soc. Nephrol. 14 (2003) 530–537. N. Bank, Mechanisms of diabetic hyperfiltration, Kidney Int. 40 (1991) 792–807. R. Zatz, B. Brenner, Pathogenesis of diabetic microangiopathy: the hemodynamic view, Am. J. Med. 80 (1986) 443–453. H. Lervang, S. Jensen, J. Brochner-Mortensen, J. Ditzel, Early glomerular hyperfiltration and the development of late nephropathy in type 1 (insulin-dependent) diabetes mellitus, Diabetologia 31 (1988) 723–729. T. Jensen, K. Borch-Johnsen, T. Deckert, Changes in blood pressure and renal function in patients with type 1 (insulindependent) diabetes mellitus prior to clinical diabetic nephropathy, Diabetes Res. 4 (1987) 159–162. C. Mogensen, Microalbuminuria as a predictor of clinical diabetic nephropathy, Kidney Int. 31 (1987) 673–689. B. Feldt-Rasmussen, E. Mathiesen, T. Deckert, Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes, Lancet 2 (1986) 1300–1304. C. Christensen, C. Mogensen, Effect of antihypertensive treatment on progression of disease in incipient diabetic nephropathy, Hypertension 7 (1985) 109–114. The ACE Inhibitors in Diabetic Nephropathy Trialist Group, Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data, Ann. Intern. Med. 134 (2001) 370–379. B. Perkins, L. Ficociello, K. Silva, D. Finkelstein, J. Warram, A. Krolewski, Regression of microalbuminuria in type 1 diabetes, N. Engl. J. Med. 348 (2003) 2285–2293. F. Giorgino, L. Laviola, P. Cavallo Perin, B. Solnica, J. Fuller, N. Chaturvedi, Factors associated with progression to macroalbuminuria in microalbuminuric type 1 diabetic patients: the EURODIAB Prospective Complications Study, Diabetololgia 47 (2004) 1020–1028. B. Chavers, R. Bilous, E. Ellis, M. Steffes, S. Mauer, Glomerular lesions and urinary albumin excretion in type 1 diabetes without overt proteinuria, N. Engl. J. Med. 13 (1989) 966–970. P. Fioretto, M. Steffes, M. Mauer, Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria, Diabetes 43 (1994) 1358–1364.

[28] A. Rule, Understanding estimated glomerular filtration rate: implications for identifying chronic kidney disease, Curr. Opin. Nephrol. Hypertens. 16 (2007) 242–249. [29] A. Grubb, H. Lofberg, Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis, Proc. Natl. Acad. Sci. U.S.A. 79 (1982) 3024–3027. [30] E. Vinge, B. Lindergard, P. Nilsson-Ehle, A. Grubb, Relationships among serum cystatin C, serum creatinine, lean tissue mass and glomerular filtration rate in healthy adults, Scand. J. Clin. Lab. Invest. 59 (1999) 587–592. [31] G. Tan, A. Lewis, T. James, P. Altmann, R.P. Taylor, J. Levy, Clinical usefulness of cystatin C for the estimation of glomerular filtration rate in type 1 diabetes: reproducibility and accuracy compared with standard measures and iohexol clearance, Diabetes Care 25 (2002) 2004–2009. [32] B. Perkins, R. Nelson, B. Ostrander, K. Blouch, A. Krolewski, B. Myers, et al., Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study, J. Am. Soc. Nephrol. 16 (2005) 1404–1412. [33] R. MacIsaac, C. Tsalamandris, M. Thomas, E. Premaratne, S. Panagiotopoulos, T. Smith, et al., Estimating glomerular filtration rate in diabetes: a comparison of cystatin-C- and creatinine-based methods, Diabetologia 49 (2006) 1686– 1689. [34] E. Premaratne, R. MacIsaac, S. Finch, S. Panagiotopoulos, E. Ekinci, G. Jerums, Serial measurements of cystatin C are more accurate than creatinine-based methods in detecting declining renal function in type 1 diabetes, Diabetes Care 31 (2008) 971–973. [35] B. Perkins, L. Ficociello, B. Ostrander, K. Silva, J. Weinberg, J. Warram, et al., Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes, J. Am. Soc. Nephrol. 18 (2007) 1353–1361. [36] R. Lindeman, J. Tobin, N. Shock, Longitudinal studies on the rate of decline in renal function with age, J. Am. Geriatr. Soc. 33 (1985) 278–285. [37] B. Perkins, L. Ficociello, B. Roshan, J. Warram, A. Krolewski, Decline in renal function to end stage renal disease begins soon after the onset of microalbuminuria (MA) in Type 1 Diabetes (T1DM): results of 12-year follow-up, J. Am. Soc. Nephrol. 18 (2007) 44A. [38] E. Rosolowsky, L. Ficociello, N. Maselli, M. Niewczas, A. Binns, B. Roshan, et al., High-normal serum uric acid is associated with impaired glomerular filtration rate in nonproteinuric patients with type 1 diabetes, Clin. J. Am. Soc. Nephrol. 3 (2008) 706–713. [39] C.H. Tseng, Correlation of uric acid and urinary albumin excretion rate in patients with type 2 diabetes mellitus in Taiwan, Kidney Int. 68 (2005) 796–801. [40] S. Bo, P. Cavallo-Perin, L. Gentile, E. Repetti, G. Pagano, Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes, Eur. J. Clin. Invest. 31 (2001) 318–321. [41] K. Iseki, S. Oshiro, M. Tozawa, C. Iseki, Y. Ikemiya, S. Takishita, Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects, Hypertens. Res. 24 (2001) 691–697. [42] R. Johnson, D. Kang, D. Feig, S. Kivlighn, J. Kanellis, S. Watanabe, et al., Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41 (2003) 1183–1190. [43] D. Kang, T. Nakagawa, L. Feng, S. Watanabe, L. Han, M. Mazzali, et al., A role for uric acid in the progression of renal disease, J. Am. Soc. Nephrol. 13 (2002) 2888–2897. [44] D. Kang, S. Park, I. Lee, R. Johnson, Uric acid-induced Creactive protein expression: implication on cell

diabetes research and clinical practice 82s (2008) s46–s53

[45]

[46]

[47]

[48]

[49]

proliferation and nitric oxide production of human vascular cells, J. Am. Soc. Nephrol. 16 (2005) 3553–3562. T. Perlstein, O. Gumieniak, P. Hopkins, L. Murphey, N. Brown, G. Williams, et al., Uric acid and the state of the intrarenal renin–angiotensin system in humans, Kidney Int. 66 (2004) 1465–1470. M. Pillinger, P. Rosenthal, A. Abeles, Hyperuricemia and gout: new insights into pathogenesis and treatment, Bull. NYU Hosp. Jt. Dis. 65 (2007) 215–221. M. Niewczas, L. Ficociello, A. Johnson, W. Walker, E. Rosolowsky, B. Roshan, et al. Serum concentrations of markers of TNFa and Fas-mediated pathways and renal function in non-proteinuric patients with type 1 diabetes. Clin. J. Am. Soc. Nephrol. 2008 (in press). J. Navarro, C. Mora-Fernandez, The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications, Cytokine Growth Factor Rev. 17 (2006) 441–450. E. Galkina, K. Ley, Leukocyte recruitment and vascular injury in diabetic nephropathy, J. Am. Soc. Nephrol. 17 (2006) 368–377.

S53

[50] M. Mazzali, J. Kanellis, L. Han, L. Feng, Yi-Y. Xia, Q. Chen, et al., Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism, Am. J. Physiol. Renal Physiol. 282 (2002) F991–F997. [51] D. Kumar, J. Zimpelmann, S. Robertson, K. Burns, Tubular and interstitial cell apoptosis in the streptozotocin-diabetic rat kidney, Nephron. Exp. Nephrol. 96 (2004) e77–88. [52] D. Kumar, S. Robertson, K. Burns, Evidence of apoptosis in human diabetic kidney, Mol. Cell Biochem. 259 (2004) 67–70. [53] D. Kang, J. Kanellis, C. Hugo, L. Truong, S. Anderson, D. Kerjaschki, et al., Role of the microvascular endothelium in progressive renal disease, J. Am. Soc. Nephrol. 13 (2002) 806–816. [54] Y. Siu, K. Leung, M. Tong, T. Kwan, Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level, Am. J. Kidney Dis. 47 (2006) 51–59.