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Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for several adverse outcomes among patients with diabetic kidney disease. Yet, optimal timing for SGLT2i after acute kidney injury (AKI) is uncertain, as are the providers responsible for post-AKI SGLT2i initiation. Using a retrospective cohort of United States Veterans with diabetes mellitus type 2 and proteinuria, we examined encounters by provider specialty before SGLT2i initiation and subsequent all-cause mortality after hospitalization with AKI, defined by a 50% or more rise in serum creatinine. Covariates included recovery, defined by return to a 110% or less of baseline creatinine, and time since AKI hospitalization. Among 21,330 eligible Veterans, 7,798 died (37%) and 6,562 received a SGLT2i (31%) over median follow-up of 2.1 years. Post-AKI SGLT2i use was associated with lower mortality risk [adjusted hazard ratio 0.63 (95% confidence interval 0.58-0.68)]. Compared with neither SGLT2i use nor recovery, mortality risk was similar with recovery without SGLT2i use [0.97 (0.91-1.02)] but was lower without recovery prior to SGLT2i use [0.62 (0.55-0.71)] and with SGLT2i use after recovery [0.60 (0.54-0.67)]. Finally, the effect of SGLT2i was stable over time (P for time-interaction 0.19). Thus, we observed reduced mortality with SGLT2i use after AKI among Veterans with diabetic kidney disease whether started earlier or later or before or after observed recovery. Hence, patients with diabetic kidney disease who receive a SGLT2i earlier after AKI experience no significant harm impacting mortality and experience a lower mortality risk than those who do not., (Copyright © 2024 International Society of Nephrology. All rights reserved.)

Diabetic kidney disease (DKD) is a highly heterogenous disease, including the proteinuric and the nonproteinuric pattern. Oxidized low-density lipoprotein (ox-LDL) is progressively increased in DKD and causes direct damage to kidney tubular epithelial cells through a mechanism similar to that underlying the deleterious effect of lipid peroxides in the vascular endothelium. We aimed to examine the association between plasma ox-LDL cholesterol and clinical endpoints in DKD patients. Ninety-one patients with established proteinuric DKD and diabetic retinopathy were enrolled and prospectively followed for 10 years or the occurrence of death, or at least 30% decline in eGFR, or progression to end-stage kidney disease (ESKD) requiring renal replacement therapy (primary outcome). At the end of the study, both eGFR and proteinuria were reassessed. Secondary outcomes of the study were the percentage change in eGFR and proteinuria over time for each patient. At baseline, patients were divided into 2 groups according to the median ox-LDL value (i.e., below or equal and above 66.22 U/L). Both Kaplan-Meier curves ( p = 0.001, log-rank test) and univariate Cox regression analysis showed that high ox-LDL was associated with the primary outcome (HR = 3.42, 95%CI = 1.55 - 7.56, p = 0.002). After adjustment for various well-known cofounders, multivariate Cox analysis showed that the association between increased circulating ox-LDL levels and the composite kidney endpoint remained significant (HR = 2.87, 95%CI = 1.14-7.20, p = 0.025). Regarding the secondary outcome of eGFR decline, the assessment of areas under the curves (AUC) showed that ox-LDL outperformed several cofounding factors (AUC 71%, 95%CI = 0.59 - 0.83, p = 0.001) and had better accuracy to predict deterioration of eGFR over time than baseline proteinuria (AUC 67%, 95%CI = 0.54 - 0.79, p = 0.014). Increased ox-LDL might be associated with disease progression in proteinuric DKD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Stefanos Roumeliotis et al.)

Objective: We examined the association of urine complement proteins with progression to end-stage renal disease (ESRD) or death in people with type 2 diabetes and proteinuric diabetic kidney disease (DKD)., Research Design and Methods: Using targeted mass spectrometry, we quantified urinary abundance of 12 complement proteins in a predominantly Mexican American cohort with type 2 diabetes and proteinuric DKD ( n = 141). The association of urine complement proteins with progression to ESRD or death was evaluated using time-to-event analyses., Results: At baseline, median estimated glomerular filtration rate (eGFR) was 54 mL/min/1.73 m 2 and urine protein-to-creatinine ratio 2.6 g/g. Sixty-seven participants developed ESRD or died, of whom 39 progressed to ESRD over a median of 3.1 years and 40 died over a median 3.6 years. Higher urine CD59, an inhibitor of terminal complement complex formation, was associated with a lower risk of ESRD (hazard ratio [HR] [95% CI per doubling] 0.50 [0.29-0.87]) and death (HR [95% CI] 0.56 [0.34-0.93]), after adjustment for demographic and clinical covariates, including baseline eGFR and proteinuria. Higher urine complement components 4 and 8 were associated with lower risk of death (HR [95% CI] 0.57 [0.41-0.79] and 0.66 [0.44-0.97], respectively); higher urine factor H-related protein 2, a positive regulator of the alternative complement pathway, was associated with greater risk of death (HR [95% CI] 1.61 [1.05-2.48]) in fully adjusted models., Conclusions: In a largely Mexican American cohort with type 2 diabetes and proteinuric DKD, urine abundance of several complement and complement regulatory proteins was strongly associated with progression to ESRD and death., (© 2018 by the American Diabetes Association.)

Background: Several studies have demonstrated that levels of circulating inflammatory markers such as tumour necrosis factorα (TNFα), are associated with early progression of diabetic nephropathy (DN). The aim of this study was to investigate whether there is an association between circulating TNFα receptor and disease progression in patients with advanced type 2 DN and severe proteinuria., Methods: Between 2006 and 2011, we measured levels of circulating soluble TNFα receptor 1 (TNFR1) and soluble TNFα receptor 2 (TNFR2) at baseline and 4 and 12 months in 101 patients included in a multicenter randomized controlled trial to compare the effect of optimal doses of renin-angiotensin system blockers in monotherapy or in combination (dual blockade) to slow progression of established type 2 DN. The primary composite endpoint was a >50% increase in baseline serum creatinine, end-stage renal disease, or death., Results: The median follow-up was 32 months (IQR, 18-48), during which time 28 patients (22.7%) achieved the primary endpoint. The TNFR1 level, but not the TNFR2 level, was correlated with other inflammatory markers. Cox regression analysis showed that the highest TNFR1 levels (HR, 2.60; 95%CI, 1.11-86.34) and baseline proteinuria (HR 1.32; 95%CI 1.15-1.52) were associated with the primary endpoint. The mixed model analysis revealed that TNFR1 and the TNFR2 levels did not change after starting treatment with renin-angiotensin system blockers., Conclusions: Our results show that the highest levels of TNFR1 are independently associated with progression of renal disease and death in type 2 DN. The renin angiotensin blockers have no effect on these inflammatory markers., (© 2016 Asian Pacific Society of Nephrology.)

Background: Several risk factors were associated with poor outcomes in diabetic patients with chronic kidney disease (CKD). However, few studies addressed the prognostic implications of these factors in advanced CKD. Our study aimed to provide more evidence for risk factor stratification of diabetic patients with advanced CKD., Method: A total of 447 diabetic patients with advanced CKD, age of 18-80, who visited the nephrology out-patient clinic were enrolled. All patients were in stage 3B-5 CKD. The primary outcomes included long-term renal replacement therapy and mortality. The occurrence of cardiovascular events was also analyzed as secondary outcome. Multivariate Cox regression models were used to address each risk factor in this cohort. We also used this cohort to evaluate the validity of the modified diabetic nephropathy score., Results: Patients with lower estimated glomerular filtration rate (eGFR) were associated with higher degree of proteinuria. In the multivariate Cox regression model, eGFR and the degree of proteinuria were both strong outcome predictors. The effects of glycosylated hemoglobin and blood pressure in this advanced CKD cohort were minimal. Elder patients with advanced CKD had a higher mortality rate, but commenced less renal replacement therapy. Applying these indicator analyses, we proposed a modified diabetic nephropathy score for outcome prediction., Conclusions: Our analysis demonstrated the impact of eGFR and proteinuria in the advanced CKD group. Indicators in early CKD possessed a different prognostic profile in this advanced CKD cohort, therefore, necessitating a modified scoring system.

Background and Objectives: Proteinuric diabetic kidney disease frequently progresses to ESRD. Control of BP delays progression, but the optimal BP to improve outcomes remains unclear. The objective of this analysis was to evaluate the relationship between BP and renal outcomes in proteinuric diabetic kidney disease., Design, Setting, Participants, & Measurements: BP data from all 1448 randomized participants in the Veterans Affairs Nephropathy in Diabetes Trial were included in a post hoc analysis. The associations of mean on-treatment BP with the primary end point (decline in eGFR, ESRD, or death), renal end point (decline in eGFR or ESRD), rate of eGFR decline, and mortality were measured., Results: The median (25th, 75th percentile) follow-up time was 2.2 (1.2, 3.0) years. There were 284 primary end points. In univariate analyses, both mean systolic and mean diastolic BPs were strongly associated (P<0.001) with the primary end point. After multivariate adjustment, the hazard of developing the primary end point became progressively higher as mean systolic BP rose from <120 to ≥ 150 mmHg (P=0.02), with a significantly higher hazard ratio for 140-149 versus 120-129 mmHg (1.51 [1.06, 2.15]; P=0.02). There was also a significant association of mean diastolic BP with the hazard of developing the primary end point (P<0.01), with a significantly higher hazard ratio when mean diastolic BP was 80-89 versus 70-79 mmHg (1.54 [1.05, 2.25]; P=0.03); there was also a strong trend when mean diastolic BP was <60 mmHg. Associations between BP and both renal end point and rate of eGFR decline were similar to those with the primary end point. No association of BP with mortality was observed, possibly because of the limited number of mortality events., Conclusions: In patients with proteinuric diabetic kidney disease, mean systolic BP ≥ 140 mmHg and mean diastolic BP ≥ 80 mmHg were associated with worse renal outcomes., (Copyright © 2015 by the American Society of Nephrology.)

Aims: Patients with type 2 diabetes and macroalbuminuria are at high risk for end stage renal disease (ESRD), cardiovascular disease and death, but remission of proteinuria may improve prognosis. We examine the effectiveness of currently recommended treatments on inducing remission of proteinuria, and on morbidity and mortality., Methods: Observational study of 78 patients with type 2 diabetes (46 male) with mean age (SD) of 61.5 (11) years, with a urinary albumin/creatinine ratio (ACR)≥50 mg/mmol. All were treated with agents blocking the renin-angiotensin system. Follow-up was from recognition of ACR ≥ 50 mg/mmol until death or March 2011 (median 6 years). Remission of proteinuria was defined as ≥70 % reduction from peak ACR, sustained for ≥1 year., Results: Only 22 of 78 patients (28%) achieved remission of proteinuria. Thirty-six (46%) had at least one major event (death, dialysis or cardiovascular). Remission of proteinuria was associated with lower incidence of ESRD/death (9% vs 36%; p=0.02) but cardiovascular events were not reduced (32% vs 30%). A third of patients had no retinopathy when albuminuria was first recognised, suggesting that non-diabetic renal pathologies were prominent. There was a significant interaction between the severity of diabetic retinopathy and remission of proteinuria on the risk of ESRD/death (p=0.0003)., Conclusions: Remission of proteinuria was achieved in only a third of patients despite efforts to achieve blood pressure targets <130/80 mmHg. Failure to attain remission of proteinuria was associated with increased risk of ESRD or death, a risk compounded by the presence of severe diabetic retinopathy., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aim: Although some patients with diabetic nephropathy with overt proteinuria have microscopic haematuria, the pathological characteristics and clinical significance related to microscopic haematuria have not yet been clarified. The aim of the present study was to clarify the pathological characteristics and clinical significance of microscopic haematuria., Methods: Eighty-four type 2 diabetes patients with overt proteinuria and biopsy-confirmed diabetic nephropathy were enrolled. The clinical and histological findings were compated between the patients with persistent haematuria (group 1, n=25) and those with persistent non-haematuria (group 2, n=23) after renal biopsy. The association between persistent haematuria and renal outcome at 5 years was examined. Histological scoring was made according to the original system and that of Tervaert et al., Results: Thirty-six patients (43%) had microscopic haematuria at the time of renal biopsy. Age was significantly smaller and blood pressure was significantly greater in group 1 than in group 2 (age: group 1, 56 ± 10 years; group 2, 62 ± 9 years; P=0.03, systolic blood pressure: group 1, 152 ± 16 mm Hg; group 2, 140 ± 16 mm Hg; P=0.01). There were no significant differences in histological parameters between the two groups. A logistic regression model demonstrated that arteriolar hyalinosis was significantly associated with persistent haematuria (OR=2.81; P=0.04). There were no significant differences in changes in reciprocal serum creatinine and rates of doubling of serum creatinine after renal biopsy between the two groups., Conclusion: Although arteriolar hyalinosis was associated with persistent haematuria, the clinical significance of microscopic haematuria was minor in diabetic nephropathy in type 2 diabetes patients with overt proteinuria., (© 2013 The Authors. Nephrology © 2013 Asian Pacific Society of Nephrology.)

Peripheral arterial disease is common in diabetic chronic kidney disease (CKD) and is characterized either by abnormally low or high ankle-brachial index (ABI). Whether low or high ABI carries similar prognostic value is unknown. The association of baseline ABI with all-cause mortality over 40 ± 21 months (mean ± SD) was ascertained in 167 proteinuric diabetics (age 57 ± 7 years; median urine protein-creatinine, 2.5 mg/mg). Association of change in ABI with all-cause mortality was determined in 75 subjects with normal ABI (0.9 - 1.3) at baseline. Among 167 participants, 41% had an abnormal ABI: < 0.9, 18%; and > 1.3 or non-compressible arteries, 23%. Only individuals with low ABI had a significantly higher risk for all-cause mortality (hazards ratio (95% confidence interval), HR: 2.23 (1.07, 4.65)). In subjects with normal ABI at baseline with follow-up measurement (n = 75), vascular disease worsened in 39% over 23 ± 6 months: 17% had either a decrease in ABI by ≥ 0.1 or a final ABI < 0.9, and 21% had a final ABI > 1.3 or noncompressible arteries. Only individuals who had a decrease in ABI over time had a significantly higher risk for death (adjusted HR, 7.41 (1.63, 33.65)). Peripheral arterial disease is not uncommon and progresses rapidly in individuals with diabetes and proteinuria. Low or declining ABI is a strong predictor of all-cause mortality. Routine measurement of ABI is a simple bed-side procedure that may permit easy risk-stratification in diabetic CKD patients.

Background: Estimated glomerular filtration rate (eGFR) is a powerful predictor of mortality in diabetic patients with limited proteinuria data. In this study, we tested whether concomitant proteinuria increases the risk of mortality among patients with type 2 diabetes., Methods: Participants included 6523 patients > 30 years with type 2 diabetes who were enrolled in a management program of a medical center before 2007. Renal function was assessed by eGFR according to the Modification of Diet in Renal Disease Study equation for Chinese. Proteinuria was assessed by urine dipstick., Results: A total of 573 patients (8.8%) died over a median follow-up time of 4.91 years (ranging from 0.01 year to 6.42 years). The adjusted expanded cardiovascular disease (CVD)-related mortality rates among patients with proteinuria were more than three folds higher for those with an eGFR of 60 mL/min/1.73 m2 or less compared with those with an eGFR of 90 mL/min/1.73 m2 or greater [hazard ratio, HR, 3.15 (95% confidence interval, CI, 2.0-5.1)]. The magnitude of adjusted HR was smaller in patients without proteinuria [1.98 (95% CI, 1.1-3.7)]. An eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 significantly affected all-cause mortality and mortality from expanded CVD-related causes only in patients with proteinuria. Similarly, proteinuria affected all outcomes only in patients with an eGFR of <60 mL/min/1.73 m2., Conclusion: The risks of all-cause mortality, as well as expanded and non-expanded mortality from CVD-related causes associated with proteinuria or an eGFR of 90 mL/min/1.73 m2 or greater are independently increased. Therefore, the use of proteinuria measurements with eGFR increases the precision of risk stratification for mortality.

Objective: Diabetic nephropathy is a common cause of end stage renal disease. Notwithstanding, wide inter-individual variations in the speed of progression of diabetic nephropathy are frequent. We have used the score of the HUGE formula to predict progression of kidney disease in a group of diabetic nephropathy patients., Design and Methods: The sample consisted of 84 type 2 diabetic patients. At treatment entry, the mean age was 62.1 ± 12.5 years and 59.5% were male. Blood pressure was measured at office at each visit. Serum creatinine, urea, hematocrit and 24h proteinuria were analyzed every 6 months. HUGE score was calculated from gender, urea and hematocrit., Results: Mean HUGE score was 0.99 ± 3.88. Using as cut off point 1.5, those patients who had a score equal or higher (n=31) showed a bigger increase in serum creatinine after one year (41.8 ± 62.1%) than those subjects with score<1.5 (n=53) (18.7 ± 38.6%, p=0.041). 5 patients with low HUGE score reached end stage renal failure (9.4%) and 10 patients in the high HUGE score group (32.3, p=0.008). When logistic regression analysis was performed only a HUGE score higher than 1.5 (p=0.003) and proteinuria higher than 2g/day (p=0.041) were independently associated to CRF progression (creatinine increment>25%)., Conclusions: In diabetic nephropathy patients the HUGE equation may be useful to detect the subjects prone to progressive renal failure. Wider samples will be needed to confirm this finding and, most important, its applicability to other kinds of nephropathy., (Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Vascular calcification is common and severe in chronic kidney disease. Because the consequences of calcification may differ by vascular beds, we sought to test the hypothesis that patients who have diabetes with proteinuria and have significant renal artery calcification (RAC) have a higher risk for progression to ESRD., Design, Setting, Participants, & Measurements: Using electron-beam computed tomography, RAC was computed as the sum of Agatston scores at each of the two renal ostia and renal arteries. Time-to-event analysis was conducted to compare the risk in individuals with or without significant RAC (total score >10)., Results: Of 172 patients with type 2 diabetes and overt proteinuria studied (estimated GFR 56 ± 25 ml/min per 1.73 m(2)), significant RAC was present in 31%. In 33 ± 21 months, 41 progressed to ESRD and 65 reached a composite outcome (ESRD or death). Serum phosphorus was a significant predictor of progression to ESRD but was replaced by the significant RAC in multivariate models that included the latter. Individuals with significant RAC had a higher risk for reaching the composite outcome. In contrast, there was no association between coronary artery calcification scores and progression to ESRD., Conclusions: Significant RAC was an independent predictor of progression to ESRD as well as reaching the composite outcome. Understanding the pathogenesis of RAC would allow determination of whether this risk is potentially modifiable.

In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin-angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria. The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events. This paper discusses the design and key methodological issues that arose during the planning of the study.

Type 2 diabetes is the leading cause of end-stage renal disease (ESRD) in most industrialized countries in Europe. The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) Study evaluated the renal protective effects of losartan versus placebo on a background of non-ACE-I/non-AIIA conventional antihypertensive therapy in 1513 patients with type 2 diabetes and nephropathy. Losartan reduced the incidence of doubling of serum creatinine, end-stage renal disease (ESRD), or death by 16% (P=0.022) and reduced the risk of progression to ESRD, defined as the initiation of dialysis or transplantation, by 29% (P=0.002). We set out to estimate the potential effect of losartan on the burden and costs associated with ESRD over 3.5 years in the European Union (EU). The risk reduction in new cases of ESRD was calculated by combining type 2 diabetes population estimates for the EU with the percent absolute risk reduction of ESRD in patients treated with losartan as observed in RENAAL. The number of days each patient experienced ESRD was defined as the length of time from onset of ESRD until the minimum of death or 3.5 years. ESRD-free person-years avoided with losartan treatment were calculated by combining the population estimate with the ESRD days avoided divided by number of days in a year. ESRD costs from Germany were used to approximate the potential cost savings from reduced time with ESRD and fewer ESRD cases on a EU wide basis. There are approximately 700,000 diagnosed type 2 diabetes patients with proteinuria (urine albumin/creatinine >or=300 mg/g) in the EU. The addition of losartan to the treatment regimen of these patients is expected to lead to a reduction of 44,100 cases of ESRD, 64,400 fewer person-years with ESRD, and reduce ESRD-related costs by euro 2.6 billion over 3.5 years based on RENAAL data. Treatment with losartan not only reduced the incidence of ESRD, but also can result in substantial cost savings in the European Union.

Background: Recently, the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study demonstrated the benefit of losartan in reducing renal outcomes in patients with type 2 diabetes and proteinuria. Additional questions concerning the reduction of proteinuria and its relationship to end-stage renal disease (ESRD) as well as cardio-renal outcomes and the safety and tolerability of losartan remain to be addressed., Methods: Three analyses were performed: (a) the impact of losartan on the relationship between the reduction of proteinuria and ESRD; (b) a time-to-event analysis of the cardio-renal composite endpoint of ESRD, myocardial infarction, stroke or all-cause death; and (c) additional analyses of adverse events, particularly in patients with serum creatinine >or=2.0 mg/dL., Results: After adjusting the values for proteinuria over the entire study, the reduction of proteinuria accounted for approximately half of the treatment effect of losartan on the risk reduction for ESRD. In addition, losartan was associated with a 21% risk reduction for the composite cardio-renal outcome (P=0.003). The addition of losartan to a conventional antihypertensive regimen did not increase the overall incidence of adverse events, regardless of severity of renal impairment., Conclusions: Losartan significantly reduced the risk of cardiorenal outcomes and was well tolerated by patients, including those with serum creatinine levels >or=2.0 g/dL. In addition, although this study shows that the reduction of proteinuria does not completely explain the impact of intervention on outcomes such as ESRD, reduction of proteinuria must remain an important consideration when treating patients with type 2 diabetes and nephropathy. However, the reduction of outcomes such as ESRD should remain the goal of therapy when evaluating renal protection in this patient population.

Background: The causes and mechanisms of increased mortality of patients with diabetic nephropathy are unclear, and its natural history is poorly understood., Aim: To evaluate risk factors for mortality in type 2 diabetic patients with nephropathy., Design: Retrospective study of clinical and biochemical parameters in diabetic nephropathic patients and controls sampled from a secondary care register., Methods: We studied 170 type 2 diabetic patients (from 1987 to 1995) with nephropathy (proteinuria >0.5 g/24 h) and 170 non-nephropathic patients. Follow-up was until death or December 1997. Details of demographics, clinical and treatment history were obtained from medical records., Results: Mean follow-up was 5.3 years. Of the patients with nephropathy at baseline, 63 (37%) died compared with 14 (8%) non-nephropathic patients (chi(2)=53.8, p<0.0001). Age- and sex-adjusted all-cause mortality rates were 8.1 (6.4, 9.8) and 1.4 (0.5, 2.2) deaths per 100 person-years, respectively (rate ratio 5.8). Forty-four patients (57%) died from cardiovascular causes (rate ratio 5.4). Mortality was directly proportional to degree of proteinuria: 0.5-2 g/24 h, 4.6 (2.9-7.1); >2 g/24 h, 9.9 (7.3-13.5) per 100 patient-years. A 36% (5-78%) excess risk of mortality was observed for each log unit increase in proteinuria. Multivariate Cox regression analyses confirmed a five-fold excess risk for all-cause and cardiovascular mortality in patients with nephropathy compared with those without. This was independent of other risk factors including baseline age [5% (1-8%)/year], creatinine [2.5 (1.12-5.6)/10 micromol/l] and glycaemic control (HbA(1c)) [15% (1-31%) per 1% rise]., Conclusions: Proteinuria is a potentially preventable and reversible risk factor associated with high mortality in type 2 diabetic patients. Prevention of the development of overt nephropathy and improvement in diabetes control may reduce mortality in these patients.