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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 2  |  Page : 392-402
Progression of diabetic nephropathy, risk of end-stage renal disease and mortality in patients with type-1 diabetes

1 Department of Nephrology, Medical School, University Mohamed First, Oujda, Morocco
2 Department of Endocrinology, Medical School, University Mohamed First, Oujda, Morocco
3 Department of Medicine, Medical School, University Mohamed First, Oujda, Morocco
4 Medical Emergency Department, Ibn Sina University Hospital; Laboratory of Biostatistics, Clinical and Epidemiological Research, Medical School, University Mohamed V, Rabat, Morocco

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Date of Web Publication26-Mar-2013


Numerous studies have shown that diabetic nephropathy (DNP) is associated with an elevated risk of progression toward end-stage renal disease (ESRD) as well as increased cardiovascular mortality. The majority of these studies are from the developed countries. The factors leading to the progression of DNP may not be quite the same in the developing countries. The aim of this study was to evaluate the risk factors of progression toward ESRD and mortality among type-1 diabetes (T1D) patients with DNP in a developing country. This prospective study was conducted enrolling 72 patients with T1D in September 2006, including T1D patients with DNP defined as microalbuminuria, proteinuria, and/or renal failure, and following them up for five years. The mean age was 29.5±7.5 years with a mean duration of diabetes of 17 (11-20) years. At the time of enrollment, 43.1% had arterial hypertension, 69.4% had proliferative retinopathy, 44.4 had clinical neuropathy, 25% lived in rural areas, and 51.4% had macroalbuminuria. Progression toward ESRD was observed in 34.7% of cases. In multivariate analysis, diastolic blood pressure (P = 0.006) and blood hemoglobin (P = 0.003) were identified as the risk factors associated with ESRD. Death occurred in 18.3% of cases, including 92.3% on hemodialysis with a median hemodialysis duration of six (1-60) months. In multivariate analysis, the ESRD was identified as risk factor for death (P <0.001). DNP due to T1D remains a disease involving a heavy burden of morbi-mortality and is difficult to manage in a developing country because of the low socioeconomic level of patients and the lack of reliable epidemiological data.

How to cite this article:
Bentata Y, Haddiya I, Latrech H, Serraj K, Abouqal R. Progression of diabetic nephropathy, risk of end-stage renal disease and mortality in patients with type-1 diabetes. Saudi J Kidney Dis Transpl 2013;24:392-402

How to cite this URL:
Bentata Y, Haddiya I, Latrech H, Serraj K, Abouqal R. Progression of diabetic nephropathy, risk of end-stage renal disease and mortality in patients with type-1 diabetes. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2022 May 18];24:392-402. Available from: https://www.sjkdt.org/text.asp?2013/24/2/392/109617

   Introduction Top

Diabetic nephropathy (DNP) is associated with an increased risk of progression toward end-stage renal disease (ESRD) and cardiovascular mortality. [1],[2],[3],[4] DNP is the major cause of ESRD in many countries around the world and its incidence has increased in the last decades. [3],[5],[6] Approximately 25% of patients with type-1 diabetes (T1D) develop DNP. [7],[8]

Microalbuminuria has been recognized for several years as a powerful predictive marker of DNP. [1],[9],[10] Nevertheless, the presence of microalbuminuria that indicates the early stage of DNP does not explain by itself the progression of DNP toward ESRD. Thus, other factors including poor glycemic and lipid control, arterial hypertension, smoking, as well as genetic and environmental factors have been widely implicated. [11],[12]

Most of these data have been reported from the developed countries. The situation with regard to progression of DNP may not be quite the same in the developing countries, where socioeconomic conditions constitute a real obstacle to patients' medical management. The aim of this study was to evaluate the progression of DNP, identify the risk factors of ESRD progression, and determine the mortality rate in a cohort of T1D patients in a developing country.

   Materials and Methods Top

This was a prospective study that included all the patients with T1D who presented with DNP in September 2006 and were followed up regularly for five years in specialized nephrology referral center for chronic diseases at Oujda in the eastern region of Morocco. T1D was defined as a diagnosis made before 36 years of age, requiring regular insulin treatment within one year of diagnosis. DNP was defined as the presence of microalbuminuria, macroalbuminuria and/or renal failure after elimination of other etiologies of renal failure. Microalbuminuria was defined as an albumin excretion rate (AER) ranging between 30 and 300 mg/24 h. Macroalbuminuria was defined as an AER exceeding 300 mg/24 h. The urinary assays were performed using the immunological methods. Urinary assays done on admission were repeated on three specimens at three-monthly intervals. Renal failure was defined as creatinine clearance below 60 mL/min estimated by the Modification of Diet in Renal Disease (MDRD) equation. Patients presenting with gestational diabetes, DNP patients with less than one year of nephrological follow-up, patients lost to follow-up and/or having another renal pathology were excluded from the study. Arterial hypertension (AHT) was defined as systolic arterial pressure (SAP) ≥140 mmHg and diastolic arterial pressure (DAP) ≥90 mmHg. Lipid levels were categorized based on The National Cholesterol Education Program and American Heart Association guidelines as follows: high total cholesterol >5.2 mmol/L and high triglycerides >1.7 mmol/L. [13],[14]

The following demographic data were obtained from all patients at the time of enrollment: age, gender, body mass index, duration of diabetes, family history of diabetes, smoking, diabetic retinopathy, diabetic neuropathy, diabetic arteriopathy, and blood pressure.The following biochemical parameters were studied at admission and every year for five years: plasma concentrations of creatinine, urea, glycated hemoglobin (HbA1C), total cholesterol, and triglycerides, as well as hemoglobin, 24-h urinary albumin excretion, and cytobacteriological urine analysis. During the follow-up period, we ensured strict nephrological follow-up (two to four consultations per year depending on the stage of renal disease) and we intensified nephroprotection by initiating treatment based on renin-angiotensin system blockers. We compared different clinical and bio-chemical parameters at the time of enrollment to the study and also during the progression to ESRD and/or the occurrence of death. We also studied the progression of renal parameters in the group of surviving patients who did not develop ESRD.

   Statistical Analysis Top

Quantitative variables were expressed as mean ± SD or as median and interquartile range following their distribution. Qualitative variables were expressed as frequency and percentage. Comparison of quantitative variables between two groups was performed by Student's t-test if the variable showed symmetrical distribution or by Mann-Whitney test if the variable showed asymmetrical distribution. Comparison for repeated measures of albumin excretion was carried out by the Friedman test. Bonferroni's post-hoc test was used to locate the significance. Comparison of qualitative variables between two groups was performed using Chi-square test or Fisher's exact test. Logistic regression was used to identify the risk factors in univariate and multivariate analysis. Results are presented as the odds ratio (OR) and 95% confidence interval (CI). A two-tailed P value of <0.05 was considered significant. Statistical analyses were carried out using SPSS for Windows, version 13.0 (SPSS, Inc., Chicago, IL, USA).

   Results Top

A total of 72 patients (50 males) with T1D were included in the study. Mean age was 29.5 ± 7.5 years (16-45 years). Of these patients, 63.9% had duration of diabetes exceeding 15 years and 84% of the patients had not received regular diabetes care. 85.7% of the patients had never had a nephrological consultation before and 84.7% of the patients had never benefited from specialized nutritional education sessions. Clinical characteristics of T1D patients at admission in the first nephrology consultation are shown in [Table 1].
Table 1: Characteristics of 72 T1D patients with diabetic nephropathy at the time of enrollment.

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After an average follow-up of 3.5 ± 1.5 years, we compared the parameters of patients as two groups according to whether they developed ESRD or not. A statistically significant difference was found concerning the age of onset of diabetes (17 ± 6.5 vs. 12.5 ± 7 years, P = 0.006), duration of diabetes (15 ± 7 vs. 18.5 ± 6 years, P = 0.04), male gender (59.6% vs. 88%, P = 0.01), smoking (21.3% vs. 48%, P = 0.03), diabetic retinopathy (53.2% vs. 100%, P <0.001), diabetic neuropathy (30.4% vs. 75%, P = 0.001), lower extremity arterial disease (11.1% vs. 47.8%, P = 0.002), SAP (125 ± 18 vs. 157 ± 17 mmHg, P <0.001), DAP (72.5 ± 9 vs. 98 ± 10 mmHg, P <0.001), blood hemoglobin (12.2 ± 1.2 vs. 9.1 ± 2.1 g/dL, P <0.001), total triglycerides [0.89 (0.76-1.36) vs. 1.24 (0.85-1.59) mmol/L, P= 0.04], AER [98 (60-460) vs. 1300 (310-3500) mg/24 h, P <0.001], and glomerular filtration rate (GFR) by MDRD [109 (75-139) vs. 13 (9-37) mL/min, P <0.001]. Comparison of clinical and biological parameters at the time of enrollment between the two groups is shown in [Table 2]. Independent factors associated with ESRD were as follows: Diastolic blood pressure (OR = 152.99, 95% CI = 14.69-1593.20, P <0.001) and blood hemoglobin (OR = 1.17, 95% CI = 1.02-1.34, P = 0.01).
Table 2: Comparison of socio-demographic, clinical, and biological parameters at the time of enrollment between patients who developed ESRD with those who did not during follow-up.

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We also compared the parameters of two groups of patients according to the occurrence of death. Death was observed in 19.4% of cases. 92.8% of deaths occurred in patients on intermittent hemodialysis with a median duration of dialysis of six (1-30) months. A statistically significant difference was found in the age of onset of diabetes (16 ± 6.5 vs. 11 ± 6 years, P = 0.009), duration of diabetes (16 ± 7 vs. 19.5 ± 3.5 years, P = 0.04), diabetic retinopathy (62.1% vs. 100%, P = 0.004), diabetic neuropathy (40.4% vs. 69.2%, P = 0.05), lower extremity arterial disease (17% vs. 58.3%, P = 0.003), SAP (133 ± 21 vs. 151 ± 15 mmHg, P = 0.004), DAP (78 ± 10 vs. 96 ± 11 mmHg, P <0.001), blood hemoglobin (11.7 ± 1.7 vs. 8.7 ± 2.2 g/dL, P <0.001), AER [180 (64-602) vs. 1200 (165-2750) mg/24 h, P = 0.001], and GFR by MDRD [89 (55-128) vs. 12 (9-33) mL/min, P <0.001). Comparison of clinical and biochemical parameters at the time of enrollment between these two groups is shown in [Table 3]. The independent factor associated with mortality was ESRD (OR = 14.15, 95% CI= 1.70-74.01, P = 0.002). Independent factors associated with ESRD in TD1 patients were as follows: blood hemoglobin (OR = 3.18; 95% CI, 1.47-6.87; P = 0.0003) and diastolic blood pressure (OR = 1.15; 95% CI, 1.04-1.27; P = 0.0006) as demonstrated in [Table 4].
Table 3: Comparison of socio-demographic, clinical, and biological parameters of patients at admission between the dead patients and those survived during follow-up.

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Table 4: Risk factors for ESRD in type-1 diabetes patients with diabetic nephropathy.

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Regarding the progression of DNP in survivors who did not develop ESRD, there was a statistically significant difference in the AER (mg/24 h) at the time of enrollment with that at two years of follow-up [95 (60-405) vs. 90 (60-220), P = 0.03). Similar difference was found at three years [95 (60-405) vs. 86 (36-190), P = 0.05], four years [95 (60-405) vs. 72 (36-109), P = 0.004], and five years of follow-up [95 (60-405) vs. 102 (35-119), P = 0.006). Progression of AER in survivors without ESRD is shown in [Figure 1].
Figure 1. Progression of albumin excretion rate (AER) in patients who survived without reaching ESRD (n = 45).

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There was also a statistically significant difference in the progression of the GFR estimated by MDRD (mL/min) at the time of enrollment and at one year of follow-up [109 (76-141) vs. 108 (75-139), P = 0.004]. Similar finding was also found at two years of follow-up [109 (76-141) vs. 101 (67-131), P <0.001], three years [109 (76-141) vs. 101 (60-121), P = 0.001], four years [109 (76-141) vs. 94 (61-124), P <0.001], and at five years [109 (76-141) vs. 94 (59-123), P <0.001]. Progression of GFR in survivors without ESRD is shown in [Figure 2].
Figure 2. Progression of glomerular filtration rate (GFR) in patients who survived without reaching ESRD (n = 45).

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No statistically significant difference was noted concerning the evolution of glycosylated hemoglobin (HbA 1 C) levels, or SAP and DAP at the time of enrollment and at five years of follow-up.

   Discussion Top

About 30%-60% of patients with T1D develop microalbuminuria within the 10-20 years following the onset of diabetes. [15],[16] Chronic Kidney Failure (CKD) generally appears 15-20 years after the onset of microalbuminuria, and ESRD appears in 50% of patients with macroalbuminuria within ten years and in 75% within the following 15years.

Microalbuminuria has been widely recognized since the 1980s as the main predictive factor of DNP in T1D. [1],[10] However, this concept is currently a subject of considerable controversy due to the new observations being reported. In fact, recent studies have observed that microalbuminuria regressed in approximately 50% of cases to normoalbuminuria, [17],[18] while progression toward macroalbuminuria was observed in only 15%-25% of cases. [17],[18],[19],[20] Moreover, in many cases, when microalbuminuria appears, histologic renal lesions are already in place and the process of renal function decline has already begun. These new findings are at the origin of a new concept in the natural progression of DNP in T1D, called early renal function decline (ERFD) which denotes a progressive loss of renal function independent of the progression of urinary excretion of albumin. [21] These two phenomena are certainly independent in terms of progression, but probably share the same pathophysiological mechanism. Thus, whatever the model, microalbuminuria seems to play a fundamental role in the initial development of DNP, while macroalbuminuria is a factor of DNP progression and ESRD evolution. This would be a reason to target decrease in urinary albumin excretion in the treatment of DNP.

According to the classical concept of natural progression of DNP in T1D, ESRD generally occurs beyond 25 years. However, in our study, macroalbuminuria was found in 51.4% of patients at the time of inclusion in the study, with duration of diabetes being 17 ± 6 years, and ESRD occurred in 34.7% with duration diabetes being 18.5 ± 6 years. Thus, the progression of microalbuminuria in itself does not explain the progressive decline of renal function, which suggests the involvement of other factors. Diabetic imbalance and AHT are the two main factors involved in the progression of DNP.

Glycemic imbalance is strongly correlated with the occurrence of ESRD and cardiovascular disease in T1D. In the FinnDiane cohort, HbA1C was elevated in the ESRD group contrary to the non-ESRD group (9.4 ± 1.6% vs. 8.8 ± 1.4%, P <0.05). In this cohort, glycemic control was linearly related to the cumulative incidence of ESRD. [22] In the Joslin cohort, the risk of ESRD increased with increase of baseline HbA1C and the effects of a 1% increase in HgA1C and a doubling of albumin/creatinine ratio (ACR) were approximately equivalent. [23] In addition, glycemic balance remains a difficult goal to achieve in these patients. In our study, we observed glycemic imbalance at admission and throughout follow-up. This may be explained by the poor adherence of patients to their diet and treatment, low socioeconomic level, younger age of patients, and their unawareness of the seriousness of complications.

Hyperglycemia and the duration of exposure to hyperglycemia explain only 11% of the risk of developing microvascular complications in T1D. [24] The remaining risk must be explained by other factors, such as the presence of hypertension, which is known to be especially related to the development and progression of nephropathy. [20],[25] AHT in diabetic patients is strongly correlated with the occurrence of major complications such as retinopathy, nephropathy, and cardiovascular disease. [26],[27],[28] It is an important risk factor for the development and progression of DNP. Analysis of United Kingdom Prospective Diabetes Study (UKPDS) showed that every 10 mmHg reduction in systolic blood pressure is associated with a 13% reduction in the risk of microvascular complications, with the smallest risk among those patients with systolic blood pressure <120 mmHg. [29] This raises the probable need to re-define the blood pressure objectives in diabetic patients with DNP.

Smoking is another risk factor for DNP and its progression. In the FinnDiane cohort, 36% of type-1 diabetics were smokers in the ESRD group versus 43% in the group alive without ESRD (P <0.05). [22] In the Pittsburgh Epidemiology of Diabetes Complications cohort, 53.9% of patients with T1Dwere smokers in the macroalbuminuria group versus 17% in the normoalbuminuric group. [30] Yet, other studies did not bring out this relationship. [23],[31] However, we feel that cessation of tobacco use is to be strongly recommended whatever the stage of DNP.

Qualitative and quantitative lipid abnormalities are often present in subjects with T1D and are related to glycemic control. [32] In T1D, increased serum triglycerides and total cholesterol were associated with micro- and macro-albuminuria. [33] A rise in total blood cholesterol is also a risk factor for GFR decrease in T1D patients with macroalbuminuria. [34] Recent studies have shown that the use of statins improved the pre-ESRD mortality rate and the incidence of ESRD. [35],[36] In FinnDiane cohort, blood cholesterol was strongly associated with the incidence of ESRD and pre-ESRD mortality. [22] However, in Joslin clinic cohort, poor glycemic control was not associated with the occurrence of ESRD. [23]

Body mass has been identified as a DNP risk factor in several studies. In FinnDiane cohort, body mass was also a predictor of cumulative incidence of ESRD. [22] On the other hand, in Joslin clinic cohort, body mass was not identified as an ESRD risk factor in T1D patients with macroalbuminuria. [23] However, the mean body mass reported in the various studies is relatively high in type 1 diabetic patients with DNP and can reach up to 27 kg/m 2 . [22],[23] In our study, however, the mean body mass remained low (around 22 kg/m 2 ).This is related to genetic and environmental factors and/or the low socioeconomic level of our population.

With regard to ethnicity, the prevalence of DNP varies according to ethnicity; it is higher in African-Americans, Asians, and Native Americans than in Caucasians. [37] No studies have been published concerning the relationship between genetics, ethnicity, and the pre-disposition to the progression of DNP in our population. The profile of our population probably does not correspond closely to those of the populations in the studies cited.

ESRD risk remains high among T1D patients despite the reinforcement provided by antihypertensive and renal protection treatments. The risk of ESRD per 100 person-years was 5.8 in the Joslin cohort and 5.1 in the FinnDiane cohort, which corresponded in the two studies to a mortality rate of 40%and 35%, respectively. [22],[23] Muhlhausser et al also found 34.8% of ESRD in diabetic patients with macroalbuminuria. [38] In Pittsburgh cohort (EDC), ESRD occurred in 24% of T1D patients with macroalbuminuria. [30] In Steno cohort, the risk of ESRD was only 17%. [39] In our study, 33.8% of T1D patients developed ESRD. This rate, which corresponds to findings in the literature, is rather surprising, since in our context, previous strict medical follow-up was almost absent and there was much difficulty in achieving optimal glycemic and blood pressure control, related to the low socioeconomic level of our population.

About 19.4% of patients had ESRD at the time of entry to the study, which attests to the great delay in diagnosis and management of DNP in T1D. 18.6% (11 cases) of patients developed ESRD during follow-up, but those patients had already presented a low GFR and a high AER. In contrast, patients who did not develop ESRD had a normal GFR [109 (76-141) mL/min)] and a relatively low AER [95 (60-405) mg/24 h] at the time of entry, despite the absence of optimal glycemic and blood pressure control at admission and throughout the follow-up. This implies that the values of GFR and AER on the time of entry are important predictive factors for the progression from DNP to ESRD.

Mortality in T1D remains high in ESRD patients, mainly among those in ESRD requiring dialysis. In Joslin clinic cohort, 42% mortality was found in ESRD patients under dialysis and 70% mortality in ESRD patients without dialysis, and the ten-year cumulative mortality after the onset of ESRD was 56.6%. [23] In this cohort, 69% of deaths were attributable to cardiovascular disease. Mortality was 31% and 29.1%, respectively, in T1D patients with ESRD requiring dialysis in FinnDiane cohort and Muhlhauser et al's study. [22],[38] In our study, death occurred in 52% of T1D patients with ESRD requiring dialysis, and the median duration of dialysis was only six [1],60 months.

Socioeconomic status has been identified as an important predictor for prognosis in T1D in several studies. [40],[41] To a great extent, our results can also be attributed to the low socio-economic level of our patients, as shown by the lack of health care coverage in 90.2%. This low socioeconomic level hinders patients' access to health care and treatments.

In Joslin clinic cohort, mortality rate was only 1% in type-1 diabetic patients in ESRD who had benefited from preemptive kidney transplant. In our study, no patient received a kidney transplant. This was due to the lack of health care coverage and not because of the unfeasibility of performing the double-kidney and pancreas transplant in Morocco. Renal and pancreatic transplantation performed preemptively remains the best treatment for type-1 diabetic patients in ESRD.

The exact pathogenesis of DNP is complex and not completely understood. This makes the medical management of DNP difficult and requires a multidisciplinary approach targeting control of all the factors that influence its progression. Optimal glycemic control by insulin therapy remains an essential objective in the management of patients with T1D. Renin-angiotensin system blockers and statins are widely prescribed and recommended for these patients even with subnormal arterial pressure and lipid profile. In addition, they permit the regression of microalbuminuria toward normoalbuminuria in T1D. [42],[43] Our first objective concerning our cohort of patients with T1D was to establish a strict medical follow-up system so as to optimize the medical treatment based on renin-angiotensin system blockers and statins and intensify glycemic and blood pressure control, in view of improving the renal and general prognosis of these patients.

After five years of evaluation, we are relatively satisfied with the results, since our rates of ESRD and mortality in patients with T1D are relatively similar to those in the literature. Also, having not developed ESRD and having survived, patients maintained stable GFR and AER at five years of evolution in relation to these rates at admission. However, several questions remain unanswered, such as the role of ethnicity, genetics, and environment in the physiopathology of DNP in our population. We hope to find answers through solid and validated studies over the course of coming years.

The limits of this study are the small size of the sample (72 patients) and the absence of a national and/or at least a regional register of type-1 diabetic patients. On the other hand, the low socioeconomic level of patients with T1D and the absence of health care coverage means that patients do not benefit in an optimal manner from the same therapeutic strategies.

T1D is a frequent pathology that involves a heavy burden of morbimortality. Blindness due to retinopathy, ESRD requiring dialysis resulting from the nephropathy, and mortality related to cardiovascular disease mean that T1D must be considered a serious pathology with very significant human and economic consequences. DNP is even more difficult to manage in developing countries, where patients are referred to nephrologists at a late stage of their disease. In this context, early detection of DNP is an important step in the treatment of these patients and the improvement of their prognosis.

Conflict of Interest

The authors declare that there is no conflict of interest associated with this manuscript.

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Correspondence Address:
Yassamine Bentata
Department of Nephrology, Medical School, University Mohamed First Oujda, Oujda
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.109617

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