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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2015  |  Volume : 26  |  Issue : 4  |  Page : 702-707
Improvement in glomerular filtration rate may decrease mortality among type-2 diabetics with chronic kidney disease lacking proteinuria: A retrospective study

1 Department of Nephrology, Southern Arizona Veterans Affairs Health Care System; Department of Nephrology, University of Arizona College of Medicine, Tucson, AZ, USA
2 Department of Nephrology, University of Arizona College of Medicine, Tucson, AZ, USA

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Date of Web Publication8-Jul-2015


Twenty percent of patients with type-2 diabetes mellitus without albuminuria progress to chronic kidney disease (CKD). The various factors related to development of CKD, the natural course of renal dysfunction as well as mortality in this sub-group of diabetics has not been studied in detail. The medical records of 121 patients (all males) above the age of 40 years with type-2 diabetes mellitus and CKD, and without proteinuria, were reviewed in this retrospective study. The outcomes measured included: (a) all-cause mortality, (b) need for hemodialysis (HD), (c) appearance of proteinuria and (d) trend in kidney function. The all-cause mortality was 33%, with mean age at death being 75.9 years. Sixty-three percent of the patients had improvement in estimated glomerular filtration rate (eGFR) at the end of the follow-up period. The mortality was higher in patients with worsening eGFR compared with those with improvement in eGFR (61% vs 39%, P = 0.040). 5.8% of the patients ended up on HD and 16.51% developed proteinuria at the end of the follow-up period. Patients who developed proteinuria showed a higher tendency for progression of renal failure. Multivariate logistic regression for trend toward improving versus worsening of the eGFR revealed no statistically significant predictors. This observational study suggests that in type-2 diabetic patients with CKD, a substantial number of patients will have improvement in eGFR over time. Careful search for potential reversible causes of kidney damage could help in reducing mortality.

How to cite this article:
Thajudeen B, Budhiraja P, Meister E, Popovtzer M. Improvement in glomerular filtration rate may decrease mortality among type-2 diabetics with chronic kidney disease lacking proteinuria: A retrospective study. Saudi J Kidney Dis Transpl 2015;26:702-7

How to cite this URL:
Thajudeen B, Budhiraja P, Meister E, Popovtzer M. Improvement in glomerular filtration rate may decrease mortality among type-2 diabetics with chronic kidney disease lacking proteinuria: A retrospective study. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2022 Jan 26];26:702-7. Available from: https://www.sjkdt.org/text.asp?2015/26/4/702/160148

   Introduction Top

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD) in the developed world and accounts for nearly 44% of all new incident cases of ESRD in the United States. [1] Although ESRD patients account for only 1% of the Medicare population, they account for nearly 6.4% of Medicare costs. [2] Thus, prevention of the development of ESRD in diabetic patients is a top priority.

DN, especially in type-1 diabetics, usually progresses through various stages starting with glomerular hyperfiltration, progressing to microalbuminuria and macro-albuminuria, and eventually leading to chronic kidney disease (CKD) and ESRD. Renal pathology and structural- functional relationship has been less well studied in type-2 diabetic patients despite the fact that 80% of diabetic ESRD patients have type-2 diabetes mellitus (DM). About 20% of the diabetics, especially those with type 2, progress to renal failure without albuminuria. [3] This sub-group of diabetics with CKD has not been studied in great detail. The aim of the present study is to explore the risk factors for development of CKD in type-2 diabetic patients without proteinuria and outcome measurements including progression of CKD, appearance of proteinuria over a period of time and mortality.

   Patients and Study Design Top

The charts of 121 patients above the age of 40 years (115 whites, two African Americans and four others) with type-2 DM and CKD and, without proteinuria, being followed-up at the Southern Arizona Veterans Affairs Health Care System (SAVAHCS) were reviewed between January 2002 and January 2010. Subjects were identified through the clinical database maintained at the SAVAHCS. To be eligible for inclusion, there should be absence of dipstick proteinuria at the time of diagnosis of CKD. Absent dipstick proteinuria indicates <10 mg/dL protein in a random urine sample. [4] For this study, dipstick protein in urine should have been negative for three consecutive years. CKD was defined by estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 for three consecutive years. The average of three eGFR values was taken as the baseline. Variables like age, sex, presence of retinopathy, systolic blood pressure, diastolic blood pressure, glycosylated hemoglobin (HbA1C), lipid profile, duration of diabetes and body mass index (BMI) were extracted from the chart. History of smoking, hypertension, use of angiotensinconverting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), statins and nonsteroidal anti-inflammatory drugs (NSAIDS) at time of diagnosis of CKD were also looked into. Presence of retinopathy was defined as any stage of retinopathy documented in the ophthalmology consult note around the time of diagnosis of CKD. Systemic hypertension was defined as any documented history of hypertension with systolic blood pressure >130 mm Hg and diastolic blood pressure >80 mm Hg. Documentation stating use of more than ten cigarettes per day was considered as significant smoking history. Significant use of NSAIDS was defined as use of any medication under the category of NSAIDS except acetaminophen. All patient charts were reviewed until January 2010.

Outcomes measured included the following: (a) all-cause mortality, (b) appearance of proteinuria at the end of the follow-up period, (c) trend in the kidney function expressed as any improvement or worsening of eGFR compared with the baseline eGFR and (d) requirement of hemodialysis (HD) at the end of the follow-up period.

   Statistical analysis Top

Continuous data are expressed as mean, standard deviation and categorical data as counts and percentages except where specified. Serum creatinine values are expressed as mean. Differences in continuous variables were compared using Student's independent t-tests for two-group comparisons. Differences in categorical variables were compared using the chisquare test. Pearson correlation was used to investigate univariate associations between mortality, appearance of proteinuria and improvement/worsening of renal failure. Logistic regression was used for multivariate analysis of mortality status as a dependent outcome variable. Level of P <0.05 was considered statistically significant. Statistical analysis was performed using IBM-SPSS Version 19.0 (Chicago, IL, USA).

   Results Top

A total of 121 charts were reviewed and the mean follow-up period was 5.1 years. [Table 1] presents the clinical and laboratory data of all patients who were available at the time of diagnosis of CKD. In our sample of patients, 85% had hypertension, 72% were on ACEI, 62% were on statins, 44% had history of use of NSAIDS, 43% were active smokers, 26% had retinopathy and 42% had BMI >30 [Table 1].
Table 1: Descriptive statistics of the patients.

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The all-cause mortality was 33% and the mean age at death was 75.9 years. The exact cause of death could be traced only in 19 patients. Of those 19 patients, 73% (14/19) died due to cardiovascular-related causes and two died of liver disease-related complications. One death each was attributed to the following: Malignancy, chronic obstructive pulmonary disease and sepsis. The mortality was found to be higher in patients who had worsening eGFR over time compared with those who had improvement in eGFR (61% vs 39%, P = 0.040) [Figure 1]. 16.51% of the patients developed proteinuria toward the end of the follow-up period. These patients showed a tendency for increased risk of progression to renal failure than patients who did not develop proteinuria [Odds Ratio (OR) = 2; P = 0.4]. The proportion of patients ending up on HD was 5.8%. All patients who were started on HD had proteinuria at the time of initiation. We noted that 63% of patients registered improvement in renal function at the end of the follow-up period as evident in the rising trend of their eGFR. Multivariate logistic regression for improving versus worsening eGFR revealed no statistically significant predictors among blood pressures, BMI, glycolsylated hemoglobin, smoking status, the use of NSAIDS, use of ACEI or ARB.
Figure 1: Bar diagram showing the relation between mortality and change in eGFR.

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   Discussion Top

One of the key observations in this study is that 63% of the patients had improvement in eGFR at end of the follow-up period. We can argue that their renal impairment may have been due to non-glomerular disease, which would account for their improvement over time. [5] The likely pathogenesis includes hemodynamic disturbances without much renal parenchymal involvement (presence of heart failure, use of diuretics for heart failure) or tubulo-interstitial disease (from use of NSAIDS), which are all reversible with appropriate interventions. The presence of retinopathy in only 26% of the patients at a mean duration of diabetes of 13 years supports the above argument. Retinopathy has been a marker for microvascular disease in type-1 and type-2 diabetic patients, which usually correlates with the glomerular disease. [6],[7] Pham et al, based on their retrospective analysis of native kidney biopsy on type-2 diabetic patients, showed that 53% had non-diabetic renal disease, 27% had findings consistent with diabetic glomerulosclerosis and 19% had findings of both nondiabetic renal disease and diabetic glomerulosclerosis, which further endorses the argument. [8] These observations point toward the inappropriateness of labeling this group of patients as having CKD secondary to classical DN.

In this study, 16% of the subjects developed proteinuria at the end of the follow-up period. Although the difference was statistically insignificant, patients who developed proteinuria showed a greater tendency for progression of renal disease compared with those who did not have proteinuria. In the UK Prospective Diabetes Study (UKPDS) over a median of 15 years, 40% of the subjects developed albuminuria. [9] Even though the study population and number of patients in this study and in the UKPDS study are not comparable, it can be assumed that at the end of a similar follow-up period, more subjects will develop albuminuria.

At end of the follow-up period, only 5.8% ended up on dialysis. There is not much data on progression of renal failure in patients without proteinuria. It is based on observational studies of limited sample size and studies of specific ethnic groups at high risk of diabetes and its complications (Pima Indians and Asians). [10],[11],[12] Rossing et al, in a study of 227 type-2 diabetic patients with proteinuria, observed that 7% of the patients ended up being on HD after a mean follow-up period of 6.5 years. [13] Thus, the rate of progression of renal failure in proteinuric and non-proteinuric diabetics may be similar. This view is also supported by Maclsaac et al, who found that the rate of decline of eGFR in non-proteinuric diabetic patients was similar to proteinuric patients. [14] But, it is also interesting to find that all patients who ended up on dialysis had proteinuria.

In this study population, the all-cause mortality was 33%. Even though we do not have information on the cause of death of the majority of patients, of 19 deaths in whom the exact cause of death was identified, 14 patients (73%) died of cardiovascular-related causes. Rossing et al in their study on type-2 diabetic patients with proteinuria followed-up over a mean period of 6.7 years observed an all-cause mortality rate of 35%. Cardiovascular causes accounted for 69% of the total deaths. [13] It seems that cardiovascular cause for mortality is high in type-2 diabetic patients irrespective of their proteinuria status. Some of the possible explanations for high cardiovascular mortality in this group include: (a) delay in cardiac interventions because of CKD; a recent analysis showed that primary percutaneous coronary intervention (PCI) should be the treatment of choice irrespective of CKD status, [15] (b) aspirin resistance, [16] (c) high incidence of hypertensive heart disease, [17] (d) decreased accuracy of exercise and of pharmacological myocardial perfusion imaging in CKD patients, [18] (e) absence of the classic triad of ischemic symptoms, elevated cardiac biomarkers and electrocardiographic changes, [19] (f) labeling of elevated troponins as secondary to CKD and not due to ischemic heart disease [20] and (g) most anti-platelet and anticoagulant agents are metabolized through the kidneys and hence they need dose adjustment in CKD patients. This could interfere with the actual efficacy of these medications. [21] Patients who were found to have worsening renal function were found to have higher mortality than patients who had improvement in creatinine. This agrees with the already established observation that development of CKD itself is associated with decreased survival in patients with type-2 DM and CKD. [22] The survival is further worsened once they develop ESRD. [23]

The major limitations of this study include the retrospective observational design, limited number of patients, use of dipstick for detection of proteinuria and the absence of renal biopsy for clinico-pathological correlation. Proteinuria assessed by dipstick is a crude quantification of urinary protein and it is affected by urine concentration or dilution. Hence, to establish true negativity, we decided to take the urine dipstick results for three consecutive years. Dipstick protein analysis can also miss early microalbuminuria. [6] However, one can argue that this category of patients can progress to renal failure without passing through the stage of macro-albuminuria. This leads us to the importance of performing quantitative rather than qualitative protein analysis to detect patients with significant proteinuria who might be missed by dipstick proteinuria. Another drawback of the study was the absence of renal biopsy, which can differentiate glomerular versus non-glomerular causes for proteinuria. However, we believe that whether our patients actually had glomerular or nonglomerular disease is not the primary issue; our purpose was to determine the outcomes in patients with diabetes without proteinuria and impaired renal function. Further research is needed with a much more expansive data set to more adequately substantiate our results.

   Conclusion Top

The most striking finding in this cohort study is that the majority of patients with diabetes with CKD, yet without detectable proteinuria, manifested improved kidney function over time. This observation suggests that in this sub-group of diabetics with CKD, functional renal impairment may stem from reversible factors. Hence, a careful search for potentially reversible causes of kidney damage is recommended for this sub-group. The present study also confirms previous observations showing correlation between progression of renal failure and increased mortality. Thus, preservation of kidney function has to be evaluated as a possible life-saving therapeutic goal.

   Acknowledgment Top

This material is the result of work supported with resources and the use of facilities of the Southern Arizona Veterans Affairs Healthcare System.

Conflict of interest: None declared

We certified that this manuscript nor one with substantially similar content under our authorship has been published or is being considered for publication elsewhere, and all the data collected during the study is presented in this manuscript and no data from the study has been or will be published separately

   References Top

Centers for Disease Control and Prevention (CDC). Incidence of end-stage renal disease attributed to diabetes among persons with diagnosed diabetes - United States and Puerto Rico, 1996-2007. MMWR Morb Mortal Wkly Rep 2010;59:1361-6.  Back to cited text no. 1
Mitka M. Report notes increase in kidney disease. JAMA 2008;300:2473-4.  Back to cited text no. 2
Rigalleau V, Lasseur C, Raffaitin C, et al. Normoalbuminuric renal-insufficient diabetic patients: A lower-risk group. Diabetes Care 2007;30:2034-9.  Back to cited text no. 3
Carroll MF, Temte JL. Proteinuria in adults: A diagnostic approach. Am Fam Physician 2000;62:1333-40.  Back to cited text no. 4
Christensen PK, Gall MA, Parving HH. Course of glomerular filtration rate in albuminuric type 2 diabetic patients with or without diabetic glomerulopathy. Diabetes Care 2000; 23 Suppl 2:B14-20.  Back to cited text no. 5
Durham JT, Herman IM. Microvascular modifications in diabetic retinopathy. Curr Diab Rep 2011;11:253-64.  Back to cited text no. 6
Parving HH, Hommel E, Mathiesen E, et al. Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes. Br Med J (Clin Res Ed) 1988;296:156-60.  Back to cited text no. 7
Pham TT, Sim JJ, Kujubu DA, Liu IL, Kumar VA. Prevalence of nondiabetic renal disease in diabetic patients. Am J Nephrol 2007;27:322-8.  Back to cited text no. 8
Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 2006;55:1832-9.  Back to cited text no. 9
Nelson RG, Bennett PH, Beck GJ, et al. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med 1996;335:1636-42.  Back to cited text no. 10
Ueda H, Ishimura E, Shoji T, et al. Factors affecting progression of renal failure in patients with type 2 diabetes. Diabetes Care 2003;26:1530-4.  Back to cited text no. 11
Nosadini R, Velussi M, Brocco E, et al. Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes 2000;49:476-84.  Back to cited text no. 12
Rossing K, Christensen PK, Hovind P, Tarnow L, Rossing P, Parving HH. Progression of nephropathy in type 2 diabetic patients. Kidney Int 2004;66:1596-605.  Back to cited text no. 13
MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ, Jerums G. Nonalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care 2004;27:195-200.  Back to cited text no. 14
Charytan DM, Wallentin L, Lagerqvist B, et al. Early angiography in patients with chronic kidney disease: A collaborative systematic review. Clin J Am Soc Nephrol 2009;4:1032-43.  Back to cited text no. 15
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Vandenberg BF, Rossen JD, Grover-McKay M, Shammas NW, Burns TL, Rezai K. Evaluation of diabetic patients for renal and pancreas transplantation: Noninvasive screening for coronary artery disease using radionuclide methods. Transplantation 1996;62:1230-5.  Back to cited text no. 18
Sosnov J, Lessard D, Goldberg RJ, Yarzebski J, Gore JM. Differential symptoms of acute myocardial infarction in patients with kidney disease: A community-wide perspective. Am J Kidney Dis 2006;47:378-84.  Back to cited text no. 19
Freda BJ, Tang WH, Van Lente F, Peacock WF, Francis GS. Cardiac troponins in renal insufficiency: Review and clinical implications. J Am Coll Cardiol 2002;40:2065-71.  Back to cited text no. 20
Tsai TT, Maddox TM, Roe MT, et al. Contraindicated medication use in dialysis patients undergoing percutaneous coronary intervention. JAMA 2009;302:2458-64.  Back to cited text no. 21
Fink JC. Chronic kidney disease as a potent risk modifier for CAD in diabetics. JACC Cardiovasc Imaging 2010;3:746-8.  Back to cited text no. 22
Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238-48.  Back to cited text no. 23

Correspondence Address:
Bijin Thajudeen
University of Arizona College of Medicine, 1501 N Campbell Ave, Tucson, AZ, 85724
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DOI: 10.4103/1319-2442.160148

PMID: 26178541

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