Clinical Challenges in Diagnosis and Management of Diabetic Kidney Disease

doi:10.1053/j.ajkd.2013.10.050

American Journal of Kidney Diseases

Volume 63, Issue 2, Supplement 2, February 2014, Pages S3-S21

https://doi.org/10.1053/j.ajkd.2013.10.050 Get rights and content

Diabetic kidney disease (DKD) is a major and increasing worldwide public health issue. There is a great need for implementing treatments that either prevent or significantly slow the progression of DKD. Although there have been significant improvements in management, the increasing numbers of patients with DKD illustrate that current management is not wholly adequate. The reasons for suboptimal management include the lack of early diagnosis, lack of aggressive interventions, and lack of understanding about which interventions are most successful. There are a number of challenges and controversies regarding the current management of patients with DKD. Understanding of these issues is needed in order to provide the best care to patients with DKD. This article describes some of the clinically important challenges associated with DKD: the current epidemiology and cost burden and the role of biopsy in the diagnosis of DKD. Treatment controversies regarding current pharmacologic and nonpharmacologic approaches are reviewed and recommendations based on the published literature are made.

Section snippets

Executive Summary

Diabetic kidney disease (DKD) accounts for a large proportion of nephrology practice, and there is an overwhelming need to implement treatments that will either prevent the development or significantly slow the progression of DKD. Current approaches are not adequate because the number of patients who develop DKD or have progressive DKD continues to increase. Many controversies exist regarding standard approaches to patients with both diabetes and renal disease. This review discusses some of the

Epidemiology: How Prevalent is DKD?

Chronic kidney disease (CKD; defined as estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m² or urine albumin-creatinine ratio > 30 mg/g) is estimated to affect 13.1% of the US population, according to the 2012 US Renal Data Survey (USRDS) report.¹ Diabetes is the most prevalent cause of end-stage kidney disease, with hypertension second in the cohort in 2005-2010. Data from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA, report that there are approximately 22 million

Diagnosis: Is a Kidney Biopsy Indicated?

The diagnosis of DKD usually is based on a clinical history of diabetes and an appropriate sediment (generally bland, but a small number of red blood cells may be present) and absence of signs and symptoms of another kidney disease. In general, people with type 1 diabetes do not show clinical signs of kidney disease (decreased GFR and/or increased urine albumin-creatinine ratio) until about 3-5 years after the diagnosis of type 1 diabetes, whereas in people with type 2 diabetes, DKD may be

Overview

The primary interventions that slow the progression of DKD are control of glycated hemoglobin (HbA_1c) levels,46, 47, 48, 49, 50, 51 control of blood pressure (BP),52, 53, 54, 55 smoking cessation,56, 57 and lowering of urine albumin levels.58, 59 Furthermore, weight loss60, 61 also may play an important role in prevention and slowing the progression of DKD. Blood glucose management issues are discussed in detail elsewhere in this supplement.⁶² Two excellent reviews of overall BP management in

Conclusion

Much has been learned in the past 30 years that has led to significant improvements in treatments for DKD that slow progression and interventions for the prevention of DKD, yet DKD is a major, ever increasing, worldwide public health problem. The primary goals of the health care system need to be focused on the prevention and slowing of progression of DKD. The nephrology community has a dual task: to determine the best approach for both diagnosis and management. However, further education also

Acknowledgements

For the data reported here that were supplied by the USRDS, the interpretation and reporting of these data are the responsibility of the author and in no way should be seen as an official policy or interpretation of the US government.

Support: The development of this journal supplement was funded by Novo Nordisk. Technical editing was provided by Watermeadow Medical, funded by Novo Nordisk. Costs associated with publication were funded by Novo Nordisk. The author received no remuneration for

References (134)

M. Wilchesky et al.
Validation of diagnostic codes within medical services claims
J Clin Epidemiol
(2004)
R.L. Hanson et al.
ELMO1 variants and susceptibility to diabetic nephropathy in American Indians
Mol Genet Metab
(2010)
C.W. McDonough et al.
A genome-wide association study for diabetic nephropathy genes in African Americans
Kidney Int
(2011)
W.G. Couser et al.
The contribution of chronic kidney disease to the global burden of major noncommunicable diseases
Kidney Int
(2011)
Q.L. Zhang et al.
Prevalence of chronic kidney disease in population-based studies: systematic review
BMC Public Health
(2008)
B. Najafian et al.
Progression of diabetic nephropathy in type 1 diabetic patients
Diabetes Res Clin Pract
(2009)
R.E. Gilbert et al.
The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury?
Kidney Int
(1999)
Y. Ohkubo et al.
Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study
Diabetes Res Clin Pract
(1995)
P. Hovind et al.
Remission and regression in the nephropathy of type 1 diabetes when blood pressure is controlled aggressively
Kidney Int
(2001)
A.N. Lasaridis et al.
Diabetic nephropathy and antihypertensive treatment: what are the lessons from clinical trials?
Am J Hypertens
(2003)

H.J. Heerspink et al.

The kidney in type 2 diabetes therapy

Rev Diabet Stud

(2011)

KDOQI clinical practice guideline for diabetes and CKD: 2012 update

Am J Kidney Dis

(2012)

P. Ruggenenti et al.

The RAAS in the pathogenesis and treatment of diabetic nephropathy

Nat Rev Nephrol

(2010)

Centers for Disease Control and Prevention. Diabetes report card 2012: national and state profile of diabetes and its...

A. Sessa et al.

IgA nephropathy complicating diabetic glomerulosclerosis

Nephron

(1998)

H. Bi et al.

Nondiabetic renal disease in type 2 diabetic patients: a review of our experience in 220 cases

Ren Fail

(2011)

T.T. Pham et al.

Prevalence of nondiabetic renal disease in diabetic patients

Am J Nephrol

(2007)

W.M. Michels et al.

Performance of the Cockcroft-Gault, MDRD, and new CKD-EPI formulas in relation to GFR, age, and body size

Clin J Am Soc Nephrol

(2010)

M. Afkarian et al.

Kidney disease and increased mortality risk in type 2 diabetes

J Am Soc Nephrol

(2013)

E.B. Jude et al.

Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes

QJM

(2002)

P. Muntner et al.

Age-specific association of reduced estimated glomerular filtration rate and albuminuria with all-cause mortality

Clin J Am Soc Nephrol

(2011)

T. Ninomiya et al.

Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes

J Am Soc Nephrol

(2009)

C. Couchoud et al.

End-stage renal disease epidemic in diabetics: is there light at the end of the tunnel?

Nephrol Dial Transplant

(2013)

M.E. Pavkov et al.

Diabetic nephropathy in American Indians, with a special emphasis on the Pima Indians

Curr Diab Rep

(2008)

S. Debnath et al.

Diabetic nephropathy among Mexican Americans

Clin Nephrol

(2012)

A.J. Collins et al.

The state of chronic kidney disease, ESRD, and morbidity and mortality in the first year of dialysis

Clin J Am Soc Nephrol

(2009)

E.D. Crook et al.

Diabetic nephropathy in African-American patients

Curr Diab Rep

(2004)

C.W. McDonough et al.

Genetic analysis of diabetic nephropathy on chromosome 18 in African Americans: linkage analysis and dense SNP mapping

Hum Genet

(2009)

E. Ritz et al.

Nephropathy in patients with type 2 diabetes mellitus

N Engl J Med

(1999)

P. Finne et al.

Incidence of end-stage renal disease in patients with type 1 diabetes

JAMA

(2005)

A. Rodriguez-Poncelas et al.

Prevalence of chronic kidney disease in patients with type 2 diabetes in Spain: PERCEDIME2 Study

BMC Nephrol

(2013)

J. Lv et al.

Corticosteroid therapy in IgA nephropathy

J Am Soc Nephrol

(2012)

K. Kiryluk et al.

Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis

PLoS Genet

(2012)

Y. Cao et al.

Diabetes and hypertension have become leading causes of CKD in Chinese elderly patients: a comparison between 1990-1991 and 2009-2010

Int Urol Nephrol

(2012)

G. Wolf et al.

Association of diabetic retinopathy and renal function in patients with types 1 and 2 diabetes mellitus

Clin Nephrol

(2007)

Cited by (84)

Utilization of the corticomedullary difference in magnetic resonance imaging-derived apparent diffusion coefficient for noninvasive assessment of chronic kidney disease in type 2 diabetes
2024, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Accumulating data demonstrated that the cortico-medullary difference in apparent diffusion coefficient (ΔADC) of diffusion-weighted magnetic resonance imaging (DWI) was a better correlation with kidney fibrosis, tubular atrophy progression, and a predictor of kidney function evolution in chronic kidney disease (CKD).
We aimed to assess the value of ΔADC in evaluating disease severity, differential diagnosis, and the prognostic risk stratification for patients with type 2 diabetes (T2D) and CKD.
Total 119 patients with T2D and CKD who underwent renal MRI were prospectively enrolled. Of them, 89 patients had performed kidney biopsy for pathological examination, including 38 patients with biopsy-proven diabetic kidney disease (DKD) and 51 patients with biopsy-proven non-diabetic kidney disease (NDKD) and Mix (DKD + NDKD). Clinicopathological characteristics were compared according to different ΔADC levels. Moreover, univariate and multivariate-linear regression analyses were performed to explore whether ΔADC was independently associated with estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR). The diagnostic performance of ΔADC for discriminating DKD from NDKD + Mix was evaluated by receiver operating characteristic (ROC) analysis. In addition, an individual's 2- or 5-year risk probability of progressing to end-stage kidney disease (ESKD) was calculated by the kidney failure risk equation (KFRE). The effect of ΔADC on prognostic risk stratification was assessed. Additionally, net reclassification improvement (NRI) was used to evaluate the model performance.
All enrolled patients had a median ΔADC level of 86 (IQR 28, 155) × 10⁻⁶ mm²/s. ΔADC significantly decreased across the increasing staging of CKD (P < 0.001). Moreover, those with pathological-confirmed DKD has a significantly lower level of ΔADC than those with NDKD and Mix (P < 0.001). It showed that ΔADC was independently associated with eGFR (β = 1.058, 95% CI = [1.002,1.118], P = 0.042) and UACR (β = −3.862, 95% CI = [-7.360, -0.365], P = 0.031) at multivariate linear regression analyses. Besides, ΔADC achieved an AUC of 0.707 (71% sensitivity and 75% specificity) and AUC of 0.823 (94% sensitivity and 67% specificity) for discriminating DKD from NDKD + Mix and higher ESKD risk categories (≥50% at 5 years; ≥10% at 2 years) from lower risk categories (<50% at 5 years; <10% at 2 years). Accordingly, the optimal cutoff value of ΔADC for higher ESKD risk categories was 66 × 10⁻⁶ mm²/s, and the group with the low-cutoff level of ΔADC group was associated with 1.232 -fold (95% CI 1.086, 1.398) likelihood of higher ESKD risk categories as compared to the high-cutoff level of ΔADC group in the fully-adjusted model. Reclassification analyses confirmed that the final adjusted model improved NRI.
ΔADC was strongly associated with eGFR and UACR in patients with T2D and CKD. More importantly, baseline ΔADC was predictive of higher ESKD risk, independently of significant clinical confounding. Specifically, ΔADC <78 × 10⁻⁶ mm²/s and <66 × 10⁻⁶ mm²/s would help to identify T2D patients with the diagnosis of DKD and higher ESKD risk categories, respectively.
Potential effects of bisphenol A on diabetes mellitus and its chronic complications: A narrative review
2023, Heliyon
Diabetes mellitus (DM) is a metabolic disease caused by multiple factors such as genetics, environment, and lifestyle. Bisphenol A (BPA), as one of the most common endocrine-disrupting chemicals (EDCs), has been strongly implicated in the development of type 2 diabetes mellitus (T2DM). BPA exposure is associated with target organ damage in DM and may exacerbate the progression of some chronic complications of DM. This paper reviews relevant epidemiological, in vivo, and in vitro studies to better understand BPA's potential risk associations and pathological mechanisms in several chronic diabetic complications.
Development of a metabolite-based deep learning algorithm for clinical precise diagnosis of the progression of diabetic kidney disease
2023, Biomedical Signal Processing and Control
Diabetic kidney disease (DKD) is one of the most important microvascular complications of diabetes mellitus (DM). Early recognition and intervention in the treatment of DKD may delay the progression to end-stage kidney disease, but it is still a challenging task of early diagnosis of DKD and monitoring of its progression. Blood metabolites reflect the complex situation of human beings and provide a possible direction for disease diagnosis in clinics. In this paper, inspired by the recent success of deep neural networks in medical data understanding, we designed a learning-based method to capture the metabolic complexity and diagnose DKD accurately. Particularly, we trained a convolutional neural network (CNN) and fully connected network (FC) based on the metabolite dataset from 1521 clinical participants acquired by GC–MS. We proposed a novel data pre-processing method that translates the collected metabolite data into corresponding images followed by a normalization function, which is efficient for the deep neural network to extract robust features from metabolite data and mining the potential biomarkers of diseases. A metabolite-based deep neural network was firstly constructed, which is mainly used for the early stage of DKD (accuracy: 83.3%, sensitivity: 83.2%, specificity 80.2%) and the advanced stage of DKD (accuracy: 83.3%, sensitivity: 82.9%, specificity 81.0%) diagnosis. Meanwhile, it can also be applied to diagnosis of DM (accuracy: 83.3%, sensitivity: 83.4%, specificity: 80.4%) and CKD (accuracy: 87.0%, sensitivity: 83.7%, specificity: 81.2%). Our work presents the potential of using the metabolite data to construct an AI-enabled disease diagnosis system and finally being applied in real-world clinics, as well as provides new data types for AI application in medicine.
Causal knowledge graph construction and evaluation for clinical decision support of diabetic nephropathy
2023, Journal of Biomedical Informatics
Many important clinical decisions require causal knowledge (CK) to take action. Although many causal knowledge bases for medicine have been constructed, a comprehensive evaluation based on real-world data and methods for handling potential knowledge noise are still lacking.
The objectives of our study are threefold: (1) propose a framework for the construction of a large-scale and high-quality causal knowledge graph (CKG); (2) design the methods for knowledge noise reduction to improve the quality of the CKG; (3) evaluate the knowledge completeness and accuracy of the CKG using real-world data.
We extracted causal triples from three knowledge sources (SemMedDB, UpToDate and Churchill's Pocketbook of Differential Diagnosis) based on rule methods and language models, performed ontological encoding, and then designed semantic modeling between electronic health record (EHR) data and the CKG to complete knowledge instantiation. We proposed two graph pruning strategies (co-occurrence ratio and causality ratio) to reduce the potential noise introduced by SemMedDB. Finally, the evaluation was carried out by taking the diagnostic decision support (DDS) of diabetic nephropathy (DN) as a real-world case. The data originated from a Chinese hospital EHR system from October 2010 to October 2020. The knowledge completeness and accuracy of the CKG were evaluated based on three state-of-the-art embedding methods (R-GCN, MHGRN and MedPath), the annotated clinical text and the expert review, respectively.
This graph included 153,289 concepts and 1,719,968 causal triples. A total of 1427 inpatient data were used for evaluation. Better results were achieved by combining three knowledge sources than using only SemMedDB (three models: area under the receiver operating characteristic curve (AUC): p < 0.01, F1: p < 0.01), and the graph covered 93.9 % of the causal relations between diseases and diagnostic evidence recorded in clinical text. Causal relations played a vital role in all relations related to disease progression for DDS of DN (three models: AUC: p > 0.05, F1: p > 0.05), and after pruning, the knowledge accuracy of the CKG was significantly improved (three models: AUC: p < 0.01, F1: p < 0.01; expert review: average accuracy: + 5.5 %).
The results demonstrated that our proposed CKG could completely and accurately capture the abstract CK under the concrete EHR data, and the pruning strategies could improve the knowledge accuracy of our CKG. The CKG has the potential to be applied to the DDS of diseases.
The Renal Pathology of Obesity: Structure-Function Correlations
2021, Seminars in Nephrology
Citation Excerpt :
An increased incidence of obese patients with CKD in the general population suggests that patients with biopsy-diagnosed ORG represents only the tip of the iceberg and that a vast number of obese subjects showing insidious proteinuria may have the potential to progress to overt nephropathy and ESKD. This is quite analogous to the situation of diabetic nephropathy as a kidney complication of diabetes, in which the initial symptom is microalbuminuria, which then progresses to overt proteinuria and ESKD.80 Likewise, ORG patients and obese patients with subclinical proteinuria likely represent different stages or grades of the same disease entity of obesity-proteinuria syndrome (Fig. 5).
The kidney is one of the target organs that may show health disorders as a result of obesity. Obesity-related glomerulopathy (ORG) is a kidney disease category based on a biopsy diagnosis that may occur secondary to obesity. Detailed clinicopathologic observations of ORG have provided significant knowledge regarding obesity-associated renal complications. Glomerulomegaly with focal segmental glomerulosclerosis of perihilar locations is a typical renal histopathologic finding in ORG, which has long been considered to represent a state of single-nephron glomerular hyperfiltration. This hypothesis was recently confirmed in ORG patients by estimating single-nephron glomerular filtration rate using a combined image analysis and biopsy-based stereology. Overshooting in glomerulotubular and tubuloglomerular interactions may lead to glomerular hyperfiltration/hypertension, podocyte failure, tubular protein-traffic overload, and tubulointerstitial scarring, constituting a vicious cycle of a common pathway to the further loss of functioning nephrons and the progression of kidney functional impairment.
Betacyanins attenuates diabetic nephropathy in mice by inhibiting fibrosis and oxidative stress via the improvement of Nrf2 signaling
2021, Journal of Functional Foods
Citation Excerpt :
Diabetic nephropathy (DN) is one of the most frequent complications in diabetes mellitus, and is a major cause for mortality in patients with either type 1 or type 2 diabetes worldwide (Stanton, 2014; Tervaert, Mooyaart, & Amann, et al., 2010).
Diabetic nephropathy (DN) is a major cause of mortality in patients with diabetes, but there is a lack of effective therapeutic drugs for the disease treatment. Betacyanins (BCN) derived from plants exhibits anti-oxidative, anti-tumor and anti-inflammatory activities. However, its effects on DN have not been reported. In this study, we found that BCN supplementation markedly alleviated metabolic disorder and renal dysfunction in db/db mice. Additionally, BCN treatment obviously mitigated podocyte damage in diabetic mice, as evidenced by the decreased glomerular basement membrane thickness and the foot process width. Pathological analysis demonstrated that renal fibrosis was significantly inhibited by BCN through suppressing transforming growth factor (TGF)-β1/SMADs signaling in diabetic mice. Furthermore, diabetes-induced oxidative stress in kidney samples was evidently reduced in mice supplemented with BCN by improving nuclear factor erythroid-derived 2-related factor 2 (Nrf2) nuclear expression. The anti-fibrotic and anti-oxidant activities of BCN were confirmed in high glucose (HG)-stimulated podocytes in vitro. Importantly, we found that Nrf2 suppression could further exacerbate HG-induced collagen accumulation and reactive oxygen species (ROS) production in podocytes. Meanwhile, BCN-ameliorated fibrosis and oxidative stress were almost abrogated by the Nrf2 knockdown in HG-incubated podocytes. These findings elucidated that BCN could alleviate DN through reducing collagen and ROS deposition mainly through improving the Nrf2 signaling, subsequently alleviating renal dysfunction. Thus, BCN could be considered as a promising therapeutic agent for DN treatment.

View all citing articles on Scopus

: This article is part of a supplement that was developed with funding from Novo Nordisk.

View full text

Clinical Challenges in Diagnosis and Management of Diabetic Kidney Disease

Section snippets

Executive Summary

Epidemiology: How Prevalent is DKD?

Diagnosis: Is a Kidney Biopsy Indicated?

Overview

Conclusion

Acknowledgements

J Clin Epidemiol

Mol Genet Metab

Kidney Int

Kidney Int

BMC Public Health

Diabetes Res Clin Pract

Kidney Int

Diabetes Res Clin Pract

Kidney Int

Am J Hypertens

Am J Kidney Dis

Kidney Int

Diabetes Res Clin Pract

Kidney Int

Am J Kidney Dis

Adv Chronic Kidney Dis

Am J Hypertens

Am J Kidney Dis

Kidney Int

Kidney Int

Am J Kidney Dis

Kidney Int

Kidney Int

US Renal Data System 2012 annual data report

Am J Kidney Dis

Diabetic nephropathy: diagnosis, prevention, and treatment

Diabetes Care

The kidney in type 2 diabetes therapy

Rev Diabet Stud

KDOQI clinical practice guideline for diabetes and CKD: 2012 update

Am J Kidney Dis

The RAAS in the pathogenesis and treatment of diabetic nephropathy

Nat Rev Nephrol

IgA nephropathy complicating diabetic glomerulosclerosis

Nephron

Nondiabetic renal disease in type 2 diabetic patients: a review of our experience in 220 cases

Ren Fail

Prevalence of nondiabetic renal disease in diabetic patients

Am J Nephrol

Performance of the Cockcroft-Gault, MDRD, and new CKD-EPI formulas in relation to GFR, age, and body size

Clin J Am Soc Nephrol

Kidney disease and increased mortality risk in type 2 diabetes

J Am Soc Nephrol

Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes

QJM

Age-specific association of reduced estimated glomerular filtration rate and albuminuria with all-cause mortality

Clin J Am Soc Nephrol

Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes

J Am Soc Nephrol

End-stage renal disease epidemic in diabetics: is there light at the end of the tunnel?

Nephrol Dial Transplant

Diabetic nephropathy in American Indians, with a special emphasis on the Pima Indians

Curr Diab Rep

Diabetic nephropathy among Mexican Americans

Clin Nephrol

The state of chronic kidney disease, ESRD, and morbidity and mortality in the first year of dialysis

Clin J Am Soc Nephrol

Diabetic nephropathy in African-American patients

Curr Diab Rep

Genetic analysis of diabetic nephropathy on chromosome 18 in African Americans: linkage analysis and dense SNP mapping

Hum Genet

Nephropathy in patients with type 2 diabetes mellitus

N Engl J Med

Incidence of end-stage renal disease in patients with type 1 diabetes

JAMA

Prevalence of chronic kidney disease in patients with type 2 diabetes in Spain: PERCEDIME2 Study

BMC Nephrol

Corticosteroid therapy in IgA nephropathy

J Am Soc Nephrol

Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis

PLoS Genet

Diabetes and hypertension have become leading causes of CKD in Chinese elderly patients: a comparison between 1990-1991 and 2009-2010