Abstract
The increasing global prevalence of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has prompted research efforts to tackle the growing epidemic of diabetic kidney disease (DKD; also known as diabetic nephropathy). The limited success of much of this research might in part be due to the fact that not all patients diagnosed with DKD have renal dysfunction as a consequence of their diabetes mellitus. Patients who present with CKD and diabetes mellitus (type 1 or type 2) can have true DKD (wherein CKD is a direct consequence of their diabetes status), nondiabetic kidney disease (NDKD) coincident with diabetes mellitus, or a combination of both DKD and NDKD. Preclinical studies using models that more accurately mimic these three entities might improve the ability of animal models to predict clinical trial outcomes. Moreover, improved insights into the pathomechanisms that are shared by these entities — including sodium–glucose cotransporter 2 (SGLT2) and renin–angiotensin system-driven glomerular hyperfiltration and tubular hyper-reabsorption — as well as those that are unique to individual entities might lead to the identification of new treatment targets. Acknowledging that the clinical entity of CKD plus diabetes mellitus encompasses NDKD as well as DKD could help solve some of the urgent unmet medical needs of patients affected by these conditions.
Key points
-
Cardiovascular mortality and progression to end-stage renal disease are the two major unmet medical needs in patients with chronic kidney disease (CKD) plus diabetes mellitus.
-
In patients with diabetes mellitus, primary prevention of kidney disease, regardless of aetiology (diabetic kidney disease (DKD; also known as diabetic nephropathy)) or nondiabetic kidney disease (NDKD)), is essential and includes appropriate control of glucose, blood pressure, and body weight and avoidance of nephrotoxic drugs.
-
The clinical entity CKD plus diabetes encompasses DKD and NDKD or a combination of the two; diagnosis of these entities by kidney biopsy is important for disease management and research.
-
Biopsy studies show that NDKD is common in patients with type 2 diabetes mellitus (T2DM); as most patients with T2DM entering clinical diabetes trials do not undergo kidney biopsy, the pathophysiology underlying their kidney disease remains uncertain.
-
A disconnect exists between animal models used in preclinical studies of DKD and clinical studies with regard to differences in age, obesity status, renal function at onset, and use of co-medications; this disconnect might contribute to the poor predictability of animal studies for clinical trial outcomes.
-
Findings from clinical trials suggest that hyperfiltration driven by the sodium–glucose cotransporter 2 and the renin–angiotensin system is a common upstream mechanism that drives kidney disease in both DKD and NDKD in the context of diabetes mellitus.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
International Diabetes Federation. IDF Diabetes Atlas — 7th Edition. Diabetes Atlas http://www.diabetesatlas.org/ (2015).
Zoungas, S. et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol 5, 431–437 (2017).
American Diabetes, A.. Standards of medical care in diabetes 2017. Diabetes Care 40, S1–S106 (2017).
Group, A. S. et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N. Engl. J. Med. 364, 818–828 (2011).
Dabelea, D. et al. Association of type 1 diabetes versus type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood. JAMA 317, 825–835 (2017).
Tervaert, T. W. et al. Pathologic classification of diabetic nephropathy. J. Am. Soc. Nephrol. 21, 556–563 (2010).
ERA-EDTA Registry. ERA-EDTA Registry Annual Report 2014 (Department of Medical Informatics, Amsterdam, The Netherlands, 2016).
Bello, A. K. et al. Assessment of global kidney health care status. JAMA 317, 1864–1881 (2017).
Saran, R. et al. US Renal Data System 2016 Annual Data Report: Epidemiology of kidney disease in the United States. Am. J. Kidney Dis. 69, A7–A8 (2017).
Hill, N. R. et al. Global Prevalence of chronic kidney disease — a systematic review and meta-analysis. PLoS ONE 11, e0158765 (2016).
Gonzalez Suarez, M. L., Thomas, D. B., Barisoni, L. & Fornoni, A. Diabetic nephropathy: Is it time yet for routine kidney biopsy? World J. Diabetes 4, 245–255 (2013).
Sharma, S. G. et al. The modern spectrum of renal biopsy findings in patients with diabetes. Clin. J. Am. Soc. Nephrol. 8, 1718–1724 (2013).
Fiorentino, M. et al. Renal biopsy in patients with diabetes: a pooled meta-analysis of 48 studies. Nephrol. Dial Transplant. 32, 97–110 (2017).
Levin, A. et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet 390, 1888–1917 (2017).
[No authors listed.] Diabetic Kidney Disease. The mechanisms and pathophysiology underlying diabetic nephropathy and its progression. National Institute of Diabetes and Digestive and Kidney Diseases https://www.niddk.nih.gov/research-funding/research-programs/diabetic-kidney-disease (2018).
Wan, Q., Xu, Y. & Dong, E. Diabetic nephropathy research in China: Data analysis and review from the National Natural Science Foundation of China. J. Diabetes 7, 307–314 (2015).
Navaneethan, S. D. et al. Diabetes control and the risks of ESRD and mortality in patients with CKD. Am. J. Kidney Dis. 70, 191–198 (2017).
Ingelfinger, J. R. & Rosen, C. J. Cardiac and renovascular complications in type 2 diabetes — is there hope? N. Engl. J. Med. 375, 380–382 (2016).
Prospective Diabetes, U. K. Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352, 854–865 (1998).
Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).
Zinman, B. et al. Empagliflozin, Cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).
Neal, B. et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377, 644–657 (2017).
Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016).
Rawshani, A. et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N. Engl. J. Med. 376, 1407–1418 (2017).
Gregg, E. W. et al. Changes in diabetes-related complications in the United States, 1990–2010. N. Engl. J. Med. 370, 1514–1523 (2014).
Parving, H. H., Hommel, E., Jensen, B. R. & Hansen, H. P. Long-term beneficial effect of ACE inhibition on diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int. 60, 228–234 (2001).
Zhang, M. Z. et al. Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS−/− db/db mice. Am. J. Physiol. Renal Physiol. 302, F433–F438 (2012).
Wanner, C. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375, 323–334 (2016).
Mann, J. F. E. et al. Liraglutide and renal outcomes in type 2 diabetes. N. Engl. J. Med. 377, 839–848 (2017).
Anders, H. J., Davis, J. M. & Thurau, K. Nephron protection in diabetic kidney disease. N. Engl. J. Med. 375, 2096–2098 (2016).
Lewis, E. J. et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 345, 851–860 (2001).
Parving, H. H. et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N. Engl. J. Med. 345, 870–878 (2001).
de Zeeuw, D. et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 369, 2492–2503 (2013).
Parving, H. H. et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N. Engl. J. Med. 367, 2204–2213 (2012).
Voelker, J. et al. Anti-TGF-β1 antibody therapy in patients with diabetic nephropathy. J. Am. Soc. Nephrol. 28, 953–962 (2017).
Berhane, A. M., Weil, E. J., Knowler, W. C., Nelson, R. G. & Hanson, R. L. Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death. Clin. J. Am. Soc. Nephrol. 6, 2444–2451 (2011).
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. Suppl. 3, 1–150 (2013).
Chatzikyrkou, C. et al. Predictors for the development of microalbuminuria and interaction with renal function. J. Hypertens. 35, 2501–2509 (2017).
Oh, S. W. et al. Clinical implications of pathologic diagnosis and classification for diabetic nephropathy. Diabetes Res. Clin. Pract. 97, 418–424 (2012).
Adler, A. I. et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 63, 225–232 (2003).
Ahmad, T., Ulhaq, I., Mawani, M. & Islam, N. Microalbuminuria in type-2 diabetes mellitus; the tip of iceberg of diabetic complications. Pak. J. Med. Sci. 33, 519–523 (2017).
Wiseman, M. J., Saunders, A. J., Keen, H. & Viberti, G. Effect of blood glucose control on increased glomerular filtration rate and kidney size in insulin-dependent diabetes. N. Engl. J. Med. 312, 617–621 (1985).
Skupien, J. et al. Improved glycemic control and risk of ESRD in patients with type 1 diabetes and proteinuria. J. Am. Soc. Nephrol. 25, 2916–2925 (2014).
Fioretto, P., Barzon, I. & Mauer, M. Is diabetic nephropathy reversible? Diabetes Res. Clin. Pract. 104, 323–328 (2014).
Tonneijck, L. et al. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J. Am. Soc. Nephrol. 28, 1023–1039 (2017).
McKnight, A. J., Duffy, S. & Maxwell, A. P. Genetics of diabetic nephropathy: a long road of discovery. Curr. Diab Rep. 15, 41 (2015).
Vallon, V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu. Rev. Med. 66, 255–270 (2015).
Zeni, L., Norden, A. G. W., Cancarini, G. & Unwin, R. J. A more tubulocentric view of diabetic kidney disease. J. Nephrol. 30, 701–717 (2017).
Goligorsky, M. S. Vascular endothelium in diabetes. Am. J. Physiol. Renal Physiol. 312, F266–F275 (2017).
van Sloten, T. T. et al. Endothelial dysfunction plays a key role in increasing cardiovascular risk in type 2 diabetes: the Hoorn study. Hypertension 64, 1299–1305 (2014).
Frati Munari, A. C. Medical significance of endothelial glycocalyx. Part 2: Its role in vascular diseases and in diabetic complications [Spanish]. Arch. Cardiol. Mex. 84, 110–116 (2014).
Fu, J., Lee, K., Chuang, P. Y., Liu, Z. & He, J. C. Glomerular endothelial cell injury and cross talk in diabetic kidney disease. Am. J. Physiol. Renal Physiol. 308, F287–F297 (2015).
Nieuwdorp, M. et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 55, 480–486 (2006).
Kashihara, N., Watanabe, Y., Makino, H., Wallner, E. I. & Kanwar, Y. S. Selective decreased de novo synthesis of glomerular proteoglycans under the influence of reactive oxygen species. Proc. Natl Acad. Sci. USA 89, 6309–6313 (1992).
Bock, F. et al. Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc. Natl Acad. Sci. USA 110, 648–653 (2013).
Isermann, B. et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat. Med. 13, 1349–1358 (2007).
Mason, R. M. & Wahab, N. A. Extracellular matrix metabolism in diabetic nephropathy. J. Am. Soc. Nephrol. 14, 1358–1373 (2003).
Kriz, W. et al. Accumulation of worn-out GBM material substantially contributes to mesangial matrix expansion in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 312, F1101–F1111 (2017).
Ziyadeh, F. N. et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc. Natl Acad. Sci. USA 97, 8015–8020 (2000).
Bai, Y. et al. High ambient glucose levels modulates the production of MMP-9 and alpha5(IV) collagen by cultured podocytes. Cell Physiol. Biochem. 17, 57–68 (2006).
Dalla Vestra, M., Saller, A., Mauer, M. & Fioretto, P. Role of mesangial expansion in the pathogenesis of diabetic nephropathy. J. Nephrol. 14(Suppl. 4), S51–S57 (2001).
Pagtalunan, M. E. et al. Podocyte loss and progressive glomerular injury in type II diabetes. J. Clin. Invest. 99, 342–348 (1997).
Stieger, N. et al. Impact of high glucose and transforming growth factor-β on bioenergetic profiles in podocytes. Metabolism 61, 1073–1086 (2012).
Susztak, K., Raff, A. C., Schiffer, M. & Bottinger, E. P. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55, 225–233 (2006).
Regoli, M. & Bendayan, M. Alterations in the expression of the alpha 3 beta 1 integrin in certain membrane domains of the glomerular epithelial cells (podocytes) in diabetes mellitus. Diabetologia 40, 15–22 (1997).
Schiffer, M. et al. Apoptosis in podocytes induced by TGF-β and Smad7. J. Clin. Invest. 108, 807–816 (2001).
Wang, X. X. et al. SGLT2 Protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation, and the development of nephropathy in diabetic mice. J. Biol. Chem. 292, 5335–5348 (2017).
Li, X. et al. Nephrin preserves podocyte viability and glomerular structure and function in adult kidneys. J. Am. Soc. Nephrol. 26, 2361–2377 (2015).
Doublier, S. et al. Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II. Diabetes 52, 1023–1030 (2003).
Quack, I. et al. PKCα mediates β-arrestin2-dependent nephrin endocytosis in hyperglycemia. J. Biol. Chem. 286, 12959–12970 (2011).
Tossidou, I. et al. Podocytic PKC-α is regulated in murine and human diabetes and mediates nephrin endocytosis. PLoS ONE 5, e10185 (2010).
Teng, B. et al. CIN85 Deficiency prevents nephrin endocytosis and proteinuria in diabetes. Diabetes 65, 3667–3679 (2016).
Madhusudhan, T. et al. Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nat. Commun. 6, 6496 (2015).
Madhusudhan, T. et al. Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function. Blood 130, 1445–1455 (2017).
Welsh, G. I. et al. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 12, 329–340 (2010).
Wharram, B. L. et al. Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J. Am. Soc. Nephrol. 16, 2941–2952 (2005).
Lasagni, L., Lazzeri, E., Shankland, S. J., Anders, H. J. & Romagnani, P. Podocyte mitosis — a catastrophe. Curr. Mol. Med. 13, 13–23 (2013).
Fufaa, G. D. et al. Urinary monocyte chemoattractant protein-1 and hepcidin and early diabetic nephropathy lesions in type 1 diabetes mellitus. Nephrol. Dial. Transplant. 30, 599–606 (2015).
Wada, J. & Makino, H. Innate immunity in diabetes and diabetic nephropathy. Nat. Rev. Nephrol. 12, 13–26 (2016).
Menne, J. et al. C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria. Nephrol. Dial Transplant 32, 307–315 (2017).
de Zeeuw, D. et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol 3, 687–696 (2015).
Chow, F. Y., Nikolic-Paterson, D. J., Ozols, E., Atkins, R. C. & Tesch, G. H. Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. J. Am. Soc. Nephrol. 16, 1711–1722 (2005).
Sayyed, S. G. et al. An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes. Kidney Int. 80, 68–78 (2011).
Shahzad, K. et al. Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 87, 74–84 (2015).
Anders, H. J. Of inflammasomes and alarmins: IL-1β and IL-1α in kidney disease. J. Am. Soc. Nephrol. 27, 2564–2575 (2016).
Perez-Gomez, M. V. et al. Targeting inflammation in diabetic kidney disease: early clinical trials. Expert Opin. Invest. Drugs 25, 1045–1058 (2016).
Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10, 210–215 (2010).
Leemans, J. C., Kors, L., Anders, H. J. & Florquin, S. Pattern recognition receptors and the inflammasome in kidney disease. Nat. Rev. Nephrol. 10, 398–414 (2014).
Qiu, Y. Y. & Tang, L. Q. Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy. Pharmacol. Res. 114, 251–264 (2016).
Shahzad, K. et al. Caspase-1, but not caspase-3, promotes diabetic nephropathy. J. Am. Soc. Nephrol. 27, 2270–2275 (2016).
Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).
Nathan, D. M. et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N. Engl. J. Med. 353, 2643–2653 (2005).
El-Osta, A. et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J. Exp. Med. 205, 2409–2417 (2008).
Reddy, M. A., Zhang, E. & Natarajan, R. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58, 443–455 (2015).
Friso, S. & Choi, S. W. Gene-nutrient interactions in one-carbon metabolism. Curr. Drug Metab. 6, 37–46 (2005).
Junien, C. Impact of diets and nutrients/drugs on early epigenetic programming. J. Inherit. Metab. Dis. 29, 359–365 (2006).
Grahammer, F. et al. mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. Proc. Natl Acad. Sci. USA 111, E2817–E2826 (2014).
Zhong, X. et al. miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes. Diabetologia 56, 663–674 (2013).
Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B. & Thomson, A. W. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat. Rev. Nephrol. 12, 587–609 (2016).
Godel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011).
Zschiedrich, S. et al. Targeting mTOR signaling can prevent the progression of FSGS. J. Am. Soc. Nephrol. 28, 2144–2157 (2017).
Qi, W. et al. Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat. Med. 23, 753–762 (2017).
D’Agati, V. D. et al. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat. Rev. Nephrol 12, 453–471 (2016).
Wiles, K. S., Nelson-Piercy, C. & Bramham, K. Reproductive health and pregnancy in women with chronic kidney disease. Nat. Rev. Nephrol. https://doi.org/10.1038/nrneph.2017.187 (2018).
Wilke, T. et al. Epidemiology of urinary tract infections in type 2 diabetes mellitus patients: An analysis based on a large sample of 456,586 German T2DM patients. J. Diabetes Compl. 29, 1015–1023 (2015).
Haider, D. G. et al. Kidney biopsy in patients with diabetes mellitus. Clin. Nephrol. 76, 180–185 (2011).
Mayer-Davis, E. J. et al. Incidence trends of type 1 and type 2 diabetes among youths, 2002–2012. N. Engl. J. Med. 376, 1419–1429 (2017).
Zhuo, L., Ren, W., Li, W., Zou, G. & Lu, J. Evaluation of renal biopsies in type 2 diabetic patients with kidney disease: a clinicopathological study of 216 cases. Int. Urol. Nephrol. 45, 173–179 (2013).
Sharif, A. et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions. Am. J. Transplant. 14, 1992–2000 (2014).
Steinke, J. M. & Mauer, M., International Diabetic Nephropathy Study. Lessons learned from studies of the natural history of diabetic nephropathy in young type 1 diabetic patients. Pediatr. Endocrinol. Rev. 5(Suppl. 4), 958–963 (2008). G..
Tsai, C. W., Grams, M. E., Inker, L. A., Coresh, J. & Selvin, E. Cystatin C- and creatinine-based estimated glomerular filtration rate, vascular disease, and mortality in persons with diabetes in the U.S. Diabetes Care 37, 1002–1008 (2014).
Romagnani, P. et al. Chronic kidney disease. Nat. Rev. Dis. Primer 3, 17088 (2017).
Nair, V. et al. A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome. Kidney Int. 93, 439–449 (2018).
Weil, E. J. et al. Effect of losartan on prevention and progression of early diabetic nephropathy in American Indians with type 2 diabetes. Diabetes 62, 3224–3231 (2013).
Denic, A. et al. Single-nephron glomerular filtration rate in healthy adults. N. Engl. J. Med. 376, 2349–2357 (2017).
Helal, I., Fick-Brosnahan, G. M., Reed-Gitomer, B. & Schrier, R. W. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat. Rev. Nephrol. 8, 293–300 (2012).
Preisig, P. What makes cells grow larger and how do they do it? Renal hypertrophy revisited. Exp. Nephrol. 7, 273–283 (1999).
Iwai, T. et al. Diabetes mellitus as a cause or comorbidity of chronic kidney disease and its outcomes: the Gonryo study. Clin. Exp. Nephrol. https://doi.org/10.1007/s10157-017-1451-4 (2017).
Chang, T. I. et al. Renal outcomes in patients with type 2 diabetes with or without coexisting non-diabetic renal disease. Diabetes Res. Clin. Pract. 92, 198–204 (2011).
Anguiano Gomez, L., Lei, Y., Devarapu, S. K. & Anders, H. J. The diabetes pandemic suggests unmet needs for ‘CKD with diabetes’ in addition to ‘diabetic nephropathy’. Implications for pre-clinical research and drug testing. Nephrol. Dial. Transplant. https://doi.org/10.1093/ndt/gfx219 (2017).
Hodgin, J. B. et al. Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli. Diabetes 62, 299–308 (2013).
Pollock, C. et al. The establishment and validation of novel therapeutic targets to retard progression of chronic kidney disease. Kidney Int. Suppl. 7, 130–137 (2017).
Anders, H. J., Jayne, D. R. & Rovin, B. H. Hurdles to the introduction of new therapies for immune-mediated kidney diseases. Nat. Rev. Nephrol. 12, 205–216 (2016).
Xu, D. M., Chen, M., Zhou, F. D. & Zhao, M. H. Risk factors for severe bleeding complications in percutaneous renal biopsy. Am. J. Med. Sci. 353, 230–235 (2017).
Camara, N. O., Iseki, K., Kramer, H., Liu, Z. H. & Sharma, K. Kidney disease and obesity: epidemiology, mechanisms and treatment. Nat. Rev. Nephrol. 13, 181–190 (2017).
Brosius, F. C. et al. Mouse models of diabetic nephropathy. J. Am. Soc. Nephrol. 20, 2503–2512 (2009).
Nzerue, C. M. et al. Prevalence of non-diabetic renal disease among African-American patients with type II diabetes mellitus. Scand. J. Urol. Nephrol. 34, 331–335 (2000).
Pham, T. T., Sim, J. J., Kujubu, D. A., Liu, I. L. & Kumar, V. A. Prevalence of nondiabetic renal disease in diabetic patients. Am. J. Nephrol. 27, 322–328 (2007).
Mazzucco, G. et al. Different patterns of renal damage in type 2 diabetes mellitus: a multicentric study on 393 biopsies. Am. J. Kidney Dis. 39, 713–720 (2002).
Biesenbach, G., Bodlaj, G., Pieringer, H. & Sedlak, M. Clinical versus histological diagnosis of diabetic nephropathy — is renal biopsy required in type 2 diabetic patients with renal disease? QJM 104, 771–774 (2011).
Richards, N. T. et al. Increased prevalence of renal biopsy findings other than diabetic glomerulopathy in type II diabetes mellitus. Nephrol. Dial Transplant 7, 397–399 (1992).
Cordonnier, D. J. et al. Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. J. Am. Soc. Nephrol. 10, 1253–1263 (1999).
Parving, H. H. et al. Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int. 41, 758–762 (1992).
Christensen, P. K., Larsen, S., Horn, T., Olsen, S. & Parving, H. H. Causes of albuminuria in patients with type 2 diabetes without diabetic retinopathy. Kidney Int. 58, 1719–1731 (2000).
Izzedine, H., Fongoro, S., Pajot, O., Beaufils, H. & Deray, G. Retinopathy, hematuria, and diabetic nephropathy. Nephron 88, 382–383 (2001).
Bermejo, S. et al. Predictive factors for non-diabetic nephropathy in diabetic patients. The utility of renal biopsy. Nefrologia 36, 535–544 (2016).
Serra, A., Romero, R., Bayes, B., Lopez, D. & Bonet, J. Is there a need for changes in renal biopsy criteria in proteinuria in type 2 diabetes? Diabetes Res. Clin. Pract. 58, 149–153 (2002).
Castellano, I., Covarsi, A., Novillo, R., Gomez-Martino, J. R. & Ferrando, L. Renal histological lesions in patients with type II diabetes mellitus [Spanish]. Nefrologia 22, 162–169 (2002).
Rychlik, I. et al. The Czech registry of renal biopsies. Occurrence of renal diseases in the years 1994–2000. Nephrol. Dial. Transplant. 19, 3040–3049 (2004).
Mami, I. et al. Nondiabetic renal disease in patients with type 2 diabetes. Saudi J. Kidney Dis. Transpl. 28, 842–850 (2017).
Kharrat, M. et al. Renal biopsy findings in diabetes mellitus [French]. Tunis Med. 85, 216–219 (2007).
Ghani, A. A., Al Waheeb, S., Al Sahow, A. & Hussain, N. Renal biopsy in patients with type 2 diabetes mellitus: indications and nature of the lesions. Ann. Saudi Med. 29, 450–453 (2009).
Hashim Al-Saedi, A. J. Pathology of nondiabetic glomerular disease among adult Iraqi patients from a single center. Saudi J. Kidney Dis. Transpl. 20, 858–861 (2009).
Soni, S. S., Gowrishankar, S., Kishan, A. G. & Raman, A. Non diabetic renal disease in type 2 diabetes mellitus. Nephrology 11, 533–537 (2006).
Moger, V. et al. Rapidly progressive renal failure in type 2 diabetes in the tropical environment: a clinico-pathological study. Ren. Fail. 27, 595–600 (2005).
Prakash, J. et al. Diabetic retinopathy is a poor predictor of type of nephropathy in proteinuric type 2 diabetic patients. J. Assoc. Physicians India 55, 412–416 (2007).
Premalatha, G. et al. Prevalence of non-diabetic renal disease in type 2 diabetic patients in a diabetes centre in Southern India. J. Assoc. Physicians India 50, 1135–1139 (2002).
Arif, M., Arif, M. K. & Arif, M. S. An evaluation of renal biopsy in type-II diabetic patients. J. Coll. Physicians Surg. Pak 19, 627–631 (2009).
Yaqub, S., Kashif, W. & Hussain, S. A. Non-diabetic renal disease in patients with type-2 diabetes mellitus. Saudi J. Kidney Dis. Transpl 23, 1000–1007 (2012).
Chong, Y. B. et al. Clinical predictors of non-diabetic renal disease and role of renal biopsy in diabetic patients with renal involvement: a single centre review. Ren. Fail. 34, 323–328 (2012).
Liu, S. et al. Clinicopathological characteristics of non-diabetic renal disease in patients with type 2 diabetes mellitus in a northeastern Chinese medical center: a retrospective analysis of 273 cases. Int. Urol. Nephrol. 48, 1691–1698 (2016).
Bi, H. et al. Nondiabetic renal disease in type 2 diabetic patients: a review of our experience in 220 cases. Ren. Fail. 33, 26–30 (2011).
Zhang, P. P. et al. Renal biopsy in type 2 diabetes: timing of complications and evaluating of safety in Chinese patients. Nephrology 16, 100–105 (2011).
Mou, S. et al. Prevalence of non-diabetic renal disease in patients with type 2 diabetes. Diabetes Res. Clin. Pract. 87, 354–359 (2010).
Wong, T. Y. et al. Renal outcome in type 2 diabetic patients with or without coexisting nondiabetic nephropathies. Diabetes Care 25, 900–905 (2002).
Huang, F. et al. Renal pathological change in patients with type 2 diabetes is not always diabetic nephropathy: a report of 52 cases. Clin. Nephrol. 67, 293–297 (2007).
Mak, S. K. et al. Clinical predictors of non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus. Nephrol. Dial. Transplant. 12, 2588–2591 (1997).
Lin, Y. L., Peng, S. J., Ferng, S. H., Tzen, C. Y. & Yang, C. S. Clinical indicators which necessitate renal biopsy in type 2 diabetes mellitus patients with renal disease. Int. J. Clin. Pract. 63, 1167–1176 (2009).
Harada, K. et al. Significance of renal biopsy in patients with presumed diabetic nephropathy. J. Diabetes Investig. 4, 88–93 (2013).
Hironaka, K., Makino, H., Ikeda, S., Haramoto, T. & Ota, Z. Nondiabetic renal disease complicating diabetic nephropathy. J. Diabet Compl. 5, 148–149 (1991).
Tone, A. et al. Clinical features of non-diabetic renal diseases in patients with type 2 diabetes. Diabetes Res. Clin. Pract. 69, 237–242 (2005).
Akimoto, T. et al. Microscopic hematuria and diabetic glomerulosclerosis—clinicopathological analysis of type 2 diabetic patients associated with overt proteinuria. Nephron Clin. Pract. 109, c119 (2008).
Lee, E. Y., Chung, C. H. & Choi, S. O. Non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus. Yonsei Med. J. 40, 321–326 (1999).
Acknowledgements
H.-J.A. is supported by the Deutsche Forschungsgemeinschaft (DFG; AN372/24-1) and the European Union (EU)’s Research and Innovation programmes (under grant agreements Horizon 2020 and NEPHSTROM No. 634086). T.B.H. is supported by the DFG (CRC1140, CRC 992), by the Federal Ministry of Education and Research (BMBF; 01GM1518C; Germany), by the European Research Council grant 616891, and by the Horizon 2020 Innovative Medicines Initiative 2 consortium BEAt-DKD (Biomarker Enterprise to Attack DKD). M.S. was supported by BMBF grant 01GM1518A and a Fritz Thyssen Grant (10.16.2.026MN). The views expressed here are the responsibility of the authors only. The EU Commission takes no responsibility for any use made of the information set out.
Author information
Authors and Affiliations
Contributions
All authors contributed to researching data for the article, discussing the article’s content, writing the article, and reviewing and editing of the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
H.-J.A. has received consultancy fees from Roche, Bayer, Janssen, and Boehringer and lecture fees from Amgen and Fresenius. B.I., T.B.H., and M.S. declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Diabetic kidney disease
-
(DKD). Also known as diabetic nephropathy. Often defined as a clinical syndrome of albuminuria in patients with diabetes mellitus but more accurately defined as a distinct histopathological pattern of kidney injury, characterized by arteriolar hyalinosis and nodular glomerulosclerosis, induced by hyperglycaemia.
- Sodium–glucose cotransporter 2
-
(SGLT2). A transporter expressed in the S2 segment of the (convoluted) proximal tubule that reabsorbs freely filtered glucose and cotransports sodium.
- GLP1 analogue
-
Glucagon-like peptide 1 analogues are incretin mimetics that reduce meal-related hyperglycaemia and have a low risk of causing hypoglycaemia. Liraglutide reduced cardiovascular and renal end points in patients with type 2 diabetes mellitus.
- Kidney hypertrophy
-
A diffuse nephron hypertrophy that increases the size of the kidney.
- Tubuloglomerular feedback
-
An autoregulatory mechanism of glomerular perfusion that maintains a submaximal single-nephron glomerular filtration rate (SNGFR) and responds to changes in intravascular fluid volume. Hyperglycaemia deactivates tubuloglomerular feedback and leads to a persistent increase in SNGFR.
- Glomerular hyperfiltration
-
The consequence of an increase in single-nephron glomerular filtration rate due to impaired autoregulation of glomerular haemodynamics or a reduction in the nephron number:body mass ratio.
- Glomerular hypertension
-
The increased pressure gradient across the glomerular filtration barrier that occurs, for example, when glomerular hyperfiltration is not associated with a respective increase in filtration surface.
- Sterile inflammation
-
Non-infectious causes of inflammation such as those that occur in autoinflammatory or autoimmune disorders upon trauma or toxic tissue injury.
- Spiegelmer
-
L-Ribonucleic acid aptamers that mirror structures of natural RNA oligonucleotides, protecting them from enzymatic degradation. Spiegelmers can bind and neutralize small proteins.
- Danger-associated molecular patterns
-
(DAMPs). Natural cellular components, often released by dying cells, that induce inflammation via specific pattern recognition receptors of the innate immune system.
- Adipokines
-
Cytokines secreted by the adipose tissue, including leptin, adiponectin, and apelin.
- Nephron hypertrophy
-
The increased dimensions of nephrons, usually as a consequence of glomerular hypertension and hyperfiltration.
- Total GFR
-
In poorly controlled diabetes, the total glomerular filtration rate (GFR) is close to maximal GFR.
- Nephron number
-
A critical parameter for kidney function. The number of nephrons multiplied by single-nephron glomerular filtration rate (GFR) equals the total GFR.
- Kimmelstiel–Wilson lesions
-
A lesion characterized by nodular glomerulosclerosis that is commonly found in biopsy samples from patients with diabetes mellitus.
Rights and permissions
About this article
Cite this article
Anders, HJ., Huber, T.B., Isermann, B. et al. CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat Rev Nephrol 14, 361–377 (2018). https://doi.org/10.1038/s41581-018-0001-y
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41581-018-0001-y
This article is cited by
-
Causal effect of gut microbiota and diabetic nephropathy: a Mendelian randomization study
Diabetology & Metabolic Syndrome (2024)
-
Exposure to cadmium and lead is associated with diabetic kidney disease in diabetic patients
Environmental Health (2024)
-
Efficacy evaluation of Berberis aristata and Silybum marianum fixed dose combination on glycaemic and insulin resistance parameters in adult population: a systematic review and meta-analysis of randomized controlled trials
Future Journal of Pharmaceutical Sciences (2024)
-
Common mouse models of chronic kidney disease are not associated with cachexia
Communications Biology (2024)
-
Circ-Luc7l Absence Attenuates Diabetic Nephropathy Progression by Reducing Mesangial Cell Excessive Proliferation, Inflammation, and Extracellular Matrix Accumulation via Mediating the miR-205-5p/Tgfbr1 Pathway
Biochemical Genetics (2024)