Diabetic Nephropathy refers to a renal pathology that arises as a result of a preexisting diabetic condition. As we understand diabetes more and more, the complications that it can cause has been given increased scrutiny due to the prevalence and severity of said complications. While it is not a given that diabetic nephropathy will occur to any given diabetic patient, it is another ramification of diabetes that needs to be addressed for enhanced prophylaxis and increased preparedness. Also, diabetic nephropathy is currently the main culprit for chronic kidney disease in the United States.
“Diabetic kidney disease occurs in patients with diabetes mellitus (DM) and reduced kidney function that can be from many diverse causes, including hypertensive nephrosclerosis and unresolved acute kidney failure. Diabetic nephropathy is a diagnosis that refers to specific pathologic structural and functional changes seen in the kidneys of patients with DM (both type 1 and type 2 [T1/T2DM]) that result from the effects of DM on the kidney. These changes result in a clinical presentation that is characterized by proteinuria, hypertension, and progressive reductions in kidney function.”1
When thinking of diabetes, one must take into account the hemodynamic changes that take place as a result of increased blood glucose levels. The kidneys are supplied blood by microscopic arterioles and capillaries that, when damaged, can dramatically alter the function of the kidney. Due to a hyperglycemic state, glucose molecules begin attaching to glomerular proteins, a process called glycosylation. This leads to a rise in the proliferation of mesangial cells, increased lesions of endothelium vessels and excess fibrosis between nephrotic capillaries (interstitial fibrosis). The damage to these structures mean that the filtration efficacy of the kidney has been compromised. Slowly, as more and more damage occurs and healthy nephrotic cells are replaced by nodes and scarring, the kidney ultimately fails.
“The pathophysiology leading to the development of diabetic nephropathy and resultant end-stage kidney disease follows from the diabetic milieu leading to the generation and circulation of advanced glycation end products, elaboration of growth factors, and hemodynamic and hormonal changes. These lead to the release of reactive oxygen species and inflammatory mediators. Collectively, these changes result in glomerular hyperfiltration,
Glomerular hypertension, renal hypertrophy, and altered glomerular composition, which is manifested clinically as albuminuria and hypertension. Pathologically, the kidneys undergo several changes, including deposition (in primarily the mesangium) of extracellular matrix, glomerular basement membrane thickening, proliferative changes, and tubular atrophy, ultimately resulting in interstitial fibrosis and glomerulosclerosis (the final common pathway of many kidney diseases).”2
Pathophysiology of diabetic nephropathy
“The natural history of diabetic nephropathy in patients with T1DM (Type 1 Diabetes Mellitus) was initially characterized in the late 1970s by Kussman et al by examining death records of patients with juvenile-onset DM (Diabetes Mellitus) who were classified as having died of kidney failure. This analysis resulted in an understanding of the true untreated natural history of diabetic nephropathy due to T1DM as it was before the advent of therapy for this complication of DM. Based on this study, proteinuria appears 11 to 23 years after the T1DM diagnosis, serum creatinine concentration begins to increase after 13 to 25 years, and end-stage kidney disease develops after 18 to 30 years. With the subsequent development of more sensitive assays to detect urinary albumin excretion, small amounts of albumin in the urine (microalbuminuria; 30-300 mg/g creatinine) were noted to precede the development of overt proteinuria (macroalbuminuria; >300 mg/g creatinine) in most patients, occurring 5 to 10 years after the diagnosis of DM. Presently, microalbuminuria and macroalbuminuria are referred to as A2 and A3, respectively, by the KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease (CKD) guideline. The natural history of diabetic nephropathy in patients in longitudinally studied populations with T2DM is essentially identical to that in patients with T1DM. However, outside a study situation, the timing of DM onset in patients with T2DM is difficult to assess. Therefore, a patient may even present with proteinuria and on kidney biopsy have diabetic nephropathy before T2DM is diagnosed. Another important difference in the natural history of patients with T1 versus T2DM is that the major macrovascular complication, namely cardiac disease and death due to cardiac disease, can occur at any point along the course of a patient with T2DM from the onset of DM and early diabetic nephropathy, whereas the elevated risk for cardiovascular disease is not apparent until advanced kidney disease has developed in patients with T1DM.”3
For detection of Diabetic Nephropathy, a urine test is performed where albuminuria levels are determined. Normally, a healthy person will have very small trace amounts of protein present in urine but during a nephrotic syndrome, a protein called Albumin increases enough in urine to be considered albuminuria, a strong indication of a nephrotic condition. A reading between 30 and 300 mg/24h confirms albuminuria. The GFR (Glomerular Filtration Rate) also shows signs of waning and at the cardiac and vascular level, high blood pressure ensues. These combinations of symptoms are all typical behavior of Diabetic Nephropathy.
A differential diagnosis still needs to be performed because as mentioned before, diabetes might not be the actual cause of kidney disease. The following signs should lead a physician to discern between one cause and another for an accurate treatment plan:
- Hematuria (presence of blood in urine)
- Urinary Casts
- Renal Hypoplasia (renal shrinkage)
- A lower glomerular filtration rate
- Steep increase of proteinuria
- Absenteeism of Diabetic Retinopathy
“Nodular diabetic glomerulosclerosis has a variety of pathological features but still should be differentiated from another mesangial nodular sclerosing glomerulopathy, which usually has similar light microscopic manifestations. It is necessary and essential to include manifestations, immunofluorescence staining (IF), and EM (electron microscopy) into the distinction of lesions caused by immune complex or monoclonal protein. Nodular lesions could be observed in various renal primary and secondary diseases, such as membranoproliferative glomerulonephritis, renal amyloidosis, type III collagen glomerulopathy, monoclonal immunoglobulin or light chain deposition disease, fibronectin nephropathy, and cryoglobulinemia glomerulosclerosis.”4
“Differential diagnosis is usually based on the history, physical examination, laboratory evaluation, and imaging of the kidneys. Renal biopsy is only recommended in special situations. The diagnosis of diabetic nephropathy is easily established in long-term type 1 diabetic patients (10 years diabetes duration), especially if retinopathy is also present. Typical diabetic nephropathy is also likely to be present in proteinuric type 2 diabetic patients with retinopathy. However, diagnostic uncertainty exists in some patients with type 2 diabetes since the onset of diabetes is unknown and retinopathy is absent in a significant proportion (28%) of these patients.”5
The natural history of DN is divided into five stages
“Stage 1: Renal pathology develops at the onset of diabetes. The growth of the kidney increases by several centimetres. By the time of diagnosis, the GFR and urinary albumin excretion (UAE) have been increased. It can be controlled at this level by onset of insulin.
Stage 2: The second phase typically lasts for 5-15 years after diagnosis of diabetes. The characteristics of the second phase include:
- GFR remains elevated due to hyperfiltration.
- Kidneys remain hypertrophied and UAE rate stays normal.
Stage 3: The characteristics of stage three are:
- Microalbuminuria is present. It occurs in 30-50% of patients after diabetes onset, 80% of whom go on to develop overt nephropathy over 10-15 years.
- GFR remains elevated or returns to normal range
- Blood pressure starts to rise in 60% of patients
- Histological changes-progression is as seen in stage two.
Stage 4: This stage is also known as clinical nephropathy or overt nephropathy. The characteristic histological features of stage four are formation of the Kimmelstiel-Wilson nodule (focal glomerular sclerosis) and macroproteinuria. It can progress to nephrotic in 30% of patients or may decline in 80% depending on deterioration of GFR.
Stage 5: As the GFR continues to decline, ESRD may develop. DN is considered the most common cause of ESRD because of associated autoimmune neuropathy and cardiac disease.
The stages of chronic kidney disease (CKD) are mainly based on measured or estimated GFR. There are five stages but kidney function is normal in stage 1 and minimally reduced in stage 2.”6
“It is particularly important to investigate retinopathy. Ideally, this should be done by an experienced ophthalmologist, since retinopathy is frequent in the presence of diabetic nephropathy and is a clue for its diagnosis. Prospective studies in type 2 diabetic patients showed that diabetic retinopathy was a predictor of later development of diabetic nephropathy. Retinopathy is probably a risk marker and not a risk factor in itself, since these microvascular complications (diabetic nephropathy and diabetic retinopathy) share common determinants, such as poor glycemic, blood pressure, and lipid control. Other complications of diabetes, such as peripheral and autonomic neuropathy, should also be evaluated, since they are seen more frequently in patients with diabetic nephropathy and are associated with increased morbidity and mortality.”7
As your doctor discards other causes and confirms Diabetic Nephropathy, he will be able to begin an appropriate strategy for treatment. Medications such as ACE inhibitors (Angiotensin-Converting Enzyme) and ARBs (Angiotensin II Receptor Blockers) are used for treatment along with other daily life modifications such as a healthier diet, increased exercise, maintaining blood glucose levels low, smoking cessation and the management of hypertension.
Diabetic Nephropathy shows little to no signs of symptoms early on. Once the aforementioned signs come up, it means the kidneys have been battling for a while now. Because of the prevalence of nephrotic syndromes among diabetic patients, urinalysis should be performed at the frequency recommended by your healthcare practitioner.
“The clinical course of diabetic nephropathy has changed significantly due to improvements in patient diagnosis, follow-up, and treatment. The availability and implementation of major guidelines play an important role in clinical treatment by supporting physicians to make evidence-based clinical decisions. Nowadays, the gold standard of diabetic nephropathy therapy involves intensive treatment of hyperglycemia and hypertension, mostly through RAS blockade. Additional beneficial effects on the pathophysiology of diabetic nephropathy could be utilized by specific oral hypoglycemic drugs (such as PPAR-γ agonists, SGLT2 inhibitors, and DPP4 inhibitors) and fibrates. These agents are important therapeutic options.”8
Key elements in the management of diabetic nephropathy with established and potential novel therapeutic agents:
(1, 2, 3) Update on Diabetic Nephropathy: Core Curriculum 2018. Umanath, K. & Lewis, J.B. American Journal of Kidney Disease. 2018. https://www.ajkd.org/article/S0272-6386(17)31102-2/pdf
(4) Classification and Differential Diagnosis of Diabetic Nephropathy. Qi, C., Mao, X.,Zhang, Z. & Wu, H. Journal of Diabetes Research. 2017. https://www.hindawi.com/journals/jdr/2017/8637138/
(5, 7) Diabetic Nephropathy: Diagnosis, Prevention, and Treatment. Gross, J.L., De Azevedo, M.J., Silveiro, S.P., Canani, L.H., Caramori, M.L. & Zelmanovitz, T. Diabetes Care. 2005. http://care.diabetesjournals.org/content/diacare/28/1/164.full.pdf
(6) Diabetic nephropathy; principles of diagnosis and treatment of diabetic kidney disease. Junaid Nazar, C.M. Journal of Nephropharmacology. 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297588/pdf/npj-3-15.pdf
(8) Improvements in the Management of Diabetic Nephropathy. Dounousi, E., Duni, A., Leivaditis, K., Vaios, V., Eleftheriadis, T. & Liakopoulos, V. The Review of Diabetic Studies. 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397987/