Introduction
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in developed countries, including the United States.[1] It is considered a microvascular complication and occurs in both diabetes mellitus type 1 (T1DM) and diabetes mellitus type 2 (T2DM). The disorder presents with persistent albuminuria and a progressive decline in the glomerular filtration rate. There is substantial evidence that early treatment can delay or prevent the progression of the disorder.
Reliable tests for diagnosis and monitoring include urine albuminuria and the estimated GFR (eGFR). Optimizing glycemia and reasonable blood pressure control are pivotal in halting the progression of DKD.[2]
Causes
Thirty to 40 percent of patients with diabetes mellitus (DM)develop diabetic nephropathy.[3] The exact cause of diabetic nephropathy remains unknown, but insulin resistance, genetics, hyperglycemia, and an autoimmune process may be the causes.
Risk Factors
While patients with type 2 diabetes mellitus may present with albuminuria at the time the diabetes is detected, diabetic nephropathy develops in type 1 diabetes 15 to 20 years later. This difference is mainly because the precise onset of type 2 diabetes is difficult to discern. Structural and functional changes occur in the kidney on account of diabetes and result in proteinuria, hypertension, and progressive reduction of kidney function, which is the hallmark of diabetic nephropathy.
Certain racial groups like African Americans, Native Americans, and Mexican Americans are at high risk of developing diabetic nephropathy. Studies have noted familial clustering, hinting that genetics plays a part in the risk of developing nephropathy.
Assessment
Increasing duration of DM, poor glycemic control, and uncontrolled hypertension are strong risk factors for the development of diabetic nephropathy (DN). A family history of hypertension and cardiovascular events in first-degree relatives is also a strong risk factor for developing diabetic nephropathy. Obesity, smoking, and hyperlipidemia are risk factors for DN. This, along with family clustering, suggests genetic factors could also be at play. Several genes, including polymorphisms in angiotensin-converting enzyme (ACE) and angiotensin receptor, are being studied. Males are at higher risk of developing diabetic nephropathy.
Diabetic nephropathy is diagnosed by persistent albuminuria on two or more occasions, separated at least by three months on early morning urine samples. Persistent albuminuria is greater than 300 mg over 24 hours or greater than 200 micrograms per minute. Moderately increased albuminuria is when the urine albumin excretion rate is between 30 to 300 mg over 24 hours and is a marker of early DN. It is critical to exclude a urinary tract infection as the cause of albuminuria by a urinalysis.
Early in the course of the disease, patients are often asymptomatic and are diagnosed during screening with levels of 30 to 300 mg/g creatinine. Once nephropathy sets in, patients present with fatigue, foamy urine (urine protein greater than 3.5 g per day), and pedal edema due to hypoalbuminemia and nephrotic syndrome. They may also have associated peripheral vascular disease, hypertension, coronary artery disease, and diabetic retinopathy.
Evaluation
Proteinuria is the hallmark of diabetic nephropathy. The absence of retinopathy makes diabetic nephropathy less likely in T1DM.
The scenario is more difficult in T2DM than with T1DM. The exact time of the onset of T2DM is unclear in most patients. History and physical exam play a crucial role in diagnosing diabetic nephropathy in T2DM.
Medical Management
Treatment of diabetic nephropathy targets four areas: cardiovascular risk reduction, glycemic control, control of blood pressure, and inhibition of the renin-angiotensin system (RAS).
Risk-factor modification, including tobacco cessation and optimal lipid control strategies, are crucial for cardiovascular risk reduction.
Studies have shown a significant reduction in the risk of developing proteinuria and microalbuminuria with intensive diabetes control in T1DM.[4] These studies include DCCT (Diabetes Control and Complications Trial) and EDIC (Epidemiology of Diabetes Interventions and Complications study). The benefits of good glycemic control early in the onset of disease carried over even after a long time, despite glycemic control being similar in both groups on longer follow up. This effect is "metabolic memory," a term coined by DCCT/EDIC investigators.
In T2DM, UKPDS (United Kingdom Prospective Diabetes Study) showed that targeting an HbA1C of 7% led to a lower risk of microvascular complications, including nephropathy.[5] However, blood pressure (BP) control also led to a decrease in cardiovascular mortality.
Studies have shown the benefit of ARBs (angiotensin receptor blockers) in delaying the progression of kidney disease.[6][7] These include studies like RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study) and IDNT (Irbesartan Diabetes Nephropathy Trial), which also showed that the BP achieved, better-predicted kidney outcome rather than BP at entry, emphasizing the need for BP control. UKPDS showed the benefit of BP control on any DM-related complication such as death, adverse cardiovascular events, and the composite of microvascular events. However, aggressive control of systolic BP to less than 120 mm Hg, as opposed to standard therapy (less than 140 mm Hg systolic), found no difference in cardiovascular outcome or end-stage renal disease. The Eighth Joint National Committee (JNC 8) guidelines recommend a goal BP less than 140/90 mm Hg for most patients with T2DM and diabetic nephropathy, but with individualization.[8] Recent diabetic society guidelines suggest goals of 130/80 for people with diabetes.
While RAS blockade is crucial to prevent the development of diabetic nephropathy, multiple studies show that early therapy in patients with T1DM is ineffective in preventing the development of microalbuminuria. However, studies, including ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention), have shown that RAS blockade can prevent the development of microalbuminuria in T2DM.[9]
Studies like IRMA2 (Irbesartan in Microalbuminuria, Type 2 Diabetic Nephropathy Trial) have shown the benefit of ARB in preventing proteinuria in patients with microalbuminuria.[10] Studies in patients with T1DM and overt proteinuria have also shown that ACE inhibitors slow the progress of diabetic nephropathy. The IDNT and RENAAL studies have shown similar benefits in T2DM patients. These studies provide clear evidence of the benefit of RAS-blocking medication on slowing progression of diabetic nephropathy, independent of their effect on BP. However, the use of more than one RAS-blocking agents resulted in multiple adverse outcomes, including acute renal failure, and has fallen out of favor.
Newer drugs like a third-generation mineralocorticoid receptor antagonist, finerenone, has shown albuminuria reduction in diabetic nephropathy at 90 days, on patients already on ARB.[11] The EMPAREG and CANVAS studies showed that SGLT2 (sodium-glucose co-transporter 2) inhibitors that prevent reabsorption of glucose via the renal tubules reduced cardiovascular mortality.[12] In these cardiovascular outcome trials, the SGLT2 inhibitors had positive effects on kidney outcomes, namely albuminuria reduction and a reduction in the occurrence of a composite renal outcome. However, since these are secondary outcomes of trials designed to test cardiovascular benefit, many studies are now underway to test the actual potential of this group of drugs to prevent the progression of diabetic nephropathy.
Renal Replacement
Once the end-stage renal disease develops with a GFR of 10-15 ml/min, renal replacement therapy may be required. There are several options for dialysis, including peritoneal, hemodialysis, and renal transplant. Renal transplant is considered the best option, and this alternative must be discussed early with the family.
Coordination of Care
Interdisciplinary clinical teams have been crucial in reducing cardiovascular risk factors, glycemic control, and decreased risk of complications, across multiple countries [13]. The current recommendation is that the patient also is included as a member of this interprofessional treatment team for optimal outcomes. The nurse should educate the patient on the importance of glucose control and a healthy diet, whereas the pharmacist should educate the patient on medication compliance. Further, these patients should be taught how to monitor and treat their blood glucose levels at home. Studies show that patients who remain compliant with home monitoring of blood glucose tend to have a delay in renal dysfunction.[14]
Health Teaching and Health Promotion
Protein intake should be around 0.8 g per kilogram body weight.
Discharge Planning
The current recommendation is that the patient also is included as a member of this interprofessional treatment team for optimal outcomes. The nurse should educate the patient on the importance of glucose control, exercise, follow up, and a healthy diet, whereas the pharmacist should educate the patient on medication compliance and blood pressure control. A dietary consult should be made to educate the patient on low protein foods, and a social worker should ensure that the patient has the support and financial resources for treatment. The nephrologist and dialysis nurses should educate the patient on renal replacement options, and the transplant nurse should educate the patient on the indications and benefits of a transplant.
Further, these patients should be taught how to monitor and treat their blood glucose levels at home. Studies show that patients who remain compliant with home monitoring of blood glucose tend to have a delay in renal dysfunction.[14]
Evidence shows that working in an interprofessional team with open communication offers patients the best outcomes. [15]
Evidence-Based Issues
Evidence shows that working in an interdisciplinary team with open communication offers patients the best outcomes. [15] [Level 5]
Pearls and Other issues
Diabetic nephropathy is a serious disorder with life long repercussions and a high mortality rate. There is no cure for the disorder, and all treatments have limitations. The key today is to prevent nephropathy from developing. Thus an Interdisciplinary clinical team is crucial in reducing cardiovascular risk factors, glycemic control, and decreased risk of complications across multiple countries [13].
