Non Diabetic Causes of Chronic Kidney Disease in Type 2 Diabetic Patients

Diabetes mellitus (DM) is one of the most important health problems worldwide, and its prevalence is increasing. One of the complications of DM is diabetic kidney disease (DKD), which is responsible for over 40% of cases of chronic kidney disease requiring dialysis or kidney transplantation in the Western world.

The natural history of DKD in patients with type 1 DM is well characterized because we know the precise time of DM onset. Classically, these patients develop microalbuminuria, followed by macroalbuminuria in the first 15 years of DM. After 20 years of DM, progressive loss of glomerular filtration rate (GFR) develops. The majority of these patients have diabetic retinopathy. However, the natural history of renal disease in adults with DM type 2 is controversial. Before diagnosis, type 2 DM has usually evolved over several years but has remained unnoticed.

In 2007, KDOQI guidelines described characteristics of diabetic patients that indicate DKD involvement, namely the presence of macroalbuminuria or microalbuminuria with diabetic retinopathy in both types of DM, and in type 1 DM patients, over 10 years of DM. In addition, the guidelines summarize the characteristics that suggest the presence of non-diabetic kidney disease (NDKD): absence of diabetic retinopathy, fast decline of renal function, fast increase in proteinuria or nephrotic syndrome, refractory hypertension, active urinary sediment or signs or symptoms of systemic disease or>30% reduction in GFR within 2-3 months after starting the blockade of the renin-angiotensin-aldosterone system (RAAS).Yuan 2017 addressed the accuracy of a clinical diagnosis of DKD among diabetic patients following the criteria proposed by the KDOQI guidelines. Around 20% of patients did not meet KDOQI criteria for DKD in type 2 DM, suggesting a significant over estimation of DKD in this population. This high proportion of NDKD matches previous publications which demonstrated that about a third of patients with DM have biopsy-proven NDKD. The gold standard for diagnosis is renal biopsy. Renal biopsy in diabetic patients has focused on identifying NDKD, because these patients have different prognosis and therapy. The most frequent biopsy indications in diabetic patients are nephrotic syndrome, nephrotic proteinuria in patients with < 5 years of DKD evolution, microhaematuria, acute kidney injury and unexplained decline of renal function. Several groups have studied renal biopsies from diabetic patients, showing that the most frequent NDKD diagnoses are IgA nephropathy, membranous nephropathy and focal segmental glomerulosclerosis.

Different studies have shown that patients with DKD have a worse renal prognosis and that the prevalence of NDKD is high in diabetic patients. Therefore, it is important to accurately classify diabetic patients for DKD or NDKD. Yuan 2017 studied the differential characteristics between patients meeting clinical criteria to diagnose DKD according to KDOQI and misclassified patients. They showed that those patients lacking KDOQI-predicted DKD were more likely to have an active urine sediment and less likely to have developed macroalbuminuria or retinopathy prior to end-stage renal disease. Using the logistic regression analysis, diabetic retinopathy was the only factor independently associated with patients who met KDOQI criteria.

Kidney biopsy studies in diabetic patients have found predictive factors for NDKD: absence of diabetic retinopathy, low glycosylated haemoglobin, worse renal function, lower level of proteinuria, the presence of microscopic haematuria, older age and shorter DM evolution. Although the Yuan 2017 cohort is small and the diagnostic method was usually not renal biopsy, the results are in line with prior reports. However, recent studies have shown that patients with biopsy-proven DKD may be normoalbuminuric. Thus, further studies with larger cohorts and ideally renal biopsy confirmation are necessary to find factors better predicting NDKD in type 2 diabetic patients. These studies may help to design novel diagnostic tools to be applied by physicians in daily clinical practice. New therapeutic agents for the treatment of DKD have recently been characterized. Endothelin receptor antagonists, sodium glucose co-transporter2 inhibitors, incretins and agents targeting inflammation/fibrosis are probably the most promising candidates on top of the classical RAAS blockers. Therefore, it is mandatory that patients with diabetic renal disease are adequately classified, differentiating clearly those with DKD and those with NDKD. In addition, among those with DKD, a reliable classification within different pathological categories will be of great value to individualize treatment strategies.