<\/a>Histological evidence<\/h2>\nRenal biopsy in patients with diabetes is usually performed in those with significant renal manifestations such as severe proteinuria, microscopic haematuria, rapid and unexplained worsening of kidney function, or a decrease of more than 30% in eGFR after starting RAAS inhibitors.6<\/span>\u00a0Currently, renal biopsy is not routinely indicated in these patients; however, it is still the gold standard for diagnosing diabetic nephropathy (DN), and recent evidence favours determining the histology of renal disease in patients with diabetes.23,24<\/span>\u00a0Therefore, very few studies have analysed renal histological alterations in the early stages of diabetes.25<\/span><\/p>\nA recent study from necropsies found that a significant percentage of patients with diabetes without early clinical signs of DKD such as microalbuminuria already show moderate to severe histological involvement related to DN; however, comorbidities and renal progression factors did not significantly differ from patients with albuminuria.26<\/span> These findings suggest early renal involvement in patients with NA-DKD.<\/p>\nThe tubulointerstitium is composed of tubular epithelium, vascular structures and interstitium, and accounts for 90% of renal tissue.27<\/span>\u00a0The classical pathological interstitial changes in DN include tubular basement membrane thickening, interstitial fibrosis, tubular atrophy and arteriosclerosis.28<\/span>\u00a0A study found that interstitial expansion was independently associated with reduced kidney function in T1DM.29<\/span>\u00a0Another investigation in patients with DN showed that interstitial fibrosis contributes to further kidney function decline compared with glomerular injury, and this decline was independent of albuminuria.30<\/span>\u00a0This suggests that eGFR decline is partly related to interstitial injury in T2DM. Ekinci et al. found that three of eight (37.5%) patients with NA-DKD had interstitial and vascular lesions by renal biopsy, and only 1 in 23 (4.3%) patients with albuminuric DKD had interstitial and vascular lesions.31<\/span><\/p>\nBeyond the histological evidence, the prevailing underlying pathology of NA-DKD might be macroangiopathy instead of microangiopathy. Moreover, some findings suggest that renal impairment in NA-DKD is not mainly caused by hyperglycaemia or microangiopathy, and that genetic susceptibility, ageing and arteriosclerosis might contribute more to this specific phenotype.32<\/span>\u00a0In accordance, investigations reported that eGFR decline without albuminuria was associated with age-dependent arterial stiffness in patients with and without diabetes.33,34<\/span>\u00a0This may explain why other renal conditions such as hypertensive nephropathy or age-related nephrosclerosis have similar phenotypes.<\/p>\nNovel biomarkers<\/h2>\n
Conventional approaches to evaluating and monitoring the early stages of DKD have focused on changes in the glomerulus. However, the current standard screening tools, albuminuria, and eGFR are especially insufficient in detecting early tubular and other kidney damage.35<\/span>\u00a0Therefore, many tubular biomarkers have been suggested.35<\/span><\/p>\nAs albuminuria is a marker for glomerular damage, biomarkers that reflect other pathological mechanisms of DKD, such as tubular injury, would be acceptable complementary DKD markers to albuminuria. Tubular injury markers such as\u00a0\u03b1<\/span>1-microglobulin (A1M), liver-type fatty acid-binding protein (L-FABP), N-acetyl-\u03b2<\/span>-D-glycosaminidase (NAG), urinary immunoglobulin G and M, and kidney injury molecule-1 (KIM-1) are associated with DKD.36<\/span><\/p>\nMore recently, proteomic and metabonomic analyses have shown promise in evaluating the NA-DKD phenotype. Metabonomic assessment is a relatively new biological approach that provides global metabolic information in biological samples. Hippurate and allantoin are associated with reduced eGFR and are potential markers of nephrotoxicity and tubular dysfunction.37<\/span>\u00a0Proteomics is a large-scale experimental analysis of proteins through protein purification and mass spectrometry. Proteomic studies have revealed collagen fragments as a potential biomarker of DKD, even 3\u20135\u00a0years before the onset of microalbuminuria in patients with diabetes.38<\/span><\/p>\nTherapeutic tools<\/h2>\n
Optimal management of NA-DKD is complex and not entirely known. Nonetheless, multifactorial intervention is needed to target kidney disease progression and cardiovascular disease risk factors. Initial therapy consists of lifestyle modification, including dietary counselling, physical activity and smoking cessation support. Furthermore, controlling hypertension, dyslipidaemia and hyperglycaemia is essential, as in patients with albuminuric DKD (Figure 1<\/span><\/em>).39<\/span><\/p>\n<\/p>\n
Recently, first-line drug therapy proposed by the Kidney Disease Improving Global Outcomes (KDIGO) 2020 clinical practice guideline for diabetes management in CKD includes RAAS blockade, metformin, SGLT2 inhibitors and statins.40<\/span>\u00a0Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) are widely recommended in patients with DKD and albuminuria. However, less evidence exists for patients with NA-DKD. Some studies have found that lisinopril, enalapril and losartan are effective at reducing progression of kidney disease and controlling blood pressure in patients with NA-DKD.41,42<\/span><\/p>\nSGLT2 inhibitors have several cardiovascular and renal benefits in patients with diabetes.43\u201346<\/span>\u00a0In addition to reducing blood pressure and improving metabolic parameters such as glycated haemoglobin (HbA1c) and weight, SGLT2 inhibitors provide renal protection by correcting glomerular hyperfiltration, reducing albuminuria, improving kidney hypoxia and reducing proinflammatory and profibrotic pathways.47<\/span>\u00a0Although there is no subgroup analysis of albuminuria in the pivotal studies of the different SGLT2 inhibitors, the EMPA-REG OUTCOME,46<\/span>\u00a0CANVAS44<\/span>\u00a0and DECLARE-TIMI 5843<\/span>\u00a0studies analysed empagliflozin, canagliflozin and dapagliflozin, respectively, and included both non-albuminuric and albuminuric patients. Of note, DECLARE-TIMI 58 demonstrated the effect of dapagliflozin in earlier stages of kidney disease, as 65% of the patients showed no expression of any renal markers (eGFR <60\u00a0mL\/min\/1.73\u00a0m2<\/span>, micro- or macroalbuminuria; 93% showed eGFR >60 mL\/min\/1.73\u00a0m2<\/span>\u00a0and\u00a0<\/span>69% showed normal albuminuria) and 59% of patients had no previous cardiovascular disease.43<\/span>\u00a0Interestingly, dapagliflozin seems to prevent and reduce DKD progression compared with placebo in T2DM patients with or without established atherosclerotic cardiovascular disease, most of whom had preserved renal function.43,44<\/span>\u00a0Although the possible mechanisms of benefit were multiple and incompletely understood, in most cases this benefit, seen in all SGLT2 inhibitors, has been independently associated with glycaemic control.48<\/span>\u00a0On the contrary, one exploratory analysis of the EMPA-REG OUTCOME study found no significant between-group difference in the rate of albuminuria.49<\/span>\u00a0New clinical trials explicitly testing the effect of SGLT2 inhibition in patients with NA-DKD are needed.<\/p>\nThe next step of the therapy proposed by the KDIGO guidelines is GLP1-RAs and non-steroidal mineralocorticoid receptor antagonists (NS-MRAs).50\u201352<\/span>\u00a0However, in pivotal studies for GLP1-RAs, baseline albuminuria levels were not specified, although a trial testing semaglutide did not exclude normoalbuminuric patients.53<\/span>\u00a0GLP1-RAs in patients with T2DM and CKD are safe and well tolerated, and significantly improve cardiovascular and renal variables.50<\/span>\u00a0On the other hand, in NS-MRA studies, there were no patients with NA-DKD;49<\/span>\u00a0thus, current recommendations are unavailable for these patients.<\/p>\nFinally, given the inflammatory activities associated with diabetes, some anti-inflammatory drugs, such as the tumour necrosis factor-\u03b1<\/span>\u00a0inhibitor pentoxifylline, decrease or stabilize the progression of DN with additional renoprotective effects.54,55<\/span>\u00a0Because patients with NA-DKD have elevated levels of tumour necrosis factor-\u03b1<\/span>\u00a0and other cytokines, they could respond to pentoxifylline. Further studies investigating this and other anti-inflammatory drugs in patients with NA-DKD are needed.<\/p>\nConclusion<\/h1>\n
Diagnosing and managing the NA-DKD phenotype represents a real challenge for the nephrology community, as more accurate diagnosis methods are needed alongside albuminuria. Detecting biomarkers early may help to avoid DKD progression. The rapid rise of new agents such as SGLT2 inhibitors, GLP1-RAs, NS-MRAs and their combinations may contribute to improving the outcomes of patients with NA-DKD, though further study is needed.<\/p>\n","protected":false},"excerpt":{"rendered":"
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide.1,2\u00a0For this reason, early diagnosis and treatment are relevant to prevent the progression of this disease. Currently, the urinary albumin excretion rate and the estimated glomerular filtration rate (eGFR) are widely accepted as diagnosis criteria, and the […]<\/p>\n","protected":false},"author":77788,"featured_media":26105,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_relevanssi_hide_post":"","_relevanssi_hide_content":"","_relevanssi_pin_for_all":"","_relevanssi_pin_keywords":"","_relevanssi_unpin_keywords":"","_relevanssi_related_keywords":"","_relevanssi_related_include_ids":"","_relevanssi_related_exclude_ids":"","_relevanssi_related_no_append":"","_relevanssi_related_not_related":"","_relevanssi_related_posts":"","_relevanssi_noindex_reason":"","footnotes":""},"categories":[1],"tags":[],"acf":[],"_links":{"self":[{"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/posts\/34801"}],"collection":[{"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/users\/77788"}],"replies":[{"embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/comments?post=34801"}],"version-history":[{"count":11,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/posts\/34801\/revisions"}],"predecessor-version":[{"id":35495,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/posts\/34801\/revisions\/35495"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/media\/26105"}],"wp:attachment":[{"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/media?parent=34801"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/categories?post=34801"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/tags?post=34801"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}