Dijabetesna nefropatija: klinička slika, tok i savremene mogućnosti lečenja Diabetic nephropathy: clinical presentation, course, and novel treatment possibilities

Diabetic kidney disease (DBD) is one of the major complications of diabetes (DM) and the leading cause of chronic kidney disease (CKD) worldwide. About 10% of patients with DBD progress to terminal HBB, and the rest die mostly due to cardiovascular disorders and infection even before they need treatment for kidney replacement. The main strate-gies to prevent the development and alleviate the progression of DBB in recent decades have been intensive glycemic control and blockade of the renin-angiotensin-aldosterone system. However, this approach did not achieve optimal results. Taking into account the increase in patients with DBB, high spending from the health care budget and the development of new therapeutic possibilities with significant kidney protection, the International Society of Nephrology issued in 2020. (Kidney Disease: Improving Global Outcomes (KDIGO) Guideline) is the first guide to treating patients with DBB. This review paper aims to point out phenotypic variability and present recent advances in the treatment of DBB.


Introduction
Recently, three important nephrology societies International Society of Nephrology -ISN, American Society of Nephrology -ASN, and European Renal Association -European Dialysis and Transplant Association -ERA -EDTA published the statement that kidney diseases are a "hidden or silent epidemic" with a global prevalence of 9.1% of CKD of all stages, which makes 697,5 million cases in the world 1 . The majority of kidney diseases are asymptomatic and undiscovered until the late stages of the disease and CKD. At the same time, CKD has got a progressive course to the terminal phase (which requires kidney function replacement therapy), followed by significant comorbidities and shorter life expectancy. Progressive CKD, leading to grave uremic complications, is a "systemic" disease influencing almost all organ systems [2][3][4] .
Besides hypertension, one of the leading causes of CKD in many countries is diabetes mellitus -DM 5 . According to the World Health Organization data, there is a global pandemic of DM. The prediction is that by 2040 the prevalence of DM patients will be 642 million 6 . Simultaneously, there`s an increase in the number of DM patients with kidney disease. Considering the increase of DM patients with CKD, high health budget costs 7 , and the development of novel therapeutic possibilities with significant kidney protection, the International Society of nephrology published (Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines) the first guidelines for the treatment of patients with DM and CKD in 2020 8 . This review paper aims to point out the phenotype variability and present recent advances in the treatment of DKD.
The kidney disease developing as a part of DM was called diabetic nephropathy (DN), until recently 9,10 . This microvascular complication appears in 30% of patients with type 1 diabetes (DM1) and 40% of patients with type 2 diabetes (DM2), mostly 10−20 years from DM diagnosis. When it develops it`s an important death predictor in DM patients 11 . In some smaller studies, the prevalence of DN goes up to 70% in patients with DM2 12 . But only 10% of these patients progress to terminal kidney disease -stage 5 CKD and the majority die even before they need kidney function replacement therapy, most often due to cardiovascular diseases and infections. Although a great improvement has been made in decreasing mortality and slowing down DN, the percentage of patients with DN progressing into the terminal phase of chronic kidney disease hasn`t significantly decreased 13 .

The clinical course of the kidney disease in diabetes
Classically, DN is defined as a clinical syndrome characterized by persistent albuminuria (>300 mg/day or 300 mg/g of creatinine or 30 mg/mmol of creatinine), progressive decrease in glomerular filtration rate (GFR), presence of diabetic retinopathy, and hypertension, but without lab and clinical signs of other kidney diseases or urinary tract infections 14 . Historically, it was believed the patients start with normal or 20% increased GFR, called hyperfiltration, this phase being more obvious in DM1, due to hyperglycemia, and moderately increased albuminuria was the earliest detected clinical biomarker 14 . However, it turned out that the clinical presentation and course of DN differ between patients with DM1 and DM2, and the absence of retinopathy in patients with DM2 doesn`t exclude the presence of DN. Furthermore, the research done in the last decades showed that besides classical clinical presentation of DN, there are patients with non-classical clinical presentation of DN (Scheme 1) 15, 16 . In Scheme 1 there are four phenotype variations of DN: 1. classical phenotype of DKD, characterized by persistent and high albuminuria, and subsequent progressive decrease in GFR, until the stage 5 of CKD (line 1 in the Scheme 1), mostly present in persons with poor glycemic control; 2. The albuminuria regression in patients with diabetes (line 2 in Scheme 1), and for those is still unknown whether GFR will decrease in time; 3. The patients with a fast decrease -drop of GFR (more than 5 ml/min/1,73m 2 a year) (pathway 3 in Scheme 1), and most often, very promptly, develop terminal kidney disease; and 4. The patients with decreased GFR, without albuminuria or proteinuria (pathway 4 in Scheme 1) who have got slower loss of GFR when compared to those with proteinuria or albuminuria 16−18 . These phenotype variations have also got different histologic features 16 . It is assumed that the variations in the clinical course of DN are the consequence of the change in the prevalence of comorbidities, such as an increase in the hypertension prevalence and the population age, a decrease in smoking prevalence, improvement in glycemic control, blood pressure, and lipids, and use of antihypertensive drugs which act as renin-angiotensin-aldosterone system inhibitors (RAAS), and antihyperglycemics: sodium-glucose cotransporter-2 (SGLT2) inhibitors have got renoprotective properties and reduce the risk of cardiovascular death, at the same time. These findings led to more often use of the terms "diabetic kidney disease" or "chronic diabetic kidney disease", or "kidney disease in diabetes". In accordance, American Diabetes Association -ADA defines diabetic kidney disease (DBD) as albuminuria and/or reduced GFR, but in the absence of signs and symptoms of other primary causes of kidney disease 19 . O N L I N E F I R S T 1. bolesnici sa klasičnom slikom DBB, 2. bolesnici sa DBB i povlačenjem -regresijom albuminurije do normalnih vrednosti, 3. bolesnici sa brzim smanjenjem -padom JGF (više od 5 ml/min/1,73m 2 godišnje) i 4. bolesnici sa sniženom JGF bez albuminurije ili proteinurije.
The risk of progression of CKD is shown in KDIGO guidelines from 2012 (white fields -the lowest risk, the markers of kidney damage are not present, green fields -the highest risk): the higher the CKD stage (G1 > G5) and the amount of albumins in the urine (30 > 300 mg/g of creatinine) the higher the degree of kidney damage 15 .

Risk factors for kidney disease in diabetes
The risk factors for DKD are classified as sensitivity factors for initiation and progression of the disease (Table  1) 20 . Some of the factors are unmodifiable. Of those that are modifiable, two factors are the most important -hyperglycemia and hypertension. Either singularly or jointly they damage the parenchyma and kidney function. Hyperglycemia causes metabolic processes and hemodynamic changes in the kidney leading to dysfunction of endothelial cells, glomerular hyperfiltration, and infection in early diabetes stages. The presence of systemic hypertension adds to causing intraglomerular hypertension. All of this leads to glomerular damage, especially in podocytes and tubulointerstitium, increasing the permeability of glomeruli for albumins, fibrosis, and consequently the reduction of GFR.
of: the increase of microalbuminuria into macroalbuminuria (above 300 mg/g or 30 mg/mmol of creatinine), reduction of kidney function, and accompanying cardiovascular diseases 8 . Accordingly, intensive glycemic control, antihypertensive treatment by blocking the RAAS system, and statin therapy which modifies lipids are a cornerstone of DBD treatment in the last quarter of the century 8,12,21 .
Arterial hypertension is the main risk factor in the development and progression of DKD, and a permanent decrease in blood pressure is probably the most effective singular intervention for slowing down DBD progression in type 1 and 2 DM 22 . Hypertension is 1,5−2,0 times more common in diabetics than in non-diabetics 22 . In patients with DM1, blood pressure values are usually normal on diagnosis, and therefore hypertension onset is intimately linked to DKD occurance 23 . In persons with DM2, approximately one third has high blood pressure when diabetes is first diagnosed. 24 The prevalence of hypertension is almost 100% when DKD is manifested 24 . Tabela 1. Faktori rizika za nastanak bolesti bubrega tokom dijabetesa 11,20
Numerous studies showed the simultaneous presence of hypertension and DKD, with albuminuria, significantly raises the risk of diabetic microvascular complications and the development of DKD 25,26 . Even in normotensive patients with DM2 and albuminuria, the use of RAAS blockers may be useful in controlling DKD 27 . On the other hand, patients with DM and hypertension have a lower risk of DKD progression when albuminuria is normal (< 30 mg/g [3 mg/mmol] of creatinine), and use of antihypertensive drugs (including RAAS inhibitors, calcium channel blockers, diuretics) aims to lower the risk of cardiovascular complications in this group of patients 8 .
The research conducted on patients in the early stages of DM1 or DM2 showed that intensive glycemic control, early in the disease, lowers the risk of DKD development in later longer follow-up period 28 . This "hereditary effect", also called "metabolic memory", suggests intensive glycemic control in the early stage may prevent irreversible damage connected to hyperglycemia 28 . In patients with DM1, when compared to patients with hemoglobin A1c (HbA1c) higher than 7%, strict glycemic control with HbA1c below 7% lowers the risk of microalbuminuria by 34% and macroalbuminuria by 56% during a nine-year follow-up period 29 . After 22 years of follow-up, the group with intensive therapy and strict glycemic control had about a 50% lower risk of reduction of GFR below 60 ml/min/1,73 m 2 , and an average loss of GFR was significantly lower: from 1,56 ml/min/1,73 m 2 a year, with standard therapy to 1,27 ml/min/1,73 m 2 a year, with intensive therapy 30 .
Similarly, in patients with newly diagnosed DM2, intensive glycemic control with HbA1c up to 7% during 10 year period led to a reduction of the development of microvascular complications, including DKD by 24% compared to patients with HbA1c above 7%. After 12 years, intensive glycemic control resulted in lowering the risk of microproteinuria or pathologic proteinuria by 33%, and a significant reduction in the number of patients who had twice as high creatinine serum levels compared to starter levels when compared to the group of patients with conventional therapy (0,9% : 3,5%) 31 .

Treatment of patients with kidney disease and diabetes
Patients with CKD and diabetes should be treated comprehensively, using the strategy for lowering the risk of progression of kidney and cardiovascular diseases. The treatment plan, or rather lifestyle change and use of hypoglycemics in patients with DM2 and CKD is shown in Algorithm 1.

b) Kontrola krvnog pritiska i primena blokatora RAAS
Preporuka KDIGO vodiča iz 2020. godine je da se započne lečenje inhibitorom angiotenzin konvertujućeg enzima Patients with DKD are advised to eat food rich in vegetables, fruits, wholegrain cereals, fibers, legumes, plant proteins, unsaturated fats, nuts, less processed meat, and refined carbohydrates. It is suggested to keep protein intake at 0,8 g of protein/kg of body weight /day for those with DM and CKD who are not dialyzed. The intake of sodium should be less than 2 g a day (or < 90 mmol of sodium = < 5 g of sodium chloride a day).
These patients are advised physical activity of moderate intensity, for at least 150 minutes a week or up to the level agreeable with their cardiovascular system and physical tolerance. It`s recommended to quit smoking 8 .
Ciljni krvni pritisak kod bolesnika sa DBB u različitim stadijumima HBB u zavisnosti od tipa DM i starosti bolesnika prikazan je u Tabeli 2 34 . RAAS inhibitors have a double favorable effect on kidneys -they lead to albuminuria regression 32 and reduce kidney function deterioration independently of their influence on blood pressure 33 . Their favorable effects come from their ability to lower intraglomerular pressure in DKD.
Targeted blood pressure values in DKD patients, in different stages of CKD, depending on the diabetes type and patient`s age are shown in Table 2

c) Glycemic control
For glycemic follow-up and control, the guidelines recommend measuring HbA1c in patients with DM and CKD. It should be taken into account that the accuracy of HbA1c values is lower in persons with GFR below 30 ml/min/1,73 m 2 , and due to the shorter half-life of the erythrocytes or use of erythropoiesis stimulators for anemia treatment in patients with CKD stages 4−5 and those who are dialysed 35 .
The other way of control is a continuous glycemic follow-up, which is a useful method in patients in whom HbA1c doesn`t correlate directly with glycemia readings 36 . Besides, continuous glycemia follow-up enables the patient to control and titrate short-term drug use, prevents hypoglycemia, and improves glycemic control 36 . Glycemic follow-up is especially important because of the risk of hypoglycemia in those using insulin and sulfonylureas (prolonged drug half-life in CKD, gluconeogenesis disorder, weight loss, diet).
Individual target HbA1c is recommended, ranging from < 6,5% to < 8,0% in patients with DM and CKD who are not dialysed. The factors that should be taken care of in patients with DM and CKD are shown in Scheme 2 8,19 . Stricter criteria, such as HbA1C 6,5% are applied to patients with shorter diabetes duration, younger age, with no complications, and longer life expectancy. In patients with hypoglycemia risk, recommended target HbA1c is 7,0%.
It`s recommended to start the treatment of the majority of patients with DM, CKD with eGFR ≥ 30 ml/min/1,73 m 2 by using the first-line drugs (Algorithm 1): Metformin is cheap and generally well tolerated; it effectively lowers blood glucose or SGLT2i, which significantly lower the risk of CKD and cardiovascular diseases. When these drugs aren`t available or are poorly tolerated, or are not enough for reaching individual glycemic targets, we should use additional drugs based on the patient`s wishes, comorbidities, GFR, and costs. However, Metformin is excreted via kidneys, so with kidney function change Metformin is accumulated in the body thus raising the risk of lactate acidosis 8 .
Many studies proved that SGLT2s slow down CKD progression in patients with DKD and different levels of GFR, and varying albuminuria 39,40 . Although the decrease of relative risk reduction of kidney disease is similar in patients with normal and increased albuminuria, the reduction of the absolute risk is higher in patients with albuminuria ≥ 300 mg/day. They not only slow down the progression of DKD but also reduce the risk of cardiovascular diseases, including heart failure in all patients 19 .
In the beginning, it was believed that introduction of SGLT2s should be avoided in patients with GFR < 25 to 30 ml/min/1,73 m 2 because their hypoglycemic effect is lower with the reduction of GFR. Recently, Food and Drug Administration -FDA approved them also for those whose GFR drops below 25 ml/min/1,73 m 2 up until dialysis start or after the kidney transplant 41 . SGLT2s may be combined with RAAS blockers but not with diuretics, especially in persons who are already hypovolemic 39 . These drugs should be used with caution in patients with previous lower extremity amputation or the risk of amputation (ie. Lower extremity ulcerations and periphery artery disease).
GLP1 is a peptide hormone produced by enteroendocrine L cells in the terminal ileum and colon wall. Numerous stimuli lead to GLP1 release, including nutrients, neuroendocrine factors, bacteria metabolic products, immune system, and cytokines from immune cells. The presence of monosaccharides in the intestines, including glucose, galactose, fructose, and methyl-a-glucopyranose, stimulates the postprandial increase of GLP1. This results in stimulating insulin excretion from the pancreatic β-cells, after the carbohydrate intake, suppression of glucagon excretion from pancreatic α-cells, slowing down the stomach evacuation, and causing the feeling of satiety by directly affecting the central nervous system 42 . GLP1 agonists act by binding to specific receptors in the pancreas, lungs, liver, stomach, inside the kidney, and they are found in the endothelial cells, proximal tubule, and juxtaglomerular cells. In healthy people, incretin release is responsible for almost 50−70% of insulin secretion, as a re-O N L I N E F I R S T tubula i jukstaglomerularnim ćelijama. Kod zdravih osoba, oslobađanje inkretina odgovorno je za skoro 50−70% sekrecije insulina kao odgovor na unos ugljenih hidrata. Međutim, poremećaj uticaja inkretina kod osoba sa DM2 je najverovatnije posledica rezistencije GLP-1 42 .
Similarly to native GLP-1, all products, GLP-1 receptor agonists lead to an increased insulin excretion caused by postprandial hyperglycemia, thus obtaining good HbA1c control, suppressing glucagon secretion in hyper-or euglycemia, slowing down stomach emptying and preventing high glycemic spikes after a meal and decrease in calory intake and body weight 42 .
It turned out the GLP1s have numerous protective effects on kidneys, including inhibition of inflammatory influences of angiotensin II, inhibition of oxidative stress, and albuminuria, as well as the ability to alleviate albuminuria, glomerular hyperfiltration, glomerular hypertrophy, and expansion of mesangial matrix in animal models 42 . Similarly, GLP1 agonists lower the risk of progression of albuminuria to macroalbuminuria and potentially slow down GFR reduction in patients with DM2 42 . Furthermore, numerous longacting GLP1 agonists lower the risk of cardiovascular events in patients with DM2 42 .
DPP4 inhibitors are oral hypoglycemics preventing the inactivation of GLP1 by inhibiting the DPP4 enzyme, therefore increasing the concentration of endogenous GLP1 42 . Thus, DPP4 inhibitors indirectly stimulate insulin excretion, depending on glucose, and lower glucagon excretion from pancreatic α-cells by increasing the level of endogenous GLP1. Compared to GLP1 agonists, DPP4 inhibitors have milder effects on stomach emptying and weight loss 42 . DPP4 inhibitors haven`t got a clear influence on the kidney function outcomes, although, they decrease the occurrence or deterioration of existing albuminuria 42 .
Mineralocorticoid receptor antagonists. Mineraolcorticoid receptors are found in collecting nephron tubules, but in colon, myocardium, and blood vessels as well. Their basic activity is the control of water excretion and sodiumpotassium exchange, but an increased activity alleviates inflammation and tissue fibrosis, so therefore they are part of the kidney and cardiovascular disease development. On the other hand, Mineralocorticoid Receptor Antagonists -MRAs show renoprotective effects, and decrease albuminuria, and blood pressure in patients with CKD 43 . Besides RAAS, they are used in heart failure treatment. In later meta-analyses it was proved that these steroid MRAs are effective in decreasing proteinuria in patients who were already treated with RAAS blockade 44 . Despite this potential benefit for the kidneys, they are insufficiently used in CKD patients due to hyperkalemia, especially in those with already low GFR 44 .

Zaključak
Uzimajući u obzir brzorastući zdravstveni problem vezan za porast bolesnika sa HBB u okviru DM, napravljen je prikaz vodiča za njihovo lečenje koji je objavljen 2020. godine. Lečenje bolesnika sa DBB evoluiralo je tokom poslednjih pet godina sa naglaskom na dugotrajnu zaštitu funkcije srca i bubrega. Ispitivanja inhibitora SGLT2, GLP-1 RA i na kraju nesteroidnih MRA ukazuju na značajne prednosti za usporavanje progresije HBB i kardiovaskularnih obolevanja. Ipak, potreban je kontinuirani rad kako bi se utvrdio uticaj kombinacija klasične i najnovije terapije na krajnje tačke -srce i bubrege kod bolesnika sa DM. ent albuminuria categories, and a full dose of ACEi or ARBs, show that these MRAs decrease progressive damage of kidney function (measured as a double increase in serum creatinine and development of terminal kidney disease), decrease albuminuria, and the frequency of cardiovascular events (death due to heart disease reasons, myocardial infarction, stroke, or hospitalization due to heart failure) in patients with DM2 and DKD, and they affect blood pressure less 45 . Therefore, the addition of non-steroid selective MRA inhibitors is recommended (especially Finerenone), where available, and if potassium serum levels are lower or equal to 4,8 mmol/l, alongside ACEi or ARBs. Side effects include hyperkaliemia, possible hypotension, and hyponatremia.

Conclusion
Considering the fast-growing health issue of an increase in the number of patients with CKD, as a part of DM, we reviewed the guidelines for its treatment, published in 2020. The treatment of patients with DKD evolved during the last five years, with the emphasis on the long-term protection of the heart and kidney function. The research on SGLT2s, GLP-1 RAs, and finally non-steroidal MRAs point out their significant advantages in slowing down the progression of CKD and cardiovascular diseases. However, continuous work is needed to establish the influence of the combination of classic and novel therapy on the endpoints -heart and kidneys in DM patients.