In the light of broad range of science, universe, earth, evoluation of lives and medical matters, some perspectives about renal and cardial topics would be introduced here [1].The Earth and Moon were formed 4.6 billion years ago [2]. The first life was born 4 billion years ago, in which this point would be set for January 1^st with its water pressure 10mmHg. After that, the lives moved from the sea onto the land 360 million years ago, that was December 1^st with 50-100mmHg. Vertebrate species have evolved from fish to amphibians, reptiles, birds, and mammals. Fish is categorized into 2 types. Saltwater fish actively excrete salts through their gills and excrete a small amount of urine of the same concentration as their body fluids. Freshwater fish actively take in salts through their gills and excrete a large amount of dilute urine.

About 200 thousand years ago, new types of human such as homo sapiens have appeared, which was Dec 31st afternoon with blood pressure 120/80 mmHg. Human being has not gills but kidneys, which could regulate the balance of sodium and water [3]. Our renal function includes the following 5 roles or functions, which are producing urine, maintaining a constant balance in the body's internal environment, regulating blood pressure, producing blood, and activating vitamins.

 Among these, necessary factors were found during the period of moving from the sea, to freshwater and onto the land. Once living on the land, it was not certain whether salt and water will always be available. For this situation, human mechanism has developed to retain water and salt in the body, and the kidneys became responsible for this maintenance [4]. From genetic research, human has certain signaling system that can weaken the function of retaining the salt. The kidneys were the last organs to develop during the evolutionary process for the land animals from the sea to the land. Consequently, kidneys would be the essential organs for maintaining the primordial sea with balanced salt and water [5]. More than 90% of ingested sodium (Na) is excreted in urine by the kidneys. Then, the kidneys are evaluated as important organ for regulating the amount of Na in the body. Since most ingested Na is always excreted in urine, the amount of Na daily intake can be roughly estimated by measuring the amount of Na excreted in urine per day.

The evolution of the renal function of the vertebrate is supposed for saltwater (dark area) and freshwater (light area) changed environments (Figure 1) [6,7] (Chevalier, Smith). Schematic nephrons are shown for changing process. The evolutionary tree showed the process from primitive fish to mammals associated with the adaptation to the earth environment. The changes were observed for the differentiation of the proximal and distal tubules and also the loop of Henle.

Figure 1: General perspectives of evolution of vertebrae species and change in the nephrons.

Over the last few decades, medical research has progressed around the world, and the level of medical care has improved. There have been advances in the diagnosis and treatment of many diseases. On the other hand, the characteristics of kidney diseases have become clear to some extent, but unlike other areas, there are still many unknowns. The characteristics of kidney diseases include slow progression, no immediate life-threatening, lack of obvious symptoms. Furthermore, various difficulties exist in detection, medical classification, diagnosis, and therapeutic measures. In clinical settings, proteinuria has been detected for a long time, and in recent years, microalbumin measurement has become prevalent. Therefore, it has been revealed that diabetic patients with microalbuminuria have about 8.5 times higher risk of progression to overt nephropathy than patients with normal albuminuria [8].

The measurement of microalbumin has contributed much for the risk evaluation for future prognosis of the hypertension and diabetes. As a protocol, 590 hypertensive cases with T2D and present microalbuminuria were investigated [9]. They were treated by irbesartan with the dose of 150mg or 300 mg per day, or placebo for three groups and followed up for 2 years. The primary outcome was the apparent onset of diabetic nephropathy. As a result, the ratio of the cases that reached the primary end point was 5.2% for 300mg, 9.7% for 150mg and 14.9% for placebo group, respectively. It showed hazard ratios (HR) 0.30 (0.14 to 0.61, p<0.001). Consequently, irbesartan showed renoprotective effect for T2D patients with microalbuminuria.

With the advancement of medical research and the level of medical diagnosis and treatment, various anti-hypertensive agents (AHAs) have been developed to date. In recent years, new types of beneficial drugs related to hypertension and diabetes have been introduced to clinical practice. Among them, some notable agents will be mentioned here. Aldosterone not only constricts the efferent arteriole, but also enhances the dilation of the afferent arteriole. Then, mineralocorticoid receptor antagonists (MRA) are expected to improve glomerular hyperfiltration [10]. Historically speaking, there are several cardio-reno-protective key agents [11]. They are angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blockers (ARBs), erythropoiesis-stimulating agent (ESA) /hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHI), sodium-glucose cotransporter-2 inhibitors (SGLT2-i) [12], glucagon-like peptide-1 receptor agonists (GLP-1Ra), MRA and nuclear factor erythroid 2-related factor 2 (Nrf2) activation [13].

Recently, angiotensin receptor-neprilysin inhibition (ARNI) has been introduced to clinical practice. ARNI is an AHA that includes ARB (valsartan) and neprilysin inhibitor. Neprilysin is an enzyme that breaks down BNP, and neprilysin inhibitors were developed for protecting cardiac function by suppressing the breakdown of BNP [14]. In actual medical practice, “Sacubitril Valsartan Sodium Hydrate” (Entresto^R) has been already provided to the patients with heart failure and hypertension. The phase III study (n=1161) showed significant decrease of mean sitting systolic blood pressure (msSBP) for 5.01 mmHg [3.06-6.95] at 8 weeks [15].

From the latest report, nationwide Japan Chronic Kidney Disease Database (J-CKD-DB) were analyzed for patients with CKD and T2D (n=2053) treated by SGLT2-i [16]. They showed detail relationship among RAS inhibitors, diuretics, SGLT2-i, proteinuria, initial GFR decline, that contributes perspectives for future research development.

In summary, impressive historical progress of cardiovascular and nephrological axes have been shown. Recent development of novel pharmacological agents will contribute beneficial results in our clinical practice and research.

Conflict of interest: The authors declare no conflict of interest.

Funding: There was no funding received for this paper.

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