Chronic Kidney Disease: Etiology, Pathophysiology, and Management Strategies to Increase Quality of Life

Abstract

Chronic kidney disease (CKD) refers to a variety of pathophysiologic conditions linked to poor kidney function and persistent reduction in glomerular filtration rate. According to the National Kidney Foundation’s guidelines, CKD can be classified based on the amount of glomerular filtration rate. There are numerous etiologies for the occurrence of CKD. Various medications used to treat CKD will include slowing the progression, which is medical treatment, as well as employing natural products. Many strategies can be used to improve the quality of life of a CKD patient. This book chapter will further discuss etiology, pathophysiology, clinical manifestation, investigation, and management of patients in renal replacement therapy and also usage of medication to increase the quality of life.

1. Introduction

1.1 Chronic kidney disease (CKD)

CKD, or known as chronic renal failure (CRF), describes all degrees of decreased kidney function, ranging from damaged-at-risk to mild, moderate, and severe chronic kidney failure [1]. A patient can be confirmed as CKD when the estimated glomerular filtration rate (eGFR) becomes less than 60 ml/min per 1.73 square meters, persisting for 3 months or more. It is a progressive loss of kidney function that eventually necessitates renal replacement therapy (dialysis or transplantation). This activity reviews the etiology, evaluation, and management of chronic kidney disease and emphasizes the roles of the interprofessional team in the care of chronic kidney disease patients. Pathologic abnormalities in urinary sediment, abnormalities in urinary albumin excretion rates, or increased urinary albumin excretion rates are all examples of kidney damage. The Kidney Disease Improving Global Outcome (KDIGO) has classified details about the causes of CKD, and it is classified into six categories based on eGFR, as stated in Table 1. Stage 3 has been classified into 3a and 3b in the year of 2012 according to the eGFR and clinical manifestation. It also includes albuminuria staging (A1, A2, and A3), with each stage of CKD subcategorized based on the urinary albumin-creatinine ratio in (mg/gm) or (mg/mmol) in an early morning “spot” urine sample as in Table 2 [2]. The Kidney Disease Outcome Quality Initiative (KDOQI) provides a guideline to classify CKD developed in 1997 that was revised in 2012. Albuminuria has been added as a predictor outcome as well [3].

Stage	Description	GFR (mL/min/1.73m^2)
1	Kidney damage with normal or high GFR	>90
2	Mild decrease in GFR	60–89
3a	Mild-to-moderate decrease in GFR	45–59
3b	Moderate to deVere decrease in GFR	30–44
4	Severely decrease GFR	15–29
5	Kidney failure	<15 or dialysis

Table 1.

Classification of CKD by GFR (KDIGO 2012).

Category	Albumin excretion rate (mg/24 h)	Albumin: creatinine ratio (mg/mmol)	Terms
A1	<30	<3	Normal to mildly increased
A2	30–300	3–30	Moderately increased
A3	>300	>30	Severely increased

Table 2.

Albuminuria categories in CKD (KDIGO 2012).

1.2 Etiology of CKD

The causes of CKD vary globally, and the following are the most common primary diseases that cause CKD and, ultimately, end-stage renal disease (ESRD) has been demonstrated in Figure 1.

1. Diabetes mellitus type 2

   The kidney’s filtering units are filled with tiny blood vessels. High blood sugar levels can cause these vessels to narrow and clog over time. When there is insufficient blood, the kidneys suffer damage, and albumin passes through these filters and ends up in the urine, where it should not be.

2. Diabetes mellitus type 1

   About 30% of Type 1 (juvenile-onset) diabetes patients and 10 to 40% of Type 2 (adult-onset) diabetes patients will eventually develop kidney failure.

3. Hypertension

   High blood pressure can constrict and narrow blood vessels, causing them to become damaged and weak throughout the body, including the kidneys. Blood flow is reduced due to the narrowing. If the blood vessels in your kidneys are damaged, they may no longer function properly. When this occurs, kidneys are unable to remove all waste and excess fluid from body. Extra fluid in the blood vessels can raise blood pressure even higher, starting a dangerous cycle that can lead to kidney failure.

4. Primary glomerulonephritis

   Chronic inflammation of glomerulus causes long-term kidney damage and decline in function. Chronic kidney disease is defined as kidney damage or decreased function lasting 3 months or longer. Chronic kidney disease can progress to end-stage kidney disease, requiring dialysis or a kidney transplant.

5. Chronic tubulointerstitial nephritis (TIN)

   GFR is reduced in acute TIN due to interstitial edema, lymphocyte and plasma cell infiltration, and poor tubular function. The decrease in GFR in chronic TIN is caused by fibrosis of the interstitium rather than edema. If prolonged, acute interstitial inflammatory reactions can lead to accumulation of extracellular matrix that causes irreversible impairment of renal function with interstitial fibrosis and tubular atrophy.

6. Hereditary or Cystic Disease

   Cystic kidney disease (CKD) refers to a group of conditions that result in the formation of cysts (fluid-filled sacs) in or around the kidneys. Kidney cysts can obstruct the kidneys’ ability to filter water and waste from your blood. Kidney failure can result from cystic kidney disease.

7. Plasma Cell Dyscariasis or Neoplasm

   Renal disease in myeloma is typically characterized by renal insufficiency and proteinuria. Patients with myeloma may occasionally present with renal tubular dysfunction, including acidification and concentration defects and, in rare cases, the Fanconi syndrome.

8. Sickle Cell Nephropathy

   Sickle cell disease causes damage to multiple structures within the kidney.

   Chronic anemia’s hemodynamic changes, renal hypoxia caused by recurrent vaso-occlusion, and hemolysis-related endothelial dysfunction can all lead to functional and structural changes that can progress to CKD.

Figure 1.

Examples of diseases related to chronic kidney disease (CKD).

1.3 Pathophysiology of CKD

The rate of renal blood flow, which is approximately 400 ml/100 g of tissue per minute, is significantly higher than that observed in other well-perfused vascular beds such as the heart, liver, and brain. When there are any harmful circulating agents or substances, there is a higher chance that renal tissue might be exposed to them [4]. In contrast to other capillary beds, glomerular filtration is dependent on relatively high intra- and trans-glomerular pressure, even under physiological settings, which makes glomerular capillaries prone to hemodynamic damage. The details of the disease process are shown in Figure 2.

Figure 2.

Diagrammatic representation of the glomerulus function in the process of reabsorption and secretion.

The major contributors to the progression of chronic kidney disease could be hypertension and hyperfiltration. Negatively charged molecules in the glomerular filtration membrane act as a barrier, slowing anionic macromolecules. When this electrostatic barrier is breached, as occurs in many types of glomerular damage, plasma protein gains access to the glomerular filtrate. The sequential organization of the nephron’s microvasculature and the downstream position of the tubule with respect to the glomeruli not only maintains the glomerulo-tubular balance but also allows glomerular injury to spread to the tubulointerstitial compartment in disease, exposing tubular epithelial cells to abnormal ultrafiltrate [5]. Due to the peritubular vasculature underpins the glomerular circulation, some mediators of the glomerular inflammatory response may overflow into the peritubular circulation, contributing to the interstitial inflammatory responses commonly observed in glomerular illness. Tubulointerstitial injury and tissue remodeling will occur due to decrease in preglomerular or glomerular perfusion [6]. Therefore, the concept of the nephron as a functional unit relates not only to renal physiology but also to renal disease pathology. There are some main reasons that kidney can go into impairment such as immunologic reaction, tissue hypoxia, and ischemia, exogenic agents as drugs, endogenous substance as glucose or paraproteins, and hereditary [7].

1.4 Stages of CKD

CKD can be divided into five stages and six categories that range from 1 to 5. The determination of CKD with stages is done by blood investigation known as estimated glomerular filtration rate (eGFR). Stage 1 kidney disease has an estimated glomerular filtration of 90 or higher with a progressive kidney involvement of more than 3 months. The estimated glomerular filtration rate is an absolute indicator of kidneys function in the filtration of excess fluid from blood [8]. At every stage of CKD, the kidneys function progressively deteriorates and requires different treatment to slow down the damage to kidney that will keep them functioning as long as possible. A patient with renal failure will need to go on renal replacement therapy such as hemodialysis, peritoneal dialysis, or renal transplant to sustain life [9].

1.4.1 CKD stage 1

Stage 1 CKD is considered mild, and no significant clinical manifestation exists to address it. GFR is 90 mls/min. This stage is considered mild. It may have proteinuria, whereby there is leakage of protein in the urine allowed by glomeruli. Sometimes, changes can be noticed through ultrasound or microalbumin in the urine. Many times, patients may complain that they have foamy urine that is caused by excessive amounts of urine albumin.

To reduce the progression of kidney disease, it is advisable to monitor patients’ blood pressure to be in health range under 120/80 mmHG. Also, it is important to control salt intake less than 2300 milligrams (mg) per day. There are also patients having difficulty in identifying hidden salt. If patients are known case of diabetes, they should have good control of their glucose [10].

1.4.2 CKD stage 2

The damage is still considered mild, yet the kidneys will be functioning to the optimum level with 20–40% normal function. GFR will 60-89 ml/min. The symptoms still remain as foamy urine.

A recommended lifestyle modification will include losing weight and considering a healthy diet. To delay the progress of CKD stage 2, a few conservative managements are recommended. For obese patients, it is recommended for them to lose weight through exercise. Quitting smoking can help lower blood pressure and reduce stress on the kidneys. Encouraging the patient to get enough sleep and manage stress will influence blood pressure as well. For diabetic patients, it is recommended to consume medication such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, or Kerendia which can slow down the progress of CKD.

1.4.3 CKD stage 3

At this stage, the patient will have symptoms that indicate enough damage to start producing symptoms. This happens when 15% of the function of normal kidney remains is attained. Stage 3 can be categorized into 3a and 3b. Stage 3a is kidney function having mild-to-moderate function loss with GFR 45–59 mL/min, whereas 3b is moderate-to-severe loss of kidney function with GFR 30–44 mL/min. At this point, a CKD patient may have developed anemia and renal osteodystrophy [11].

Clinical manifestations of stage 3a CKD may include:

• Polyuria or some patients may experience oliguria

• Fatigue and tiredness

• Dry or itchy skin

• Nausea

• Los of appetite

• Unintended weight loss

Clinical manifestations for CKD stage 3b may include:

• Unable to focus

• Muscle aches and cramping especially lower limbs

• Shortness of breath

• Peripheral edema (swelling in the arms, legs, hands, or feet)

• Peripheral neuropathy (numbness and tingling sensation in the hands and feet)

At this stage, the patient will be prescribed statin drugs to reduce cholesterol; administration of a diuretic will promote urination, reduce blood pressure, and reduce peripheral edema. For mineral bone disease, it is advisable to take calcium and vitamin D supplements. Anemia can be managed with iron supplements.

1.4.4 CKD stage 4

At this stage, kidneys have been impaired, moderate to severe with eGFR 15-29 mL/min. The complication of disease markedly increases like anemia, high blood pressure, bone disease, and metabolic acidosis. Also, there will be hyperkalemia and hyperphosphatemia that leads to cardiac dysrhythmia. Patients may experience persistent lower back pain, insomnia, ammonia breath smell, and microscopic or gross hematuria. At this stage, there is a need for treatment, and it includes dietary adjustment that the patients need for protein restriction. Low phosphate diet and low potassium diet will minimize the complication of electrolyte imbalance. Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), cephalosporins, statins, insulin, and proton pump inhibitors should be avoided. Low hemoglobin level can be treated using erythropoiesis-stimulating agents (ESAs). Although the treatment for CKD stage 4 uses medication to control symptoms, this medication itself can damage the kidney as well.

1.4.5 CKD stage 5

Stage 5 of CKD is the most alarming stage where the patient experiences kidney failure with eGFR<15 mls/min. The kidney function at this stage GFR drops to less than 15 mL/min, and if only 10% of the remaining kidney is there, this is considered as End-Stage Renal Disease (ESRD). Stage 5 is associated with uremia, whereby the waste product accumulates in the blood [12]. The patient will experience dyspnea, pruritus, chest pain, nausea and vomiting, restless leg syndrome, abnormal bruises, hiccups, seizure, and coma. At this stage, the treatment will include renal replacement therapy that is dialysis, either hemodialysis or peritoneal dialysis or kidney transplant.

CKD is linked to various unfavorable clinical consequences, including cardiovascular events, mortality, and diminished quality of life [13]. Table 3 explains the complication of CKD on system in the body function.

System	Complication
Central nervous system	Difficulty concentrating, mood swing, seizure, depression, uremic encephalopathy, and coma.
Circulatory blood	Anemia, fluid and electrolyte imbalance, edema, metabolic acidosis, hyperkalemia, hyperphosphatemia, hypocalcemia, and bleeding tendency.
Cardiovascular system	Hypertension, cardiac dysrhythmia, left ventricular hypertrophy, tachycardia, and hypervolemia.
Respiratory system	Pulmonary edema, difficulty in breathing due to excess fluid, Kussmaul respiration due to metabolic acidosis.
Gastrointestinal system	Gastrointestinal bleeding, nausea and vomiting, loss of appetite due to uremia, metallic taste in the mouth, hiccup, and uremic halitosis.
Integumentary system	Uremic frost, pruritus, bruises, and pallor with edema.
Musculoskeletal system	Mineral bone disease or osteodystrophy.
Endocrine system	Hyperparathyroidism.
Immune system	High risk for immune suppression and infection.

Table 3.

Complication of CKD on multiple systems in body.

2. Pharmacological therapies for CKD in various stages

2.1 Mineralocorticoid receptor antagonist (MRA): Finerenone, spironolactone, eplerenone, esaxerenone, apararenone

Among the class of medications known as mineralocorticoid receptor antagonists (MRAs) are the classic steroid antagonists, spironolactone and eplerenone. We can differentiate between the nonsteroidal MRAs, such as apararenone, esaxerenone, and eplerenone [14]. Simpson et al. isolated aldosterone in 1953 [15]. The adrenal glands’ glomerulosa cells are primarily responsible for producing it. The heart, blood arteries, and adipocytes can create aldosterone under specific conditions [16]. Human coronary arteries from multi-organ donors have demonstrated elevated expression of aldosterone synthetase (AS), which is also elevated in people suffering renal failure and coincides with the vascular expression of osteoblastic transforming factor: core-binding factor alpha 1 (CBFa1) [17].

In contrast to spironolactone or eplerenone, which is found primarily in the kidneys, the nonsteroidal MRA finerenone exhibits a balanced distribution between the heart and kidneys. Another important difference is that finerenone has a shorter half-life and no active metabolites, which may lessen its long-term impact on the sodium-potassium balance [18]. Despite a rise in hyperkalemia, classic mineralocorticoid receptor (MR) antagonists have been beneficial in reducing cardiovascular events and death in individuals with heart failure and reduced ejection fraction (EF). Activation of MR causes detrimental effects on the heart through several mechanisms that have been covered in this study. Nonsteroidal aldosterone antagonists may provide higher benefits in critical renal and cardiovascular variables due to their potential for increased cardiorenal protective capability and decreased risk of hyperkalemia. Two clinical trials involving finerenone will provide the definitive answer. The first trial, called FIDELIO-DKD (Finerenone in reducing kidney failure and disease progression in diabetic kidney disease), examines the effectiveness of finerenone in relation to placebo in reducing major renal and cardiovascular (CV) events in subjects with diabetes mellitus type 2 (DM-2) and chronic kidney disease (CKD) treated with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonists (ARA2) [19]. The second trial, called FIGARO-DKD (Finerenone in reducing CV mortality and morbidity in diabetic kidney disease), examines the safety and efficacy of finerenone in relation to placebo in patients with DM-2 and CKD [20].

2.2 Methylxanthine derivative: Pentoxifylline

Pentoxifylline (PTF) is a derivative of methylxanthine having a variety of pharmacologic actions, including immunological modulation, enhanced cellular membrane fluidity, fibrinolysis stimulation, anticoagulant effects, and altered fibroblast physiology [21]. PTF, a nonselective phosphodiesterase (PDE) inhibitor, has been shown to have strong inhibitory effects on the growth of cells, inflammation, and the buildup of extracellular matrix (ECM) [22]. It is widely accepted that PTF, by its hemorheological action as well as its anti-TNF α activity, can lessen proteinuria in diabetic individuals [23]. In a recent investigation on early-stage type 2 diabetic nephropathy, pentoxifylline was found to further decrease urine protein and N-acetyl-π-glucosaminidase excretion in patients receiving treatment with an ACE inhibitor or an angiotensin-receptor blocker (ARB) [24]. Based on these results, there is clinical evidence that PTF and renin-angiotensin-aldosterone system (RAAS) blockage together may further preserve kidney function.

Studies in humans and animals have shown that adding PTF to current CKD treatment might make it even better. In a randomized experiment conducted in 2012, the pharmacological therapy of 91 patients resulted in a one-year decrease in blood levels of fibrinogen, tumor necrosis factor α (TNF-α), and high-sensitivity C-reactive protein (hs-CRP), while eGFR rose by 2.4 mL/min/1.73 m² [25]. The results from this experiment demonstrated that 24 patients from the control group (13 started dialysis therapy and 11 had a twofold increase in serum creatinine) and 11 patients from the PTF group (seven started dialysis and four observed a double increase in serum creatinine) experienced renal events during follow-up. Irrespective of the existence of diabetes mellitus, the potential protective impact of PTF was more significant in individuals with albuminuria. PTF treatment decreased renal events by 35% as compared to the control group in a Cox model that incorporated basal renal function, albuminuria, and diabetes mellitus into account. With PTF therapy, cardiovascular mortality was considerably lower (2 patients vs. 10 in the control group). When age and diabetes mellitus were considered, PTF therapy decreased cardiovascular mortality by 55%. Another study has demonstrated that PTF administration lowers proteinuria and enhances renal function in people with chronic kidney disease [26]. In summary, PTF has been shown to have renoprotective properties in individuals with chronic kidney disease. To find out if PTF might improve renal outcomes in individuals undergoing proven-effective treatments, more clinical trials are required.

2.3 Glucagon-like peptide-1 (GLP-1) receptor agonists: Exenatide, lixisenatide, semaglutide, liraglutide

As a relatively recent class of antidiabetic medications, glucagon-like peptide-1 (GLP-1) receptor agonists are already in widespread usage. They modify the function of incretin GLP-1, a protein generated by small intestinal cells, by interfering with the GLP-1 receptor. By increasing glucose-dependent insulin secretion and decreasing glucagon secretion, stomach emptying, and food intake, this lowers HbA1c levels [27]. GLP-1 receptor agonists, in terms of CKD, play a role in lowering risk factors by reducing blood pressure, insulin, glucose, and inducing weight reduction [28]. The kidneys’ GLP-1 receptor has been found in a few locations. Research carried out on animal models revealed that GLP-1 receptor messenger RiboNucleic Acid (mRNA) was expressed in the glomerulus and the first segment of the proximal convoluted tubes but not in any other area of the nephron [29]. GLP-1 receptors have also been detected in human kidneys, namely in proximal tubular cells and preglomerular vascular smooth muscle cells [30].

GLP-1 and GLP-1R agonists have been shown in experimental investigations to decrease renal RAAS activation indicators, such as angiotensin II levels and their detrimental effects on the glomerulus. These findings may point to additional possible renal protective mechanisms in diabetic kidney disease (DKD) [31]. Nevertheless, there is currently no solid data to support the impact of short- or long-term GLP-1R agonist therapy on circulating RAAS components. A little decrease in low-density lipoprotein levels is linked to inflammation in diabetes, according to GLP-1 receptor agonist treatment. Increased vascular inflammation and fibrosis have been linked to profibrotic growth factors, cytokines, and inflammatory cells in the pathophysiology of diabetic nephrotic (DN). GLP-1 affects inflammation at several places, including blood vessels and the kidneys, according to recent research [32]. It is possible to lower reactive oxygen species (ROS) generation in the diabetic kidney by activating the cyclic adenosine monophosphate–protein kinase A (cAMP–PKA) pathway. Since GLP-1 receptor activation stimulates the cAMP–PKA pathways, which have antioxidative properties, it is likely that GLP-1 shields the kidney from oxidative [33]. All of these results will serve as the foundation for the next clinical research examining whether GLP-1R agonists may enhance renal outcomes when DKD is present. SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and LEADER (Liraglutide Effect and Action in Diabetes) were two randomized, double-blind, placebo-controlled studies that were carried out [34]. The benefits of once-weekly and once-daily semaglutide and liraglutide on several clinically significant kidney outcomes have been shown by analysis of these studies. These outcomes include changes in albuminuria, changes in the annual slope of the estimated glomerular filtration rate change, time to persistent proportional estimated glomerular filtration rate reductions of 40 and 50% from baseline, and a composite endpoint (time from randomization to first occurrence of kidney failure/death or proportional estimated glomerular filtration rate decline). The study’s findings imply that patients with type 2 diabetes and diabetic kidney disease may have more alternatives for kidney-protective therapy if they take the glucagon-like peptide-1 receptor agonists such as semaglutide and liraglutide. Kidney Disease Improving Global Outcomes (KDIGO) recommends long-acting GLP-1 receptor agonists for patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) who have not reached individualized glycemic targets despite using metformin and SGLT2i treatment, or who are unable to use those medications [35].

2.4 Sodium-glucose cotransporter-2 (SGLT2) inhibitors: Empagliflozin, dapagliflozin, canagliflozin

Since the first SGLT2 inhibitor was introduced in 2012 [36], the class of drugs has expanded to include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin in the Americas and Europe, with other members of the class starting to gain traction in other areas [37]. SGLT2 inhibitors are glucose-lowering medications that decrease the renal filtrate’s ability to absorb glucose, hence eliminating excess glucose through a glucosuric action [38]. Even though SGLT2 inhibitors have been developed to lower hyperglycemia and help with body weight control in people with type 2 diabetes, further therapeutic prospects for these drugs to treat the cardiorenal consequences and comorbidities of the disease are now identified. A growing number of research studies indicate that SGLT2 inhibitors can prevent DKD from developing and reduce the course of the condition both independently and in combination with RAAS inhibition.

The renal composite (doubling of serum creatinine, eGFR <45 ml/min/1.73 m², commencement of renal replacement therapy, or death from kidney disease) was 46% lower in the empagliflozin-treated groups in the EMPA-REG OUTCOME study [39]. According to the DECLARE-TIMI 58 study, dapagliflozin treatment was linked to a 47% lower renal composite of new end stage kidney disease (ESKD), mortality from renal cause, and a sustained drop in estimated glomerular filtration rate (eGFR) of ≥40% to <60 ml/min/1.73 m² [40]. Dapagliflozin was associated with a 46% reduction in eGFR decline (from >40% to <60 ml/min/1.73 m²) as well as substantial reductions in ESKD and renal mortality. Dapagliflozin also reduced new-onset macroalbuminuria by 46% and new-onset albuminuria by 21% [41]. These study results demonstrate that SGLT2 inhibitors have a range of effects on the kidney, including acute and long-term nephroprotective effects that slow the progression of diabetic kidney disease and may even partially reverse its hallmark indicators. These effects are both directly and indirectly linked to decreased glucose reabsorption.

2.5 Pharmacological treatment using natural product for CKD in various stages

Plants, algae, and fungi have been used as natural remedies throughout history [42]. Natural products are regarded as an acceptable, cost-effective, readily available, and relatively safe source of many active pharmacological chemicals [43]. Many medicinal plants and their extracts have already been shown to improve kidney function via antioxidant action, with concomitant advantages for inflammation and fibrosis. For preclinical research, in vitro and in vivo tests with natural product-based medicines show some significant therapeutic advantages.

Wang et al. [44] found that Shen shuaining capsules containing Rheum officinale, Radix pseudostellariae, Coptis chinensis, Carthamus tinctorius, the rhizome of Salvia miltiorrhiza, and Bidentate achyranthes significantly reduced serum creatinine and blood urea nitrogen, increased hemoglobin, and improved overall efficacy of CKD symptoms and signs. A decoction of the roots of two Chinese herbs, Astragalus membranaceus and Angelica sinensis, has exhibited antifibrotic effects in rats with chronic kidney disorders and improved renal blood flow in rats with acute ischemic renal injury [45]. Aqueous extracts of Fructus Corni and Radix Astragali reduced urine protein levels and altered protein patterns, indicating that Fructus Corni and Radix Astragali could play a significant role in maintaining renal function in nephropathy mice [46].

Cordyceps sinensis and Tripterygium wilfordii polyglycosidium protected the podocytes of rats with diabetic nephropathy [47]. Cordyceps cicadae may inhibit renal fibrosis in vivo through the TGF-β1/CTGF pathway. According to the researchers, the usage of Cordyceps cicadae could provide a sensible strategy for fighting renal fibrosis [48]. Elsholtzia ciliata ethanol extract (ECE) may function by inhibiting the activation of TGF-ß and inflammatory cytokines, resulting in the breakdown of the extracellular matrix accumulation pathway. Based on these findings, ECE may be a more effective treatment for renal fibrosis [49].

Treatment with Azuki beans (an aqueous extract of Vigna angularis) improved renal function parameters and significantly reduced glucose levels, triglycerides, VLDL, alanine aminotransferase, uric acid, and creatinine, while also significantly increasing high-density lipoprotein (HDL) levels in rats subjected to a model of moderate chronic kidney disease [50]. Shenkang granules (SKGs) are a Chinese herbal medicinal formula consisting of rhubarb (Rheum palmatum), Salvia miltiorrhiza, milkvetch root (Astragalus membranaceus), and safflower (Carthamus tinctorius L.). SKG was shown to reduce renal damage in a rat model of chronic renal failure (CRF). Thus, SKG may have a positive therapeutic effect on CRF [51].

The hydro-ethanolic extract of Euphorbia neriifolia significantly restored antioxidant enzyme levels in the kidney and demonstrated a significant dose-dependent protective effect against N-nitrosodiethylamine-induced nephrotoxicity, which can be attributed primarily to the extract’s antioxidant properties [52]. The hydroalcoholic extract of Rubia cordifolia roots (HARC) protects against ethylene glycol-induced urolithiasis by reducing and inhibiting the formation of urinary stones. As a result, HARC can help prevent the condition from recurring because it has been shown to influence the early stages of stone growth. The mechanism underlying this benefit may be mediated by an antioxidant, nephroprotection, and its influence on urinary stone-forming ingredients and risk factors [53]. Aunaea procumbens efficiently protects rats’ kidneys from CCl₄-induced oxidative damage via the antioxidant and free radical scavenging properties of flavonoids and saponins in the fractions [54]. Another study reported that grape seed extract reduced inflammation by lowering CRP and triglyceridemia while counteracting anemia and thrombocytopenia. Supplementation with 2 g GSE/day for 6 months improved various kidney function parameters in CKD patients, and this therapeutic effect of Grape seed extract appears to be mediated at least partially by its antioxidant and anti-inflammatory characteristics [55]. Jimenez-Osorio et al. [42] reported that curcumin administration lowers oxidative stress in Mexican patients with nondiabetic or diabetic proteinuric CKD.

There is no disagreement that natural products represent a significant untapped source of novel CKD therapy. Clinical and preclinical trials of plant extracts have occasionally shown benefits; however, some research has also shown that plant extracts can cause chronic organ dysfunction when administered over time due to the presence of toxic compounds. Natural products are frequently regarded as safer than standard drugs, and many of our current medications are developed from herbs. Nonetheless, several researchers are concerned about their safe use.

2.6 Management of CKD patients in stage 4 and stage 5

2.6.1 Renal replacement therapy

Renal replacement therapy (RRT) is a medical intervention that substitutes the essential functions of the kidneys in individuals with severe kidney failure of End-stage renal disease (ESRD). This therapy is necessary when the kidneys are no longer able to adequately filter waste products and excess fluids from the blood [56]. The three modalities of RRT are hemodialysis, peritoneal dialysis, and kidney transplantation. The choice of treatment is the patient’s preference and according to their condition.

2.7 Hemodialysis

Hemodialysis is a complex procedure for renal failure patients that require frequent dialysis center visits or hospitalizations that may be encountered 3 to 4 times per week [57]. The goal of dialysis is to remove the end product of protein metabolism from the blood. Maintain a safe concentration of serum electrolytes. Correct the acidosis, replenish the body’s bicarbonate buffer system, and remove excess fluid from the blood. Hemodialysis is needed when the eGFR drops below 20 ml/min/1.73 m² or when there is a rapid progression of kidney disease to end-stage renal disease. Gotch and Sargent established the Kt/V urea as a measure in their National Cooperative Dialysis study (1985). In contrast to a Kt/V of more than 1.0, which resulted in a favorable outcome, it was shown that Kt/V of less than 0.8 was linked to increased morbidity or treatment failure [58].

It is a dimensionless ratio calculated by dividing the amount of plasma cleared of urea (Kt) by the distribution volume of urea (V). The urea-free plasma volume is the product of blood urea clearance (K) and dialysis session length (t). A Kt/V ratio of 1.0 indicates that the total blood volume cleansed during a session equals the urea distribution volume. Dialysis can be intermittent or continuous. Continuous intravascular procedures are preferred for patients who are hemodynamically unstable or have a high-volume overload. A dialyzer will connect the circuits. Side ports in the veins are used for saline or heparin infusion, air entrance detection, and pressure measurement. The dialysate is pushed through the dialysate compartment which is isolated from the blood compartment by the dialyzer’s semi-permeable membrane. Regenerated cellulose, with its very hydrophilic character, permits miniaturization of the dialyzer and lower membrane thickness. Biocompatible synthetic membranes composed of polysulfone have a semi-permeable surface and lower complement cascade activation than previous bioincompatible ones. The temperature and concentration of dissolved components in dialysis fluid are controlled. A blood leak detector pauses dialysis when it detects blood products in the outflow dialysate. Approximately 25% of patients having uremia need hospital administration for the procedure preparation and management of complications. The distal arteriovenous (AV) fistula serves as the gold standard for hemodialysis access. If the patients’ superficial veins are exhausted, the alternative methods will be intrajugular cannulation (IJC), femoral catheter, permanent catheter, and synthetic graft. Patients that need to undergo dialysis treatment can make appointments in the dialysis unit and schedule their time according to their daily routine. Some of the patients will need three times per week [59].

2.8 Peritoneal dialysis

This is another type of renal replacement therapy that uses the patient’s own peritoneum cavity as a natural permeable membrane that allows water and solutes to equilibrate [60]. Peritoneal dialysis is a more suggested procedure for patients than hemodialysis due to less physiological stress, does not require vascular access, and can be done at home, and the patients have more flexibility. Although this is the most suggested procedure, it still needs more patient involvement than in-center hemodialysis. The sterile technique is very important for this procedure. Two processes involved in this procedure are osmosis and diffusion. In this procedure, the usage of dialysate is the mainstay for the dialysis, and it is instilled using a Tenckhoff catheter. Peritoneal dialysis can be done manually or by using an automated device [61].

Manual methods of peritoneal dialysis include:

• Continuous ambulatory peritoneal dialysis (CAPD) that does not require a machine for exchange. For an adult, approximately 2 to 3 L of dialysate can be used four to five times per day. Dialysate is a glucose solution for the process of osmosis.

• Intermittent peritoneal dialysis is used for immediate management of acute kidney injury. Warm dialysate will be instilled for 10 to 15 minutes. Frequent exchange will be needed for almost 12 to 48 hours.

Using machines for peritoneal dialysis are as follows:

• Continuous cyclic peritoneal dialysis (CCPD) will need 12 to 5 hours of dwelling time and 3 to 6 nighttime exchanges using automated cycler.

• Noctural intermittent peritoneal dialysis (NIPD) will need nighttime exchange, and the patient will not need daytime exchange.

• Tidal peritoneal dialysis involves the remaining dialysate fluid in the peritoneum for one exchange to another, which may allay frequent repositioning.

Although peritoneal dialysis is a recommended procedure, it still can be a failure for patients if an aseptic technique is not applied. Therefore, all the patients with peritoneal dialysis will be given training and health education to maintain the aseptic technique and adhere to the procedure without the main complication, which is peritonitis [62].

3. Renal transplant

It is known that when a CKD patient has been scheduled for a kidney transplant, they are considered to have a gift of life. Patients that have 10–15% of remaining kidney function are known to be in the condition of end-stage renal disease (ESRD), and kidney transplant is performed to prolong and improve the quality of life (QOL) for them [63]. This surgery has been developed for over 50 years. This procedure has better long-term survival. There is evidence that patients undergoing renal transplants have survived more than 10 years. The first renal transplant was successfully conducted by Dr. Joseph Murray in 1954with major development in immunology and transplant procedure. If the patients have no contraindications, the nephrologist will refer the patients for transplant workup plan. There is a clear survival benefit for kidney transplant recipients over those who remain on dialysis.

There are many complications and comorbidities from kidney disease for ESRD patients. Therefore, careful screening is needed for both donor and recipient. They will need to undergo investigation such as cardiovascular assessment, renal angiogram, human leukocyte antigen (HLA) compatibility, cerebellar vascular disease screening, frailty test, gastrointestinal evaluation, hematologic disease screening, infectious disease screening, and pulmonary assessment. There are three types of kidney donors: living-related donor, living nonrelated donor, and cadaveric donor [64]. Living related can be parents, siblings, and other blood-related. Living nonrelated can be husband and wife or friends, and cadaveric donor is the deceased donor that is broken down to brain death.

Currently, there is robotic surgery for transplants. Access is achieved to the intraperitoneal space to insert the port. The left kidney’s ureter and gonadal vein are discovered at the pelvic brim after the left colon is released from peritoneal attachments and tracked cephalad to locate and isolate the renal vein and artery [65]. The adrenal gland is separated from the upper pole of the kidney, and the adrenal vein has been divided. Once the kidney is fully mobilized and only connected by the artery, vein, and ureter, a slightly bigger incision is created to prepare for rapid extraction. The distal ureter is divided with clips, and the hilar arteries are separated with a laparoscopic vascular-load stapler. Some changes in dissection exist depending on which kidney is obtained. To access the right kidney, the liver is retracted, and the right colon and duodenum are partially mobilized. Following extraction, the organ is moved off the pitch and ready for implantation on the back table.

The open surgical approach for living donor procurement involves making a subcostal incision and exposing the retroperitoneal region. Before extraction, the ureter is followed down to the iliac vessels, where it is split. The kidney will be isolated on its vascular pedicle, and when the recipient team is ready, the renal artery and vein are transacted before the organ is transferred. The tributary stumps are then ligatured or oversewn. The remaining perinephric fat is trimmed while the kidney is prepared for implantation.

Patients with CKD and ESRD depend on hemodialysis and peritoneal dialysis before the initiation of the transplant. Once the transplant was set in gear, the survival rate of ESRD patients increased. Those who went for renal transplants experienced a better quality of life than those on dialysis treatment. CKD, concomitant diseases, and its treatment impose significant burdens on patients’ health-related quality of life. Kidney illness, including polycystic kidney disease and nephrotic syndrome, is associated with significant QOL impairment.

4. Quality of life for CKD patients’

Monitoring patient-reported outcomes to capture CKD’s effect on health-related quality of life (QOL) is critical for both population and individual care. Patients with CKD require more practice and clinically relevant patient-reported outcome measures [66]. QOL declines with increasing CKD severity; patients at earlier CKD stages have smaller but still significant QOL impairments compared to the general and hypertensive populations. Those patients with CKD stage 5 who are about to start dialysis report physical health lower than the general population.

4.1 Methods to increase CKD patients’ quality of life

1. Education and empowerment provides comprehensive education about CKD including its cause, progression, treatment options, and self-management strategies. Empowering patients with knowledge helps them make informed decisions and actively participate in their care.

2. Dietary management can collaborate with a registered dietitian to develop a personalized nutrition plan that addresses the patient’s specific dietary needs including restrictions on sodium, potassium, phosphorus, and protein intake. A well-balanced diet tailored to CKD can help manage symptoms and slow disease progression.

3. Physical activity is needed, and it should be within the patients’ capabilities. Exercise can improve cardiovascular health, muscle strength, and overall well-being. Recommend activities such as walking, swimming, or light resistance training, considering the individual’s fitness and any physical limitations.

4. Medication adherence by ensuring that patients adhere to their prescribed medication regimen, including medications to control blood pressure, manage symptoms, and treat comorbid conditions such as diabetes or cardiovascular disease. Monitor for any adverse effects and adjust medications as needed.

5. Symptom management by identifying fatigue, nausea, itching, and pain through appropriate interventions, including medication adjustments, lifestyle modifications, and supportive therapies. Managing symptoms effectively can enhance the patient’s comfort and quality of life.

6. Psychological support is important to recognize and address the emotional impact of CKD, which may include anxiety, depression, stress, and adjustment difficulties. Offer psychological support through counseling, support groups, or referrals to mental health professionals.

7. Social support and community engagement by fostering connections and encouraging participants in support groups or community activities. Social support can provide emotional comfort, practical assistance, and opportunities for socialization, which are essential for maintaining overall well-being.

8. Palliative care and hospice service can be considered for patients with advanced CKD, focusing on symptom management, pain relief, and improving the quality of life. These services provide comprehensive support for patients and their families during the end-of-life stage.

9. Advanced care planning facilitates discussions about advanced care planning to help patients articulate their healthcare preferences, values, and goals of care. Advance directives, including living wills and surfable power of attorney for healthcare, ensure that patient’s wishes are honored, particularly in critical or end-of-life situations.

10. Regular monitoring and follow-up are needed to monitor kidney function, assess treatment efficacy, and address any concerns or complications promptly. Close monitoring allows for timely adjustments to the treatment plan, optimizing outcomes and quality of life.

11. Financial assistance and resources will provide information about financial assistance programs, insurance coverage options, and community resources available to support CKD patients in managing the financial aspects of their care. Access to affordable healthcare and medication is crucial for improving quality of life and treatment adherence.

By implementing these strategies, healthcare providers can effectively enhance the quality of life for CKD patients and support them in managing their condition.

5. Conclusion

This book chapter delves into the intricate landscape of chronic kidney disease (CKD), offering a comprehensive exploration of its multifaceted dimensions. Through a meticulous examination of the underlying causes, diagnostic criteria, and progression of CKD, we have gained valuable insights into the complex interplay of genetic, environmental, and lifestyle factors that contribute to its development. Furthermore, the discussion on the various stages of CKD underscores the importance of detection and intervention, emphasizing the potential for preventive measures to mitigate the advancement of this silent yet pervasive condition. The nuanced exploration of treatment modalities, including pharmacological interventions and lifestyle modifications, highlights the evolving landscape of CKD management and the promising avenues for improving patients’ outcomes. As we navigate the intricate web of complications associated with CKD, ranging from cardiovascular issues to metabolic alterations, a holistic approach to patient care emerges as a central theme. The integration of multidisciplinary strategies, encompassing nephrology, cardiology, endocrinology, and lifestyle interventions, underscores the imperative of a collaborative and patient-centered paradigm.

Moreover, this chapter not only serves as a valuable resource for healthcare professionals but also empowers patients with the knowledge to actively engage in their journey toward optimal kidney health. This exploration of CKD contributes to the ongoing discourse on public health initiatives, emphasizing the need for early detection, preventive measures, and comprehensive management strategies to alleviate the burden of CKD on individuals and healthcare system alike. As we continue to unravel the complexities of CKD, this chapter serves as a stepping stone to a deeper understanding and more effective management of the pervasive health challenge.