CKD

Burden of chronic kidney disease

Professor Vlado Perkovic, from the University of New South Wales in Australia, describes the complications and burden of chronic kidney disease.

Chronic kidney disease (CKD) is an immensely debilitating condition that is often diagnosed late in the disease cycle and can require a lifetime of dialysis or a kidney transplant at the later stages²⁹. Around 700 million people have all-stage CKD; more than the number of people with diabetes, osteoarthritis, chronic obstructive pulmonary disease (COPD), asthma, or depressive disorders⁶.

What is the global burden of chronic kidney disease?

In 2017, CKD resulted in 1.2 million deaths⁶. This number is projected to increase to around two to four million by 2040⁶.

Globally, CKD resulted in more deaths in 2017 than tuberculosis or HIV, and nearly as many deaths due to road accidents⁶

While prevalence estimates vary from approximately 2% to 44%, CKD prevalence is considered to be increasing in various countries around the world²⁹. A useful proxy for CKD prevalence is the number of patients undergoing renal replacement therapies³⁰. Figure 3 highlights the prevalence of renal replacement therapy, including haemodialysis, peritoneal dialysis and kidney transplantation per one million people by country³⁰.

Figure 3. Global prevalence of renal replacement therapy (Adapted³⁰).

The broad range in prevalence highlights the wide variety of unmet clinical, humanistic, and economic needs around the world²⁹.

An analysis by the Kidney Early Evaluation Program (KEEP) found that the prevalence of CKD was highest in people aged ≥80 years and was as high as 44% in those ≥65 years³¹. Similar estimates were seen in the elderly of 23.4% to 44% in^31,32:

• Australia
• Canada
• China
• Iceland
• Italy
• Japan
• Mexico
• Netherlands
• Norway
• Singapore
• Spain
• Switzerland
• Thailand
• USA

Adding to the complexity of the disease burden, notable increases in the prevalence estimates for modifiable risk factors that affect the initiation and/or progression of CKD have also been observed²⁹.

What is the clinical burden of chronic kidney disease?

The symptom burden experienced by patients with CKD is high regardless of the stage of the disease with prevalent symptoms including³³:

• Fatigue
• Feeling drowsy
• Pain
• Pruritus
• Dry skin

In particular, people with more advanced stages of CKD can experience a particularly high symptom burden that impacts on their daily life³³.

The Global Burden of Disease study has reported an increasing burden of CKD over the past 20 years, to which diabetes is the most significant contributor^34,35. Mortality rates associated with CKD have also increased over the past 25 years; ranked originally at 25^th in 1990, CKD became the 17^th highest cause of mortality in 2015^35–37. CKD now contributes to 1.35% of the global burden of disability life years lost^35–37.

CKD mortality is associated with decreases in estimated glomerular filtration rate (eGFR) and increases in albuminuria³⁸, which is notably highest in patients on kidney replacement therapy; a 40–50% rate of 5-year survival of those on dialysis³⁰.

Improved prospects are seen with patients receiving a kidney transplant, with 5-year survival rates of 86% and 93% for patients receiving deceased or living donor kidneys, respectively³⁰.

Moreover, life expectancy is only one third of the age and sex­matched general population for patients on dialysis compared to patients who receive a kidney transplant with a life expectancy of 45–85% of the general population³⁰.

What is the quality of life burden of chronic kidney disease?

The patient perspective is an essential component of care for a patient with a chronic disease that has no cure. Patient perspectives drive the understanding of illness experience, treatment expectations, and unmet needs.

Across various studies, the most burdensome conditions commonly reported by CKD patients are^39–45:

• Cognitive impairment
• Dementia
• Sleep disturbance
• Pain
• Emotional dysfunction
• Physical dysfunction

Of these conditions, physical dysfunction was considered to be the most pervasive and debilitating^39–45. Perception of general health was noted as being low across all eGFR groups, mental health component scores were similarly low in patients with a decrease in eGFR and an increase in illness severity, and reduced eGFR was associated with significantly reduced physical component scores^39,45. Health related quality of life was also seen to decline with the progression of CKD (Figure 4)⁴¹.

Figure 4. Health-related quality of life and progression of chronic kidney disease (CKD) by stage (Adapted⁴¹). Statistical significance for trend across three CKD stages within each domain P<0.001. CKD, chronic kidney disease; KDQOL-36, Kidney Disease Quality of Life – 36.

Modifiable risk factors associated with lower quality of life in CKD patients were^39,44,45:

• Less education
• Lower exercise
• Depression
• History of cardiovascular disease
• Lower income
• Unemployment

Economic burden of chronic kidney disease

As CKD is progressive it produces a significant economic burden through the increased resource utilisation and escalating costs due to increased disease severity and deterioration of health. A range of studies have shown that 12 to 24 months before dialysis, patients with CKD accrue substantial costs due to hospitalisation^46–55.

Employers also face a significant impact with a continually aging population, which is gaining greater numbers of individuals older than 65 years in the workplace^56–59. Moreover, anaemia-related morbidity in the workplace is increasingly becoming a concern as the burden and costs for patients with CKD with anaemia are significantly higher than those with only CKD^60-61. Prior to dialysis, Treatment for anaemia was found to improve work productivity by 91.5%, reduced absenteeism by 52.3 days per year, and reduce health care costs^56,59.

Risk factors for chronic kidney disease

Dr George Bakris provides insight into the risk factors for CKD.

The interlaced nature of CKD risk factors and comorbid illnesses can complicate the characterisation of CKD. Patients can have either risk factors that predispose them to developing CKD, risk factors that contribute to disease progression, or both²⁹.

The ideal approach to CKD prevention therefore requires the identification of the incidence, prevalence, and distribution of these risk factors and appropriate mitigation strategies⁶².  

Who is most at risk of developing chronic kidney disease?

Professor Vlado Perkovic outlines the concordant comorbidities and key risk factors for chronic kidney disease (CKD).

Multiple risk factors and comorbid illnesses can lead to the progression of CKD and an increased mortality⁶³.

A variety of patient characteristics are known to be non-modifiable risk factors for the development of CKD (Table 1)²⁹. Age and gender are notable examples of a non-modifiable risk factor for CKD⁶⁴. All stages of CKD are most common in people >65 years; however, the probability of developing end-stage renal disease (ESRD) is greater among people ≤65 years⁶⁴.

While the prevalence of CKD is higher in women than in men, men are more likely to go on to develop end-stage renal failure⁶⁴

As seen in table 1, a wide variety of known risk factors, emerging risk factors, and biomarkers have been reported⁶⁵.

Table 1. Common chronic kidney disease risk categories and risk factors (Adapted²⁹). Modifiable risk factors in bold. CKD, chronic kidney disease.

A number of these risk factors, including diabetes and cardiovascular disease, are modifiable and may be delayed with early and appropriate identification and treatment.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines, focusing on topics related to the prevention or management of individuals with kidney diseases, prioritise blood pressure, diabetes, and cardiovascular disease (CVD) as prominent risk factors in CKD^23,25The lack of data from large cardiovascular outcome trials in the high-risk group of patients with CKD is a call to investigate new therapeutic options in dedicated trials in the CKD population; especially in people with advanced CKD²⁶.

What are the risks associated with chronic kidney disease comorbidities?

In high-income and middle-income countries, diabetes mellitus and hypertension are the most common underlying diseases associated with CKD (Table 2)^37,62. Specifically, CKD prevalence is suggested as being as high as 30–40% in people with diabetes³⁰. However, it is not known if the CKD present in these patients is a direct result of their diabetes or due to microvascular disease that is associated with diabetes³⁰.

The two leading causes of end-stage renal failure are diabetes and hypertension, respectively⁶⁶

Traditional cardiovascular risk factors are highly prevalent in patients with CKD. The contribution of such factors to atherosclerotic vascular disease is especially relevant in earlier CKD stages²⁶. Non-traditional risk factors of vascular disease in CKD include vascular calcification and inflammation²⁶.

In low- and middle-income countries, CKD is associated with infectious diseases, glomerulonephritis, and the inappropriate use of medications, such as nephrotoxins, NSAIDs and nephrotoxic antibiotics^67,68.

Table 2. Relevant global risk factors for chronic kidney disease (Adapted⁶²). ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; B, billion; BP, blood pressure; CKD, chronic kidney disease; HIC high-income countries; LMIC, low- and middle-income countries; M, million; SE, southeast; YR, years.

With shifting socio­economic statuses and ageing populations in low- and middle-income countries, diabetes and hypertension may become the prominent aetiological causes for CKD³⁰.

Due to the association between CKD and low birthweight, millions of children have a high risk of developing CKD later in life and typically comprise the youngest patients that develop the disease^69,70

Children can also be born with a risk of CKD in later life due to low birthweight caused by preterm birth or intrauterine growth restriction; the risk of preterm birth and low birthweight are estimated to be ~10% and ~15%, respectively^69,70.

An analysis using the OpenSAFELY health analytics platform, which includes data from more than 17 million people in the UK, assessed the risk factors for COVID-19 mortality associated with CKD. In the analysis it was found that patients with CKD are at higher risk of COVID-19-associated mortality than those with other risk factors, such as chronic heart and lung disease⁷¹.

Notably, the Chronic Renal Insufficiency Cohort study and the CKD Prognosis Consortium meta-analyses are two ongoing studies that are researching kidney function and CKD progression risk factors in diverse and complex patient populations^69,70.

Can someone be genetically predisposed to chronic kidney disease?

Genetic abnormalities can lead to the development of CKD through a variety of mechanisms, such as nephrocalcinosis, cystic degeneration, weakening epithelial integrity, and abnormal processing or storage of metabolites or glycoproteins^72-74.

In terms of risk, the probability of developing ESRD compared to the general population is 3-9 times higher in people with a family history of CKD⁷⁵. Genetic testing has also shown that approximately 20% of early onset CKD can be attributed to a monogenic cause⁷⁶.

At-risk populations or people should be screened, diagnosed, and treated early to prevent onset and delay disease progression⁶²

Moreover, specific ethnic populations have been associated with a higher incidence of CKD⁷⁷:

• Aboriginal Australians
• African Americans
• People of Spanish descent in Central and South America
• Indigenous populations in Canada
• South and East Asians
• Pacific Islanders

This may be due to specific mutations in these populations, for example mutations associated with focal and segmental glomerulosclerosis have been associated with people of African descent⁷⁸.

However, endemic forms of CKD may also suggest regional triggers, such as specific infections, toxins, behaviours or climate related factors⁷⁹. For example, a correlation between agricultural work in Latin America, Sri Lanka, India, Cameroon, Mexico, and Australia and chronic interstitial nephritis has previously been observed^79-81.

To appropriately diagnose a patient, an understanding of the pathogenesis of CKD is essential.

Help us create relevant CKD content for you

Chronic kidney disease pathogenesis

Chronic kidney disease (CKD) describes a range of heterogeneous diseases that can compromise the structure and function of the kidneys. While the expression of CKD can be highly variable due to differing pathologies, severity, and progression rate, most forms of this burdensome disease are progressive and irreversible⁸².

What is chronic kidney disease?

Chronic kidney disease (CKD) can be described as the ongoing loss of renal function and excessive accumulation of extracellular matrix in the glomeruli and tubular interstitium over time⁸³. Kidney dysfunction can manifest as hypertension, oedema, changes in urine output or quality, and delayed growth in children³⁰.

Chronic kidney disease can be idiopathic or caused by a wide array of conditions, including⁸²:

• systemic diseases, such as diabetes and hypertension
• autoimmune reactions and renal transplant rejection
• drugs, toxins and metals
• infections
• mechanical damage
• ischaemia
• urinary tract obstruction
• genetic alterations

What is the consequence of nephron loss in chronic kidney disease?

During gestation, a person will generate an average of 950,000 nephrons per kidney (ranging from 200,000 to >2.5 million)⁸⁴. Following this period, new nephrons cannot be generated. Nephrons will instead increase in size to meet renal demands⁸⁵.

Figure 5. Contributing factors to nephron loss throughout life (Adapted³⁰). T2DM, type 2 diabetes mellitus.

While nephrons can adapt to temporary increases in filtration load by increasing glomerular filtration rate (GFR) without structural changes, using their renal reserve, various circumstances can lead to persistently increased GFR; promoting nephron hypertrophy and the eventual loss of nephrons (Figure 5)⁸⁶.

Why does nephron hypertrophy occur in chronic kidney disease?

In response to the loss of nephrons, glomerular hypertension can induce hypertrophy; an increase in size of the remaining nephrons. This hypertrophy is triggered through a persistently increased GFR and filtration pressure across the glomerular filtration barrier resulting in glomerular hyperfiltration³⁰.

The increase in nephron hypertrophy occurs through the activation of the renin–angiotensin system (RAS) in addition to increased transforming growth factor­α (TGF-α) and epithelial growth factor receptor (EGFR) expression. These activities are increased to reduce intraglomerular pressure while maintaining the glomerular filtration rate^87,88. However, while this increased activity reduces glomerular hypertension due to the increased filtration surface, it also further promotes nephron hypertrophy and further nephron loss⁸⁹.

Increased GFR and nephron hypertrophy can enable the appearance of an apparent ‘normal’ renal function even following a nephron loss of 50%³⁰

While hyperfiltration can maintain a ‘normal’ renal function despite a loss of nephrons, increases in glomerular size through hyperfiltration can be damaging³⁰.

Specialised epithelial cells that cover the outer surfaces of glomerular capillaries, known as podocytes, undergo hypertrophy to maintain the glomerular filtration barrier of the nephron. However, the increasing hypertrophy eventually hits a threshold where too much shear stress is placed on the podocytes³⁰.

Figure 6. Injury, hyperfiltration and hypertrophy of the nephron in chronic kidney disease (Adapted³⁰). CKD, chronic kidney disease; EGFR, epidermal growth factor receptor; FSGS, focal segmental glomerulosclerosis; PEC, parietal epithelial cells; RAS, renin-angiotensin system; TGFα, transforming growth factor-α.

In the later stages of the disease, the increased shear stress on the podocytes promotes their detachment. The consequential development of proteinuria also inhibits the replacement of lost podocytes by parietal epithelial cells (PECs). Instead, scar formation occurs through focal segmental glomerulosclerosis (FSGS)³⁰.

This eventually leads to a feedback loop causing further nephron loss and increases in the GFR of the remaining nephrons (Figure 6)³⁰.

How does glomerular filtration become impaired in chronic kidney disease?

Podocyte hypertrophy and glomerular hyperfiltration are maintained through the production of angiotensin II and mechanistic target of rapamycin (mTOR) signalling. This leads to heightened podocyte loss and further proteinuria. Angiotensin II, a peptide hormone of RAS, induces vasoconstriction and the secretion of aldosterone. This triggers a consequential rise in blood pressure and sodium retention³⁰.

The inhibition of PECs, consequential reduction of podocyte replacement, and formation of FSGS lesions may also involve angiotensin II⁹⁰. A marker of the nephron damage that has occurred is the presence of proteinuria due to the structural changes at the glomerulus. Proteinuria is predictive for CKD progression and is defined as a GFR reduction of >5 ml/min/1.73 m² per year, which is approximately seven times the rate associated with loss due to aging^87,91,92.

When does fibrosis develop in chronic kidney disease?

Figure 7. The development of interstitial fibrosis in advanced-stage chronic kidney disease (Adapted³⁰). CKD, chronic kidney disease.

As a consequence of nephron loss, wound healing occurs through responses such as interstitial fibrosis (Figure 7). Interstitial inflammation and fibrosis are promoted by proinflammatory and pro­fibrotic mediators that are released as a result of immune cell and albuminuria infiltration and proximal tubular epithelial cell activation⁹³. In diabetes, the activation of proximal tubular epithelial cells is further enhanced by glucosuria⁹³.

Interstitial fibrosis may also drive further nephron injury due to the development of renal ischaemia⁹³; however, scar formation may have the ability to stabilise the remaining nephrons⁹⁴. Increased secondary tubular injury due to the increased tubular transport workload of the remaining nephrons is also promoted through a variety of mechanisms including^88,95: 

• anaerobic metabolism
• intracellular acidosis
• endoplasmic reticulum stress

What are the systemic complications of chronic kidney disease?

Due to the key role kidneys play in various complex processes, such as blood homeostasis, bone integrity, acid-base balance, electrolyte levels and blood pressure, nephron declines cause a number of complications in these systems³⁰:

• Metabolic acidosis
• Anaemia
• Mineral bone disorder; vitamin D deficiency, hyperparathyroidism, hyperkalaemia, and hyperphosphataemia
• Arterial hypertension
• Hyperuricaemia and expansion of effective circulating fluid volume
• Childhood dyslipidaemia, endocrine abnormalities, and growth impairment

The symptoms of these complications can include, fatigue, anorexia, weight loss, pruritis, nausea, vomiting, muscle cramping, oedema and shortness of breath³⁰. Notably, dyslipidaemia, hyperuricaemia, and hypertension are associated with cardiovascular disease; the leading cause of CKD patient death worldwide³⁶.

Learn about the importance of early CKD diagnosis

References

1. De Nicola L, Minutolo R. Worldwide growing epidemic of CKD: fact or fiction? Kidney Int. 2016;90(3):482–484.
2. Ng JKC, Li PKT. Chronic kidney disease epidemic: How do we deal with it? Nephrology. 2018;23:116–120.
3. Mangione F, Canton AD. The epidemic of chronic kidney disease: Looking at ageing and cardiovascular disease through kidney-shaped lenses. J Intern Med. 2010;268(5):449–455.
4. McCullough KP, Morgenstern H, Saran R, Herman WH, Robinson BM. Projecting ESRD incidence and prevalence in the United States through 2030. J Am Soc Nephrol. 2019;30(1):127–135.
5. Tuttle KR. SGLT2 inhibition and chronic kidney disease outcomes: in diabetes and beyond. Lancet Diabetes Endocrinol. 2021;9(1):3–5.
6. Bikbov B, Purcell CA, Levey AS, Smith M, Abdoli A, Abebe M, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709–733.
7. Mallappallil M, Friedman EA, Delano BG, Mcfarlane SI, Salifu MO. Chronic kidney disease in the elderly: Evaluation and management. Clin Pract. 2014;11(5):525–535.
8. Fishbane S, Hazzan AD, Halinski C, Mathew AT. Challenges and opportunities in late-stage chronic kidney disease. Clin Kidney J. 2015;8(1):54–60.
9. Hallan SI, Matsushita K, Sang Y, Mahmoodi BK, Black C, Ishani A, et al. Age and association of kidney measures with mortality and end-stage renal disease. JAMA - J Am Med Assoc. 2012;308(22):2349–2360.
10. van der Tol A, Lameire N, Morton RL, Van Biesen W, Vanholder R. An international analysis of dialysis services reimbursement. Clin J Am Soc Nephrol. 2019;14(1):84–93.
11. Elshahat S, Cockwell P, Maxwell AP, Griffin M, O’Brien T, O’Neill C. The impact of chronic kidney disease on developed countries from a health economics perspective: A systematic scoping review. PLoS One. 2020;15(3):e0230512.
12. George C, Mogueo A, Okpechi I, Echouffo-Tcheugui JB, Kengne AP. Chronic kidney disease in low-income to middle-income countries: The case f increased screening. BMJ Glob Heal. 2017;2(2):e000256.
13. Kessler M, Frimat L, Panescu V, Briançon S. Impact of nephrology referral on early and midterm outcomes in ESRD: Epidémiologie de l’insuffisance REnale chronique terminale en Lorraine (EPIREL): Results of a 2-year, prospective, community-based study. Am J Kidney Dis. 2003;42(3):474–485.
14. Schwenger V, Morath C, Hofmann A, Hoffmann O, Zeier M, Ritz E. Late referral - A major cause of poor outcome in the very elderly dialysis patient. Nephrol Dial Transplant. 2006;21(4):962–967.
15. Blunt I, Bardsley M, Strippoli GFM. Pre-dialysis hospital use and late referrals in incident dialysis patients in England: A retrospective cohort study. Nephrol Dial Transplant. 2015;30(1):124–129.
16. Curtis S, Komenda P. Screening for chronic kidney disease: Moving toward more sustainable health care. Curr Opin Nephrol Hypertens. 2020;29(3):333–338.
17. Luyckx VA, Tonelli M, Stanifer JW. The global burden of kidney disease and the sustainable development goals. Bull World Health Organ. 2018;96(6):414-422C.
18. Gross O, Licht C, Anders HJ, Hoppe B, Beck B, Tönshoff B, et al. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012;81(5):494–501.
19. Gheewala PA, Zaidi STR, Jose MD, Bereznicki L, Peterson GM, Castelino RL. Effectiveness of targeted screening for chronic kidney disease in the community setting: a systematic review. J Nephrol. 2018;31(1):27–36.
20. Tonelli M, Dickinson JA. Early Detection of CKD: Implications for Low-Income, Middle-Income, and High-Income Countries. J Am Soc Nephrol. 2020;31(9):1931–1940.
21. Piccoli G, Cabiddu G, Breuer C, Jadeau C, Testa A, Brunori G. Dialysis Reimbursement: What Impact Do Different Models Have on Clinical Choices? J Clin Med. 2019;8(2):276.
22. Neale EP, Middleton J, Lambert K. Barriers and enablers to detection and management of chronic kidney disease in primary healthcare: A systematic review. BMC Nephrol. 2020;21(1):1–17.
23. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020;98(4):S1–S115.
24. Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: A guidance statement update from the American college of physicians. Ann Intern Med. 2018;168(8):569–576.
25. Cheung AK, Chang TI, Cushman WC, Furth SL, Hou FF, Ix JH, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021;99(3):S1–S87.
26. Jankowski J, Floege J, Fliser D, Böhm M, Marx N. Cardiovascular Disease in Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options. Circulation. 2021;143:1157–1172.
27. Williams B, Mancia G, Spiering W, Rosei EA, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for themanagement of arterial hypertension. Eur Heart J. 2018;39(33):3021–3104.
28. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC IS. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):17–18.
29. Braun LA, Sood V, Hogue S, Lieberman B, Copley-Merriman C. High burden and unmet patient needs in chronic kidney disease. Int J Nephrol Renovasc Dis. 2012;5:151–163.
30. Romagnani P, Remuzzi G, Glassock R, Levin A, Jager KJ, Tonelli M, et al. Chronic kidney disease. Nat Rev Dis Prim. 2017;3.
31. Stevens LA, Li S, Wang C, Huang C, Becker BN, Bomback AS, et al. Prevalence of CKD and Comorbid Illness in Elderly Patients in the United States: Results From the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis. 2010;55(3 SUPPL. 2). doi:10.1053/j.ajkd.2009.09.035.
32. Zhang QL, Rothenbacher D. Prevalence of chronic kidney disease in population-based studies: Systematic review. BMC Public Health. 2008;8:117.
33. Almutary H, Bonner A, Douglas C. Symptom burden in chronic kidney disease: A review of recent literature. J Ren Care. 2013;39(3):140–150.
34. Jager KJ, Fraser SDS. The ascending rank of chronic kidney disease in the global burden of disease study. Nephrol Dial Transplant. 2017;32(suppl_2):ii121–ii128.
35. Kassebaum NJ, Arora M, Barber RM, Brown J, Carter A, Casey DC, et al. Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1603–1658.
36. Thomas B, Matsushita K, Abate KH, Al-Aly Z, Ärnlöv J, Asayama K, et al. Global cardiovascular and renal outcomes of reduced GFR. J Am Soc Nephrol. 2017;28(7):2167–2179.
37. Wang H, Naghavi M, Allen C, Barber RM, Carter A, Casey DC, et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459–1544.
38. Nitsch D, Grams M, Sang Y, Black C, Cirillo M, Djurdjev O, et al. Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: A meta-analysis. BMJ. 2013;346(7895). doi:10.1136/bmj.f324.
39. Porter A, Fischer MJ, Brooks D, Bruce M, Charleston J, Cleveland WH, et al. Quality of life and psychosocial factors in African Americans with hypertensive chronic kidney disease. Transl Res. 2012;159(1):4–11.
40. Nulsen RS, Yaqoob MM, Mahon A, Stoby-Fields M, Kelly M, Varagunam M. Prevalence of cognitive impairment in patients attending pre-dialysis clinic. J Ren Care. 2008;34(3):121–126.
41. Mujais SK, Story K, Brouillette J, Takano T, Soroka S, Franek C, et al. Health-related quality of Life in CKD patients: Correlates and evolution over time. Clin J Am Soc Nephrol. 2009;4(8):1293–1301.
42. Molsted S, Prescott L, Heaf J, Eidemak I. Assessment and clinical aspects of health-related quality of life in dialysis patients and patients with chronic kidney disease. Nephron - Clin Pract. 2007;106(1). doi:10.1159/000101481.
43. Krishnan A V., Kiernan MC. Neurological complications of chronic kidney disease. Nat Rev Neurol. 2009;5(10):542–551.
44. Gorodetskaya I, Zenios S, McCulloch CE, Bostrom A, Hsu CY, Bindman AB, et al. Health-related quality of life and estimates of utility in chronic kidney disease. Kidney Int. 2005;68(6):2801–2808.
45. Chin HJ, Song YR, Lee JJ, Lee SB, Kim KW, Na KY, et al. Moderately decreased renal function negatively affects the health-related quality of life among the elderly Korean population: A population-based study. Nephrol Dial Transplant. 2008;23(9):2810–2817.
46. Vekeman F, Yameogo ND, Lefebvre P, Bailey RA, McKenzie RS, Piech CT. Healthcare costs associated with nephrology care in pre-dialysis chronic kidney disease patients. J Med Econ. 2010;13(4):673–680.
47. St. Peter WL, Khan SS, Ebben JP, Pereira BJG, Collins AJ. Chronic kidney disease: The distribution of health care dollars. Kidney Int. 2004;66(1):313–321.
48. Mix TCH, St. Peter WL, Ebben J, Xue J, Pereira BJG, Kausz AT, et al. Hospitalization During Advancing Chronic Kidney Disease. Am J Kidney Dis. 2003;42(5):972–981.
49. Alexander M, Bradbury BD, Kewalramani R, Barlev A, Mohanty SA, Globe D. Chronic kidney disease and us healthcare resource utilization in a nationally representative sample. Am J Nephrol. 2009;29(5):473–482.
50. Smith DH, Gullion CM, Nichols G, Keith DS, Brown JB. Cost of Medical Care for Chronic Kidney Disease and Comorbidity among Enrollees in a Large HMO Population. J Am Soc Nephrol. 2004;15(5):1300–1306.
51. Khan SS, Kazmi WH, Abichandani R, Tighiouart H, Pereira BJG, Kausz AT. Health care utilization among patients with chronic kidney disease. Kidney Int. 2002;62(1):229–236.
52. Robbins JD, Kim JJ, Zdon G, Chan WW, Jones J. Resource use and patient care associated with chronic kidney disease in a managed care setting. J Manag Care Pharm. 2003;9(3):238–247.
53. London R, Solis A, Goldberg GA, Wade S, Chan WW. Examination of resource use and clinical interventions associated with chronic kidney disease in a managed care population. J Manag Care Pharm. 2003;9(3):248–255.
54. Kubacki M, Carter C, Herrera ADL, Wang J, Lopez JM, Piech CT. Health plan retention and pharmacy costs of newly diagnosed patients with chronic kidney disease in a managed care population. Am Heal Drug Benefits. 2009;2(7):283–290.
55. Baumeister SE, Böger CA, Krämer BK, Döring A, Eheberg D, Fischer B, et al. Effect of chronic kidney disease and comorbid conditions on health care costs: A 10-year observational study in a general population. Am J Nephrol. 2010;31(3):222–229.
56. Papatheofanis F, Bookhart BK, Muser E, Piech CT. An examination of productivity and resource utilization associated with epoetin alfa treatment in employees with predialysis chronic kidney disease. J Occup Environ Med. 2008;50(5):584–589.
57. Sullivan S. Employer challenges with the chronic kidney disease population. J Manag Care Pharm. 2007;13(9 SUPPL. D). doi:10.18553/jmcp.2007.13.9-d.19.
58. Taylor TN, Salinitri FD, Satterthwaite DW. Puk9 Medical Care Spending Associated With Chronic Kidney Disease By Stage of Disease: a Population-Based Study. Value Heal. 2011;14(3):A75.
59. Moyneur É, Bookhart BK, Mody SH, Fournier AA, Mallett D, Duh MS. The economic impact of pre-dialysis epoetin alfa on health care and work loss costs in chronic kidney disease: An employer’s perspective. Dis Manag. 2008;11(1):49–58.
60. Ershler WB, Chen K, Reyes EB, Dubois R. Economic burden of patients with anemia in selected diseases. Value Heal. 2005;8(6):629–638.
61. Nissenson AR, Collins AJ, Hurley J, Petersen H, Pereira BJG, Steinberg EP. Opportunities for improving the care of patients with chronic renal insufficiency: Current practice patterns. J Am Soc Nephrol. 2001;12(8):1713–1720.
62. Luyckx VA, Tuttle KR, Garcia-Garcia G, Gharbi MB, Heerspink HJL, Johnson DW, et al. Reducing major risk factors for chronic kidney disease. Kidney Int Suppl. 2017;7(2):71–87.
63. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal Follow-up and Outcomes among a Population with Chronic Kidney Disease in a Large Managed Care Organization. Arch Intern Med. 2004;164(6):659–663.
64. Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease - A systematic review and meta-analysis. PLoS One. 2016;11(7):e0158765.
65. Kronenberg F. Emerging risk factors and markers of chronic kidney disease progression. Nat Rev Nephrol. 2009;5(12):677–689.
66. Merker L. Nephropathy in diabetes. MMW-Fortschritte der Medizin. 2021;163(8):48–51.
67. Stanifer JW, Kilonzo K, Wang D, Su G, Mao W, Zhang L, et al. Traditional Medicines and Kidney Disease in Low- and Middle-Income Countries: Opportunities and Challenges. Semin Nephrol. 2017;37(3):245–259.
68. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: Global dimension and perspectives. Lancet. 2013;382(9888):260–272.
69. Khalsa DDK, Beydoun HA, Carmody JB. Prevalence of chronic kidney disease risk factors among low birth weight adolescents. Pediatr Nephrol. 2016;31(9):1509–1516.
70. Charlton JR, Springsteen CH, Carmody JB. Nephron number and its determinants in early life: a primer. Pediatr Nephrol. 2014;29(12):2299–2308.
71. Gansevoort RT, Hilbrands LB. CKD is a key risk factor for COVID-19 mortality. Nat Rev Nephrol. 2020;16(12):705–706.
72. Eckardt KU, Alper SL, Antignac C, Bleyer AJ, Chauveau D, Dahan K, et al. Autosomal dominant tubulointerstitial kidney disease: Diagnosis, classification, and management - A KDIGO consensus report. Kidney Int. 2015;88(4):676–683.
73. Trautmann A, Bodria M, Ozaltin F, Gheisari A, Melk A, Azocar M, et al. Spectrum of steroid-resistant and congenital nephrotic syndrome in children: The podoNet registry cohort. Clin J Am Soc Nephrol. 2015;10(4):592–600.
74. Oliveira B, Kleta R, Bockenhauer D, Walsh SB. Genetic, pathophysiological, and clinical aspects of nephrocalcinosis. Am J Physiol - Ren Physiol. 2016;311(6):F1243–F1252.
75. Faronato PP, Maioli M, Tonolo G, Brocco E, Noventa F, Piarulli F, et al. Clustering of albumin excretion rate abnormalities in caucasian patients with NIDDM. Diabetologia. 1997;40(7):816–823.
76. Vivante A, Hildebrandt F. Exploring the genetic basis of early-onset chronic kidney disease. Nat Rev Nephrol. 2016;12(3):133–146.
77. Komenda P, Lavallee B, Ferguson TW, Tangri N, Chartrand C, McLeod L, et al. The Prevalence of CKD in Rural Canadian Indigenous Peoples: Results From the First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis (FINISHED) Screen, Triage, and Treat Program. Am J Kidney Dis. 2016;68(4):582–590.
78. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science (80- ). 2010;329(5993):841–845.
79. Gifford FJ, Gifford RM, Eddleston M, Dhaun N. Endemic Nephropathy Around the World. Kidney Int Reports. 2017;2(2):282–292.
80. Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: A worldwide epidemic with social, occupational and environmental determinants. Nephrol Dial Transplant. 2017;32(2):234–241.
81. Glaser J, Lemery J, Rajagopalan B, Diaz HF, García-Trabanino R, Taduri G, et al. Climate change and the emergent epidemic of CKD from heat stress in rural communities: The case for heat stress nephropathy. Clin J Am Soc Nephrol. 2016;11(8):1472–1483.
82. López-Novoa JM, Rodríguez-Peña AB, Ortiz A, Martínez-Salgado C, López Hernández FJ. net Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications. J Transl Med. 2011;9(1):1–26.
83. Bohle A, Kressel G, Müller CA, Müller GA. The Pathogenesis of Chronic Renal Failure. Pathol Res Pract. 1989;185(4):421–440.
84. Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE. Human nephron number: Implications for health and disease. Pediatr Nephrol. 2011;26(9):1529–1533.
85. Fattah H, Layton A, Vallon V. How Do Kidneys Adapt to a Deficit or Loss in Nephron Number? Physiology (Bethesda). 2019;34(3):189–197.
86. Benghanem Gharbi M, Elseviers M, Zamd M, Belghiti Alaoui A, Benahadi N, Trabelssi EH, et al. Chronic kidney disease, hypertension, diabetes, and obesity in the adult population of Morocco: how to avoid “over”- and “under”-diagnosis of CKD. Kidney Int. 2016;89(6):1363–1371.
87. Laouari D, Burtin M, Phelep A, Martino C, Pillebout E, Montagutelli X, et al. TGF-α mediates genetic susceptibility to chronic kidney disease. J Am Soc Nephrol. 2011;22(2):327–335.
88. Ruggenenti P, Cravedi P, Remuzzi G. Mechanisms and treatment of CKD. J Am Soc Nephrol. 2012;23(12):1917–1928.
89. Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: Definitions, mechanisms and clinical implications. Nat Rev Nephrol. 2012;8(5):293–300.
90. Rizzo P, Perico N, Gagliardini E, Novelli R, Alison MR, Remuzzi G, et al. Nature and mediators of parietal epithelial cell activation in glomerulonephritides of human and rat. Am J Pathol. 2013;183(6):1769–1778.
91. Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol. 2006;17(11):2974–2984.
92. Clark WF, Macnab JJ, Sontrop JM, Jain AK, Moist L, Salvadori M, et al. Dipstick proteinuria as a screening strategy to identify rapid renal decline. J Am Soc Nephrol. 2011;22(9):1729–1736.
93. Schnaper HW. The Tubulointerstitial Pathophysiology of Progressive Kidney Disease. Adv Chronic Kidney Dis. 2017;24(2):107–116.
94. Kaissling B, LeHir M, Kriz W. Renal epithelial injury and fibrosis. Biochim Biophys Acta - Mol Basis Dis. 2013;1832(7):931–939.
95. Peired A, Angelotti ML, Ronconi E, La Marca G, Mazzinghi B, Sisti A, et al. Proteinuria impairs podocyte regeneration by sequestering retinoic acid. J Am Soc Nephrol. 2013;24(11):1756–1768.