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Disinformation:

This site pushed illegitimate information on alternative "medicine" for Chronic Kidney Disease with the intent to mislead patients. It sells natural supplements intended to "cure" CKD, and backs them up with likely fake user reviews.

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If the patient recognizes the symptoms of kidney failure on time and chooses the proper method for treatment, along with starting caring for their health, he can reverse kidney disease. Reverse kidney disease treatment depends on the condition and stage of the disease, and Ayurveda is one of the best ways to cure any disease with no side effects. In Ayurveda, we work on the root causes of the disease. In allopathic, there is no cure for the kidney. They only have only two options first is dialysis, and the second last is a transplant, but Ayurveda cures the kidney and starts naturally functioning.

So here, you will get to know how you can reverse your kidney disease with the help of ayurvedic treatment.

Usually, kidney failure occurs when the kidney loses the ability to perform its functions. The kidney decreases its functioning and wastes materials like creatinine, urea, sodium, and potassium start accumulating in the body. So, every kidney patient needs to balance the expected level of potassium to reverse kidney disease. The kidney sends toxins to the bladder, which the body later removes toxins during urination.

Some factors can affect the kidney's health and function:

Sometimes, the overloaded body with toxins can be life-threatening if left untreated. Such as:

In Sai Sanjeevani, we provide Kidney Function Restoration Treatment (KFRT), which helps control the root cause of kidney failure (hypertension, diabetes, IgA nephropathy, and polycystic kidney) and reverse kidney disease.

Leading cause of kidney damage.

1. High blood pressure damages the small blood vessels in the kidneys. The kidneys cannot filter the blood precisely due to the shrinkage in the blood vessel. High blood pressure also develops heart disease. It is necessary to control the blood pressure to High blood pressure: reverse kidney disease.

2. Diabetes: Diabetes is a condition characterized by high blood glucose (sugar) levels. High levels of sugar in the blood damage the millions of tiny filtering units within each kidney. It can eventually lead to kidney failure.

3. Taking multiple pills: We are taking various pills for minor illnesses like cold, fever, headache, stomach ache, etc., which leads to chemical reactions and causes kidney damage. The combination of numerous medicines with caffeine makes the kidney worse.

4. Alcohol: Alcohol is a hazardous drug that damages the kidney and lungs. Nowadays, every alcoholic drinker is suffering from kidney damage. So a person needs to avoid alcohol to reverse kidney disease.

5. Heart and blood vessel disease: High blood pressure shrinks the blood vessel, and because of shrinkage kidney can't filter blood, and waste develops in a considerable amount.

Symptoms of kidney disease:

Having more than one symptom may be a sign of severe kidney problems. So, if you notice any of these symptoms, you should contact your doctor as soon as possible to reverse your kidney disease.

Abdominal (belly) pain: Patients may feel side belly pain. Pain can be worse and average. Collection of the vast amount of waste product and fluid can cause Abdominal (belly) pain.

More tired, less energy: It is very typical that if kidney function decreases, it can build up toxins and waste material in the blood. Eventually, this can cause people to feel tired, weak, and it isn't easy to concentrate on work. Anemia is one of the other complications of kidney disease, which leads to weakness and fatigue.

Trouble sleeping: When the kidneys cannot work properly, toxins stay in the blood instead of leaving the body through urine, making it difficult for a person to sleep. So if we talk about trouble sleeping, it is usually most common in a person suffering from chronic kidney disease compared to the general population.

Dry and itchy skin: The kidney performs much essential work in our body, as it removes the waste material and extra fluid from the body to make the red blood cells or keep bones strong that will help maintain the right amount of minerals in your blood. So that dry and itchy skin can be a sign of mineral and bone disease.

A patient with Urinate more often: kidney failure usually feels like urinating more often, especially at night. Increase in the urge to urinate more often especially happens when the kidney filters are damaged. Maybe sometimes it can also be a sign of urinary infection.

Blood in the urine: The kidney primarily works to keep the blood cells in the body while filtering the waste from the blood to create urine. But when the function of the kidney decreases, these blood cells start to leak out into the urine. Even blood in the urine can also be an indication of kidney stones or an infection.

Foamy urine: Bubbles in the urine that require flushing several times before they go away indicate protein in the urine. It looks like a kind of foam that you usually see while scrambling eggs. For example, the protein found in urine is similar to the protein that is found in eggs.

Puffiness around eyes: Puffiness around the eyes happens because kidneys leak a large amount of protein in the urine rather than keeping it in the body. If we talk about the protein in the urine, it is one of the early signs that kidney filters have been damaged.

Ankles and feet are swollen: Swelling in the ankles and feet is caused due to sodium retention, which happens because of decreased function of the kidney. It can also be a symptom of liver disease and heart disease.

Poor appetite is one of the very general symptoms of Poor appetite: kidney failure, as the buildup of toxins results in reduced kidney function.

Muscles cramps: The main reason behind muscle cramps is low calcium level and poorly controlled phosphorus. Also, electrolyte imbalances can result from impaired kidney function.

Nausea and vomiting: Nausea and vomiting include the buildup of uremic toxins, medications, gastroparesis, ulcers, gastroesophageal reflux disease, gallbladder disease, and it is very common in kidney patients.

Shortness of breath: Shortness of breath can be related to the kidneys in two ways:-

1. Extra fluid in the body can be built up in the lungs

2. Shortage of oxygen-carrying red blood cells can leave your body oxygen-starved and short of breath

Healthy and proper diet: Following a healthy and paper diet (Including a variety of grains (primarily whole grains), fresh fruits, and vegetables) and less sodium (salt) intake can help a patient to reverse kidney disease. In Ayurveda treatment, we provide a personalized diet chart to every patient.

Keep blood pressures in control to reverse kidney disease: Blood pressure should be controlled to less than 120/80 if you have CKD. Keep managing stress levels because stress increases high blood pressure. To maintain your stress level in control, do some yoga and breathing exercises.

Keep blood sugar or diabetes in control: The diet must include lots of fruits, whole grains, vegetables, turkey, chicken, and fish in your diet. You should be aware that your diet does not hold high levels of sugar and calories. The diet should also not have high levels of salt and sodium.

Exercise regularly: Exercise is beneficial for kidney patients. It helps patients to be healthy and energetic. the patient should include walking for 30 minutes three times a week or more in lifestyle.

Conclusion

If a person is facing any symptoms of kidney disease, then they are advised to do some tests like KFT and urine tests.

At SRIAAS, Dr. Puru Dhawan helps to reverse kidney disease by providing a customized diet and curated therapy to increase the GFR and reduce the creatinine from the body. With the help of Ayurveda, the results of kidney treatment can be seen within a month.

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If the patient recognizes the symptoms of kidney failure on time and chooses the proper method for treatment, along with starting caring for their health, he can reverse kidney disease. Reverse kidney disease treatment depends on the condition and stage of the disease, and Ayurveda is one of the best ways to cure any disease with no side effects.

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Disinformation:

This site uses a personal story to make unlikely claims which are aimed at selling the sites cook-books, courses, and magazines. It claims that in this individual, CKD was reversed, her gout was cured, lowered her blood pressure, cured arthritis, and improved energy within three weeks. There was no evidence based research, but rather anecdotal evidence.

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Reversing Chronic Kidney Disease with a Plant-Based Diet

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Yvonne shares how she is reversing chronic kidney disease, has cured her gout, and has lowered her blood pressure in a short timejust by changing her diet.

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Misinformation:

This Facebook group provides a place for people affected with CKD to share their experience and connect with others. While this may be a great place for support, there is often inaccurate information shared about diet or treatment. Additionally, personal information related to prognosis and treatment is shared, which varies for everyone.

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Log into Facebook to start sharing and connecting with your friends, family, and people you know.

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Misinformation:

This instagram blog aims to share "Miss CKD"'s experience and advice with the chronic kidney disease. While some information she shares might be helpful, she is simply sharing her own experience or opinions. There is no evidence based information provided, and it is purely based on her perspective and understanding of the illness. An example of this advice was in one of her posts, where she recommended individuals, "stack up on pain relief".

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Credible Information:

This source was published to the National Quality Forum, a non-profit, non-partisan organization with the goal of improving health outcomes and equity. This specific technical report was funded by the Department of Health and Human Services.

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Renal disease is a leading cause of morbidity and mortality in the United States. More than 20 million adults in the United States (10 percent of the population) have chronic kidney disease (CKD). Untreated CKD can result in end-stage renal disease (ESRD) and a host of other health complications. Currently, over half a million people in the United States have received a diagnosis of ESRD, which is the only chronic disease covered by Medicare for people under the age of 65. Considering the high mortality rates and high healthcare utilization and costs associated with ESRD, the need to focus on quality measures for patients with renal disease is particularly important. On June 18 and 19, 2018, NQF convened a multi-stakeholder Standing Committee composed of 25 individuals to evaluate two new measures and make recommendations for endorsement. On January 30 and 31, 2019, the Committee re-evaluated the two measures based on the developer's reconsideration request. Ultimately, the Committee did not recommend either measure for endorsement. The CSAC upheld the Committee's recommendation to not endorse either measures.

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Renal Spring 2018-Fall 2018 Cycle - Technical Report

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Renal disease is a leading cause of morbidity and mortality in the United States. More than 20 million adults in the United States (10 percent of the population) have chronic kidney disease (CKD). Untreated CKD can result in end-stage renal disease (ESRD) and a host of other health complications.

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Credible Information:

This source compiled information from many evidence based, peer reviewed references. Funding for this report was provided by an unrestricted educational grant.

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Abstract

Chronic kidney disease is a progressive condition that affects >10% of the general population worldwide, amounting to >800 million individuals. Chronic kidney disease is more prevalent in older individuals, women, racial minorities, and in people experiencing diabetes mellitus and hypertension. Chronic kidney disease represents an especially large burden in low- and middle-income countries, which are least equipped to deal with its consequences. Chronic kidney disease has emerged as one of the leading causes of mortality worldwide, and it is one of a small number of non-communicable diseases that have shown an increase in associated deaths over the past 2 decades. The high number of affected individuals and the significant adverse impact of chronic kidney disease should prompt enhanced efforts for better prevention and treatment.

Keywords: chronic kidney disease, mortality, prevalence, risk factors

Graphical abstract

Chronic kidney disease (CKD) has emerged as one of the most prominent causes of death and suffering in the 21 st century. Due in part to the rise in risk factors, such as obesity and diabetes mellitus, the number of patients affected by CKD has also been increasing, affecting an estimated 843.6 million individuals worldwide in 2017.¹ Although mortality has declined in patients with end-stage kidney disease (ESKD),² the Global Burden of Disease (GBD) studies have shown that CKD has emerged as a leading cause of worldwide mortality.³,⁴ It is, therefore, paramount that CKD is identified, monitored, and treated, and that preventative and therapeutic measures addressing CKD are systematically implemented worldwide. This narrative review summarizes information about global CKD prevalence, its trends over time, its various determinants, and its associated mortality. Other aspects of kidney disease epidemiology, such as CKD in pediatric patients, CKD incidence, progression to ESKD, or various clinical (e.g., cardiovascular disease) and patient-reported outcomes caused by CKD, are mentioned briefly or not discussed.

Definitions of CKD and its pitfalls in epidemiologic studies

The diagnosis of CKD is made by laboratory testing, most often by estimating glomerular filtration rate (GFR) from a filtration marker, such as serum creatinine or cystatin C, using various formulas, or by testing urine for the presence of albumin or protein (or a combination of these).⁵ The classification schemas advocated by various professional organizations in the past 2 decades⁵ have laid the groundwork for the systematic detection and monitoring of CKD worldwide, resulting in an improved understanding of its prevalence and the resulting impact on outcomes, such as mortality. Most studies have used estimated GFR (eGFR) to determine the presence of CKD (and, therefore, report on the prevalence of CKD stages 3-5), whereas other studies have combined albuminuria (typically defined as an albumin-to-creatinine ratio of >30 mg/g) and decreased eGFR to report on CKD stages 1-5. Finally, to differentiate CKD (which is considered to be a chronic progressive disease) from conditions such as acute kidney injury or from transient fluctuations in kidney function unrelated to kidney damage, the standard definition of CKD includes a so-called "chronicity criterion" (i.e., that the low eGFR or elevated urine albumin should be detectable for at least 90 days, requiring the presence of repeated measurements over time).⁵ There is currently no consensus on the length of time used in the assessment of CKD when applying the chronicity criterion, with epidemiologic studies applying various algorithms, from single measurements to any repeated measurements past 90 days, or limiting the repeated measurement(s) to 90 to 365 days, and from requiring consecutive repeated markers of CKD to accepting CKD markers interspersed with markers not conforming to CKD criteria. The potential impact of using 6 different definition algorithms (5 laboratory measurement based and one based on International Classification of Diseases [ICD] diagnostic codes) to ascertain the prevalence of CKD was recently examined in a population-based cohort from Northern Denmark.⁶ The prevalence of CKD varied considerably between the various laboratory-based definitions, ranging from 8327 cases per 100,000 population when using a single eGFR value to 4637 cases per 100,000 population when using a time-limited repeated eGFR-based definition. Furthermore, when using an ICD diagnostic code-based definition, the prevalence of CKD was markedly lower, at 775 cases per 100,000 population. Studies assessing the prevalence of CKD have applied a variety of definitions of CKD, and thus their results (and especially the results of studies aggregating their findings, as described below) must be interpreted with caution.

Prevalence and global burden of CKD

The prevalence of CKD has been reported in an increasing number of studies worldwide (the individual discussion of which is beyond the scope of this review), which has made it possible to aggregate their findings and to derive information about global CKD prevalence overall, as well as in various patient subgroups and geographic regions. A study assessing the prevalence and burden of CKD in 2010 pooled the results of 33 population-based representative studies from around the world and reported an age-standardized global prevalence of CKD stages 1-5 in individuals aged ≥20 years of 10.4% among men and 11.8% among women.⁷ The study reported important differences by geographic region classified by income level, with a CKD age-standardized prevalence of 8.6% and 9.6% in men and women, respectively, in high-income countries, and 10.6% and 12.5% in men and women, respectively, in low- and middle-income countries. The age-standardized global prevalence of CKD stages 3-5 in adults aged ≥20 years in the same study was 4.7% in men and 5.8% in women. A more recent study performed a comprehensive systematic review and meta-analysis of 100 studies comprising 6,908,440 patients, and reported a global prevalence of 13.4% for CKD stages 1-5 and 10.6% for CKD stages 3-5.⁸ The prevalence of the individual CKD stages was 3.5% (stage 1), 3.9% (stage 2), 7.6% (stage 3), 0.4% (stage 4), and 0.1% (stage 5).⁸ On the basis of the results of studies examining the global prevalence of CKD, the current total number of individuals affected by CKD stages 1-5 worldwide was estimated to be 843.6 million.¹

Changes in CKD prevalence over time

There are significantly fewer studies examining changes in CKD prevalence over time, as this requires a reassessment of the same population using similar methods. In the United States, the Centers for Disease Control and Prevention CKD Surveillance System reported that the prevalence of CKD stages 1-4 was 11.8% in 1988 to 1994, and it increased to 14.2% in 2015 to 2016.⁹ This increase was not linear, as was reported by a study examining data from the National Health and Nutrition Examination Survey; this study showed that although the prevalence of CKD stage 3-4 increased from the 1990s to the 2000s, it has remained largely stable since.¹⁰ A similarly stable prevalence of CKD stages 1-5 was reported in Norway for the time period between 1995 and 2008.¹¹ Interestingly, the prevalence of CKD stages 3-5 declined significantly over 7 years in the United Kingdom based on the nationally representative Health Survey for England. In this study, the adjusted odds ratio of an eGFR <60 ml/min per 1.73 m ² comparing 2003 with 2009/2010 was 0.73 (95% confidence interval, 0.57-0.93).¹² The reasons for recently reported stabilized or improved CKD prevalence are unclear. These trends have occurred despite a concomitant increase in common risk factors of CKD, such as diabetes and obesity, although hypertension control has improved over this time period.¹² It is worth mentioning that, due to population growth, a stable trend in CKD prevalence still represents an increase in the absolute number of patients with CKD. The reason(s) for the observed dynamic changes in CKD prevalence (and the discrepancies observed between the data from different countries) is difficult to determine. Disease prevalence could vary due to changes in disease incidence, but information about CKD incidence is much sparser in the literature, and the results of published studies cannot be interpreted in the context of prevalence estimates performed in different populations and different eras, 13, 14, 15, 16, 17 due to the major impact of characteristics, such as age, sex, or race, on incidence values. Prevalence can also change because of changes in survival or longer lifetime duration of diagnosed CKD (e.g., from better screening); it is possible that the aggregate change in CKD prevalence may be the result of a combination of factors.

Effect of patient characteristics and comorbidities on CKD prevalence

The prevalence of CKD is affected by both its definition and its pathophysiology. Because most CKD cases are identified using eGFR, its determinants will impact the estimates of CKD prevalence. Most important, higher age results in lower eGFR independent of the other components of the equation; hence, even with a stable serum creatinine concentration, an individual can develop CKD as a result of advancing age due to the assumption that age-related losses in muscle mass will obscure the decrease in age-associated losses in GFR. Indeed, the aforementioned meta-analysis by Hill et al. assessed the impact of age on CKD prevalence and reported a linearly higher prevalence for CKD stages 1-5 associated with advancing age, ranging from 13.7% in the 30- to 40-year-old group to 27.9% in patients aged >70 to 80 years.⁸ Similar trends were reported in the United States during 2015 to 2016, where the prevalence of CKD stages 1-4 was 5.6% among individuals aged 20 to 39 years and 44% among those aged >70 years.⁹ Notwithstanding the biological plausibility of age-associated loss of GFR, the pathologic significance of early-stage (i.e., stage 3a) CKD that is solely a result of advanced age (and characterized by normal urine albumin and serum creatinine values) continues to be debated.¹⁸

The prevalence of CKD has been reported to be higher in females than in males. In the United States, the age-adjusted prevalence of CKD stages 1-4 in 2015 to 2016 was 14.9% in females and 12.3% in males,⁹ similar to the sex-based differences reported in the global studies mentioned above.⁷,⁸ The reasons for these differences are unclear and are likely to be complex. Although GFR estimating equations include a correction factor for sex, a single cutoff of <60 ml/min per 1.73 m ² for CKD definition may result in overdiagnosing CKD in women.¹⁹ The higher CKD prevalence described in women also contrasts with experimental data showing the protective effects of estrogen and potential deleterious effects of testosterone on nondiabetic CKD,²⁰ as well as data that indicate a higher incidence of kidney failure in men.²¹,²² A meta-analysis of 30 studies examining sex-stratified data concluded that CKD progression was faster in men compared with women,²³ although other studies have cautioned that such differences may be due to nonbiological factors, such as lifestyle, cultural, and socioeconomic factors.²⁴ Better characterization of the effects of sex on CKD incidence, prevalence, and progression requires further examination, including the study of potential development of sex-specific disease markers.¹⁹

Racial differences in the incidence and prevalence of CKD and kidney failure are well described in the United States, 25, 26, 27 but a global and systematic evaluation of such differences is difficult because variances between countries are complex and represent a combination of risk factors (including differences in race). Furthermore, within-country comparisons may not always be possible due to racial/ethnic homogeneities and/or local restrictions on reporting individuals' race and ethnicity. An additional challenge is the inaccuracy of GFR estimation formulas in individuals of different races, and an ongoing debate in the United States over the exclusion of the correction factor for self-reported African American race from the existing estimation formulas as a means to alleviate racial disparities.²⁸ In the United States, the age-adjusted prevalence of CKD stages 1-4 among non-Hispanic Whites, non-Hispanic Blacks, and Mexican Americans in 2015 to 2016 was 13%, 16.5%, and 15.3%, respectively.⁹ The reasons for race-associated differences are complex, and include differences in the prevalence of CKD risk factors (such as diabetes mellitus, hypertension, and obesity), genetic causes, lifestyle and cultural differences, and socioeconomic disparities. 29, 30, 31, 32

Diabetes mellitus has emerged as the most important risk factor for CKD in the developed world; this is reflected in studies examining CKD prevalence. In the United States, the prevalence of CKD stages 3-4 among diagnosed diabetics was 24.5% in 2011 to 2014, whereas in prediabetics it was 14.3% and in nondiabetics it was 4.9%.⁹ The association between diabetes mellitus and the prevalence of CKD was also reported in a meta-analysis that included 82 global studies.⁸ The effect of diabetes mellitus on kidney function and on the development and progression of CKD is well established.³³ Nevertheless, epidemiologic studies examining CKD in diabetics have to contend with the fact that diabetic populations (especially type 2 diabetics) often experience multiple other comorbid conditions, such as hypertension or vascular disease, which are themselves independent risk factors for CKD. A study examining a national cohort of US veterans with newly diagnosed type 2 diabetes mellitus reported a crude prevalence of CKD stages 1-5 of 31.6%, half of whom had CKD stages 3-5.³⁴ Although the timing of incident type 2 diabetes mellitus is difficult to ascertain, the high prevalence of CKD in this study suggests that at least some of the CKD cases diagnosed in diabetics may not be a direct result of diabetes-related mechanisms.

Hypertension is the strongest cardiovascular risk factor worldwide and is also closely associated with CKD.³⁵ The prevalence of CKD among hypertensive US adults was 35.8% in 2011 to 2014, compared with a prevalence of 14.4% in prehypertensives and 10.2% among nonhypertensive individuals.⁹ A significant association between hypertension and the prevalence of CKD was also reported in a meta-analysis that included 75 global studies.⁸

Mortality associated with CKD

CKD is now widely recognized as one of the leading causes of death worldwide. The GBD reports have been tracking causes of death across the globe for the past decade. The 2013 GBD report indicated that although relative death rates decreased for most communicable and noncommunicable diseases, CKD (defined as all stages, including patients on dialysis) was one of only a handful of conditions to show an increase since 1990.³,⁴ The global all-age mortality rate attributed to CKD increased by 41.5% between 1990 and 2017.³⁶ Besides being one of the leading causes of death, CKD also became the 19th leading cause of years of life lost (which is calculated from the number of deaths attributable to CKD and the life expectancy of individuals in various age groups at the time of their death from CKD³) in 2013, compared with being the 36th leading cause in 1990.³ Subsequent GBD reports indicate that the rise of CKD among the list of causes of death has continued, occupying the 13th place in 2016³⁷ and 12th place in 2017,³⁶ with predictions suggesting that it will become the fifth highest cause of years of life lost globally by 2040.³⁸ The GBD reports also shed light on the disproportionate nature of the burden imparted by CKD-associated death in different world regions, with Latin America, the Caribbean region, Southeast Asia and East Asia, Oceania, North Africa, and the Middle East being especially affected. Among high-income nations, CKD was among the top 10 causes of death in Singapore, Greece, and Israel ( Figure 1 ).³,⁴ These reports are especially noteworthy when considering that they did not include deaths that were caused indirectly by CKD, such as those related to acute kidney injury or to various cardiovascular causes, both of which can be caused or potentiated by CKD.⁴

Conclusions

CKD is extremely common and has emerged as one of the leading noncommunicable causes of death worldwide. It is projected to affect an increasing number of individuals over time and to further rise in importance among the various global causes of death. CKD affects populations in different regions of the world unequally, likely as a result of differences in population demographic characteristics, their comorbidities, and access to health care resources. The common nature and devastating effects of CKD should prompt major efforts to develop and implement effective preventative and therapeutic efforts aimed at lowering the development of CKD and slowing its progression.

Disclosure

This article is published as part of a supplement sponsored by Bayer AG.

CPK is a consultant for Abbott, Akebia, AstraZeneca, Bayer, Cara Therapeutics, CSL Behring, Dr. Schar, Reata, Rockwell, Takeda, Tricida and Vifor. CPK received no personal funding for this article.

Acknowledgments

Development of this article was funded by an unrestricted educational grant from Bayer AG. CPK would like to acknowledge Jo Luscombe, PhD, of Chameleon Communications International, who provided editorial assistance with funding via an unrestricted educational grant from Bayer AG.

References

5. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1-150. [ Google Scholar]

Articles from Kidney International Supplements are provided here courtesy of Elsevier

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Epidemiology of chronic kidney disease: an update 2022

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Chronic kidney disease is a progressive condition that affects >10% of the general population worldwide, amounting to >800 million individuals. Chronic kidney disease is more prevalent in older individuals, women, racial minorities, and ...

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Credible Information:

This source is the leading charity for Kidney health, thus making it not-for-profit. Its main goal is to help prevent CKD, as well as to make treatment of CKD equitable.

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What is living donation? Living donation takes place when a living person donates an organ (or part of an organ) for transplantation to another person. The living donor can be a family member, such as a parent, child, brother or sister (living related donation). Living donation can also come from someone who doesn’t have an emotional relationship with the recipient, such as a friend of a friend, coworker, fellow member at their place of worship, neighbor or someone that hears through social media.

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Credible Information:

The Mayo Clinic is one of the most prestigious nonprofit medical centers in the country, with an emphasis on academic developments and specialization.

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Overview

What is kidney disease? An expert explains

Learn more from kidney doctor Andrew Bentall, M.D.

I'm Dr. Andrew Bentall, a kidney doctor at Mayo Clinic. I look after patients with kidney disease, either in the early stages, or with more advanced kidney disease considering dialysis and transplantation as treatment options. In this video, we'll cover the basics of chronic kidney disease. What is it? Who gets it? The symptoms, diagnosis and treatment. Whether you are looking for answers for yourself or for someone you love, we're here to give you the best information available.

Chronic kidney disease is a disease characterized by progressive damage and loss of function in the kidneys. It's estimated that chronic kidney disease affects about one in seven American adults. And most of those don't know they have it. Before we get into the disease itself, let's talk a little bit about the kidneys and what they do. Our kidneys play many important roles keeping our bodies in balance. They remove waste and toxins, excess water from the bloodstream, which is carried out of the body in urine. They helped to make hormones to produce red blood cells, and they turn vitamin D into its active form, so it's usable in the body.

There are quite a few things that can cause or put you at higher risk for chronic kidney disease. Some of them are not things that can be avoided. Your risk is simply higher if you have a family history of certain genetic conditions like polycystic kidney disease or some autoimmune diseases like lupus or IgA nephropathy. Defects in the kidney structure can also cause your kidneys to fail, and you have an increased risk as you get older. Sometimes, other common medical conditions can increase your risk. Diabetes is the most common cause of kidney disease. Both type 1 and type 2 diabetes. But also heart disease and obesity can contribute to the damage that causes kidneys to fail. Urinary tract issues and inflammation in different parts of the kidney can also lead to long-term functional decline. There are things that are more under our control: Heavy or long-term use of certain medications, even those that are common over-the-counter. Smoking can also be a contributing factor to chronic kidney disease.

Often there are no outward signs in the earlier stages of chronic kidney disease, which is grouped into stages 1 through 5. Generally, earlier stages are known as 1 to 3. And as kidney disease progresses, you may notice the following symptoms. Nausea and vomiting, muscle cramps, loss of appetite, swelling via feet and ankles, dry, itchy skin, shortness of breath, trouble sleeping, urinating either too much or too little. However, these are usually in the later stages, but they can also happen in other disorders. So don't automatically interpret this as having kidney disease. But if you're experiencing anything that concerns you, you should make an appointment with your doctor.

Even before any symptoms appear, routine blood work can indicate that you might be in the early stages of chronic kidney disease. And the earlier it's detected, the easier it is to treat. This is why regular checkups with your doctor are important. If your doctor suspects the onset of chronic kidney disease, they may schedule a variety of other tests. They may also refer you to a kidney specialist, a nephrologist like myself. Urine tests can reveal abnormalities and give clues to the underlying cause of the chronic kidney disease. And this can also help to determine the underlying issues. Various imaging tests like ultrasounds or CT scans can be done to help your doctor assess the size, the structure, as well as evaluate the visible damage, inflammation or stones of your kidneys. And in some cases, a kidney biopsy may be necessary. And a small amount of tissue is taken with a needle and sent to the pathologist for further analysis.

Treatment is determined by what is causing your kidneys to not function normally. Treating the cause is key, leading to reduced complications and slowing progression of kidney disease. For example, getting better blood pressure control, improved sugar control and diabetes, and reducing weight are often key interventions. However, existing damage is not usually reversible. In some conditions, treatment can reverse the cause of the disease. So seeking medical review is really important. Individual complications vary, but treatment might include high blood pressure medication, diuretics to reduce fluid and swelling, supplements to relieve anemia, statins to lower cholesterol, or medications to protect your bones and prevent blood vessel calcification. A lower-protein diet may also be recommended. It reduces the amount of waste your kidneys need to filter from your blood. These can not only slow the damage of kidney disease, but make you feel better as well. When the damage has progressed to the point that 85 to 90 percent of your kidney function is gone, and they no longer work well enough to keep you alive, it's called end-stage kidney failure. But there are still options. There's dialysis, which uses a machine to filter the toxins and remove water from your body as your kidneys are no longer able to do this. Where possible, the preferred therapy is a kidney transplant. While an organ transplant can sound daunting, it's actually often the better alternative, and the closest thing to a cure, if you qualify for a kidney transplant.

If you have kidney disease, there are lifestyle choices. Namely quit smoking. Consuming alcohol in moderation. If you're overweight or obese, then try to lose weight. Staying active and getting exercise can help not only with your weight, but fatigue and stress. If your condition allows, keep up with your routine, whether that's working, hobbies, social activities, or other things you enjoy. It can be helpful to talk to someone you trust, a friend or relative who's good at listening. Or your doctor could also refer you to a therapist or social worker. It can also be helpful to find a support group and connect with people going through the same thing. Learning you have chronic kidney disease and learning how to live with it can be a challenge. But there are lots of ways to help you to be more comfortable for longer before more drastic measures are needed. And even then, there is plenty of hope. If you'd like to learn even more about chronic kidney disease, watch our other related videos or visit mayoclinic.org. We wish you well.

Chronic kidney disease, also called chronic kidney failure, involves a gradual loss of kidney function. Your kidneys filter wastes and excess fluids from your blood, which are then removed in your urine. Advanced chronic kidney disease can cause dangerous levels of fluid, electrolytes and wastes to build up in your body.

In the early stages of chronic kidney disease, you might have few signs or symptoms. You might not realize that you have kidney disease until the condition is advanced.

Treatment for chronic kidney disease focuses on slowing the progression of kidney damage, usually by controlling the cause. But, even controlling the cause might not keep kidney damage from progressing. Chronic kidney disease can progress to end-stage kidney failure, which is fatal without artificial filtering (dialysis) or a kidney transplant.

One of the important jobs of the kidneys is to clean the blood. As blood moves through the body, it picks up extra fluid, chemicals and waste. The kidneys separate this material from the blood. It's carried out of the body in urine. If the kidneys are unable to do this and the condition is untreated, serious health problems result, with eventual loss of life.

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Symptoms

Signs and symptoms of chronic kidney disease develop over time if kidney damage progresses slowly. Loss of kidney function can cause a buildup of fluid or body waste or electrolyte problems. Depending on how severe it is, loss of kidney function can cause:

Nausea

Vomiting

Loss of appetite

Fatigue and weakness

Sleep problems

Urinating more or less

Decreased mental sharpness

Muscle cramps

Swelling of feet and ankles

Dry, itchy skin

High blood pressure (hypertension) that's difficult to control

Shortness of breath, if fluid builds up in the lungs

Chest pain, if fluid builds up around the lining of the heart

Signs and symptoms of kidney disease are often nonspecific. This means they can also be caused by other illnesses. Because your kidneys are able to make up for lost function, you might not develop signs and symptoms until irreversible damage has occurred.

When to see a doctor

Make an appointment with your doctor if you have signs or symptoms of kidney disease. Early detection might help prevent kidney disease from progressing to kidney failure.

If you have a medical condition that increases your risk of kidney disease, your doctor may monitor your blood pressure and kidney function with urine and blood tests during office visits. Ask your doctor whether these tests are necessary for you.

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Causes

Chronic kidney disease occurs when a disease or condition impairs kidney function, causing kidney damage to worsen over several months or years.

Diseases and conditions that cause chronic kidney disease include:

Type 1 or type 2 diabetes

High blood pressure

Glomerulonephritis (gloe-mer-u-low-nuh-FRY-tis), an inflammation of the kidney's filtering units (glomeruli)

Interstitial nephritis (in-tur-STISH-ul nuh-FRY-tis), an inflammation of the kidney's tubules and surrounding structures

Polycystic kidney disease or other inherited kidney diseases

Prolonged obstruction of the urinary tract, from conditions such as enlarged prostate, kidney stones and some cancers

Vesicoureteral (ves-ih-koe-yoo-REE-tur-ul) reflux, a condition that causes urine to back up into your kidneys

Recurrent kidney infection, also called pyelonephritis (pie-uh-low-nuh-FRY-tis)

Risk factors

Factors that can increase your risk of chronic kidney disease include:

Diabetes

High blood pressure

Heart (cardiovascular) disease

Smoking

Obesity

Being Black, Native American or Asian American

Family history of kidney disease

Abnormal kidney structure

Older age

Frequent use of medications that can damage the kidneys

Complications

Chronic kidney disease can affect almost every part of your body. Potential complications include:

Fluid retention, which could lead to swelling in your arms and legs, high blood pressure, or fluid in your lungs (pulmonary edema)

A sudden rise in potassium levels in your blood (hyperkalemia), which could impair your heart's function and can be life-threatening

Anemia

Heart disease

Weak bones and an increased risk of bone fractures

Decreased sex drive, erectile dysfunction or reduced fertility

Damage to your central nervous system, which can cause difficulty concentrating, personality changes or seizures

Decreased immune response, which makes you more vulnerable to infection

Pericarditis, an inflammation of the saclike membrane that envelops your heart (pericardium)

Pregnancy complications that carry risks for the mother and the developing fetus

Irreversible damage to your kidneys (end-stage kidney disease), eventually requiring either dialysis or a kidney transplant for survival

Prevention

To reduce your risk of developing kidney disease:

Follow instructions on over-the-counter medications. When using nonprescription pain relievers, such as aspirin, ibuprofen (Advil, Motrin IB, others) and acetaminophen (Tylenol, others), follow the instructions on the package. Taking too many pain relievers for a long time could lead to kidney damage.

Maintain a healthy weight. If you're at a healthy weight, maintain it by being physically active most days of the week. If you need to lose weight, talk with your doctor about strategies for healthy weight loss.

Don't smoke. Cigarette smoking can damage your kidneys and make existing kidney damage worse. If you're a smoker, talk to your doctor about strategies for quitting. Support groups, counseling and medications can all help you to stop.

Manage your medical conditions with your doctor's help. If you have diseases or conditions that increase your risk of kidney disease, work with your doctor to control them. Ask your doctor about tests to look for signs of kidney damage.

Chronic kidney disease care at Mayo Clinic

Show references

1. Goldman L, et al., eds. Chronic kidney disease. In: Goldman-Cecil Medicine. 26th ed. Elsevier; 2020. http://www.clinicalkey.com. Accessed April 27, 2021.

2. Chronic kidney disease (CKD). National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/kidney-disease/chronic-kidney-disease-ckd#:~:text=Chronic kidney disease (CKD) means,family history of kidney failure. Accessed April 26, 2021.

3. Rosenberg M. Overview of the management of chronic kidney disease in adults. https://www.uptodate.com/contents/search. Accessed April 26, 2021.

4. Chronic kidney disease (CKD) symptoms and causes. National Kidney Foundation. https://www.kidney.org/atoz/content/about-chronic-kidney-disease. Accessed April 26, 2021.

5. Chronic kidney disease. Merck Manual Professional Version. https://www.merckmanuals.com/professional/genitourinary-disorders/chronic-kidney-disease/chronic-kidney-disease?query=Chronic kidney disease. Accessed April 26, 2021.

6. Ammirati AL. Chronic kidney disease. Revista da Associação Médica Brasileira. 2020; doi:10.1590/1806-9282.66.S1.3.

7. Chronic kidney disease basics. Centers for Disease Control and Prevention. https://www.cdc.gov/kidneydisease/basics.html. Accessed April 26, 2021.

8. Warner KJ. Allscripts EPSi. Mayo Clinic; April 21, 2021.

9. Office of Patient Education. Chronic kidney disease treatment options. Mayo Clinic; 2020.

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# data[].attributes.attachment_link.title
Chronic kidney disease - Symptoms and causes

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Learn about kidney failure symptoms, tests, diagnosis and treatment options, including medication, dialysis and kidney transplant.

# data[].attributes.body
Credible Information:

The Center of Disease Control is the largest national public health agency, with its main goal being to promote public health outcomes. They used evidence based information in their resources, and lead current novel research in the topic.

# data[].attributes.attachment_link.readable_text
Preventing chronic kidney disease (CKD) and its complications is possible by managing risk factors and treating the disease to slow its progression and reduce the risk of complications. To keep healthy kidneys, it is important to control those risk factors for CKD that can be modified.

Get Tested for CKD

If you are at risk, get tested for CKD regularly. Ask your doctor to test your blood or urine.

Find it early. Treat it early.

If you have diabetes, get tested yearly.

Healthy Kidney Tips

Lose weight if you are overweight.

Get active. Physical activity helps control blood sugar levels.

Quit smoking.

Getting a checkup? Make sure to get your kidneys checked too.

Take medications as directed.

Keep your blood pressure below 140/90, or ask your doctor what the best blood pressure target is for you.

If you have diabetes, stay in your target blood sugar range as much as possible.

Stay in your target cholesterol range.

Eat foods lower in salt.

Eat more fruits and vegetables.

Keep your kidneys healthy by controlling your blood sugar and blood pressure.

Managing Risk Factors for CKD

Among people with diabetes and high blood pressure, blood sugar and blood pressure control have been shown to lower the risk of developing kidney disease.

Several studies have shown the possibility for preventing or delaying the start of diabetic kidney disease by treating patients who have diabetes with blood pressure-lowering drugs. In addition to lowering blood pressure, these medications reduce protein in the urine, a risk factor for developing kidney disease.

Managing blood sugar, blood pressure, and cholesterol levels is very important because these are all risk factors for heart disease and stroke.

Because having kidney disease increases the chances of also having heart disease and stroke, early detection and treatment of kidney disease is important for people with diabetes to help prevent or delay cardiovascular death and kidney failure.

Learn more about taking care of your kidneys [PDF - 281 KB] .

Managing CKD

Once detected, kidney disease may be addressed through:

Improved lifestyle changes (e.g. healthy eating)
Meeting with a dietitian to make a kidney-healthy eating plan

Proper use of medications (e.g. drugs to lower blood pressure)

Avoiding conditions or exposures that can harm the kidneys or cause a sudden drop in kidney function (called acute kidney injury), such as:

Kidney infections

Medications

Over the counter pain medicines like ibuprofen and naproxen

Certain antibiotics

Herbal supplements

Dyes that are used to make the blood vessels or organs visible on X-rays or other imaging tests

Page last reviewed:

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Find information on preventing chronic kidney disease by managing risk factors to protect your kidneys.

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Credible Information:

This source is a service provided by the National Library of Medicine, which is a part of the National Institute of Health. It provides evidence based information to the public, with the goal of improving public health outcomes.

# data[].attributes.attachment_link.readable_text
You have two kidneys, each about the size of your fist. Their main job is to filter your blood. They remove wastes and extra water, which become urine. They also keep the body's chemicals balanced, help control blood pressure, and make hormones.

Chronic kidney disease (CKD) means that your kidneys are damaged and can't filter blood as they should. This damage can cause wastes to build up in your body. It can also cause other problems that can harm your health. Diabetes and high blood pressure are the most common causes of CKD.

The kidney damage occurs slowly over many years. Many people don't have any symptoms until their kidney disease is very advanced. Blood and urine tests are the only way to know if you have kidney disease.

Treatments cannot cure kidney disease, but they may slow kidney disease. They include medicines to lower blood pressure, control blood sugar, and lower cholesterol. CKD may still get worse over time. Sometimes it can lead to kidney failure. If your kidneys fail, you will need dialysis or a kidney transplantation.

You can take steps to keep your kidneys healthier longer:

Choose foods with less salt (sodium)

Control your blood pressure; your health care provider can tell you what your blood pressure should be

Keep your blood sugar in the target range, if you have diabetes

Limit the amount of alcohol you drink

Choose foods that are healthy for your heart: fruits, vegetables, whole grains, and low-fat dairy foods

Lose weight if you are overweight

Be physically active

Don't smoke

NIH: National Institute of Diabetes and Digestive and Kidney Diseases

# data[].attributes.attachment_link.title
Chronic Kidney Disease | Kidney Disease | CKD | Medlineplus

# data[].attributes.attachment_link.description
If your kidneys are damaged and can't filter blood easily, then you may suffer from chronic kidney disease (CKD). Read about the treatments available

# data[].attributes.headline
Global Prevalence of Chronic Kidney Disease

# data[].attributes.subject
Global Prevalence of Chronic Kidney Disease

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Credible Information:

PLOS one is a peer reviewed journal, with a high editorial standard. This journal analyses this broad topic very well, demonstrating recency, many citations, ethical funding, and no competing interests.

# data[].attributes.attachment_link.readable_text
Nathan R. Hill,

Samuel T. Fatoba,

Jason L. Oke,

Jennifer A. Hirst,

Christopher A. O'Callaghan,

Daniel S. Lasserson,

F. D. Richard Hobbs

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Abstract

Chronic kidney disease (CKD) is a global health burden with a high economic cost to health systems and is an independent risk factor for cardiovascular disease (CVD). All stages of CKD are associated with increased risks of cardiovascular morbidity, premature mortality, and/or decreased quality of life. CKD is usually asymptomatic until later stages and accurate prevalence data are lacking. Thus we sought to determine the prevalence of CKD globally, by stage, geographical location, gender and age. A systematic review and meta-analysis of observational studies estimating CKD prevalence in general populations was conducted through literature searches in 8 databases. We assessed pooled data using a random effects model. Of 5,842 potential articles, 100 studies of diverse quality were included, comprising 6,908,440 patients. Global mean(95%CI) CKD prevalence of 5 stages 13·4%(11·7-15·1%), and stages 3-5 was 10·6%(9·2-12·2%). Weighting by study quality did not affect prevalence estimates. CKD prevalence by stage was Stage-1 (eGFR>90+ACR>30): 3·5% (2·8-4·2%); Stage-2 (eGFR 60-89+ACR>30): 3·9% (2·7-5·3%); Stage-3 (eGFR 30-59): 7·6% (6·4-8·9%); Stage-4 = (eGFR 29-15): 0·4% (0·3-0·5%); and Stage-5 (eGFR<15): 0·1% (0·1-0·1%). CKD has a high global prevalence with a consistent estimated global CKD prevalence of between 11 to 13% with the majority stage 3. Future research should evaluate intervention strategies deliverable at scale to delay the progression of CKD and improve CVD outcomes.

Citation: Hill NR, Fatoba ST, Oke JL, Hirst JA, O'Callaghan CA, Lasserson DS, et al. (2016) Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis. PLoS ONE 11(7): e0158765. https://doi.org/10.1371/journal.pone.0158765

Editor: Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research and Azienda Ospedaliera Ospedali Riuniti di Bergamo, ITALY

Received: November 19, 2015; Accepted: June 21, 2016; Published: July 6, 2016

Copyright: © 2016 Hill et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data are from Dryad (datadryad.org); the DOI number is doi: 10.5061/dryad.3s7rd.

Funding: NH is funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford. FDRH is part funded as Director of the National Institute for Health Research (NIHR) School for Primary Care Research (SPCR), Theme Leader in the NIHR Oxford Biomedical Research Centre (BRC), and Director of the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) Oxford. DSL is part funded by the NIHR Oxford Diagnostic Evidence Co-operative and NIHR Oxford BRC. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Chronic kidney disease (CKD) is associated with age-related renal function decline accelerated in hypertension, diabetes, obesity and primary renal disorders. [ 1] Cardiovascular disease (CVD) is the primary cause of morbidity and mortality where CKD is regarded as an accelerator of CVD risk and an independent risk factor for CVD events. [ 2] There is a graded inverse relationship between CVD risk and glomerular filtration rate (GFR) that is independent of age, sex and other risk factors. [ 3- 6] Decreased renal function is a predictor of hospitalisation [ 1, 2], cognitive dysfunction [ 7] and poor quality of life. [ 8, 9] The healthcare burden is highest in early stages due to increased prevalence, affecting around 35% of those over 70 years. [ 10]

CKD is defined by indicators of kidney damage-imaging or proteinuria (commonly using albumin to creatinine ratio, ACR)-and decreased renal function (below thresholds of GFR estimated from serum creatinine concentration). [ 11, 12] Current recommendations by Kidney Outcomes Quality Initiative (KDOQI) and National Institute for Health Excellence (NICE) [ 11, 12] are to use serum creatinine concentration to estimate GFR (eGFR) and transform it using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. [ 13] CKD-EPI replaces the Modification of Diet in Renal Disease (MDRD) equation [ 14] as a more accurate predictor of clinical risk [ 15] and both these equations correct for selected non-renal influences (age, race, gender).

CKD can be classified into five stages using KDOQI [ 11] guidelines using thresholds of eGFR within the CKD range and/or evidence of structural renal changes e.g. proteinuria. NICE have suggested that stage 3 be subdivided into 3a and 3b reflecting increasing CVD risk. [ 12] The largest stage of CKD, with over 90% of cases, has been estimated from a UK retrospective lab audit study to be CKD stage 3 with 84% stage 3a (GFR of 45 to 59 ml/min/1·73m ²) and 16% stage 3b GFR of 30 to 44 ml/min/1·73m ². [ 16]

Changes over time in CKD prevalence are contentious. Data from the American National Health and Nutrition Examination Survey demonstrate that in the period 1999 to 2004 the prevalence of CKD stages 1 to 4 increased significantly when compared to the survey period 1988 to 1994 (13·1 versus 10·0%). [ 4, 17, 18] While this high (and rising ⁴,) prevalence is in part due to the ageing population, it is also associated with increases in hypertension and diabetes mellitus[ 1]. However, conversely a UK manuscript published in 2014 examined nationally representative cross-sectional studies within the UK and found that the prevalence estimates reported declined over time. [ 19]

CKD is recognised as having changed from a subspecialty issue to a global health concern. [ 20] The authors, therefore, sought to determine the global prevalence of CKD according to KDOQI criteria in published observational studies in the adult general population, by a systematic review and meta-analysis.

Materials and Methods

Search strategy and selection criteria

The protocol has been published (PROSPERO: CRD42014009184) and conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology guidelines [ 21]. Search strategy was discussed with a librarian for optimum inclusion sensitivity. An early consensus panel on the search results expanded the criteria to include additional general populations not identified originally (e.g. laboratory based large population studies). The librarian performed iterative searches using the following repositories for published observational studies: Medline/PubMed, Embase, CINAHL, the Cochrane Register for Controlled Trials (CENTRAL), LILACS, SciELO, clinicaltrials.gov, WHO ICTRP. They used the Cochrane Collaboration's Highly Sensitive Search Strategy to optimize results. [ 22] The search strategy for clinicaltrials.gov was Condition = ("kidney disease" OR "kidney failure" OR "kidney insufficiency" OR "kidney function" OR "kidney dysfunction" OR "renal disease" OR "renal failure" OR "renal insufficiency" OR "renal function" OR "renal dysfunction") AND Outcome = prevalence. The reference lists of other systematic reviews on prevalence of CKD were searched for potentially relevant articles. All databases were searched from inception to the 1st September 2014.

Study selection and data extraction

Original peer-reviewed publications were selected by two authors (NH, SF) if they included: a >500 people, conducted from year 2000+, used MDRD/CKD-EPI formula, reported CKD prevalence using KDOQI criteria and were in the general population (even if limited-e.g. aged >65). Studies were excluded if they had no criteria for diagnosis of CKD, did not include prevalence, were in a specialist restricted population (e.g. acute hospital patient cohort, nursing home), were an audit of existing results already included or if there was a more recent updated study. Translations were sought for non-English articles.

Data extraction was with standardised forms by two independent reviewers (NH, SF) disagreement was resolved by adjudicator (DL). Data included quality assessment, prevalence of CKD, method used to calculate eGFR, study setting: year, country, the population, gender split, age, and so on. Authors of relevant articles were contacted to provide additional information whenever necessary and references of selected articles were hand searched for additional articles. The KDOQI definition of CKD stages was used [ 11] and the method, calibration and traceability of the creatinine assessment extracted.

Statistical analysis and quality assessment

CKD prevalence was defined by the studies as being calculated for Stages 1 to 5 (eGFR & ACR) or Stages 3 to 5 (eGFR alone). 95% confidence intervals (95%CI) were calculated for each prevalence value. Meta-analyses were performed in Stata version 14. A procedure for pooling proportions in the meta-analysis of multiple studies study was used and the results displayed in a forest plot. The 95%CI's are based on score(Wilson) procedures [ 23]. Heterogeneity was quantified using the I-squared measure, The I ² heterogeneity was categorised as follows: <25% low, 25 to 50% moderate and >50% high [ 24]. A Freeman-Tukey Double Arcsine Transformation [ 25] was used to stabilise the variance prior to calculation of the pooled estimates. Random effects models were selected for the meta-analyses with the assumption that CKD prevalence by country would be variable.

Subgroup analysis was undertaken by country, geographic region, age and gender. Geographic regions were defined based on the geographic proximity of the country the studies occurred in and the possible similarity in the ethnicity of the populations. Meta-regression was weighted by number of subjects unless otherwise specified [ 24]. Random effects meta-regressions using aggregate level data for CKD prevalence, study year, participant characteristics and co-morbidities were performed.

Methodological quality was assessed by one reviewer (NH) defined as adherence to STROBE (Strengthening the Reporting of Observational Studies in Epidemiology Statement) recommendations. [ 26] The STROBE 22-point checklist was used to score each manuscript, items that had subdivision recommendations scored a point for each. Serum creatinine reporting quality was assessed by two reviews (NH & SF)-traceability of assay, number of measurements per patient, assay method used, and calibration of assay. A combined quality score was generated from methodological quality- as measured by STROBE adherence- and serum creatinine reporting quality. The weighting was arbitrarily chosen to be two-thirds STROBE adherence and one-third creatinine reporting. To assess bias, quality was used to weight CKD prevalence values in a meta-analysis.

Sensitivity analyses were undertaken to investigate the individual study influence and of limited populations (high altitude, single site of recruitment in rural area, single site of recruitment in urban area, laboratory audit, age by decile, or age restricted), studies that used age adjusted prevalence and using only high quality studies-quality score threshold of 56% (mean quality). Further sensitivity analyses were undertaken using studies that examined IDMS traceable creatinine only, studies that used double measuring of creatinine, studies that achieved two or more of the serum creatinine reporting quality items, and studies that used different eGFR equations (CKD-EPI or MDRD).

Results

The search yielded 5,842 articles after duplicates had been removed and 143 articles were assessed relevant for the review by title and abstract. Forty-three were excluded on full manuscript assessment. A detailed review and data extraction was conducted on 100 manuscripts (covering 112 populations), Fig 1. No additional studies were identified by examining reference lists. All studies that were included were published after the introduction of the KDOQI 2002 CKD definition guidelines [ 11].

*112 Populations from 100 manuscripts as some manuscripts reported on more than one population or split their populations prior to analysis.

China had the highest number of population samples with seventeen. [ 27- 43] Numbers of participants ranged from 778 in a USA cohort [ 44] to 1,120,295 in a USA laboratory audit [ 2]. The S1 Appendix Study Table details the relevant details of all studies and populations.

Prevalence

The mean(95%CI) global prevalence of CKD was 13·4%(11·7-15·1%), I ² = 99.9%, for the forty-four populations that measured prevalence by all 5 stages (1 to 5) [ 4, 28, 29, 32, 33, 35- 38, 40- 43, 45- 73], and 10·6%(9·2-12·2%),I ² = 100%, in the sixty-eight populations [ 2, 10, 27, 30, 31, 34, 39, 44, 74- 123] measuring Stages 3 to 5, Fig 2.

Studies are ordered by number of participants and split by whether the report 3 stages of CKD ("Three") or five stages of CKD ("Five").

CKD prevalence breakdown was provided in seventy-four populations. [ 2, 4, 10, 27- 29, 32, 35, 37- 43, 46, 47, 50- 56, 60, 63, 65- 71, 73- 84, 86- 91, 98- 102, 106- 111, 113, 116, 118, 121, 122] The 1 to 5 stages mean CKD prevalence was higher (13·4% vs. 11·0%). The breakdown by stage using all available data was Stage-1 (eGFR>90+ACR>30): 3·5%(2·8-4·2%); Stage-2 (eGFR 60-89+ACR>30): 3·9%(2·7-5·3%); Stage-3 (eGFR 30-59): 7·6%(6·4-8·9%); Stage-4 = (eGFR 29-15): 0·4%(0·3-0·5%); and Stage-5 (eGFR<15): 0·1%(0·1-0·1%). Separate reporting of Stage 3a/3b was not possible due to lack of reporting. Sensitivity analyses determined that no individual study or group of studies (limited populations-i.e. laboratory audits, age restricted, single site recruitment-, age adjusted prevalence, etc.) were suspected of excess influence on the prevalence estimates. Further, there was no difference between studies that reported using the higher quality IDMS traceable assay and those that did not.

Effect of Age, Hypertension, BMI, Obesity, Diabetes, Smoking.

Univariate meta-regressions of CKD prevalence and covariates were undertaken. Mean population age, given in 94 of 112 populations, was significantly associated (β = 0·4%, p<0·001, R ² = 25·5), as was prevalence of diabetes (n = 82, β = 0·16%, p = 0·006, R ² = 8·0), prevalence of hypertension (n = 75, β = 0·15%, p = 0·002, R ² = 11·4) but not average BMI or prevalence of obesity. Smoking (n = 60) was negatively associated with CKD prevalence (an increase of smoking status was associated with a decreased prevalence of CKD (β = -0·14 p = 0·07, R ² = 4·2).

Prevalence of CKD increased with age, Fig 3. To determine an estimated prevalence for each age the sample population was divided by mean age into deciles. Studies measuring 5 stages of CKD mean(95%CI) were-30s: 13·7%(10·8, 16·6%), 40s: 12·0%(9·9, 14·1%), 50s: 16·0%(13·5, 18·4%), 60s: 27·6%(26·7, 28·5%), 70s: 34·3%(31·9, 36·7%). Studies measuring stages 3 to 5-30s: 8·9%(4·7, 13·1%), 40s: 8·7%(6·9, 10·5%), 50s: 12·2%(9·8, 14·5%), 60s: 11·3%(8·1, 14·5%), 70s: 27·9%(16·40, 39·3%).

There were no significant differences in prevalence between groups of studies that adjusted for age compared to those that did not. Further, a sensitivity test found that older age restricted populations did not significantly change the estimated pooled prevalence for CKD, Stages 3 to 5 mean (95%CI) 10·2%(8·4-12·0%) vs. 10·6%(9·2-12·2%) and stages 1 to 5 mean (95%CI) 11·5%(9·3-13·9%) vs. 11·4%(9·4-13·1%). A sensitivity analysis examining glomerular filtration estimating equation was planned but only 12 studies used the CKD-EPI equation making the analysis unfeasible.

Geography

CKD prevalence by geographical grouping was examined, Table 1. Geographical areas with more than one study were pooled using random effects models.

Gender

Fifty-one studies reported sex-specific prevalence of CKD. [ 27- 29, 32, 37- 39, 44, 46, 48, 50, 52- 55, 57, 58, 61, 64, 68- 71, 78, 79, 82, 83, 85, 87, 92- 94, 98, 100- 103, 105, 106, 108, 110, 115, 119] Male mean (95%CI) CKD prevalence, for studies that defined 5 stages of CKD, was 12·8%(10·8-11·9%) and for studies that used stages 3 to 5 it was 8·1%(6·3-10·2%). Female CKD prevalence for studies that defined CKD by stages 1 to 5 was 14·6%(12·7-16·7%) and for studies that used stages 3 to 5 it was 12·1%(10·6-13·8%). Thirty-eight studies [ 27- 29, 32, 37- 39, 44, 46, 50, 55, 64, 69- 71, 78, 79, 83, 85, 87, 92, 98, 100- 103, 105, 106, 108, 110, 115, 119] reported that CKD was more prevalent in women than in men with the pattern reversed in thirteen studies. [ 39, 44, 48, 52- 54, 57, 58, 61, 68, 82, 93, 94]

Quality

The methodological quality of studies ranged from 32·1% [ 31] to 92·9%. [ 4, 68] No study complied completely with the STROBE guidelines and the mean(SD) quality was 69·6(12·5)%.

Quality of serum creatinine measurement was assessed. Two studies scored 100%- four methods. [ 115, 122] Thirty-six studies scored 0% [ 30- 32, 34, 39, 40, 48, 49, 52, 57- 60, 62, 64, 71, 72, 74, 76, 81, 82, 85, 87, 89, 92, 95, 102, 103, 105, 106, 109, 113, 116, 117], thirty-five studies scored 25%-one method-[ 2, 28, 29, 33, 35- 38, 41, 43, 47, 51, 53, 61, 65, 67- 70, 75, 77- 79, 83, 84, 97- 100, 108, 110, 114, 121], twenty-seven scored 50%-two methods-[ 4, 27, 42, 44, 46, 50, 54- 56, 66, 74, 80, 88, 90, 101, 104, 107, 111, 112, 118, 119, 123] and ten scored 75%-three methods. [ 10, 45, 63, 73, 86, 91, 93, 94, 96, 120]

Sensitivity analyses determined no difference in the prevalence estimate of CKD when using only high quality studies, studies that used double measures of creatinine only or studies that had two or more factors for the measurement of creatinine.

Discussion

CKD prevalence Stages 1 to 5 was 13·4% and 10·6% in stages 3 to 5. This systematic review is the first meta-analysis of CKD prevalence globally and provides a comprehensive overview of the current literature. These estimates indicate that CKD may be more common than diabetes, which has an estimated prevalence of 8·2%. [ 124] However, the reported prevalence of CKD varied widely amongst the studies and had high heterogeneity.

CKD was more prevalent in women than in men. Two-thirds of studies -that reported gender-specific CKD prevalence- determined higher prevalence in women. Women, in general, have less muscle mass than men and muscle mass is a major determinant of serum creatinine concentration. However, the GFR estimation equations adjust for gender differences, using a correction factor for women. These findings add to the existing literature that recognise a gender-specific difference between CKD prevalence. [ 125- 127]However, these data cannot answer why this may occur. We can speculate that this finding may be partially explained by selection bias inherent within the studies due to a different age demographic for the two sexes. Alternatively it may be due to complex factors in the disease pathology that are not captured within the studies. Or that there is in fact more renal disease in men but the eGFR equations preferentially identify renal disease in women in the stage 3 zones.

Studies that were outliers in terms of reported results were of interest. Smoking was found to be negatively associated with CKD prevalence but this finding was negated when a single outlier was removed. The outlier [ 120] was a study in which smoking was defined as >100 cigarettes ever and thus 69·1% were smokers. A Spanish study [ 106] (n: 7202, Quality: 52%, CKD: 21·3%) reported 66.7% hypertension prevalence within the population compared with a global mean (from all other studies) of 31·1%. Hypertension was not defined any differently. Further, 31.5% of their sample population had diabetes and 31.1% were obese. The population was reported as unrestricted older population but although it was older than other studies (mean age 60·6yrs) these rates of co-morbidity are unexpected and were not explained. A number of studies had very high prevalence of CKD (>30%) the highest of these was a Canadian study (n: 123,499, Quality: 52%, CKD: 36·4%), a laboratory audit of patients over 65 years. The prevalence observed may be due to selection bias as the mean age of this cohort was 74 years, with 23% diabetes in the sample population, two factors associated with renal decline.

The geographical stratification of results revealed that developed areas such as Europe, USA, Canada and Australia had higher rates of CKD prevalence in comparison to areas where economies are growing such as sub Saharan Africa, India etc. With the exception of Iran that had similar high level of CKD prevalence possibly due dietary risks, high BMI, high systolic BP and co-morbid conditions within the country [ 128]. Although percentage prevalence was higher in more developed areas projected worldwide population changes will increase the absolute numbers of people in developing countries where the populations of elderly are increasing. This increase will exacerbate the double burden of dealing with communicable and non communicable disease in a developing economy[ 129].

Serum creatinine measurement bias was inherent in the majority of the studies. Serum creatinine concentrations are highly variable within individuals, up to 21% within a 2-week period. [ 130] NICE guidelines advise two measures of eGFR 3-months apart and within the last 12-months to minimise intra-individual variation. Not all countries have such guidelines only 5 manuscripts reported this in study design. Jaffe creatinine assay was the main method used but it is known to systematically overestimate serum creatinine to varying degrees. [ 131] Thirty-seven of the studied populations reported that they calibrated directly to the laboratory to minimize assay bias effect and twenty-seven studies used a minimally biased traceably assay (IDMS). A comparison of these studies to the remainder found no significant difference in prevalence estimates. A third of the studies (n = 36) made no mention of measures, traceability, or calibrations. It is further known that the MDRD equation systematically overestimates CKD in the general population [ 13] and the prevalence rates calculated may be lower. Estimated GFR is accepted as the most useful index of kidney function in health and disease, but an uncorrected, untraceable single measure inherently introduces noise and outliers into the dataset. This latter point has been very recently clarified as an epidemiological study in Morocco found that up to 30% of patients initially classified as CKD 3a using the MDRD formula had improved renal function over 12 months and therefore would not have a CKD diagnosis[ 132].

Estimation of GFR from serum creatinine is the clinical standard worldwide and the CKD the KDOQI diagnostic criteria[ 11] guidelines emphasise the importance of estimation of GFR rather than use of serum creatinine concentration. However, the 2002 KDOQI guidelines that the included studies reference have stimulated controversies and questions. In particular, there have been concerns that use of its definition of CKD has caused excessive false identification of CKD and that its staging system was not sufficiently informative about prognosis. A new KDIGO guideline was published in 2013 [ 133] that sought to address this with the splitting of the stage 3 category to emphasise the risks of mortality and other outcomes vary greatly between these groups and have further and further sub-stratified by the inclusion of urinary albuminuria. There is a limitation in our study in that unfortunately the analysis of stages 3a and 3b was not possible due to lack of reporting and studies using the previous KDOQI guidelines so no conclusions about whether the patients really have 'disease' rather than normal variation due to aging could be drawn.

Observational studies are individually subject to bias and residual confounding from unspecified sources but it is difficult to quantify how much bias and/or confounding. One study may report an effect size adjusted for several possible confounders; others may report the crude prevalence. The authors have sought to address this limitation by using STROBE quality weighting and creatinine quality factors and participant per study-weighted rates. Ideally future research should report the crude and adjusted rates based on multiple measures over time.

This systematic review and meta-analysis significantly extends existing systematic reviews in a number of ways. The search strategy allowed the detection of a large number of additional studies that had not been considered in previous systematic reviews. It increased the number of reference databases searched. The reviewers undertook to screen non-English publications through the use of translations. The studies included used the same definitions of CKD and used broadly comparable definitions for severity markers or related conditions (albuminuria, hypertension, diabetes and obesity). However, there are limitations due to the heterogeneity that arises from differences in age and sex distributions, use of creatinine assays, different sampling frames, inclusion criteria of general population based studies, and time period of the study. A proportion of the variation across studies may not be due to real differences in CKD prevalence. However, the authors did seek to provide a robust assessment of the quality and use this to determine a weighted global prevalence of CKD in the meta-analysis. The prevalence rates calculated highlight the likely numbers of people with CKD that may be of relevance to health care providers and national health programs with finite resources with which to address this epidemic.

CKD constitutes a major cost burden to healthcare systems worldwide. The high prevalence and the extensive existing evidence that intervention is effective in reducing CVD events demonstrates a need for national initiatives that will slow the progression to end stage renal disease and reduce CVD-related events in CKD patients.

This comprehensive meta-analysis of observational studies confirms that CKD has a high prevalence. Using CKD prevalence weighted by quality, using 'High' quality studies only and using studies weighted by number of participants consistently estimated a global CKD prevalence of between 11 to 13%. Future research should evaluate intervention strategies deliverable at scale to delay the progression of CKD and improve CVD outcomes. Evaluation of the roles of these interventions and the associated costs needs to be undertaken. CKD prevalence studies should report more detail on disease definitions and population demographics and state unadjusted as well as adjusted findings.

Acknowledgments

We wish to thank Ms. Nia Roberts for her extensive assistance in conducting the search and Dr Yaling Yang for her translation of a Chinese language manuscript. Systematic Review Registration: PROSPERO CRD42014009184.

Author Contributions

Conceived and designed the experiments: NH DL FDRH. Performed the experiments: SF NH DL COC FDRH. Analyzed the data: NH SF JO JH. Wrote the paper: NH SF COC JO JH DL FDRH.

# data[].attributes.attachment_link.title
Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis

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Chronic kidney disease (CKD) is a global health burden with a high economic cost to health systems and is an independent risk factor for cardiovascular disease (CVD). All stages of CKD are associated with increased risks of cardiovascular morbidity, premature mortality, and/or decreased quality of life.

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Chronic Kidney Disease Diagnosis and Management

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Chronic Kidney Disease Diagnosis and Management

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Credible Information:

This source is also published in a peer reviewed journal, with high publication standards. It demonstrates recency, many citations to other works, and promotes evidence based practices.

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Abstract

IMPORTANCE

Chronic kidney disease (CKD) is the 16th leading cause of years of life lost worldwide. Appropriate screening, diagnosis, and management by primary care clinicians are necessary to prevent adverse CKD-associated outcomes, including cardiovascular disease, end-stage kidney disease, and death.

OBSERVATIONS

Defined as a persistent abnormality in kidney structure or function (eg, glomerular filtration rate [GFR] <60 mL/min/1.73 m ² or albuminuria ≥30 mg per 24 hours) for more than 3 months, CKD affects 8% to 16% of the population worldwide. In developed countries, CKD is most commonly attributed to diabetes and hypertension. However, less than 5% of patients with early CKD report awareness of their disease. Among individuals diagnosed as having CKD, staging and new risk assessment tools that incorporate GFR and albuminuria can help guide treatment, monitoring, and referral strategies. Optimal management of CKD includes cardiovascular risk reduction (eg, statins and blood pressure management), treatment of albuminuria (eg, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers), avoidance of potential nephrotoxins (eg, nonsteroidal anti-inflammatory drugs), and adjustments to drug dosing (eg, many antibiotics and oral hypoglycemic agents). Patients also require monitoring for complications of CKD, such as hyperkalemia, metabolic acidosis, hyperphosphatemia, vitamin D deficiency, secondary hyperparathyroidism, and anemia. Those at high risk of CKD progression (eg, estimated GFR <30 mL/min/1.73 m ², albuminuria ≥300 mg per 24 hours, or rapid decline in estimated GFR) should be promptly referred to a nephrologist.

CONCLUSIONS AND RELEVANCE

Diagnosis, staging, and appropriate referral of CKD by primary care clinicians are important in reducing the burden of CKD worldwide.

Chronic kidney disease (CKD) affects between 8% and 16% of the population worldwide and is often underrecognized by patients and clinicians.1-4 Defined by a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m ², albuminuria of at least 30 mg per 24 hours, or markers of kidney damage (eg, hematuria or structural abnormalities such as polycystic or dysplastic kidneys) persisting for more than 3 months,5 CKD is more prevalent in low- and middle-income than in high-income countries.6 Globally, CKD is most commonly attributed to diabetes and/or hypertension, but other causes such as glomerulonephritis, infection, and environmental exposures (such as air pollution, herbal remedies, and pesticides) are common in Asia, sub-Saharan Africa, and many developing countries.4 Genetic risk factors may also contribute to CKD risk. For example, sickle cell trait and the presence of 2 APOL1 risk alleles, both common in people of African ancestry but not European ancestry, may double the risk of CKD.

In the United States, the average rate of GFR decline is approximately 1 mL/min/1.73 m ² per year in the general population,11,12 and the lifetime risk of developing a GFR of less than 60 mL/min/1.73 m ² is more than 50%.13 Early detection and treatment by primary care clinicians is important because progressive CKD is associated with adverse clinical outcomes, including end-stage kidney disease (ESKD), cardiovascular disease, and increased mortality.14-17 Recent professional guidelines suggest a risk-based approach to the evaluation and management of CKD. This review includes discussion of new calculators for determining risk of CKD progression that may be useful in clinical practice (eg, https://kidneyfailurerisk.com/) and focuses on the diagnosis, evaluation, and management of CKD for primary care clinicians. Considerations for referral to a nephrologist and dialysis initiation are also covered.

Methods

A literature search to April 2019 was conducted using Medline and PubMed with search terms including CKD, chronic renal failure, chronic renal insufficiency, epidemiology, incidence, prevalence, occurrence, diagnosis, assessment, identification, screening, workup, etiology, causes, management, treatment, intervention, therapy, and prevention. Results were restricted to English-language, human studies, and academic journals and guidelines. The initial search resulted in 998 articles, including clinical trials, meta-analyses, practice guidelines, and systematic reviews, and was later expanded to include review articles and observational studies, including cross-sectional studies, and more recent publications contained in reference lists of identified articles. All clinical trials for treatment or prevention of CKD were included without regard to study size or age of patient population.

Clinical Presentation

Chronic kidney disease is typically identified through routine screening with serum chemistry profile and urine studies or as an incidental finding. Less commonly, patients may present with symptoms such as gross hematuria, "foamy urine" (a sign of albuminuria), nocturia, flank pain, or decreased urine output. If CKD is advanced, patients may report fatigue, poor appetite, nausea, vomiting, metallic taste, unintentional weight loss, pruritus, changes in mental status, dyspnea, or peripheral edema.21

In evaluating a patient with known or suspected CKD, clinicians should inquire about additional symptoms that might suggest a systemic cause (eg, hemoptysis, rash, lymphadenopathy, hearing loss, neuropathy) or urinary obstruction (eg, urinary hesitancy, urgency, or frequency or incomplete bladder emptying).21 Moreover, patients should be assessed for risk factors of kidney disease, including prior exposure to potential nephrotoxins (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], phosphate-based bowel preparations, herbal remedies such as those containing aristolochic acid, antibiotic therapies such as gentamicin, and chemotherapies), history of nephrolithiasis or recurrent urinary tract infections, presence of comorbidities (eg, hypertension, diabetes, autoimmune disease, chronic infections), family history of kidney disease, and, if available, other known genetic risk factors such as sickle cell trait.9,18,21-24

A detailed physical examination may provide additional clues regarding the underlying cause of CKD and should include careful evaluation of a patient's volume status. Signs of volume depletion may reflect poor oral intake, vomiting, diarrhea, or overdiuresis, whereas signs of volume overload may be due to decompensated heart failure, liver failure, or nephrotic syndrome. The presence of arterial-venous nicking or retinopathy on retinal examination suggests long-standing hypertension or diabetes. Patients with carotid or abdominal bruits may have renovascular disease. Flank pain or enlarged kidneys should prompt consideration of obstructive uropathy, nephrolithiasis, pyelonephritis, or polycystic kidney disease. Neuropathy may be due to diabetes or less commonly vasculitis, or amyloidosis. Skin findings may include rash (systemic lupus erythematosus, acute interstitial nephritis), palpable purpura (Henoch-Schonlein purpura, cryoglobulinemia, vasculitis), telangiectasias (scleroderma, Fabry disease), or extensive sclerosis (scleroderma). Patients with advanced CKD may exhibit pallor, skin excoriations, muscle wasting, asterixis, myoclonic jerks, altered mental status, and pericardial rub.21

CKD Definition and Staging

Chronic kidney disease is defined as the presence of an abnormality in kidney structure or function persisting for more than 3 months.5,25 This includes 1 or more of the following: (1) GFR less than 60 mL/min/1.73 m ²; (2) albuminuria (ie, urine albumin ≥30 mg per 24 hours or urine albumin-to-creatinine ratio [ACR] ≥30 mg/g); (3) abnormalities in urine sediment, histology, or imaging suggestive of kidney damage; (4) renal tubular disorders; or (5) history of kidney transplantation.5 If the duration of kidney disease is unclear, repeat assessments should be performed to distinguish CKD from acute kidney injury (change in kidney function occurring within 2-7 days) and acute kidney disease (kidney damage or decreased kidney function present for ≤3 months).25 Evaluation for the etiology of CKD should be guided by a patient's clinical history, physical examination, and urinary findings ( Figure 1 ).

Once a diagnosis of CKD has been made, the next step is to determine staging, which is based on GFR, albuminuria, and cause of CKD ( Figure 2 ).5 Staging of GFR is classified as G1 (GFR ≥90 mL/min/1.73 m ²), G2 (GFR 60-89 mL/min/1.73 m ²), G3a (45-59 mL/min/1.73 m ²), G3b (30-44 mL/min/1.73 m ²), G4 (15-29 mL/min/1.73 m ²), and G5 (<15 mL/min/1.73 m ²).5 Although GFR can be directly measured by clearance of agents such as iohexol or iothalamate,26-28 the development of estimating equations (eg, the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] and Modification of Diet in Renal Disease Study [MDRD] equations) has largely replaced the need for direct measurement in clinical practice.29-31 Clinical laboratories now routinely report estimated GFR (eGFR) based on filtration markers. The most common filtration marker used is creatinine, a 113 dalton byproduct of creatine metabolism25 and one for which laboratory assays have been standardized since 2003.32 The preferred estimating equation in the United States and much of the world is the CKD-EPI 2009 creatinine equation, which is more accurate than the earlier MDRD equation, particularly for eGFR values greater than 60 mL/min/1.73 m ² ( https://www.kidney.org/professionals/kdoqi/gfr_calculator).29,30 In situations requiring additional accuracy and precision, cystatin C can be used with creatinine in the CKD-EPI 2012 creatinine-cystatin C equation.31 Adding cystatin C may be particularly useful for individuals with altered creatinine production and/or metabolism (eg, extremely high or low body size or muscle mass, limb amputation, high-protein diet, use of creatinine supplements, or use of drugs affecting tubular secretion of creatinine).5,25

Albuminuria should ideally be quantified by a urine ACR. Albuminuria staging is classified as A1 (urine ACR <30 mg/g), A2 (30-300 mg/g), and A3 (>300 mg/g).5 Guidelines recommend the use of urine ACR to stage CKD rather than urine protein-to-creatinine ratio because assays for the former are more likely to be standardized and have better precision at lower values of albuminuria.5,33 The most precise measurements come from a first morning sample or 24-hour collection, as there is high biological variability in urine albumin excretion over the course of the day. Random samples, however, are also acceptable in initial screening.5 Compared with urine protein-to-creatinine ratio, urine ACR is believed to be a more sensitive and specific marker of glomerular pathology5 since some urine proteins such as uromodulin are present (and may even be protective) in normal physiology.36-38 If tubular or overflow proteinuria is suspected, then urine protein electrophoresis or testing for the specific protein can be pursued (eg, immunoglobulin heavy and light chains, α ₁-microglobulin, and β ₂-microglobulin).5 Imaging by kidney ultrasound to assess morphology and to rule out urinary obstruction should be considered in all patients diagnosed as having CKD.5

Cause of CKD can be difficult to discern but is generally classified by the presence or absence of systemic disease and the location of anatomic abnormality. Examples of systemic disease include diabetes, autoimmune disorders, chronic infection, malignancy, and genetic disorders in which the kidney is not the only organ affected. Anatomic locations are divided into glomerular, tubulointerstitial, vascular, and cystic/congenital diseases.5 Determining the cause of CKD may have important implications on prognosis and treatment. For example, polycystic kidney disease may progress to ESKD faster than other causes and often requires evaluation for extrarenal manifestations and consideration of specific therapies such as tolvaptan, a vasopressin V2 receptor antagonist that slows decline in GFR.39,40 Patients with unexplained causes of CKD should be referred to a nephrologist.

Screening for CKD

Given that most patients with CKD are asymptomatic, screening may be important to early detection of disease.18 The National Kidney Foundation has developed a kidney profile test that includes measuring both serum creatinine for estimating GFR and urine ACR.41 A risk-based approach to screening is suggested by many clinical practice guidelines, with screening recommended in those older than 60 years or with a history of diabetes or hypertension.18-20 Screening should also be considered in those with clinical risk factors, including autoimmune disease, obesity, kidney stones, recurrent urinary tract infections, reduced kidney mass, exposure to certain medications such as NSAIDs or lithium, and prior episodes of acute kidney injury, among others ( Box).9,18,42-45 However, no randomized clinical trials have demonstrated that screening asymptomatic patients for CKD improves outcomes.

Box.

Clinical

Diabetes

Hypertension

Autoimmune diseases

Systemic infections (eg, HIV, hepatitis B virus, hepatitis C virus)

Nephrotoxic medications (eg, nonsteroidal anti-inflammatory drugs, herbal remedies, lithium)

Recurrent urinary tract infections

Kidney stones

Urinary tract obstruction

Malignancy

Obesity

Reduced kidney mass (eg, nephrectomy, low birth weight)

History of acute kidney injury

Smoking

Intravenous drug use (eg, heroin, cocaine)

Family history of kidney disease

Sociodemographic

Age >60 years

Nonwhite race

Low income

Low education

Genetic

APOL1 risk alleles

Sickle cell trait and disease

Polycystic kidney disease

Alport syndrome

Congenital anomalies of the kidney and urinary tract

Other familial causes

Other Risk Factors for CKD

There are several sociodemographic factors that contribute to increased risk of CKD, including nonwhite race, low education, low income, and food insecurity. Compared with whites, African Americans and Pacific Islanders have a substantially greater risk of ESKD.47 This is in part due to an increased prevalence of hypertension, diabetes, and obesity.11 However, genetic factors likely also contribute. More specifically, risk alleles in the gene encoding apolipoprotein L1 ( APOL1) may increase risk of kidney disease in a recessive genetic manner7,8: individuals with 2 APOL1 risk alleles (present in approximately 13% of African Americans) have a 2-fold risk of CKD progression and up to a 29-fold risk of specific CKD etiologies (eg, focal-segmental glomerulosclerosis and HIV-associated nephropathy) compared with those with 0 or 1 risk allele.11,44,45,48,49 Sickle cell trait (present in approximately 8% of African Americans) has also been associated with an increased risk of kidney disease. Compared with noncarriers, individuals with sickle cell trait have a 1.8-fold odds of incident CKD, 1.3-fold odds of eGFR decline greater than 3 mL/min/1.73 m ², and 1.9-fold odds of albuminuria.9

Management of Patients With CKD

Reducing Risk of Cardiovascular Disease

The prevalence of cardiovascular disease is markedly higher among individuals with CKD compared with those without CKD. For example, in a Medicare 5% sample, 65% of the 175 840 adults aged 66 years or older with CKD had cardiovascular disease compared with 32% of the 1 086 232 without CKD.47 Moreover, presence of CKD is associated with worse cardiovascular outcomes. For example, in the same population, the presence of CKD was associated with lower 2-year survival in people with coronary artery disease (77% vs 87%), acute myocardial infarction (69% vs 82%), heart failure (65% vs 76%), atrial fibrillation (70% vs 83%), and cerebrovascular accident/transient ischemic attack (73% vs 83%).47

Therefore, a major component of CKD management is reduction of cardiovascular risk. It is recommended that patients aged 50 years or older with CKD be treated with a low- to moderate-dose statin regardless of low-density lipoprotein cholesterol level.50-52 Smoking cessation should also be encouraged.5,53 Both the Eighth Joint National Committee (JNC 8) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines have recommended goal systolic and diastolic blood pressures of less than 140 mm Hg and less than 90 mm Hg, respectively, among adults with CKD based on expert opinion.5,54 The KDIGO guidelines further recommend that adults with urine ACR of at least 30 mg per 24 hours (or equivalent) have systolic and diastolic blood pressures maintained below 130 mm Hg and 80 mm Hg, respectively.5 More recently, the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that among individuals with increased risk of cardiovascular disease but without diabetes, more intensive blood pressure control (goal systolic blood pressure <120 mm Hg) was associated with a 25% lower (1.65% vs 2.19% per year) risk of a major cardiovascular event and a 27% lower risk of all-cause mortality compared with standard blood pressure control (goal systolic blood pressure <140 mm Hg).55 The intensive treatment group had a greater risk of at least a 30% decline in eGFR to a level below 60 mL/min/1.73 m ²; however, this may have been due to hemodynamic changes rather than true kidney function loss.55,56 Importantly, the benefits of intensive blood pressure control on cardiovascular events were similar in participants with and without baseline CKD.57

Management of Hypertension

Many guidelines provide algorithms detailing which agents should be used to treat hypertension in people with CKD.54,58 Presence and severity of albuminuria should be evaluated. Blockade of the renin-angiotensin-aldosterone system with either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) is recommended for adults with diabetes and a urine ACR of at least 30 mg per 24 hours or any adult with a urine ACR of at least 300 mg per 24 hours.5,18,58 Dual therapy with an ACE-I and an ARB is generally avoided, given associated risks of hyperkalemia and acute kidney injury.5,18,59 Aldosterone receptor antagonists may also be considered in patients with albuminuria, resistant hypertension, or heart failure with reduced ejection fraction.58,60-64

Management of Diabetes Mellitus

Optimal management of diabetes is also important. First, glycemic control may delay progression of CKD, with most guidelines recommending a goal hemoglobin A1c of ~ 7.0%.5,18,19,65-67 Second, dose adjustments in oral hypoglycemic agents may be necessary. In general, drugs that are largely cleared by the kidneys (eg, glyburide) should be avoided, whereas drugs metabolized by the liver and/or partially excreted by the kidneys (eg, metformin and some dipeptidyl peptidase 4 [DPP-4] and sodium-glucose cotransporter-2 [SGLT-2] inhibitors) may require dose reduction or discontinuation, particularly when eGFR falls below 30 mL/min/1.73 m ².18,19 Third, use of specific medication classes such as SGLT-2 inhibitors in those with severely increased albuminuria should be considered. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that, among 4401 patients with type 2 diabetes and CKD stage G2-G3/A3 (baseline eGFR 30 to <90 mL/min/1.73 m ² and urine ACR>300 to 5000 mg/24 hours) taking ACE-I or ARB therapy, those randomized to canagliflozin had a 30% lower risk (43.2 vs 61.2 events per 1000 patient-years) of developing the primary composite renal outcome (doubling of serum creatinine, ESKD, or death from a renal or cardiovascular cause) compared with those randomized to placebo.68 Prior trials have also suggested cardiovascular benefit with this class of medications, which may extend to patients with CKD who have lower levels of albuminuria.69,70

Nephrotoxins

All patients with CKD should be counseled to avoid nephrotoxins. Although a complete list is beyond the scope of this review, a few warrant mentioning. Routine administration of NSAIDs in CKD is not recommended, especially among individuals who are taking ACE-I or ARB therapy.5,18 Herbal remedies are not regulated by the US Food and Drug Administration, and some (such as those containing aristolochic acid or anthraquinones) have been reported to cause a myriad of kidney abnormalities, including acute tubular necrosis, acute or chronic interstitial nephritis, nephrolithiasis, rhabdomyolysis, hypokalemia, and Fanconi syndrome.22 Phosphate-based bowel preparations (both oral and enema formulations) are readily available over the counter and can lead to acute phosphate nephropathy.23,24 Proton pump inhibitors are widely used and have been associated with acute interstitial nephritis in case reports and incident CKD in population-based studies.71-73 In the population-based Atherosclerosis Risk in Communities cohort, the incidence of CKD was 14.2 events in those taking proton pump inhibitors and 10.7 per 1000 events in people who did not take them.71 Uniform discontinuation of proton pump inhibitors in CKD is not necessary. However, indications for use should be addressed at each primary care visit.

Drug Dosing

Adjustments in drug dosing are frequently required in patients with CKD. Of note, the traditional Cockcroft-Gault equation often poorly reflects measured GFR, whereas estimation of GFR using the CKD-EPI equation likely correlates better with drug clearance by the kidneys.74,75 Common medications that require dose reductions include most antibiotics, direct oral anticoagulants, gabapentin and pregabalin, oral hypoglycemic agents, insulin, chemotherapeutic agents, and opiates, among others.5,18 In general, use of medications with low likelihood of benefit should be minimized because patients with CKD are at high risk of adverse drug events.76-79 Gadolinium-based contrast agents are contraindicated in individuals with acute kidney injury, eGFR less than 30 mL/min/1.73 m ², or ESKD given the risk of nephrogenic systemic fibrosis, a painful and debilitating disorder characterized by marked fibrosis of the skin and occasionally other organs.5,18,80,81 Newer macrocyclic chelate formulations (eg, gadoteridol, gadobutrol, or gadoterate) are much less likely to cause nephrogenic systemic fibrosis, but the best prevention may still be to avoid gadolinium altogether. If administration of gadolinium is deemed essential, the patient must be counseled on the potential risk of nephrogenic systemic fibrosis and a nephrologist may be consulted for consideration of postexposure hemodialysis.5,18,80-82

Dietary Management

Dietary management to prevent CKD progression is controversial since large trials have had equivocal results.83-85 For example, the MDRD study evaluated 2 levels of protein restriction in 840 patients, finding that a low-protein diet compared with usual protein intake resulted in slower GFR decline only after the initial 4 months, and that a very low-protein diet compared with a low-protein diet was not significantly associated with slower GFR decline. Both levels of protein restriction appeared to have benefit in the subgroup with proteinuria greater than 3 g per day, although this group was small.83 Other, smaller trials have suggested a benefit of protein restriction in the prevention of CKD progression or ESKD.86-88 The KDIGO guidelines recommend that protein intake be reduced to less than 0.8 g/kg per day (with proper education) in adults with CKD stages G4-G5 and to less than 1.3 g/kg per day in other adult patients with CKD at risk of progression.5 The possible benefits of dietary protein restriction must be balanced with the concern of precipitating malnutrition and/or protein wasting syndrome.5,83,84,89 Lower dietary acid loads (eg, more fruits and vegetables and less meats, eggs, and cheeses) may also help protect against kidney injury.90,91 Low-sodium diets (generally <2 g per day) are recommended for patients with hypertension, proteinuria, or fluid overload.5

Monitoring of Established CKD and Treatment of Complications

Once CKD is established, the KDIGO guidelines recommend monitoring eGFR and albuminuria at least once annually. For patients at high risk, these measures should be monitored at least twice per year; patients at very high risk should be monitored at least 3 times per year ( Figure 2 ).5 Patients with moderate to severe CKD are at increased risk of developing electrolyte abnormalities, mineral and bone disorders, and anemia.92 Screening and frequency of assessment for laboratory abnormalities is dictated by stage of CKD and includes measurement of complete blood count, basic metabolic panel, serum albumin, phosphate, parathyroid hormone, 25-hydroxyvitamin D, and lipid panel ( Table ).5,50,93,94

Table.

Complication

Relevant Tests

Frequency of Repeat Testing

Management

Anemia

Hemoglobin

No anemia:
CKD stages G1-G2: when clinically indicated
CKD stage G3: at least once per year
CKD stages G4-G5: at least twice per year
With anemia:
CKD stages 3-5: at least every 3 months

Rule out other causes of anemia: iron deficiency, vitamin B ₁₂ deficiency, folate deficiency, occult bleeding
Consider iron supplementation and referral to a nephrologist for erythropoietin-stimulating agent therapy when hemoglobin <10 g/dL

Mineral and bone disorder

Serum calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin D

Calcium/phosphate:
CKD stage G3: every 6-12 months
CKD stage G4: every 3-6 months
CKD stage G5: every 1-3 months
Parathyroid hormone:
CKD stage G3: at baseline, then as needed
CKD stage G4: every 6-12 months
CKD stage G5: every 3-6 months
Vitamin D:
CKD stages 3-5: at baseline, then as needed

Consider phosphate-lowering therapy (eg, calcium acetate, sevelamer, iron-based binders) and vitamin D supplementation

Hyperkalemia

Serum potassium

At baseline and as needed

Low-potassium diet, correction of hyperglycemia and acidemia, consider potassium binders

Metabolic acidosis

Serum bicarbonate

At baseline and as needed

Oral bicarbonate supplementation (eg, sodium bicarbonate, baking soda, or sodium citrate/citric acid) for values persistently <22 mmol/L

Cardiovascular disease

Lipid panel

At baseline and as needed

Low- to moderate-dose statin therapy for patients aged ≥50 years with CKD
Statin therapy for patients aged 18-49 years with CKD and coronary artery disease, diabetes, prior ischemic stroke, or high risk of myocardial infarction or cardiovascular death

Anemia and the Role of Erythropoietin in CKD

Anemia is among the most common complications of CKD. In a study that included 19 CKD cohorts from across the world, 41% of the 209 311 individuals had low levels of hemoglobin (defined as <13 g/dL in men and <12 g/dL in women).92 The initial workup of anemia should include assessment of iron stores: those who are iron deficient may benefit from oral or intravenous iron repletion. Patients with hemoglobin levels persistently below 10 g/dL despite addressing reversible causes can be referred to a nephrologist for consideration of additional medical therapy, including erythropoietin-stimulating agents; however, erythropoietin-stimulating agents have been associated with increased risk of death, stroke, and venous thromboembolism, and these risks must be weighed against any potential benefits.93

Electrolyte, Mineral, and Bone Abnormalities in CKD

Electrolyte abnormalities are present in 3% to 11% of patients with CKD.92 Initial treatment strategies usually involve dietary restrictions and prescription of supplements. For example, primary care clinicians should recommend low-potassium diets for patients with hyperkalemia and low-phosphorus diets for patients with hyperphosphatemia.5,18,94,95 For patients with a serum bicarbonate level persistently below 22 mmol/L, oral bicarbonate supplementation should be considered, as studies have suggested that chronic metabolic acidosis is associated with faster CKD progression.5,18,96-99

Mineral and bone disorders are also common. In a study that included 42 985 patients with CKD, 58% had intact parathyroid hormone levels greater than 65 pg/mL.92 Although the optimal intact parathyroid hormone level for CKD remains unclear, most nephrologists agree that concomitant hyperphosphatemia, hypocalcemia, and vitamin D deficiency should be addressed, such as with a low-phosphate diet, phosphate binders, adequate elemental calcium intake, and vitamin D supplementation ( Table ).94,95

Prognosis of CKD

The incidence of ESKD varies by the presence of risk factors and geographical location. For example, in North America, the incidence among individuals with eGFR less than 60 mL/min/1.73 m ² ranged from 4.9 to 168.3 ESKD events per 1000 patient-years in 16 cohorts; in 15 non-North American cohorts, the incidence ranged from 1.2 to 131.3 ESKD events per 1000 patient-years.100 Most patients with CKD do not require kidney replacement therapy during their lifetime.101 Simple online tools are available to help with risk stratification. For example, the Kidney Failure Risk Equation (KFRE; https://kidneyfailurerisk.com/) predicts the 2-year and 5-year probabilities of requiring dialysis or transplant among individuals with eGFR less than 60 mL/min/1.73 m ².100,102 The KFRE, which has been validated in more than 700 000 individuals from more than 30 countries, uses readily available clinical and laboratory variables. The 4-variable equation includes age, sex, eGFR, and urine ACR, whereas the 8-variable equation further incorporates serum albumin, phosphate, calcium, and bicarbonate levels.100,102 Some health systems have tested the implementation of KFRE in clinical practice: nephrology referrals based on a 5-year KFRE greater than 3% led to shorter wait times,103 and a 2-year KFRE greater than 10% was used to guide referrals to multidisciplinary CKD clinics.104 An ongoing trial is evaluating whether a KFRE risk-based approach improves CKD management.105 For patients with eGFR less than 30mL/min/1.73m ², the CKD G4+ risk calculator ( https://www.kdigo.org/equation/) may provide additional information on the risks of cardiovascular disease and death.106,107 Importantly, risk prognostication may be helpful in not only identifying individuals at high risk of disease progression but also providing reassurance to those with mild CKD such as stage G3a A1.

Referral to a Nephrologist and Timing of Kidney Replacement Therapy

The KDIGO guidelines recommend that patients with CKD be referred to a nephrologist when eGFR falls below 30 mL/min/1.73 m ² (stage G4) and/or urine ACR increases above 300 mg per 24 hours (stage A3).5 The presence of albuminuria greater than 2200 mg per 24 hours should prompt expedited evaluation by a nephrologist and consideration of nephrotic syndrome. Additional indications for referral include the following: presence of greater than 20 red blood cells per high-power field of unclear etiology, red blood cell casts on urine microscopy or other indication of glomerulonephritis, CKD with uncontrolled hypertension despite 4 or more antihypertensive medications, persistent hypokalemia or hyperkalemia, anemia requiring erythropoietin replacement, recurrent or extensive kidney stones, hereditary kidney disease, acute kidney injury, and rapid CKD progression (a decrease in eGFR ≥25% from baseline or a sustained decline in eGFR >5 mL/min/1.73 m ²).5 In persons without CKD, even small changes in serum creatinine (eg, from 0.7 mg/dL to 1.2 mg/dL) reflect large declines in eGFR, and primary care clinicians should attempt to identify reversible causes. Indications for kidney biopsy may include but are not limited to unexplained persistent or increasing albuminuria, presence of cellular casts or dysmorphic red blood cells on urine sediment, and unexplained or rapid decline in GFR.5 Specific thresholds vary depending on patient characteristics and by institution. Patients with polycystic kidney disease, certain types of glomerulonephritis, and nephrotic-range albuminuria are at particularly high risk of progressing to ESKD.

Referral to nephrology is important for planning kidney replacement therapy and transplant evaluation. The decision to begin kidney replacement therapy is based on the presence of symptoms and not solely on level of GFR.108 Urgent indications include encephalopathy, pericarditis, and pleuritis due to severe uremia.109 Otherwise, initiation of dialysis should be individualized and considered when patients have uremic signs or symptoms (eg, nausea, vomiting, poor appetite, metallic taste, pericardial rub or effusion, asterixis, or altered mental status), electrolyte abnormalities (eg, hyperkalemia or metabolic acidosis), or volume overload (eg, pulmonary or lower extremity edema) refractory to medical management. A shared decision-making approach is best. Patients should be educated about treatment options and actively contribute to decision-making. Early education should include information on the potential complications of CKD as well as the different modalities of kidney replacement therapy. Kidney transplantation is considered the optimal therapy for ESKD, with living donor kidney transplantations performed before or shortly after dialysis initiation having the best outcomes.110,111 As such, early referral (eg, eGFR <30 mL/min/1.73 m ² and an elevated 2-year risk of ESKD) for transplant evaluation is important.112,113 Alternative therapies for ESKD may include in-center hemodialysis, home hemodialysis, peritoneal dialysis, or conservative care without dialysis.107 Patient preference should be taken into consideration when selecting dialysis modality; however, patients with multiple abdominal surgeries with resultant peritoneal scarring or unstable housing are likely poor candidates for peritoneal dialysis.107,109 Patients planning for hemodialysis who exhibit rapid decline in eGFR should be referred to an experienced vascular surgeon for arteriovenous fistula placement. The KDOQI guidelines recommend that access creation should occur when eGFR is between 15 and 20 mL/min/1.73 m ².114 Of note, dialysis initiation has been associated with accelerated functional decline and high short-term mortality among older patients with poor functional status.115,116 Patient preferences for conservative approaches to medical management should be discussed and honored.

Conclusions

Chronic kidney disease affects 8% to 16% of the population worldwide and is a leading cause of death. Optimal management of CKD includes cardiovascular risk reduction, treatment of albuminuria, avoidance of potential nephrotoxins, and adjustments to drug dosing. Patients also require monitoring for complications of CKD, such as hyperkalemia, metabolic acidosis, anemia, and other metabolic abnormalities. Diagnosis, staging, and appropriate referral of CKD by primary care clinicians are important in reducing the burden of CKD worldwide.

Funding/Support:

Dr Chen was supported by a Clinician Scientist Career Development Award from Johns Hopkins University and is supported by a George M. O'Brien Center for Kidney Research Pilot and Feasibility Grant from Yale University and award K08DK117068 from the National Institutes of Health/NIDDK. Dr Grams is supported by NIDDK grants DK1008803, DK100446, and DK115534.

Role of the Funder/Sponsor: The supporting institutions had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Footnotes

Conflict of Interest Disclosures: Dr Chen reported receipt of grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Yale University. Dr Grams reported receipt of grants from the NIDDK and the National Kidney Foundation and travel support from Dialysis Clinics Inc for an invited speakership at a directors' meeting in May 2019. No other disclosures were reported.

Submissions: We encourage authors to submit papers for consideration as a Review. Please contact Edward Livingston, MD, at Edward. gro.krowtenamaj@notsgnivil or Mary McGrae McDermott, MD, at ude.nretsewhtron@806mdm.

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# data[].attributes.attachment_link.title
Chronic Kidney Disease Diagnosis and Management: A Review

# data[].attributes.attachment_link.description
Chronic kidney disease (CKD) is the 16th leading cause of years of life lost worldwide. Appropriate screening, diagnosis, and management by primary care clinicians are necessary to prevent adverse CKD-associated outcomes, including cardiovascular disease, ...