thesis of kidney disease

• Open access
• Published: 10 January 2022

Chronic kidney disease and its health-related factors: a case-control study

• Mousa Ghelichi-Ghojogh 1 ,
• Mohammad Fararouei 2 ,
• Mozhgan Seif 3 &
• Maryam Pakfetrat 4  

BMC Nephrology volume  23 , Article number:  24 ( 2022 ) Cite this article

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Chronic kidney disease (CKD) is a non-communicable disease that includes a range of different physiological disorders that are associated with abnormal renal function and progressive decline in glomerular filtration rate (GFR). This study aimed to investigate the associations of several behavioral and health-related factors with CKD in Iranian patients.

A hospital-based case-control study was conducted on 700 participants (350 cases and 350 controls). Logistic regression was applied to measure the association between the selected factors and CKD.

The mean age of cases and controls were 59.6 ± 12.4 and 58.9 ± 12.2 respectively ( p  = 0.827). The results of multiple logistic regression suggested that many factors including low birth weight (OR yes/no  = 4.07, 95%CI: 1.76–9.37, P  = 0.001), history of diabetes (OR yes/no  = 3.57, 95%CI: 2.36–5.40, P  = 0.001), history of kidney diseases (OR yes/no  = 3.35, 95%CI: 2.21–5.00, P  = 0.001) and history of chemotherapy (OR yes/no  = 2.18, 95%CI: 1.12–4.23, P  = 0.02) are associated with the risk of CKD.

Conclusions

The present study covered a large number of potential risk/ preventive factors altogether. The results highlighted the importance of collaborative monitoring of kidney function among patients with the above conditions.

Peer Review reports

Chronic kidney disease (CKD) is a non-communicable disease that includes a range of different physiological disorders that are associated with an abnormal renal function and progressive decline in glomerular filtration rate (GFR) [ 1 , 2 , 3 ]. Chronic kidney disease includes five stages of kidney damage, from mild kidney dysfunction to complete failure [ 4 ]. Generally, a person with stage 3 or 4 of CKD is considered as having moderate to severe kidney damage. Stage 3 is broken up into two levels of kidney damage: 3A) a level of GFR between 45 to 59 ml/min/1.73 m 2 , and 3B) a level of GFR between 30 and 44 ml/min/1.73 m 2 . In addition, GFR for stage 4 is 15–29 ml/min/1.73 m 2 [ 4 , 5 ]. It is reported that both the prevalence and burden of CKD are increasing worldwide, especially in developing countries [ 6 ]. The worldwide prevalence of CKD (all stages) is estimated to be between 8 to 16%, a figure that may indicate millions of deaths annually [ 7 ]. According to a meta-analysis, the prevalence of stage 3 to 5 CKD in South Africa, Senegal, and Congo is about 7.6%. In China, Taiwan, and Mongolia the rate of CKD is about 10.06% and in Japan, South Korea, and Oceania the rate is about 11.73%. In Europe the prevalence of CKD is about 11.86% [ 8 ], and finally, about 14.44% in the United States and Canada. The prevalence of CKD is estimated to be about 11.68% among the Iranian adult population and about 2.9% of Iranian women and 1.3% of Iranian men are expected to develop CKD annually [ 9 ]. Patients with stages 3 or 4 CKD are at much higher risk of progressing to either end-stage renal disease (ESRD) or death even prior to the development of ESRD [ 10 , 11 ].

In general, a large number of risk factors including age, sex, family history of kidney disease, primary kidney disease, urinary tract infections, cardiovascular disease, diabetes mellitus, and nephrotoxins (non-steroidal anti-inflammatory drugs, antibiotics) are known as predisposing and initiating factors of CKD [ 12 , 13 , 14 ]. However, the existing studies are suffering from a small sample size of individuals with kidney disease, particularly those with ESRD [ 15 ].

Despite the fact that the prevalence of CKD in the world, including Iran, is increasing, the factors associated with CKD are explored very little. The present case-control study aimed to investigate the association of several behavioral and health-related factors with CKD in the Iranian population.

Materials and methods

In this study, participants were selected among individuals who were registered or were visiting Faghihi and Motahari hospitals (two largest referral centers in the South of Iran located in Shiraz (the capital of Fars province). Cases and controls were frequency-matched by sex and age. The GFR values were calculated using the CKD-EPI formula [ 16 , 17 ].

Data collection

An interview-administered questionnaire and the participant’s medical records were used to obtain the required data. The questionnaire and interview procedure were designed, evaluated, and revised by three experts via conducting a pilot study including 50 cases and 50 controls. The reliability of the questionnaire was measured using the test-retest method (Cronbach’s alpha was 0.75). The interview was conducted by a trained public health‌ nurse at the time of visiting the clinics.

Avoiding concurrent conditions that their association may interpreted as reverse causation; the questionnaire was designed to define factors preceding at least a year before experiencing CKD first symptoms. Accordingly participants reported their social and demographic characteristics (age, sex, marital status, educational level, place of residency), history of chronic diseases (diabetes, cardiovascular diseases, hypertension, kidney diseases, family history of kidney diseases, autoimmune diseases and thyroid diseases [ 18 ]). Also history of other conditions namely (smoking, urinary tract infection (UTI), surgery due to illness or accident, low birth weight, burns, kidney pain (flank pain), chemotherapy, taking drugs for weight loss or obesity, taking non-steroidal anti-inflammatory drugs, and taking antibiotic) before their current condition was started. Many researchers reported recalling birth weight to be reliable for research purposes [ 19 ]. Moreover, we asked the participants to report their birth weight as a categorical variable (< 2500 g or low, 2500- < 3500 g or normal, and > 3500 g or overweight). Medical records of the participants were used to confirm/complete the reported data. In the case of contradiction between the self-reported and recorded data, we used the recorded information for our study.

Verbal informed consent was obtained from patients because the majority of the participants were illiterate. The study protocol was reviewed and approved by the ethical committee of Shiraz University of Medical Sciences (approval number: 1399.865).

Sample size

The sample size was calculated to detect an association‌ between the history of using antibiotics (one of our main study variables) and CKD as small as OR = 1.5 [ 20 ]. With an alpha value of 0.05 (2-sided) and a power of 80%, the required sample size was estimated as large as n  = 312 participants for each group.

Selection of cases

The selected clinics deliver medical care to patients from the southern part of the country. In this study, patients with CKD who were registered with the above centers from June to December 2020 were studied. A case was a patient with a GFR < 60 (ml/min/1.73 m 2 ) at least twice in 3 months. According to the latest version of the International Classification of Diseases (2010), Codes N18.3 and N18.4 are assigned to patients who have (GFR = 30–59 (ml/min/1.73 m 2 ) and GFR = 15–29 (ml/min/1.73 m 2 ) respectively [ 21 ]. In total, 350 patients who were diagnosed with CKD by a nephrologist during the study period.

Selection of the controls

We used hospital controls to avoid recall-bias. The control participants were selected from patients who were admitted to the general surgery (due to hernia, appendicitis, intestinal obstruction, hemorrhoids, and varicose veins), and orthopedic wards‌ from June to December 2020. Using the level of creatinine in the participants’ serum samples, GFR was calculated and the individuals with normal GFR (ml/min/1.73 m 2 ) GFR > 60) and those who reported no history of CKD were included ( n  = 350).

Inclusion criteria

Patients were included if they were ≥ 20 years old and had a definitive diagnosis of CKD by a nephrologist.

Exclusion criteria

Participants were excluded if they were critically ill, had acute kidney injury, those undergone renal transplantation, and those with cognitive impairment.

Statistical analysis

The Chi-square test was used to measure the unadjusted associations between categorical variables and CKD. Multiple logistic regression was applied to measure the adjusted associations for the study variables and CKD. The backward variable selection strategy was used to include variables in the regression model. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. All p -values were two-sided and the results were considered statistically significant at p  < 0.05. All analyses were conducted using Stata version 14.0 (Stata Corporation, College Station, TX, USA).

In total, 350 cases and 350 age and sex-matched controls were included in the analysis. The mean age of cases and controls were 59.6 ± 12.4 and 58.9 ± 12.2 respectively ( p  = 0.83). Overall, 208 patients (59.4%) and 200 controls (57.1%) were male ( p  = 0.54). Also, 149 patients (42.6%) and 133 controls (38.0%) were illiterate or had elementary education ( p  = 0.001). Most cases (96.9%) and controls (95.7%) were married ( p  = 0.42). The mean GFR for CKD and control groups were 38.6 ± 11.4 and 78.3 ± 10.2 (ml/min/1.73 m2) respectively.

Result of univariate analysis

Table  1 illustrates the unadjusted associations of demographic and health-related variables with CKD. Accordingly, significant (unadjusted) associations were found between the risk of CKD and several study variables including education, history of chronic diseases (diabetes, cardiovascular, hypertension, kidney diseases, autoimmune diseases, and hypothyroidism), family history of kidney diseases, smoking, UTI, surgery due to illness or accident, low birth weight, burns, kidney pain, chemotherapy, taking non-steroidal anti-inflammatory drugs, and taking antibiotics) ( P  < 0.05 for all).

Results of multivariable analysis

Table  2 illustrates the adjusted associations between the study variables and the risk of CKD. Most noticeably, low birth weight (OR yes/no  = 4.07, 95%CI: 1.76–9.37, P  = 0.001), history of surgery (OR yes/no  = 1.74, 95%CI: 1.18–2.54, P  = 0.004), family history of kidney diseases (OR yes/no  = 1.97, 95%CI: 1.20–3.23, P  = 0.007), and history of chemotherapy (OR yes/no  = 2.18, 95%CI: 1.12–4.23, P  = 0.02) were significantly associated with a higher risk of CKD. On the other hand, education (OR college/illiterate or primary  = 0.54, 95%CI: 0.31–0.92, P  = 0.025) was found to be inversely associated with CKD.

The results of the present study suggested that several variables including, education, history of diabetes, history of hypertension, history of kidney diseases or a family history of kidney diseases, history of surgery due to illness or accident, low birth weight, history of chemotherapy, history of taking non-steroidal anti-inflammatory drugs, and history of taking antibiotics may affect the risk of CKD.

In our study, the level of education was inversely associated with the risk of CKD. This finding is in accordance with the results of a study conducted by K Lambert et.al, who suggested that illiteracy or elementary education may raise the risk of CKD [ 22 ]. The fact that education level is associated with health literacy, may partly explain our results that lower education and inadequate health literacy in individuals with CKD is associated with worse health outcomes including poorer control of biochemical parameters, higher risk of cardiovascular diseases (CVDs); a higher rate of hospitalization, and a higher rate of infections [ 23 ].

In the current study, the history of diabetes was associated with a higher risk of CKD. This finding is consistent with the results of other studies on the same subject [ 20 , 21 , 24 , 25 , 26 , 27 ]. It is not surprising that people with diabetes have an increased risk of CKD as diabetes is an important detrimental factor for kidney functioning as approximately, 40% of patients with diabetes develop CKD [ 27 ].

The other variable that was associated with an increased risk of CKD was a history of hypertension. Our result is consistent with the results of several other studies [ 20 , 24 , 25 , 28 ]. It is reported that hypertension is both a cause and effect of CKD and accelerates the progression of the CKD to ESRD [ 29 ].

After controlling for other variables, a significant association was observed between family history of kidney diseases and risk of CKD. Published studies suggested the same pattern [ 24 ]. Inherited kidney diseases (IKDs) are considered as the foremost reasons for the initiation of CKD and are accounted for about 10–15% of kidney replacement therapies (KRT) in adults [ 30 ].

The importance of the history of surgery due to illness or accident in this study is rarely investigated by other researchers who reported the effect of surgery in patients with acute kidney injury (AKI), and major abdominal and cardiac surgeries [ 31 , 32 ] on the risk of CKD. Also, AKI is associated with an increased risk of CKD with progression in various clinical settings [ 33 , 34 , 35 ]. In a study by Mizota et.al, although most AKI cases recovered completely within 7 days after major abdominal surgery, they were at higher risk of 1-year mortality and chronic kidney disease compared to those without AKI [ 31 ].

The present study also showed that low birth weight is a significant risk factor for CKD. This finding is consistent with the results of some other studies. However, the results of very few studies on the association between birth weight and risk of CKD are controversial as some suggested a significant association [ 19 , 36 , 37 ] whereas others suggested otherwise [ 36 ]. This may be explained by the relatively smaller size and volume of kidneys in LBW infants compared to infants that are normally grown [ 38 ]. This can lead to long-term complications in adolescence and adulthood including hypertension, decreased glomerular filtration, albuminuria, and cardiovascular diseases. Eventually, these long-term complications can also cause CKD [ 39 ].

Another important result of the current study is the association between chemotherapy for treating cancers and the risk of CKD. According to a study on chemotherapy for testicular cancer by Inai et al., 1 year after chemotherapy 23% of the patients showed CKD [ 40 ]. Another study suggested that the prevalence of stage 3 CKD among patients with cancer was 12, and < 1% of patients had stage 4 CKD [ 41 , 42 ]. Other studies have shown an even higher prevalence of CKD among cancer patients. For instance, only 38.6% of patients with breast cancer, 38.9% of patients with lung cancer, 38.3% of patients with prostate cancer, 27.5% of patients with gynecologic cancer, and 27.2% of patients with colorectal cancer had a GFR ≥90 (ml/min/1.73 m 2 ) at the time of therapy initiation [ 43 , 44 ]. The overall prevalence of CKD ranges from 12 to 25% across many cancer patients [ 45 , 46 , 47 ]. These results clearly demonstrate that, when patients with cancer develop acute or chronic kidney disease, outcomes are inferior, and the promise of curative therapeutic regimens is lessened.

In our study, the history of taking nephrotoxic agents (antibiotics or NSAIDs drugs) was associated with a higher risk of CKD. Our result is following the results reported by other studies [ 48 , 49 ]. Common agents that are associated with AKI include NSAIDs are different drugs including antibiotics, iodinated contrast media, and chemotherapeutic drugs [ 50 ].

Strengths and limitations of our study

Our study used a reasonably large sample size. In addition, a considerably large number of study variables was included in the study. With a very high participation rate, trained nurses conducted the interviews with the case and control participants in the same setting. However, histories of exposures are prone to recall error (bias), a common issue in the case-control studies. It is to be mentioned that the method of selecting controls (hospital controls) should have reduced the risk of recall bias when reporting the required information. In addition, we used the participants’ medical records to complete/ confirm the reported data. Although the design of the present study was not able to confirm a causal association between the associated variables and CKD, the potential importance and modifiable nature of the associated factors makes the results potentially valuable and easily applicable in the prevention of CKD.

Given that, chemotherapy is an important risk factor for CKD, we suggest the imperative for collaborative care between oncologists and nephrologists in the early diagnosis and treatment of kidney diseases in patients with cancer. Training clinicians and patients are important to reduce the risk of nephrotoxicity. Electronic medical records can simultaneously be used to monitor prescription practices, responsiveness to alerts and prompts, the incidence of CKD, and detecting barriers to the effective implementation of preventive measures [ 51 ]. Routine follow-up and management of diabetic patients is also important for the prevention of CKD. We suggest a tight collaboration between endocrinologists and nephrologists to take care of diabetic patients with kidney problems. In addition, surgeons in major operations should refer patients, especially patients with AKI, to a nephrologist for proper care related to their kidney function. Treatment of hypertension is among the most important interventions to slow down the progression of CKD [ 12 ]. Moreover, all patients with newly diagnosed hypertension should be screened for CKD. We suggest all patients with diabetes have their GFR and urine albumin-to-creatinine ratio (UACR) checked annually. Finally, the aging population and obesity cause the absolute numbers of people with diabetes and kidney diseases to raise significantly. This will require a more integrated approach between dialectologists/nephrologists and the primary care teams (55).

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to their being the intellectual property of Shiraz University of Medical Sciences but are available from the corresponding author on reasonable request.

Abbreviations

• Chronic kidney disease

End-stage renal disease

Glomerular filtration rate

Renal replacement treatment

Urinary tract infection

Odds ratios

Confidence intervals

Hypertension

Acute kidney injury

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Acknowledgments

This paper is part of a thesis conducted by Mousa Ghelichi-Ghojogh, Ph.D. student of epidemiology, and a research project conducted at the Shiraz University of Medical sciences (99-01-04-22719). We would like to thank Dr. Bahram Shahryari and all nephrologists of Shiraz‌ University of medical sciences, interviewers, and CKD patients in Shiraz for their voluntary participation in the study and for providing data for the study.

Shiraz University of Medical Sciences financially supported this study. (Grant number: 99–01–04-22719).

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Candidate in Epidemiology, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran

Mousa Ghelichi-Ghojogh

HIV/AIDS research center, School of Health, Shiraz University of Medical Sciences, P.O.Box: 71645-111, Shiraz, Iran

Mohammad Fararouei

Department of Epidemiology, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran

Mozhgan Seif

Nephrologist, Shiraz Nephro-Urology Research Center, Department of Internal Medicine, Emergency Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Maryam Pakfetrat

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Contributions

MGG: Conceptualization, Methodology, Statistical analysis, Investigation, and writing the draft of the manuscript. MP: were involved in methodology, writing the draft of the manuscript, and clinical consultation. MS: was involved in the methodology and statistical analysis. MF: was involved in conceptualization, methodology, supervision, writing, and reviewing the manuscript. The authors read and approved the final manuscript.

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Correspondence to Mohammad Fararouei .

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The study protocol was reviewed and approved by the ethical committee of Shiraz University of Medical Sciences (approval number: 1399.865). All methods were performed in accordance with the relevant guidelines and regulations of the Declaration of Helsinki. The participants were assured that their information is used for research purposes only. Because of the illiteracy of a considerable number of the patients, verbal informed consent was obtained from the participants. Using verbal informed consent was also granted by the ethical committee of Shiraz University of Medical Sciences.

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Ghelichi-Ghojogh, M., Fararouei, M., Seif, M. et al. Chronic kidney disease and its health-related factors: a case-control study. BMC Nephrol 23 , 24 (2022). https://doi.org/10.1186/s12882-021-02655-w

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Epidemiology of chronic kidney disease: an update 2022

Csaba p. kovesdy.

1 Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA

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.

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 decades 5 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 CKD 3 ) 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 2016 37 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

Regions and countries where chronic kidney disease is in the top 10 causes of years of life lost in 2013. On the basis of data from the Global Burden of Disease Study 2013. 3

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.

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.

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Dissertation

Studies on the Pathogenesis of Chronic Kidney Disease

In this thesis, two potential therapeutic targets for diabetic nephropathy were dentified and investigated. First, we show that glomerular clusterin is upregulated in diabetic nephropathy and demonstrated that recombinant clusterin protein can protect the podocytes against oxidative stress in vitro. 

In this thesis, two potential therapeutic targets for diabetic nephropathy were dentified and investigated. First, we show that glomerular clusterin is upregulated in diabetic nephropathy and demonstrated that recombinant clusterin protein can protect the podocytes against oxidative stress in vitro. Second, we reveal that hCN1 overexpression accelerated and aggravated diabetic nephropathy in BTBR ob/ob mice. We also studied two novel zebrafish models to investigate chronic kidney disease. We showed that lepb-/- adult zebrafish have the early signs of human diabetic nephropathy, and we demonstrated that ctns mutant adult  zebrafish have the kidney pathologic features of human nephropathic cystinosis.

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• 03 April 2024

Time to sound the alarm about the hidden epidemic of kidney disease

You have full access to this article via your institution.

Kidney disease is growing worldwide. The secretariat of the World Health Organization has welcomed the call to include it as a non-communicable disease that causes premature deaths. Credit: Vsevolod Zviryk/SPL

A quiet epidemic is building around the world. It is the third-fastest-growing cause of death globally. By 2040, it is expected to become the fifth-highest cause of years of life lost. Already, 850 million people are affected, and treating them is draining public-health coffers: the US government-funded health-care plan Medicare alone spends US$130 billion to do so each year. The culprit is kidney disease, a condition in which damage to the kidneys prevents them from filtering the blood.

And yet, in discussions of priorities for global public health, the words ‘kidney disease’ do not always feature. One reason for this is that kidney disease is not on the World Health Organization (WHO) list of priority non-communicable diseases (NCDs) that cause premature deaths. The roster of such NCDs includes heart disease, stroke, diabetes, cancer and chronic lung disease. With kidney disease missing, awareness of its growing impact remains low.

Chronic kidney disease and the global public health agenda: an international consensus

The authors of an article in Nature Reviews Nephrology this week want to change that ( A. Francis et al. Nature Rev. Nephrol . https://doi.org/10.1038/s41581-024-00820-6; 2024 ). They are led by the three largest professional organizations working in kidney health — the International Society of Nephrology, the American Society of Nephrology and the European Renal Association — and they’re urging the WHO to include kidney disease on the priority NCD list.

This will, the authors argue, bring attention to the growing threat, which is particularly dire for people in low- and lower-middle-income countries, who already bear two‑thirds of the world’s kidney-disease burden. Adding kidney disease to the list will also mean that reducing deaths from it could become more of a priority for the United Nations Sustainable Development Goals target to reduce premature deaths from NCDs by one-third by 2030.

As of now, rates of chronic kidney disease are likely to increase in low- and lower-middle-income countries as the proportion of older people in their populations increases. Inclusion on the WHO list could provide an incentive for health authorities to prioritize treatments, data collection and other research, along with funding, as with other NCDs.

Kidney disease often accompanies other conditions that do appear on the NCD list, such as heart disease, cancer and diabetes — indeed, kidney-disease deaths caused specifically by diabetes are on the list. But the article authors argue that “tackling diabetes and heart disease alone will not target the core drivers of a large proportion of kidney diseases”. Both acute and chronic kidney disease can have many causes. They can be caused by infection or exposure to toxic substances. Increasingly, the consequences of global climate change, including high temperatures and reduced availability of fresh water, are thought to be contributing to the global burden of kidney disease, as well.

The kidney glomerulus filters waste products from the blood. In people with damaged kidneys, this happens through dialysis. Credit: Ziad M. El-Zaatari/SPL

The WHO secretariat, which works closely with the nephrology community, welcomes the call to include kidney disease as an NCD that causes premature deaths, says Slim Slama, who heads the NCD unit at the secretariat in Geneva, Switzerland. The data support including kidney disease as an NCD driver of premature death, he adds.

The decision to include kidney disease along with other priority NCDs isn’t only down to the WHO, however. There must be conversations between the secretariat, WHO member states, the nephrology community, patient advocates and others. WHO member states need to instruct the agency to take the steps to make it happen, including providing appropriate funding for strategic and technical assistance.

Data and funding gaps

Three reports based on surveys by the International Society of Nephrology since 2016 highlight the scale of data gaps ( A. K. Bello et al. Lancet Glob. Health 12 , E382–E395; 2024 ). In many countries, screening for kidney disease is difficult to access and a large proportion of cases go undetected and therefore uncounted. For example, it is not known precisely how many people with kidney failure die each year because of lack of access to dialysis or transplantation: the numbers are somewhere between two million and seven million, according to the WHO. Advocates must push public-health officials in more countries to collect the data needed to monitor kidney disease and the impact of prevention and treatment efforts.

Even with better data, treatments for kidney disease are often prohibitively expensive. They include dialysis, an intervention to filter the blood when kidneys cannot. Dialysis is often required two or three times weekly for the remainder of the recipient’s life, or until they can receive a transplant, and it is notoriously costly. In Thailand, for example, it accounted for 3% of the country’s total health-care expenditures in 2022, according to the country’s parliamentary budget office.

End chronic kidney disease neglect

These costs could come down if people who have diabetes or high blood pressure, for example, could be routinely screened for impaired kidney function, because they are at high risk of developing chronic kidney disease. This would enable kidney damage to be detected early, before symptoms set in, opening the way for treatments that do not immediately require dialysis or transplant surgery.

New drugs that boost weight loss and treat type 2 diabetes could also help to prevent or reduce stress on the kidneys, but these, too, are too expensive for many people in need. That is why something needs to be done to make drugs more affordable. The pharmaceutical industry, which has become extremely profitable, has a crucial role. In Denmark, for example, the industry’s profits helped to tip the national economy from recession into growth in 2023, according to the public agency Statistics Denmark. The COVID-19 pandemic showed that making profits and making drugs available, and affordable, to a wide population need not be mutually exclusive. Similarly innovative thinking is now needed. “The whole world needs to reckon with this kidney problem,” says Valerie Luyckx, a biomedical ethicist at the University of Zurich in Switzerland.

The WHO adding kidney disease to its priority list could also attract funding for treatment, research and disease registries. That could jump-start the development of new treatments and help to make current treatments more affordable and accessible.

NCDs are responsible for 74% of deaths worldwide, but the world’s biggest donors to global health currently devote less than 2% of their budgets for international health assistance to NCD prevention and control, and not including kidney disease. Drawing more attention to the quiet rampage of kidney disease among some of the most vulnerable people would be one important step in turning these statistics around.

Nature 628 , 7-8 (2024)

doi: https://doi.org/10.1038/d41586-024-00961-5

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• 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.

• How kidneys work

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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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:

• 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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• Healthy kidney vs. diseased kidney

A typical kidney has about 1 million filtering units. Each unit, called a glomerulus, joins a tubule. The tubule collects urine. Conditions such as high blood pressure and diabetes harm kidney function by damaging these filtering units and tubules. The damage causes scarring.

• Polycystic kidney

A healthy kidney (left) eliminates waste from the blood and maintains the body's chemical balance. With polycystic kidney disease (right), fluid-filled sacs called cysts develop in the kidneys. The kidneys grow larger and gradually lose the ability to function as they should.

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:

• Heart (cardiovascular) disease
• Being Black, Native American or Asian American
• Family history of kidney disease
• Abnormal kidney structure
• 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
• 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

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

• Goldman L, et al., eds. Chronic kidney disease. In: Goldman-Cecil Medicine. 26th ed. Elsevier; 2020. http://www.clinicalkey.com. Accessed April 27, 2021.
• 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.
• Rosenberg M. Overview of the management of chronic kidney disease in adults. https://www.uptodate.com/contents/search. Accessed April 26, 2021.
• Chronic kidney disease (CKD) symptoms and causes. National Kidney Foundation. https://www.kidney.org/atoz/content/about-chronic-kidney-disease. Accessed April 26, 2021.
• 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.
• Ammirati AL. Chronic kidney disease. Revista da Associação Médica Brasileira. 2020; doi:10.1590/1806-9282.66.S1.3.
• Chronic kidney disease basics. Centers for Disease Control and Prevention. https://www.cdc.gov/kidneydisease/basics.html. Accessed April 26, 2021.
• Warner KJ. Allscripts EPSi. Mayo Clinic; April 21, 2021.
• Office of Patient Education. Chronic kidney disease treatment options. Mayo Clinic; 2020.
• Chronic kidney disease: Is a clinical trial right for me?
• Eating right for chronic kidney disease
• Effectively managing chronic kidney disease
• Kidney biopsy
• Kidney disease FAQs
• Low-phosphorus diet: Helpful for kidney disease?
• MRI: Is gadolinium safe for people with kidney problems?
• Renal diet for vegetarians

Associated Procedures

• Deceased-donor kidney transplant
• Hemodialysis
• Kidney transplant
• Living-donor kidney transplant
• Nondirected living-donor transplant
• Peritoneal dialysis
• Preemptive kidney transplant

News from Mayo Clinic

• Mayo Clinic Minute: Why Black Americans are at higher risk of chronic kidney disease March 05, 2024, 05:00 p.m. CDT
• Mayo Clinic Minute: Can extra salt hurt your kidneys? Feb. 16, 2024, 04:00 p.m. CDT
• Mayo Clinic Minute: Using AI to predict kidney failure in patients with polycystic kidney disease April 06, 2023, 04:00 p.m. CDT
• Mayo Clinic Q and A: Understanding chronic kidney disease March 23, 2023, 12:35 p.m. CDT
• Mayo Clinic Minute: Game-changing treatment for chronic kidney disease could slow down progression of the disease March 06, 2023, 04:01 p.m. CDT
• Science Saturday: Seeking a cellular therapy for chronic kidney disease Nov. 12, 2022, 12:00 p.m. CDT
• Science Saturday: Mayo Clinic researchers integrate genomics into kidney disease diagnosis, care Sept. 17, 2022, 11:00 a.m. CDT
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Editorial article, editorial: cystic kidney diseases in children and adults: from diagnosis to etiology and back.

• 1 University of Zagreb School of Medicine, Zagreb, Croatia
• 2 Division of Nephrology, Dialysis and Transplantation, Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia
• 3 Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia
• 4 Institute of Human Genetics, Center for Molecular Medicine Cologne, and Center for Rare and Hereditary Kidney Disease, Cologne, University Hospital of Cologne, Cologne, Germany

Editorial on the Research Topic Cystic kidney diseases in children and adults: from diagnosis to etiology and back

Renal cysts are often regarded as the most common abnormality associated with kidney disease ( 1 , 2 ). They are encountered in both adults and children, as isolated findings or as part of a more complex clinical condition ( 3 – 5 ). Isolated kidney cysts in adults sometimes require evaluation for kidney cancer or simple cysts may occur as a sign of age-related kidney tissue degeneration in the absence of any underlying specific kidney disease. Recent advances in understanding the underlying mechanisms have led to the concept of renal ciliopathies with more than 100 genes associated with ciliary dysfunction, resulting in conditions such as polycystic kidney disease (PKD), tuberous sclerosis complex (TSC) and nephronophthisis complex (NPHC), which may be associated with various extrarenal phenotypes ( Figure 1 ) ( 6 – 8 ). In addition to progressive CKD, these disorders are characterized by a variety of additional symptoms such as hepatic impairment, vision problems, developmental delays, intellectual disabilities, and skeletal abnormalities, which inconsistently present throughout the course of the disease ( 4 , 5 , 7 ). Furthermore, the significant phenotypic overlap makes it difficult to differentiate specific disorders, often necessitating genetic testing to reach a definite diagnosis ( 9 ). Despite a multitude of clinical and translational studies, in the majority of cases it is still challenging or even impossible to predict the individual clinical course, necessitating regular follow-up of the patients and a timely response in terms of treatment, which remains mostly symptomatic ( 10 ).

Figure 1 . Prominent syndromes and associated genes within the renal ciliopathies concept. ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; NPHC, nephronophthisis complex; TSC, tuberous sclerosis complex.

The present special issue contains seven noteworthy articles describing engaging cases of children and adults with various disorders having a common denominator in the form of kidney cysts, systematically reviewing the current literature on the clinical characteristics of an HNF1B gene variant and biomarkers of kidney disease progression in autosomal dominant PKD (ADPKD), investigating the outcome of fetal renal cystic disease and exploring the utility of magnetic resonance imaging-based kidney volume assessment for risk stratification in children with ADPKD.

In more detail, Simičić Majce et al . describe a nonconsanguineous family with three members affected by BBS caused by compound heterozygous mutations in the BBS12 gene. Despite identical genotypes, the affected family members demonstrated significant diversity in clinical characteristics (different expressivity) of the BBS phenotype emphasizing the importance of genetic testing for the early diagnosis of this rare ciliopathy. Similarly, Fištrek Prlić et al. present two clinically distinct cases of autosomal dominant tubulointerstitial kidney disease (ADTKD) diagnosed only after genetic testing, along with an extensive review of the literature and a comprehensive overview of the condition. Both patients had uninformative renal ultrasound and urinalysis findings with only elevated serum creatinine levels indicating a kidney disease. An adult patient with a positive family history of CKD had no other symptoms, while an adolescent boy with an unremarkable family history had psychomotor impairment with epilepsy. After the testing they were diagnosed with MUC1 -related ADTKD and 17q12 microdeletion syndrome causing the loss of one copy of the transcription factor HNF1B and 14 additional genes, respectively, highlighting the importance of clinical awareness in diagnosing this syndrome. Finally, the third case report by Kasahara et al. advocates an interesting option to treat the chronic pain experienced by more than half of patients with ADPKD. They describe an adolescent girl with persistent pain associated with multiple renal cysts that prevented her from participating in daily activities. After being diagnosed with attention deficit disorder (ADHD) and appropriate treatment for this condition being initiated, she experienced significant pain relief and better control of her hypertension. Therefore, in patients with ADPKD it may be important to recognize concomitant ADHD and consider a trial of ADHD medications when chronic pain associated with ADPKD is present.

In line with the exploration of important associations between cystic kidney disease and other disorders a systematic review by Nittel et al. examined the prevalence of neurodevelopmental disorders (NDD) in patients with 17q12 microdeletions vs. HNF1B point mutations. The results of a diligent literature search revealed that NDDs are frequently observed in HNF1B -associated diseases, especially in the common 17q12 microdeletion, and should hence become a routine part of clinical care for patients with HNF1B -related diseases. On the other hand, a systematic review by Sorić Hosman et al. provided a critical overview of previously examined serum and urine biomarkers with a potential for predicting disease progression or response to therapy in patients with ADPKD. A comprehensive literature review identified several prognostic molecules that are involved in various processes central to the development of the disease, such as tubular injury, inflammation, metabolism, renin-angiotensin, or vasopressin system adjustments. Interestingly, the most accurate predictive models have been achieved when incorporating such serum and urine biomarkers with the Predicting Renal Outcome in Polycystic Kidney Disease (PROPKD) score which combines underlying genetic mutations and clinical risk factors, or with the Mayo Imaging Classification (MIC) which is based on age- and height-adjusted total kidney volume (TKV) measured by magnetic resonance imaging (MRI).

MRI-based kidney volume assessment was further investigated by Yilmaz et al. in a multicenter, cross-sectional, and case-controlled study involving 89 children and adolescents with a genetically confirmed and detailly characterized diagnosis of ADPKD. The study patients were stratified according to the innovative Leuven Imaging Classification (LIC) into different risk categories, with those in the highest risk category having an increased incidence of hypertension and a higher prevalence of PKD1 mutations. Therefore, the study advocates the use of MRI for the measurement of TKV in the pediatric population, in addition to the use of ambulatory blood pressure monitoring to recognize those with hypertension.

Finally, Botero-Calderon et al. presented a retrospective study evaluating clinical and imaging data, genetic testing results and postnatal follow-up outcomes of infants identified in utero with bilateral renal cystic disease at a single referral center over a period of 11 years. Among 17 patients with suspected renal ciliopathy, the most common diagnosis was autosomal recessive PKD (ARPKD, n  = 4), followed by Bardet-Biedl syndrome (BBS, n  = 3), autosomal dominant polycystic disease (ADPKD, n  = 2), HNF1B-related disease ( n  = 2), and Meckel-Gruber syndrome (MKS, n  = 2), while four cases were not genetically resolved. In terms of postnatal management, the study revealed that the vast majority of neonatal survivors with renal ciliopathies are directed to the care of a pediatric nephrologist, while this proportion is much lower in those with genetically unresolved enlarged, echogenic kidneys, stressing the need for structured management programs for prenatally identified kidney disease.

In conclusion, our research topic provides a contemporary overview of current practices, unmet clinical needs and research gaps regarding the broad spectrum  of renal ciliopathies that may be useful to a wide range of physicians and researchers dealing with these complex disorders.

Author contributions

LL: Writing – review & editing, Writing – original draft, Visualization, Conceptualization. IV: Writing – review & editing, Conceptualization. MF: Writing – review & editing, Conceptualization. BB: Writing – review & editing, Conceptualization.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

1. Kwatra S, Krishnappa V, Mhanna C, Murray T, Novak R, Sethi SK, et al. Cystic diseases of childhood: a review. Urology . (2017) 110:184–91. doi: 10.1016/j.urology.2017.07.040

PubMed Abstract | Crossref Full Text | Google Scholar

2. De Groof J, Dachy A, Breysem L, Mekahli D. Cystic kidney diseases in children. Archives de Pédiatrie . (2023) 30(4):240–6. doi: 10.1016/j.arcped.2023.02.005

Crossref Full Text | Google Scholar

3. Mensel B, Kühn JP, Kracht F, Völzke H, Lieb W, Dabers T, et al. Prevalence of renal cysts and association with risk factors in a general population: an MRI-based study. Abdominal Radiology . (2018) 43(11):3068–74. doi: 10.1007/s00261-018-1565-5

4. McConnachie DJ, Stow JL, Mallett AJ. Ciliopathies and the kidney: a review. Am J Kidney Dis . (2021) 77(3):410–9. doi: 10.1053/j.ajkd.2020.08.012

5. Gambella A, Kalantari S, Cadamuro M, Quaglia M, Delvecchio M, Fabris L, et al. The landscape of HNF1B deficiency: a syndrome not yet fully explored. Cells . (2023) 12(2):307. doi: 10.3390/cells12020307

6. Modarage K, Malik SA, Goggolidou P. Molecular diagnostics of ciliopathies and insights into novel developments in diagnosing rare diseases. Br J Biomed Sci . (2022) 79. doi: 10.3389/bjbs.2021.10221

7. Devlin LA, Sayer JA. Renal ciliopathies. Curr Opin Genet Dev . (2019) 56:49–60. doi: 10.1016/j.gde.2019.07.005

8. Kurschat CE, Müller RU, Franke M, Maintz D, Schermer B, Benzing T. An approach to cystic kidney diseases: the clinician’s view. Nat Rev Nephrol . (2014) 10(12):687–99. doi: 10.1038/nrneph.2014.173

9. Lam BL, Leroy BP, Black G, Ong T, Yoon D, Trzupek K. Genetic testing and diagnosis of inherited retinal diseases. Orphanet J Rare Dis . (2021) 16(1):514. doi: 10.1186/s13023-021-02145-0

10. Yu ASL, Landsittel DP. Biomarkers in polycystic kidney disease: are we there? Adv Kidney Dis Health . (2023) 30(3):285–93. doi: 10.1053/j.akdh.2022.12.009

Keywords: cystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), nephronophtisis complex (NPHC), Bardet Biedl syndrome (BBS)

Citation: Lamot L, Vuković Brinar I, Fištrek Prlić M and Beck B (2024) Editorial: Cystic kidney diseases in children and adults: from diagnosis to etiology and back. Front. Pediatr. 12:1401593. doi: 10.3389/fped.2024.1401593

Received: 15 March 2024; Accepted: 29 March 2024; Published: 10 April 2024.

Edited and Reviewed by: Michael L. Moritz , University of Pittsburgh, United States

© 2024 Lamot, Vuković Brinar, Fištrek Prlić and Beck. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Lovro Lamot [email protected]

This article is part of the Research Topic

Cystic Kidney Diseases in Children and Adults: From Diagnosis to Etiology and Back

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Microbiome Pathway Implicated in Chronic Kidney Disease

Credit: Mehau Kulyk/Science Photo Library/Getty Images

TMAO (trimethylamine N-oxide) is a metabolite produced by gut bacteria and has emerged as a metabolite of interest due to its association with cardiovascular disease. Now, new findings from the Cleveland Clinic and Tufts University demonstrate high blood levels of TMAO predicts future risk of developing chronic kidney disease (CKD) over time.

The findings are published in the Journal of the American Society of Nephrology in an article titled, “ The Gut Microbial Metabolite Trimethylamine N-oxide, Incident Chronic Kidney Disease, and Kidney Function Decline in Two Community-Based Cohorts ,” and was a collaboration between a Cleveland Clinic research team led by Stanley Hazen, MD, PhD, chair of the department of cardiovascular and metabolic sciences at the Cleveland Clinic’s Lerner Research Institute and co-section head of Preventive Cardiology in the Heart, Vascular & Thoracic Institute, and investigators from the Food is Medicine Institute at the Friedman School of Nutrition Science and Policy at Tufts University, including first author Meng Wang, PhD, and co-senior author Dariush Mozaffarian, MD, DrPH.

“Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite of dietary phosphatidylcholine and carnitine,” the researchers wrote. “Experimentally, TMAO causes kidney injury and tubulointerstitial fibrosis. Little is known about prospective associations between TMAO and kidney outcomes, especially incident CKD. We hypothesized that higher plasma TMAO levels would be associated with higher risk of incident CKD and greater rate of kidney function decline.”

The findings build on more than a decade of research led by Hazen and a team related to the gut microbiome’s role in cardiovascular health and disease, including the adverse effects of TMAO, a byproduct formed by the gut bacteria from nutrients abundant in red meat, eggs, and other animal source foods.

The current study measured blood levels of TMAO over time in two large National Institutes of Health populations and followed the kidney function of more than 10,000 U.S. adults with normal kidney function at baseline over an average follow-up period of 10 years.

The researchers discovered that participants with elevated TMAO blood levels were at increased risk for future development of chronic kidney disease. Higher TMAO levels were also associated with a faster rate of declining kidney function in people with normal or impaired kidney function at baseline. These associations were independent of sociodemographic characteristics, lifestyle habits, diet, and other known risk factors for kidney disease. The findings also are consistent with earlier reported preclinical model studies showing TMAO directly fosters both kidney functional decline and tissue fibrosis.

“The findings indicate a remarkably strong clinical link between elevated TMAO and increased risk for developing chronic kidney disease,” said Hazen. “The results are from individuals of diverse ethnic and sociodemographic backgrounds who had normal kidney function at the start. The diversity of the participants helps ensure the results are generalizable.”

The study showed that TMAO levels were as strong or even stronger an indicator of chronic kidney disease risk than the well-known risk factors such as diabetes, hypertension, advancing age, and race.

“Our study is a crucial complement to studies in preclinical models supporting TMAO as a novel biological risk factor for chronic kidney disease,” said Wang, who is a research assistant professor at the Friedman School. “TMAO levels are highly modifiable by both lifestyle-like diet and pharmacologic interventions. Besides using novel drugs to lower TMAO in patients, using dietary interventions to lower TMAO in the general population could be a cost-efficient and low-risk preventive strategy for chronic kidney disease development.”

Plans for future studies include examining genetic data to help assess the potential cause-and-effect relationship between TMAO and chronic kidney disease, as well as studying more definitively whether lifestyle changes may prevent chronic kidney disease development and progression.

Eww That Smell: Key Basis for BO Production Identified

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Could kidney disease start in the gut?

• Updated: Apr. 10, 2024, 3:23 p.m. |
• Published: Apr. 10, 2024, 2:26 p.m.

The researchers show that high blood levels of a byproduct formed by the gut bacteria from nutrients abundant in red meat, eggs and other animal source foods predicts future risk of developing chronic kidney disease. AP

• Gretchen Cuda Kroen, cleveland.com

CLEVELAND, Ohio — What we eat can have a profound effect on our health. New research has shown that that’s true even of kidney disease.

Researchers at the Cleveland Clinic and Tufts University have uncovered a link between a certain set of gut microbes and Chronic Kidney Disease.

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Thursday, April 4, 2024

Scientists discover potential treatment approaches for polycystic kidney disease

Innovative disease modeling and gene editing techniques begin to answer long-standing questions.

Researchers have shown that dangerous cysts, which form over time in polycystic kidney disease (PKD), can be prevented by a single normal copy of a defective gene. This means the potential exists that scientists could one day tailor a gene therapy to treat the disease. They also discovered that a type of drug, known as a glycoside, can sidestep the effects of the defective gene in PKD. The discoveries could set the stage for new therapeutic approaches to treating PKD, which affects millions worldwide. The study, partially funded by the National Institutes of Health (NIH), is published in Cell Stem Cell .

Scientists used gene editing and 3-D human cell models known as organoids to study the genetics of PKD, which is a life-threatening, inherited kidney disorder in which a gene defect causes microscopic tubes in the kidneys to expand like water balloons, forming cysts over decades. The cysts can crowd out healthy tissue, leading to kidney function problems and kidney failure. Most people with PKD are born with one healthy gene copy and one defective gene copy in their cells.

“Human PKD has been so difficult to study because cysts take years and decades to form,” said senior study author Benjamin Freedman, Ph.D., at the University of Washington, Seattle. “This new platform finally gives us a model to study the genetics of the disease and hopefully start to provide answers to the millions affected by this disease.”

To better understand the genetic reasons cysts form in PKD, Freedman and his colleagues sought to determine if 3-D human mini-kidney organoids with one normal gene copy and one defective copy would form cysts. They grew organoids, which can mimic features of an organ’s structure and function, from induced pluripotent stem cells, which can become any kind of cell in the body.

To generate organoids containing clinically relevant mutations, the researchers used a gene editing technique called base editing to create mutations in certain locations on the PKD1 and PKD2 genes in human stem cells. They focused on four types of mutations in these genes that are known to cause PKD by disrupting the production of polycystin protein. Disruptions in two types of the protein – polycystin-1 and polycystin-2 – are associated with the most severe forms of PKD.

They then compared cells with two gene copy mutations in organoids to cells with only one gene copy mutation. In some cases, they also used gene editing to correct mutations in one of the two gene copies to see how this affected cyst formation. They found organoids with two defective gene copies always produced cysts and those that carried one good gene copy and one bad copy did not form cysts. 

“We didn’t know if having a gene mutation in only one gene copy is enough to cause PKD, or if a second factor, such as another mutation or acute kidney injury was necessary,” Freedman said. “It’s unclear what such a trigger would look like, and until now, we haven’t had a good experimental model for human PKD.”

According to Freedman, the cells with one healthy gene copy make only half the normal amount of polycystin-1 or polycystin-2, but that was sufficient to prevent cysts from developing. He added that the results suggest the need for a second trigger and that preventing that second hit might be able to prevent the disease.

The organoid models also provided the first opportunity to study the effectiveness of a class of drugs known as eukaryotic ribosomal selective glycosides on PKD cyst formation.

“These compounds will only work on single base pair mutations, which are commonly seen in PKD patients,” explained Freedman. “They wouldn’t be expected to work on any mouse models and didn’t work in our previous organoid models of PKD. We needed to create that type of mutation in an experimental model to test the drugs.”

Freedman’s team found that the drugs could restore the ability of genes to make polycystin, increasing the levels of polycystin-1 to 50% and preventing cysts from forming. Even after cysts had formed, adding the drugs slowed their growth.

Freedman suggested that a next step would be to test existing glycoside drugs in patients. Researchers also could explore the use of gene therapy as a treatment for PKD.

The research was supported by NIH’s National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institute of General Medical Sciences through awards R01DK117914, UH3TR002158, UH3TR003288, U01DK127553, U01AI176460, U2CTR004867, UC2DK126006, P30DK089507, R21DK128638, and R35GM142902; an Eloxx Pharmaceuticals Award; the Lara Nowak-Macklin Research Fund; and a Washington Research Foundation fellowship.

About the National Center for Advancing Translational Sciences (NCATS):  NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov .

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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A Narrative Review of Chronic Kidney Disease in Clinical Practice: Current Challenges and Future Perspectives

• Open access
• Published: 05 November 2021
• Volume 39 , pages 33–43, ( 2022 )

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• Marc Evans 1 ,
• Ruth D. Lewis 2 ,
• Angharad R. Morgan 2 ,
• Martin B. Whyte 3 ,
• Wasim Hanif 4 ,
• Stephen C. Bain 5 ,
• Sarah Davies 6 ,
• Umesh Dashora 7 ,
• Zaheer Yousef 8 ,
• Dipesh C. Patel 9 &
• W. David Strain 10  

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Chronic kidney disease (CKD) is a complex disease which affects approximately 13% of the world’s population. Over time, CKD can cause renal dysfunction and progression to end-stage kidney disease and cardiovascular disease. Complications associated with CKD may contribute to the acceleration of disease progression and the risk of cardiovascular-related morbidities. Early CKD is asymptomatic, and symptoms only present at later stages when complications of the disease arise, such as a decline in kidney function and the presence of other comorbidities associated with the disease. In advanced stages of the disease, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. With limited treatment options available, an increasing prevalence of both the elderly population and comorbidities associated with the disease, the prevalence of CKD is set to rise. This review discusses the current challenges and the unmet patient need in CKD.

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Introduction

Chronic kidney disease (CKD) is a complex and multifaceted disease, causing renal dysfunction and progression to end-stage kidney disease (ESKD) and cardiovascular disease. Complications associated with the disease contribute to the acceleration of CKD progression and risk of cardiovascular-related morbidities.

Despite its high prevalence and the clinical and economic burden of its associated complications, disease awareness remains profoundly low. Worldwide, only 6% of the general population and 10% of the high‐risk population are aware of their CKD statuses [ 1 ]. In addition, CKD recognition in primary care settings is also suboptimal, ranging from 6% to 50%, dependent upon primary care specialty, severity of disease, and experience. Awareness of CKD remains low in part because CKD is usually silent until its late stages. However, diagnosis of CKD during the later stages results in fewer opportunities to prevent adverse outcomes. Physician awareness of CKD is critical for the early implementation of evidence-based therapies that can slow progression of renal dysfunction, prevent metabolic complications, and reduce cardiovascular-related outcomes.

Currently CKD is not curable, and management of the disease relies on treatments which prevent CKD progression and cardiovascular disease. Despite available treatments, a residual risk of adverse events and CKD progression remains. This article reviews the challenges associated with CKD and the treatments available for patients, highlighting the unmet need for cardio-renal protection in patients with CKD.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

CKD Prevalence

CKD is a global health problem. A meta-analysis of observational studies estimating CKD prevalence showed that approximately 13.4% of the world’s population has CKD [ 2 ]. The majority, 79%, were at late stages of the disease (stage 3–5); however, the actual proportion of people with early CKD (stage 1 or 2) is likely to be much higher since early kidney disease is clinically silent [ 3 ].

Prevalence of CKD appears to be growing rapidly both in the UK and in the Western world. Based on the 2012 subnational population projections for England [ 4 ], the number of people with CKD stage 3–5 is projected to exceed 4 million by 2036 [ 5 ]. This rise in CKD prevalence is due to an increased aging population and prevalence of type 2 diabetes (T2DM), obesity, hypertension and cardiovascular disease that contribute to CKD [ 6 , 7 , 8 ].

The World Health Organization (WHO) estimated that the annual, global number of deaths caused directly by CKD is 5–10 million [ 9 ]. The presence of CKD advances mortality of comorbidities such as cardiovascular diseases, T2DM, hypertension, and infection with human immunodeficiency virus (HIV), malaria and Covid-19, thereby indirectly adding to CKD mortality [ 9 , 10 ]. A contributing cause of high morbidity and mortality associated with CKD is a lack of awareness of the disease, by both patients and providers [ 11 , 12 ]. Early stages of CKD are clinically silent and patients have no symptoms. Lack of treatment at this stage allows CKD to progress through to advanced stages of the disease, where patients may present complications and/or cardiovascular-related comorbidities, or ESKD. Raising awareness of CKD is therefore paramount to allow for early intervention and reduce the risk of comorbidities and mortality.

Classification of CKD

In order to better manage CKD and provide better care for patients, the classification of CKD was developed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative [ 13 ] and the international guideline group Kidney Disease Improving Global Outcomes (KDIGO) [ 14 ]. CKD stratification is based upon the estimated glomerular filtration rate (eGFR) and albuminuria.

There are six eGFR categories. An eGFR of less than 60 mL/min per 1.73 m 2 for more than 3 months is indicative of impaired renal function and the severity of kidney damage increases with decreasing eGFR measurements. Patients with early onset of the disease, stage 1–2, have normal to mild decreased levels of eGFR (60 to ≥ 90 mL/min per 1.73 m 2 ). Patients with stage 3a–3b have mild to moderate decreased levels of eGFR (45–59 mL/min per 1.73 m 2 , respectively). Severely decreased levels of eGFR, stage 4–5 (15–29 to < 15 mL/min per 1.73 m 2 , respectively), are indicative of advanced stages of the disease and kidney failure.

Stratification also comprises three categories of albuminuria. Patients with an albumin to creatinine ratio (ACR) of 3 to at most 30 mg/mmol are classified as having microalbuminuria and at moderate risk of adverse outcomes. Those with ACR of greater than 30 mg/mmol are classified as having macroalbuminuria and being severely at risk of developing adverse events [ 15 ]. The eGFR and albuminuria categories independently predict adverse outcomes for patients with CKD, and the combination of both increases this risk further [ 16 ]. The CKD classification system aids clinicians in carrying out accurate assessments of CKD severity and other complications which helps to inform decisions associated with the management and monitoring of patients [ 3 , 17 , 18 ].

Clinical Burden of CKD

CKD is a complex disease, involving both non-modifiable (e.g. older age, family history and ethnicity) and modifiable risk factors (e.g. T2DM, hypertension and dyslipidaemia) which are responsible for the initiation of early CKD, CKD progression (stage 3–5) and ESKD.

In early stages of CKD (stage 1–2), factors such as hypertension, obesity and T2DM can trigger kidney function impairment. This causes glomerular/interstitial damage and results in impaired glomerular filtration, leading to decreased eGFR and increased albuminuria. At this stage, even though clinical symptoms do not present, the presence of additional risk factors, including hypertension, hyperglycaemia, smoking, obesity, dyslipidaemia and cardiovascular disease, may accelerate CKD progression and result in ESKD.

As the disease progresses, the clinical and economic burden of CKD increases (Fig.  1 ) as complications such as CKD mineral bone disorder, anaemia, hypertension and hyperkalaemia may occur and advanced stages of CKD, stage 4–5, ensue. Clinical symptoms, such as fatigue, itching of the skin, bone or joint pain, muscle cramps and swollen ankles, feet or hands, are often present at this stage [ 19 ]. Further deterioration of kidney function causes tubular and glomerular hypertrophy, sclerosis and fibrosis, leading to a significant reduction in eGFR, extreme albuminuria and kidney failure.

A schematic diagram showing the association between CKD progression and clinical and economic burden. Symptoms of CKD typically present during advanced stages of the disease where patients are at increased risk of cardiovascular disease and other comorbidities

Even though CKD progression may lead to kidney failure and renal death, patients with CKD are more likely to die from cardiovascular-related complications before reaching ESKD [ 20 ]. A study using data from a meta-analysis involving 1.4 million individuals found a significant increased risk of cardiovascular-related mortality, even in stage 2 of CKD (eGFR levels < 90 mL/min per 1.73 m 2 ) [ 16 , 21 , 22 ].

As the disease progresses, the risk of cardiovascular disease is markedly increased, such that 50% of patients with late-stage CKD, stage 4–5, have cardiovascular disease. The risk of atrial fibrillation (AF) and acute coronary syndrome (ACS) is doubled in patients with eGFR < 60 mL/min per 1.73 m 2 . AF is associated with a threefold higher risk of progression to ESKD. The incidence of heart failure (HF) is also threefold greater in patients with eGFR < 60 mL/min per 1.73 m 2 compared with > 90 mL/min per 1.73 m 2 and HF is associated with CKD progression, hospitalisation and death [ 23 ].

The increased risk of cardiovascular disease in patients with CKD is due in part to the traditional risk factors associated with cardiovascular disease such as hypertension, T2DM and dyslipidaemia. For instance, a large observational database linked study (Third National Health and Nutrition Examination Survey (NHANES) III) found a strong association between CKD and T2DM combined and an increased risk of mortality [ 24 ]. In this study, the authors observed a 31.1% mortality rate in patients with CKD and diabetes, compared to 11.5% in people with diabetes only. An observational study using both US and UK linked databases showed that the presence of both CKD and T2DM was related to increased risk of major adverse cardiac events (MACE), HF and arrhythmogenic cardiomyopathy (ACM) [ 25 ]. This risk was further elevated in older patients with atherosclerotic cardiovascular disease [ 25 ]. Similarly, the presence of both CKD and T2DM leads to a significant increased risk of all-cause and cardiovascular-related mortality versus T2DM alone [ 24 ].

The direct renal effect on cardiovascular disease is due to generalised inflammatory change, cardiac remodelling, narrowing of the arteries and vascular calcification, both contributing to the acceleration of vascular ageing and atherosclerotic processes, and leading to myocardial infarction, stroke and HF [ 26 ].

Together, these studies highlight the strong relationship which exists between CKD progression, number of comorbidities and heightened risk of cardiovascular disease and cardiovascular-related mortality.

Economic Burden of CKD

In addition to the clinical burden, management of CKD also requires significant healthcare resources and utilisation. In 2009–2010, the estimated cost of CKD to the National Health Service (NHS) in England was £1.45 billion [ 27 ]. Furthermore, in 2016, US Medicare combined expenditure for CKD and ESKD exceeded $114 billion (£86 billion) [ 28 ].

Although estimating the true cost of early CKD is difficult because of the lack of data available for unreported cases, CKD progression is associated with increased healthcare costs [ 29 , 30 ]. A study by Honeycutt et al. combined laboratory data from NHANES with expenditure data from Medicare and found that costs of CKD management increased with disease progression [ 29 ]. Estimated annual medical costs of CKD per person were not significant at stage 1, $1700 at stage 2, $3500 at stage 3 and $12,700 at stage 4.

Healthcare costs associated with early CKD are more likely to be from the sequalae of comorbid disease rather than kidney disease. Hence, patients with CKD stage 1 or 2 are at increased risk of hospitalisation if they also have T2DM (9%), cardiovascular disease (more than twofold), and both cardiovascular disease and T2DM (approximately fourfold) [ 31 ].

ESKD accounts for the largest proportion of CKD management costs. In 2009–2010, 50% of the overall CKD cost to NHS (England) was due to renal replacement therapy (RRT), which accounted for 2% of the CKD population [ 27 ]. The other 50% included renal primary care costs, such as treatment costs for hypertension and tests, consultation costs, non-renal care attributable to CKD and renal secondary care costs. Approximately £174 million was estimated for the annual cost of myocardial infarctions and strokes associated with CKD [ 27 ].

More recently, an economic analysis investigated the burden associated with the management of cardiovascular-related morbidity and mortality in CKD, according to the KDIGO categorisation of both eGFR and albuminuria [ 15 ]. Decreased eGFR levels increased both the risk of adverse clinical outcomes and economic costs, and albuminuria elevated this risk significantly. Furthermore, CKD progression correlated with increased CKD management costs and bed days. Stage 5 CKD (versus stage 1 (or without) CKD) per 1000 patient years was associated with £435,000 in additional costs and 1017 bed days.

The significant economic burden associated with CKD progression and ESKD highlights the importance of optimising CKD management and the unmet need for better treatment options in slowing disease progression in this patient population. Thus, early detection and intervention to slow the progression of the disease has the potential to make substantial savings in healthcare costs.

Current CKD Management Strategies

KDIGO and National Institute for Health and Care Excellence (NICE) have produced detailed guidelines for the evaluation and management of CKD [ 3 , 32 , 33 ]. Both recommend implementing strategies for early diagnosis of the disease in order to reduce the risk of cardiovascular disease, attenuate CKD progression and decrease the incidence of ESKD in this patient population. CKD is a complex disease and thus treatment requires a multifaceted approach utilising both non-pharmacological, e.g. diet and exercise regimes and pharmacological interventions such as antihypertensive and antihyperglycemic drugs [ 34 ]. There has, however, been no significant breakthrough in this area for over 2 decades.

The effect of lifestyle intervention on reducing disease progression is still unclear, although increased physical activity has been shown to slow the rate of eGFR decline [ 35 ] and ESKD progression [ 36 ], improve eGFR levels [ 35 ] and albuminuria [ 37 ], and reduce mortality in patients with CKD [ 35 , 38 , 39 , 40 ]. Similarly, diet regimes such as low-protein diet or Mediterranean diet reduce renal function decline and mortality rate in CKD [ 41 , 42 ]. Hence, dietary advice is recommended in accordance with CKD severity to control for daily calorie, salt, potassium, phosphate and protein intake [ 3 , 33 ]. However, patients with consistently elevated serum phosphate levels or metabolic acidosis [low serum bicarbonate levels (< 22 mmol/l)], associated with increased risk of CKD progression and death, may be treated with phosphate binding agents (e.g. aluminium hydroxide and calcium carbonate) or sodium bicarbonate, respectively [ 3 ].

To reduce the risk of cardiovascular disease, KDIGO and NICE recommend active lipid management and blood pressure control [ 33 , 43 , 44 ]. In early CKD stages 1 and 2, statins are recommended for all patients over 50 years of age, whilst in stage 3 and advanced stages of the disease, stage 4–5 (eGFR < 60 mL/min per 1.73 m 2 ), a combination of statins and ezetimibe is advised [ 43 ].

Management of hypertension includes a target blood pressure of less than 140/90 mmHg for patients with CKD and hypertension and less than 130/80 mmHg for patients with CKD and T2DM, and also in patients with albuminuria [ 3 , 32 ], alongside blood pressure lowering therapies and renin–angiotensin–aldosterone system (RAAS) blocking agents, such as angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEi). As such, RAAS inhibitors (RAASi) are currently recommended to treat patients with diabetes, hypertension and albuminuria in CKD [ 45 ]. These RAAS blocking agents confer both renal and cardiovascular protection and are recommended as first-line treatment to treat hypertension in patients with CKD [ 34 , 46 ].

The clinical benefits of RAASi have been demonstrated in patients with CKD with and without diabetes [ 47 , 48 , 49 ]. These clinical benefits are in addition to their effects on reducing blood pressure and albuminuria, including a reduction in eGFR decline and a decreased risk of ESKD cardiac-related morbidity and all-cause mortality [ 47 , 48 , 49 ]. Nevertheless, despite their benefits, RAASi treatment can induce hyperkalaemia, and patients are often advised to reduce RAASi dosage or even discontinue their treatment, which prevents optimum clinical benefits of RAASi therapy being reached. In this instance, combination therapy with potassium binding agents, such as patiromer and sodium zirconium cyclosilicate, may be used alongside RAASi therapy to reduce RAASi-associated hyperkalaemia.

However long-term trials will be required to determine their effect on cardiovascular morbidity and mortality in CKD [ 50 , 51 , 52 ]. Despite these therapies being the mainstay of CKD management, there is still a residual risk of CKD progression and an unmet need for new treatments.

Novel/Emerging Treatments for CKD Management

Over the last 2 years, novel therapeutic approaches for CKD management have emerged, with particular attention on mineralocorticoid receptor antagonists (MRAs) and sodium–glucose co-transporter 2 (SGLT2) inhibitors. The clinical effectiveness of finerenone, a selective oral, non-steroidal MRA, has recently been demonstrated to lower risks of CKD progression and cardiovascular events in diabetic kidney disease (DKD) [ 53 ]. Finerenone is under review for approval by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA).

Of these new and emerging therapies, SGTL2i offers the most clinical benefit with both cardiovascular and renal protective effects, independent of glucose lowering. Clinical trials of SGTL2 in T2DM with and without CKD overall showed a 14–31% reduction in cardiovascular endpoints including hospitalisation for HF and MACE and a 34–37% reduction in hard renal-specific clinical endpoints including a sustained reduction in eGFR, progression of albuminuria and progression to ESKD [ 54 , 55 , 56 , 57 , 58 ]. CREDENCE, was a double-blind, multicentre, randomised trial in diabetic patients with albuminuric CKD (eGFR 30 to < 90 mL/min per 1.73 m 2 and ACR ≥ 30 mg/mmol) [ 57 ]. In this trial, canagliflozin reduced the relative risk of the composite of ESKD, doubling of serum creatinine and renal-related mortality by 34%, relative risk of ESKD by 34% and risk of cardiovascular-related morbidity, including myocardial infarction and stroke, and mortality.

The SGTL2i dapagliflozin has proven its effectiveness in slowing CKD progression in addition to reducing cardiovascular risk in early stages of CKD. The DECLARE-TIMI58 trial involved 17,160 diabetic patients with established atherosclerotic cardiovascular disease and early-stage CKD (mean eGFR was 85.2 mL/min per 1.73 m 2 ) and were randomised to receive either dapagliflozin or placebo. Following a median follow-up of 4.2 years, there was a significant reduction in renal composite endpoints with dapagliflozin versus placebo, with a 46% reduction in sustained decline of at least 40% eGFR to less than 60 mL/min per 1.73 m 2 and a reduction in ESKD (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR < 15 mL/min per 1.73 m 2 ) or renal death.

More recently, these cardiovascular and renal protective effects of SGTLT2i have also been demonstrated in a broad range of patients with more advanced stages of CKD (mean eGFR was 43.1 ± 12.4 mL/min per 1.73 m 2 ) without diabetes [ 58 , 59 ]. In the DAPA-CKD trial, many patients were without diabetes, including IgA nephropathy, ischemic/hypertension nephropathy and other glomerulonephritis [ 59 ]. Patients receiving dapagliflozin had a 39% relative risk reduction in the primary composite outcomes of a sustained decline in eGFR of at least 50%, ESKD and renal- or cardiovascular-related mortality and a 31% relative risk reduction of all-cause mortality compared to placebo [ 58 , 60 ]. Safety outcomes from clinical trials of dapagliflozin have also shown similar incidences of adverse events in both placebo and dapagliflozin arms [ 58 , 61 ].

The clinical benefits and safety outcomes from these trials highlight the potential use of SGTL2i in reducing cardiovascular burden and CKD progression in a broad range of CKD aetiologies at early and late stages where there is an unmet need. Currently, SGTL2i class drugs, including canagliflozin, dapagliflozin and empagliflozin, are approved by the US FDA for the treatment of T2DM and, more recently, dapagliflozin and canagliflozin for CKD and DKD respectively [ 62 , 63 ]. In addition, SGTL2i has been recommended for approval in the European Union (EU) by the Committee for Medicinal Products for Human Use (CHMP) of the EMA, for the treatment of CKD in adults with and without T2D [ 64 ]. Hence, there is now a need to raise awareness of the clinical applicability of these drugs in CKD to ensure full utilisation and maximum benefits are met, for both patients and providers.

This narrative review has summarised some of the key challenges associated with CKD. Early stages of the disease are clinically silent which prevents early intervention to slow the progression of the disease and allows progression of CKD and ESKD. At advanced stages of the disease, when clinical symptoms are present, patients with CKD are already at heightened risk of cardiovascular-related morbidity and mortality. Hence, advanced stages of CKD and ESKD are associated with poor outcomes and a significant clinical and economic burden.

At present, there are no treatments to cure CKD; as such, strategies for CKD management have been developed to target the modifiable risk factors in order to reduce cardiovascular disease morbidity in patients with CKD and slow the progression of CKD to ESKD. However, despite available treatment options, residual risk of adverse events and CKD progression remain; hence, an unmet need exists in CKD treatment. SGTL2i have the potential to fill this gap, with recent evidence from clinical trials showing a reduction in cardiovascular and renal adverse endpoints in a broad range of patients with CKD.

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Acknowledgements

This manuscript was supported by a grant from AstraZeneca UK Ltd. in respect of medical writing and publication costs (the journal’s Rapid Service and Open Access Fees). AstraZeneca has not influenced the content of the publication, and has reviewed this document for factual accuracy only.

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All authors have been involved in design of this review. Marc Evans, Ruth D. Lewis, and Angharad R. Morgan produced the primary manuscript. All authors have contributed to the drafting and revision of the manuscript and have approved the final version for publication. Marc Evans is responsible for the integrity of the work as a whole.

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Marc Evans reports honoraria from AstraZeneca, Novo Nordisk, Takeda and NAPP, and research support from Novo Nordisk outside the submitted work. Ruth D. Lewis and Angharad R Morgan are employees of Health Economics and Outcomes Research Ltd., Cardiff, UK who received fees from AstraZeneca in relation to this study. Martin B. Whyte reports investigator-led research grants from Sanofi, Eli Lilly and AstraZeneca and personal fees from AstraZeneca, Boehringer Ingelheim and MSD outside the submitted work. Wasim Hanif reports grants and personal fees from AstraZeneca, grants and personal fees from Boerhinger Inglhiem, grants and personal fees from NAPP, from MSD, outside the submitted work. Stephen C. Bain reports personal fees and other from Abbott, personal fees and other from AstraZeneca, personal fees and other from Boehringer Ingelheim, personal fees and other from Eli Lilly, personal fees and other from Merck Sharp & Dohme, personal fees and other from Novo Nordisk, personal fees and other from Sanofi-aventis, other from Cardiff University, other from Doctors.net, other from Elsevier, other from Onmedica, other from Omnia-Med, other from Medscape, other from All-Wales Medicines Strategy Group, other from National Institute for Health and Care Excellence (NICE) UK, and other from Glycosmedia, outside the submitted work. PAK reports personal fees for lecturing from AstraZeneca, Boehringer Inglhiem, NAPP, MundiPharma and Novo Nordisk outside the submitted work. Sarah Davies has received honorarium from AstraZeneca, Boehringer Ingelheim, Lilly, Novo Nordisk, Takeda, MSD, NAPP, Bayer and Roche for attending and participating in educational events and advisory boards, outside the submitted work. Umesh Dashora reports personal fees from AstraZeneca, NAPP, Sanofi, Boehringer Inglhiem, Lilly and Novo Nordisk, outside the submitted work. Zaheer Yousef reports personal fees from AstraZeneca, personal fees from Lilly, personal fees from Boehringer Ingelheim and personal fees from Novartis outside the submitted work. Dipesh C. Patel reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, non-financial support from NAPP, personal fees from Novo Nordisk, personal fees from MSD, personal fees and non-financial support from Sanofi outside the submitted work. In addition, DCP is an executive committee member of the Association of British Clinical Diabetologists and member of the CaReMe UK group. W. David Strain holds research grants from Bayer, Novo Nordisk and Novartis and has received speaker honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, NAPP, Novartis, Novo Nordisk and Takeda. WDS is supported by the NIHR Exeter Clinical Research Facility and the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula.

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Evans, M., Lewis, R.D., Morgan, A.R. et al. A Narrative Review of Chronic Kidney Disease in Clinical Practice: Current Challenges and Future Perspectives. Adv Ther 39 , 33–43 (2022). https://doi.org/10.1007/s12325-021-01927-z

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Resistant starch could help combat leading cause of end-stage kidney failure

by American Physiological Society

Combining a low dose of blood pressure medication with a higher intake of dietary-resistant starch might help stave off diabetic kidney disease, according to results from a new animal study. Kidney disease is a common diabetes complication and the leading cause of end-stage kidney failure. Researchers presented their work at the American Physiology Summit , held April 4–7 in Long Beach, California.

Although blood pressure medicines have been shown to protect kidney function, high doses can cause dehydration, very low blood pressure and electrolyte imbalance.

"Our study suggests that combining dietary interventions with a low dose of established medications for diabetic kidney disease management can provide a more feasible and lower side-effect alternative for patients to implement and improve their health outcomes by helping maintain their kidney integrity," said Claudia Carrillo, a Ph.D. student at Iowa State University, who performed the research.

Dietary-resistant starch is found in unripe bananas, cooked and cooled potatoes, legumes and whole grains. This type of carbohydrate isn't digested in the small intestine like most foods. Instead, it ferments in the large intestine, where it feeds beneficial gut bacteria.

Carrillo's research team previously showed that giving rat models of type 1 and type 2 diabetes a diet high in resistant starch—where 35% to 50% of their carbohydrates were from resistant starch—prevented symptoms of declining kidney function . Although these results were promising, a dietary intervention requiring so much resistant starch is not practical.

"In this new study, we wanted to explore a dietary intervention that was more feasible to implement for diabetic patients in their daily lives," Carrillo said. "We opted to combine this dietary intervention at a lower dosage than before—equivalent to 5% to 10% of consumed carbohydrates from resistant starch—with low-dose renin-angiotensin system inhibitor, a blood pressure medication that had been shown to elicit the same effect on kidney health."

The researchers found that compared to the control groups rat models of type 2 diabetes that consumed low-to-moderate amounts of resistant starch while also receiving blood pressure medication showed restored vitamin D blood levels and decreased loss of vitamin D and protein in the urine, which are symptoms of kidney deterioration seen during diabetes progression.

The study results, together with gene and protein expression analyses, also showed that the combined intervention imparted a protective effect on the kidney by modulating the renal renin-angiotensin system. This critical hormonal system helps regulate blood pressure and fluid balance in the body.

"Our research provides more information toward understanding diabetes complications, especially related to kidney health," Carrillo said. "This work could be used to investigate possible translatable strategies that use a whole food source and already well-used medication to minimize the risk for these complications."

The researchers are getting ready to begin a related study that will use type 1 diabetic rats to find out if the results seen with type 2 diabetes animals differ in an insulin-deficient model. They also plan to explore how other types of fiber, such as whole oats, might affect kidney health, and they want to study the microbiome's role in the drug-diet intervention .

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Genetic analysis reveals true origin of chronic kidney disease in undiagnosed patients

C hronic kidney disease (CKD) is extremely prevalent among adults, affecting over 800 million individuals worldwide. Many of these patients eventually require therapy to supplement or replace kidney functions, such as dialysis or kidney transplants.

While most CKD cases originate from lifestyle-related factors or diseases such as diabetes and hypertension, the underlying causes of CKD remain unknown for about one in every ten people with end-stage renal failure. Could CKD in these patients stem from latent, undiagnosed genetic conditions?

In a recent study published in Kidney International Reports , researchers from Tokyo Medical and Dental University (TMDU) in Japan set out to answer this question through a comprehensive genetic analysis of CKD patients.

First, the researchers acquired data from 1,164 patients who underwent dialysis in four different clinics in the Kanagawa Prefecture in November 2019. From this multicenter cohort, the researchers filtered out adults who were over 50 years old, since people at that age have a lower incidence of inherited kidney diseases. They then filtered outpatients who had an apparent cause for their CKD, leaving 90 adults with CKD of unknown origin who had consented to genetic testing.

"We conducted a comprehensive analysis of 298 genes responsible for various inherited renal diseases using next-generation sequencing," explains lead author Dr. Takuya Fujimaru. "These included polycystic kidney disease, nephronophthisis-related ciliopathies, autosomal dominant tubulointerstitial kidney disease, focal segmental glomerulosclerosis, Alport syndrome, and atypical hemolytic uremic syndrome."

The results revealed that 10 of the 90 patients (11% of the final cohort) had pathogenic variants in CKD-causing genes. Importantly, for these patients, the clinical diagnosis at the time of dialysis was incorrect. What was particularly noteworthy was that some of the hereditary renal diseases contemplated in this study, such as Fabry's disease and Alport syndrome, could be diagnosed and treated early on to slow down or halt the progression of CKD.

On top of these findings, the researchers determined that 17 patients (18.9%) had genetic variants of unknown significance (VUS) with a high probability of pathological involvement. While the relationship between these variants and kidney diseases is not clear, they should not be ignored or taken lightly.

"Although the interpretation of these VUS is currently unknown, some of them may indeed be responsible for CKD," remarks senior author Dr. Takayasu Mori. "Thus, true hereditary kidney diseases may underlie many more cases than anticipated."

This study marks one of the world's largest comprehensive genetic analysis of patients with end-stage renal failure using clinical data. As such, the conclusions derived from the results can have important implications for how CKD is diagnosed and managed in adults.

"When the primary disease underlying a case of CKD is unknown, genetic analysis could lead to accurate diagnosis and appropriate treatment before the disease progresses, which could hopefully result in a decrease in the number of patients requiring dialysis," highlights senior author Dr. Eisei Sohara. "Thus, proactive genetic analysis is recommended for adult patients without a definitive cause of CKD."

Notably, this research group has been conducting genetic analyses of hereditary kidney diseases since 2014, reaching over 1,500 families. They have recently filed a patent for a new genetic analysis system for Japanese individuals, which would assist in correctly diagnosing cases of CKD. With any luck, further efforts will pave the way to a brighter future for people with inherited kidney diseases.

More information: Takuya Fujimaru et al, Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology, Kidney International Reports (2024). DOI: 10.1016/j.ekir.2024.01.027

Provided by Tokyo Medical and Dental University