Post-Stroke Cardiovascular Complications and Neurogenic Cardiac Injury: JACC State-of-the-Art Review

Chronic Kidney Disease

Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite. Often, chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and those with a blood relative with chronic kidney disease. Chronic kidney disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia or pericarditis.

Chronic kidney disease is identified by a blood test for creatinine. Higher levels of creatinine indicate a lower glomerular filtration rate and as a result a decreased capability of the kidneys to excrete waste products. Creatinine levels may be normal in the early stages of CKD, and the condition is discovered if urinalysis (testing of a urine sample) shows that the kidney is allowing the loss of protein or red blood cells into the urine. To fully investigate the underlying cause of kidney damage, various forms of medical imaging, blood tests and often renal biopsy (removing a small sample of kidney tissue) are employed to find out if there is a reversible cause for the kidney malfunction. Recent professional guidelines classify the severity of chronic kidney disease in five stages, with stage 1 being the mildest and usually causing few symptoms and stage 5 being a severe illness with poor life expectancy if untreated. Stage 5 CKD is also called established chronic kidney disease and is synonymous with the now outdated terms end-stage renal disease (ESRD), chronic kidney failure (CKF) or chronic renal failure (CRF).

There is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. If there is an underlying cause to CKD, such as vasculitis, this may be treated directly with treatments aimed to slow the damage. In more advanced stages, treatments may be required for anemia and bone disease. Severe CKD requires one of the forms of renal replacement therapy; this may be a form of dialysis, but ideally constitutes a kidney transplant.

Genetic Analysis Reveals Unknown Causes Of Chronic Kidney Disease

Register for free to listen to this article

Thank you. Listen to this article using the player above. ✖

Want to listen to this article for FREE?

Complete the form below to unlock access to ALL audio articles.

Chronic 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 transplant. 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 online on 14 February 2024 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.

Subscribe to Technology Networks' daily newsletter, delivering breaking science news straight to your inbox every day.

Subscribe for FREE

First, the researchers acquired data from 1,164 patients who underwent dialysis in four different clinics in the Kanagawa Prefecture during 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 out patients 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 in 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. 

Reference: Fujimaru T, Mori T, Chiga M, et al. Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology. Kidney Inter Rep. 2024;9(4):994-1004. Doi: 10.1016/j.Ekir.2024.01.027

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Improving The Outlook For Chronic Kidney Disease

In chronic kidney disease, kidney function decreases over time.Credit: sasirin pamai/Shutterstock

Chronic Kidney Disease (CKD), which affects approximately 844 million people worldwide1, typically progresses silently for years before it is diagnosed. But by then, in many cases, irreversible damage has already occurred.

The risk of CKD increases with age, so as the world's population grows older, it will affect even more people. Identified as the 16th leading cause of death worldwide in 2016, CKD is predicted to become the fifth leading cause of death by 20402.

A urine test is needed to diagnose chronic kidney disease when it is in the early stages.Credit: Lothar Drechsel/iStock/Getty

Tests and treatments for early-stage CKD are relatively cheap and simple, but are not routine. Currently many health systems primarily focus on treating end-stage kidney disease rather than detecting and treating the early stage of CKD, allocating between 2-3% of their budget to end-stage kidney disease3. A collaboration between Japanese researchers and pharmaceutical companies, including AstraZeneca Japan, is seeking to change this by raising awareness of CKD and promoting early diagnosis.

In the broadest sense, CKD is a long-term condition where kidney function gradually declines over time. Once CKD begins, it progresses slowly but relentlessly every year. Early-stage symptoms are hard to detect, but they often co-occur with other non-communicable diseases, such as type 2 diabetes, hypertension and dyslipidemia.

Once symptoms eventually appear at later stages, patients may experience fatigue, nausea, loss of appetite and weight loss. Treatment at this point is costly and can have a profound effect on a patient's quality of life, including their ability to work and participate in daily activities.

Lack of diagnosis

Typically, treatments include management of underlying conditions such as hypertension and diabetes, which can slow the progression of the disease. Patients with end-stage CKD require a kidney transplant or must undergo dialysis, to clean the blood, which is a tremendously time-consuming and expensive treatment. If untreated, end stage kidney disease is life threatening.

Despite the enormous global burden of CKD on patients, caregivers, economics and the environment, diagnosis of the disease's early stages is remarkably simple.

CKD diagnosis is based on a chronic decline in estimated glomerular filtration rate (eGFR), which is a measure of how well kidneys extract waste from blood. However, in its early stages, CKD cannot be diagnosed by eGFR alone — a urine test is required, says Shoichi Maruyama, a professor at the Department of Nephrology, at Nagoya University, in Japan. This test measures the level of protein in the urine, a high level means kidney damage.

Toshiki Moriyama, a professor of nephrology at Osaka University, Japan.

"There's nothing difficult or complicated about it," agrees Toshiki Moriyama, a professor in the Department of Nephrology at Osaka University, also in Japan. "If protein is found in urine, it is a marker of disease."

Yet, he says, taking Japan as an example, 90% of stage 3 CKD cases remain undiagnosed4. "This is not a matter of science" says Moriyama, "it's a matter of awareness." He points to the fact that even though CKD has a much higher prevalence in Japan's aged population, other diseases of ageing, such as metabolic disease, are far more well known by the general public.

Low rates of urinalysis are a big barrier to early diagnosis. Even in a society such as Japan's, where many people attend annual health check-ups, early-stage CKD regularly goes undiagnosed because despite checks that include measurement of elevated protein levels in the urine, participation rate of the checks itself is not sufficient, says Maruyama.

Even when CKD is suspected, it may not be treated seriously enough because the long-term impact of CKD is not as well understood by patients and healthcare professionals, says Maruyama.

Missed opportunities

People may not go to a clinic, says Maruyama, even when they know their serum creatinine levels are a little high, because they do not understand that if CKD is diagnosed early, severe damage can be prevented. By the time patients do go to hospital, he says, a diagnosis of CKD will be registered, but by then many opportunities to slow its progression have been missed.

While pharmaceutical companies have been working on medications designed to slow or stop CKD progression, medication alone will not change the future of the disease if diagnosis rates remain unchanged.

This is why academics, such as Maruyama and Moriyama, are working in collaboration with AstraZeneca Japan — and why bodies such as The Japan Kidney Association, are engaged in a major campaign to raise awareness and create better name recognition of CKD.

Shoichi Maruyama, a professor of nephrology at Nagoya University, Japan.

Both Maruyama and Moriyama regularly speak to doctors, nurses, and other healthcare professionals to raise their awareness, encourage regular testing, and explore early treatment if CKD is diagnosed. Likewise, Moriyama often talks to local governments across Japan to make them aware of CKD and its consequences as they plan for healthcare in their regions.

Hirotaka Tsugumi, the head of cardiovascular, renal and metabolic disease area, Medical, AstraZeneca Japan, based in Osaka, says the company runs commercials in Japan to raise awareness, and hosts a website that posts up to date medical information and trial data and invites comments and questions from medical professionals.

The time is now

For Maruyama and Moriyama, robust evidence and strong tools are a critical part of successful outreach.

The Kidney Disease: Improving Global Outcomes (KDIGO) heat map, produced by an international group of nephrologists, is a matrix of eGFR and proteinuria levels and is widely used to assess a patient's CKD stage. KDIGO guidelines also recommend regular testing of eGFR and proteinuria.

In another collaboration with AstraZeneca Japan, the scientists examined the likelihood that a patient would experience a cardiovascular event based only on their position on the KDIGO heat map, which indicates their stage of CKD. The study confirmed that the more advanced CKD was, then more likely a cardiovascular event was, underlying how important healthy kidneys are to heart health.

Raised awareness of CKD, in combination with recommended treatment options, could have a huge impact on the future health of the world's population, even beyond its impact on CKD itself, says the scientists.

"The time to act for CKD is now. By building awareness and access to testing, patients can be diagnosed early and receive the treatment and care they need to slow the progression of CKD. This will improve outcomes for patients, health systems, caregivers, the economy, and the planet," agrees Tsugumi.

Z4-62461

---