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Glomerular disease: pathways in diagnosis and treatment and the new developments for patients

Professor Jonathan Barratt is the Mayer Professor of Renal Medicine and consultant nephrologist at University Hospitals of Leicester NHS Trust in the UK. He is an international expert on IgA nephropathy (IgAN). Here he gives an overview of glomerular diseases and shares his hopes for the future

Professor Jonathan Barratt is the Mayer Professor of Renal Medicine and consultant nephrologist at University Hospitals of Leicester NHS Trust. He is an international expert on IgA Nephropathy. Here he gives an overview of glomerular diseases and shares his hopes for the future

Professor Jonathan Barratt is the Mayer Professor of Renal Medicine and consultant nephrologist at University Hospitals of Leicester NHS Trust. He is an international expert on IgA Nephropathy. Here he gives an overview of glomerular diseases and shares his hopes for the future
Glomerular disease

Each of the kidneys in the human body contains about a million filters called glomeruli.1 These are “incredibly complex sieves that filter the blood 24/7”, Professor Barratt says. Glomerular disease,2 or glomerulonephritis (GN), is an umbrella term to describe the many conditions that cause inflammation of those filters. IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) are just two of those conditions.

One of the cardinal signs of inflammation in the glomeruli is the presence of blood cells and protein in the urine: the “sieve” is damaged and is leaking things into the urine that shouldn’t be there. Unfortunately, a GP who sees this in a urine test would typically make a diagnosis of a urinary tract infection, which is the most common cause of these signs.

“There are no blood tests, there’s no urine test, there’s nothing you can tell me as a patient that is going to allow me to make this diagnosis without doing a kidney biopsy. You can have lots of blood and protein in the urine, but we can’t usually see that with the naked eye,” Professor Barratt says.

“Actually getting to the nephrologist, who will perform a biopsy, is the key challenge for patients in getting a diagnosis. First, the primary care physician and any other hospital doctors you might have seen need to put two and two together.”

For people with IgA nephropathy, the added difficulty in diagnosis is that their condition is typically asymptomatic, so it is most commonly found by chance, following a urine test.

A diagnosis of focal segmental glomerulosclerosis (FSGS) is made based on the appearance of the kidney biopsy under the microscope, but further tests are then needed to determine which form of FSGS it is. “It is really important to understand the type of FSGS you have: it is not a single disease, there are multiple things that can cause it,” Professor Barratt says. When patients understand the variability within FSGS, they will understand the wide range of experiences described by other patients and caregivers.

Focal segmental glomerulosclerosis (FSGS)

FSGS may be caused by a genetic abnormality, and this is the form usually diagnosed in children, rather than in adults. Another form of FSGS is driven by an immune system abnormality, and this is seen in children and in adults. FSGS can also be caused by being overweight, having diabetes or having had a kidney removed—this form is very rarely seen in children.2

FSGS has very different courses depending on the cause. Professor Barratt says: “The form of FSGS that the patient has determines what the outlook is in terms of developing kidney failure, what it means for their family and what the right treatment should be.” For example, if a patient’s FSGS is caused by a genetic abnormality, it can be resolved by a kidney transplant, but if the FSGS is driven by the immune system, the condition can return in a transplanted kidney.

In the genetic form of FSGS, the condition gets progressively worse, ultimately leading to kidney failure. New drugs may slow the process down, but they are not going to stop it. “Fundamentally what we want in the genetic form of FSGS is to correct the gene defect,” he says. Unfortunately, this is not yet possible.

Immune-mediated FSGS (FSGS driven by an abnormality in the immune system) relapses and remits, so may go away after treatment, but it can come back in a very unpredictable fashion. “In the immune-mediated form of FSGS, you want to give tablets that interfere with the immune system. Those treatments are not without side effects, so we don’t want to give them inappropriately for the genetic form of the disease,” Professor Barratt says.

He explains that when a patient has immune-mediated FSGS, first-line treatment typically begins with high-dose corticosteroids: “These can work, but their success rate is variable. And they come with many side effects.”

If patients do not respond to that treatment over the next six to eight weeks, calcineurin inhibitors may be prescribed to target the immune system, but “these also have side effects and, paradoxically, cause kidney damage in the long term”, he says.

“We do not have a perfect treatment for this. Many patients don’t respond or only partially respond to these treatments. So, there is a massive unmet need for new treatments in this area.”

In immune-mediated FSGS, there is a risk that the patients suddenly develop nephrotic syndrome.2 This is where lots of protein leaks into the urine. The liver cannot keep up with replacing the protein that’s lost from the bloodstream, and the body reacts as if blood is being lost and the circulation is failing. 

Professor Barratt explains the consequences of this: “The body avidly retains salt from what you eat and water from what you’re drinking. The body can swell up by 30 or 40 kilogrammes with extra fluid everywhere. And this makes people feel absolutely awful. Having to carry that extra weight is incredibly uncomfortable. Your skin stretches so much that it can break down, allowing infections to get straight in.”

Other substances, such as those related to the clotting system, can leak through the damaged sieves too, so that people with FSGS are more likely to form blood clots spontaneously.2 A deep vein thrombosis (DVT) in the legs can spread to the lungs causing a pulmonary embolism (a blocked blood vessel). By losing proteins in urine, people also lose important antibodies and other elements of the immune system.

IgA nephropathy (IgAN)

IgA nephropathy doesn’t produce the devastating symptoms that FSGS does, but it does cause the progressive loss of kidney function over time.2 “The disease slowly nibbles away at those fine filters in the kidney. You start off with the number of filters you’re born with. Once those filters are damaged and lost, we haven’t got the ability to generate more,” he says.

“If you were to meet a person with IgAN, they’d look completely healthy, but the disease is still ticking over in the background. This makes an IgAN diagnosis a real challenge for patients to get their heads around.”

“Normally, the diagnosis is a bombshell because they’re feeling fine. They think there’s nothing wrong; they think it’s a storm in a teacup. 

“I have to tell them they’ve got a chronic kidney disease and we don’t really know what causes it, we’ve got no good treatments at the moment, and there’s a risk they could end up on dialysis or need a kidney transplant. And this is in people in their 20s and 30s.”

For many the uncertainty around IgAN can take a toll on mental well-being. In Professor Barratt’s experience, patients with IgAN worry not only about whether they’re going to end up on dialysis, but also whether they will be able to enjoy their life in the way they want.

“I can’t give an individual patient a clear answer as to if or when they are likely to develop kidney failure. They have to deal with that uncertainty and try to plan their life, not being sure what’s around the corner for them—even with the best will in the world and the most modern technology.

“People want to carry on doing the things they do: playing five-a-side football, walking, playing with their kids, doing their hobbies, going to work. A diagnosis of IgAN does have a significant impact on all of these aspects to varying degrees. If you’re 30 at diagnosis, you may have decades ahead of you, living with these apparently minor things that cumulatively have a massive impact on the way you live your life.”

The mental burden of an IgAN diagnosis is clear,3 but some patients also report physical symptoms too. “We’re doing a lot of studies at the moment to try to understand how unexplained symptoms might relate to IgAN,” Professor Barratt says.

Until recently, treatment options for IgAN were limited to controlling blood pressure, as for all kidney patients, and trying to reduce the amount of protein in the urine.2 There have been no specific treatments available for IgAN. Sometimes systemic corticosteroids are prescribed, as with FSGS, but Professor Barratt says “the side effects are very significant, and the benefit is unclear”.

However, there may be hope on the horizon for IgAN patients: “Lots of my patients are in studies of new treatments. And the great news is that these trials are starting to report their results.”

A “golden age” for glomerular disease research

Recent years have seen such progress with glomerular disease that Professor Barratt heralds this as potentially a “golden age” for the disease in terms of clinical trials.

New treatments and ongoing clinical trials

In the US, the FDA approved the first-ever treatment for IgAN in 20214, whereas potential future treatments with other mechanisms of action are in the process of clinical development.

Professor Barratt says: “The really exciting thing is that these drugs are targeting different bits of what’s wrong in patients with IgA nephropathy. What that means is we’ll be able to tailor a particular approach to a particular patient, because just like FSGS, not all IgAN patients are identical. Some may respond to one approach, others may respond to a different approach.”

New approaches

Genetic screening has really improved diagnostic and treatment pathways for FSGS. “We have a much better understanding of the genetics of FSGS now. We don’t know all the genes involved—new candidate genes are appearing all the time—but a paediatric nephrologist who has a patient with FSGS can send off a panel to Genomics England5 and it will be screened for all the common mutations.”

If a genetic cause is found, treatments that aren’t expected to work in that situation can be avoided. On the other hand, if a genetic cause is not found and the FSGS is related to the immune system, treatment with glucocorticoids and calcineurin inhibitors can be considered, because the disease may respond to them.2

As understanding of the genetic drivers of FSGS improves, the prospect of personalised treatment gets closer. For instance, a particular variation in the APOL1 gene is common in people with recent African ancestry. It protects against sleeping sickness, which is endemic in many Sub-Saharan countries, but in an unfortunate evolutionary trade-off, it also increases the risk of developing kidney disease.2 This type of knowledge may point to possible targets for drug development.

“Understanding the basic science to then develop treatments to target particular problems is really where we’d like to be going.”

There is no gene therapy currently available for people with FSGS, but Professor Barratt hopes that one might be developed in the future.

Professor Jonathan Barratt is the Mayer Professor of Renal Medicine and consultant nephrologist at University Hospitals of Leicester NHS Trust. He is an international expert on IgA Nephropathy. Here he gives an overview of glomerular diseases and shares his hopes for the future
Looking forward to an exciting future

Professor Barratt is thrilled about how nephrologists and patients have worked together in studies to deliver high-quality data. This has sustained the interest and involvement of pharmaceutical companies.

Just a few years ago, the landscape for glomerular disease was bleak, he says. “No one was really interested in testing new therapies, but that’s transformed over the last five years. Now we have this opportunity to really do something special in glomerular disease, with the goal that no patient with IgA nephropathy or FSGS should ever develop kidney failure. That’s our aspiration. And that’s what we should aim to achieve.”

“There’s nothing more frustrating than being passionate about a disease and no one else being interested. Now everyone is interested and that’s exhilarating.”


[1] Pollak MR, Friedman DJ. The Genetic Architecture of Kidney Disease. Clin J Am Soc Nephrol. 2020;15(2):268-275. doi:10.2215/CJN.09340819

[2] KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Available from . Accessed October 2022.

[3] Lai KN, et al. Nat Rev Dis Primers 2016



Date of preparation October 2022 UK-NA-2200163

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