KDIGO 2025 Guideline For Managing IgA Nephropathy And Vasculitis

What every clinician needs to know about IgA nephropathy and IgA vasculitis in 2025? Global most common cause of renal failure/IgA vasculitis has a major update in how to make the diagnosis, predict disease course and manage patients. Renal biopsy is confirmed as crucial for accurate diagnosis in IgA nephropathy and IgA vasculitis. Adults with suspected IgA nephropathy should undergo renal biopsy earlier, i.e. at time of first presentation with proteinuria ≥ 0.5g/day. Structured risk assessment with validated prediction tools, using biopsy findings as key prognostic variables, should become part of routine practice. Management of IgA nephropathy needs to address the two key components: first, the ‘driving forces’ underlying the disease, i.e. the immune mechanisms responsible for production of pathogenic IgA and immune complex formation, and second, the ‘maintenance’ therapy required to protect the remaining kidney function over time. This ‘new paradigm’ of IgA nephropathy is characterised by early intervention, close monitoring of proteinuria levels with a target of ≤ 0.5g/day, and long-term “maintenance” therapy, combining optimal blood pressure control, renin-angiotensin system blockade and dietary sodium restriction, with new-generation therapies aimed at preventing progressive renal failure. The optimal goal of proteinuria in patients with IgA nephropathy is now ≤ 0.3g/day.

Why It Matters

In our 2025 guidance, we give up on the hope that we can manage IgA nephropathy with a single agent, step-wise, and instead provide a two-track approach to the treatment of IgA nephropathy that begins early and continues indefinitely. IgA nephropathy almost always comes to clinical attention after years of silently causing renal damage. The new guidance suggests that patients and their physicians should not delay treatment until evidence of disease progression is observed, for by the time patients with IgA nephropathy become obviously worse, they will have lost approximately 50% of renal function. Monitoring levels of proteinuria and blood pressure, evidence of immune activation, and renal injury, and treating aggressively whenever any of these parameters are noted, to block immune- mediated injury to the kidney and to protect the remaining renal tissue from further injury, are the cornerstone of this approach.

The lower proteinuria targets. Proteinuria is damage of the kidney, and also it causes damage. Proteinuria can cause damage to kidney tubules by cytokines and chemokines activation followed by fibrosis. The updates for proteinuria targets reflect our current understanding of proteinuria and its outcomes and the motto “lower is better” in long term management of kidney disease. The goalposts for patients have changed and what is good control and what is not will change. Moreover, the non- progressions to these targets will need earlier intervention.

As clinical practice evolves and kidney disease is diagnosed earlier in its course, the health system will face greater demand. An earlier or more frequent need for kidney biopsy in selected patients will translate into an increased number of renal pathology submissions to process, and a greater need for standardised and timely reporting. Importantly, there will be a strong platform upon which to base informed shared decision-making with patients, providing them with a clear understanding of their individual risk, as well as the advantages and risks of immunosuppression.

The guidelines also mention safety concerns, particularly those related to systemic immunosuppression. Long-term use of broad-spectrum immunosuppression can lead to increased risk of infection, impaired control of diabetes mellitus, increased blood pressure, weight gain, and increased risk of osteoporosis. Where possible, systemic steroids should be used selectively and where used, the lowest effective dose should be used. Advice on safety measures to prevent infections, gastric and bone complications of immunosuppression.

To inform health-system quality improvement initiatives, the 2025 target for blood pressure levels and pharmacologic indications for kidney-protective medications will influence coverage decisions and disease pathways for several emerging therapies. In addition to increasing the level of bureaucracy to titrate to more stringent targets and use of additional indications for kidney-protective medications, these changes will affect the accessibility of optimal therapy for patients through formulary decisions, prior authorization strategies and other benefit design considerations. Value will also be placed on outcome registries and scheduled follow-up visits to assess proteinuria response and kidney function over time to determine optimal benefit from therapy.

Who It Affects

Patients and Families

In counseling patients with suspected or proven IgA nephropathy, it is helpful to understand the prognosis and risk of disease progression. The information in these guidelines will be useful to counsel adult and child patients with IgA nephropathy. Most patients present with microscopic haematuria, with recurrence of visible macrohaematuria after infections, or with proteinuria detected incidentally. Emphasis should be placed on monitoring microscopic urine sediment and quantification, and following trends over time rather than relying on a single spot urine sample. Furthermore, patients at risk of progression may be considered for disease-modifying therapy at an earlier stage, possibly around 0.5-1g/24 h of persistent proteinuria as suggested by these guidelines.

Patients with IgA vasculitis are also covered in the new guidelines. Children with this condition are a particular case of interest, given the degree to which the level of kidney involvement can affect the long-term outcome for the child. IgA vasculitis typically presents with a purpuric rash, which may be accompanied by joint or abdominal symptoms. Renal involvement may initially be silent, but children and their families need to be made aware of the need for renal monitoring, even if the symptoms of the rash are settling. The guidelines recommend against the use of systemic steroids for the purpose of nephritis prevention in patients with IgA vasculitis who have limited disease that is confined to skin and/or other organs.

Clinicians Across Settings

Unlike many medical conditions, the hereditary kidney disorders are not primarily the nephrologist’s disease. This new guideline addresses the role of all practitioners in the detection of hereditary kidney disease. Screening for symptoms of hereditary kidney disease frequently begins outside of nephrology. Primary care, outpatient clinics and hospitals will all be involved in the initial screening and repeated testing of patients for symptoms such as blood in the urine. Measurements of proteinuria, such as a protein-to-creatinine ratio or a 24-hour urine collection, and monitoring of kidney function will be performed and a timely referral to a specialist made when the results exceed certain thresholds. The emergency and urgent care clinicians are the first to see patients with gross hematuria, frequently initially attributed to a urinary infection. However, rather than simply reassuring the patient that it could be a urinary infection, appropriate follow-up evaluation should be undertaken.

Nephrologists will need to consider risk stratification, shared decision making with patients and their families, and development of a treatment plan to use combination immunosuppression. The initial treatment plan, based on data derived from adults, likely will need to be dynamic, changing as proteinuria and eGFR levels fluctuate over time. Providers must be aware of both the benefits and risks of immunosuppression, including the risk of infection, as well as the need for surveillance for metabolic complications. Pathologists and biopsy services may see an increase in demand as renal biopsy is recommended earlier in the course of disease in selected adults.

Health Systems, Payers, and Policy Leaders

For hospitals, insurers, and health systems/policymakers: following these clinical guidelines may initially increase costs, but could prevent some dialysis and transplantation. For patients: pharmacological therapies (SGLT2 inhibitors, dual-pathway OA/LOS inhibitors, and targeted-release therapies) are likely to increase costs initially, potentially inequitably in some regions, but will have large downstream benefits in terms of both cost and quality of life. For providers: developing efficient referral systems, efficient biopsy services, urine monitoring strategies (urinalysis, microscopy, etc), and treatment protocols to translate these clinical guidelines into practical reality.

What Changes

1) Earlier diagnostic clarity and risk stratification

This update strengthens the evidence in support of considering kidney biopsy earlier in the diagnostic pathway for suspected IgA nephropathy, particularly when proteinuria is leading to changes in management. Currently, there are no validated blood or urine biomarkers that are diagnostic of IgA nephropathy and can guide disease-specific treatment. Early biopsy can significantly shorten the time to diagnosis, distinguish between primary and secondary causes of IgA nephropathy and provide important histologic features to guide management and provide prognostic counseling to patients.

The biopsy report should be organised and a scoring system should be used for grading lesions. Various scoring systems for biopsy interpretation of progression of renal disease have been proposed. These include mesangial change, endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis and tubulitis and crescent formation. It is essential to correlate biopsy findings with clinical features. The implication of crescent formation may differ in patients with stable renal function, slow progression of renal disease and rapid renal functional deterioration.

Prediction tools for estimating the risk of developing nephropathy are being rapidly developed and validated. They should be used to facilitate clinical discussion, and not replace clinical decision making. Internationally validated risk calculators should be used to estimate the risk of progressive significant decline in kidney function over time, and inform patients of their prognosis and the intensity of surveillance required. They do not provide information as to specific drugs that may be effective for the individual patient with diabetes, and patient response to supportive measures and overall risk-benefit assessment remain crucial.

2) Combination of an “immune driver” with a treatment aimed at protecting the kidneys.

Clinicians caring for patients with IgA nephropathy should approach this disease from two perspectives: as an immune-mediated disease and as a chronic kidney disease. From the perspective of an immune- mediated disease, patients with IgA nephropathy are treated to decrease abnormal IgA production and deposition and to inhibit formation of immune complexes that cause renal injury. From the perspective of a chronic kidney disease, patients with IgA nephropathy are treated to prevent hyperfiltration injury in remaining functioning glomeruli, to prevent further renal scarring and to control the consequences of persistent proteinuria and of hypertension. The impression is that many patients will need to be managed from both perspectives at the same time, rather than switching to the other perspective when either approach “fails”.

Supportive care is no longer just a background process that goes on in parallel with treatment of kidney disease, but a continuous process that needs to be optimised early and maintained throughout life. Optimal control of blood pressure in all patients with kidney disease and targeted lowering to less than 130/80 mmHg in patients with diabetic kidney disease or raised urinary albumin excretion are key components of supportive care. Maximising renin–angiotensin system (RAS) blockade in tolerated doses is also important for proteinuria reduction. Counselling all patients with chronic kidney disease about the need to restrict sodium intake, achieve optimal body weight, increase physical activity and avoid smoking or vaping is also a critical component of supportive care. Counselling and assessment of cardiovascular disease is also a key component of supportive care for patients with chronic kidney disease as the major cause of illness in these patients is cardiovascular disease.

Several “kidney-protective” medications are likely to become standard treatment for many patients at risk of developing kidney disease. Several different classes of drugs are being studied, and several of the SGLT2 inhibitors already used to treat diabetes will likely be found to have benefit in IgA nephropathy patients—both those with and those without diabetes. Dual-pathway blockade may be useful in some cases as well. These drugs are not a cure for IgA nephropathy but they can take pressure off the remaining healthy kidney tissue and help to slow the decline of kidney function.

Therapies targeting the immune drivers of idiopathic AIN should be used cautiously, taking into consideration the duration and dose of therapy required, and the potential toxicity. Targeted-release budesonide should be used as a course of therapy in patients at risk of progressive renal dysfunction, if possible. For individual patients for whom targeted-release budesonide is not available, a reduced dose of systemic steroids, with appropriate prophylaxis against infections and precautions to prevent them, may be used. In addition, there are patient groups for whom additional immunomodulatory therapies can be used on the basis of local experience and practice. However, for most patients a less toxic, more precise approach to immunosuppression is preferable.

3) Clearer treatment thresholds and monitoring goals

Early detection of proteinuria is crucial in identifying patients at risk of progression to End Stage Renal Disease (ESRD) and monitoring the effects of therapy. New guidelines recommend a more stringent target for proteinuria. Persistent proteinuria ≥1g/day indicates increased risk of progression to ESRD even in the absence of declining estimated GFR. The goal of treatment of proteinuria is not just to reduce proteinuria to <0.5 g/day but, where possible, to <0.3 g/day. Achievement and maintenance of low levels of proteinuria predicts long-term outcome.

Monitoring should be both routine and pro-active. Measurement of quantified urine protein at regular intervals, measurement of eGFR and blood pressure, reassessment of overall risk, monitoring of side effects related to immunosuppression eg increased risk of infection, hyperglycaemia, effects on bone and steroid toxicity. Early monitoring parameters for patients on SGLT2 inhibitors or other medications which are claimed to have a protective effect on the kidney eg a small early decrease in eGFR which stabilises subsequently. Patients need to be informed of this so that it is not mis-interpreted as harm.

The guideline also includes longer-term realistic treatment targets for blood pressure and proteinuria in people with diabetes and hypertension and chronic kidney disease. The indicators of success are prevention of a rapid decrease in renal function; prevention of hospitalisation; reduction of cardiovascular risk; and maintenance of quality of life. From the patient’s perspective success is a long-term outcome, i.e. few or no episodes of poor kidney function; a stable, tolerable medication regimen with minimal or manageable side effects.

4) More selective use of systemic immunosuppression

Systemic steroids are not indicated for all proteinuric diseases. They are an option for certain patients after supportive therapy has reached its maximum potential, and the potential risks and benefits have been considered. Steroid toxicity can be significant, and strategies to reduce the dose of steroid medication, as well as prevent or treat steroid-induced toxicity (such as hyperglycemia and osteoporosis) should be considered before starting the treatment.

Prevention of kidney disease in patients with IgA vasculitis and skin or other organ involvement should not be achieved with use of steroids, however diagnosis of and intense management of patients with IgA vasculitis-associated nephritis can be facilitated by biopsy in adults with persistent proteinuria, deteriorating renal function, or severe organ involvement. This recommendation reflects a shift in perspective to use of steroids only when there is clear benefit.

Shared decision-making is implied as many of the treatment decisions have trade-offs for patients. Patients and their healthcare providers can decide whether the potential short-term side effects are worth the risk for long-term reduction in the likelihood of developing end stage renal disease. The guideline statements support the discussion of the likely benefits and uncertainties of treatment, as well as the need for monitoring of side effects and use of combination therapy to achieve proteinuria targets.

5) Implementation realities: what health systems need to build – What are the different components that make up a health system? How much does the configuration of a health system differ across countries? What roles do private for profit providers and private not for profit providers play in the system?

In order to translate the guidance into practice more than just awareness of the guidance among clinicians is required. Additionaly, infrastructure such as order sets for urine protein quantification, advice on blood pressure targets for patients with proteinuric kidney disease, and criteria for referral to nephrology and renal biopsy are necessary. Access to pathology expertise is also required for standardized biopsy scoring and reporting.

Decision support tools can help make and standardise guideline-based decisions. Risk calculators, scheduled monitoring tools and immunosuppression safety checklists can be used to reduce variability and speed up time to treatment. Registry and quality reporting tools will help clinics assess whether the proteinuria targets are being achieved and whether rates of kidney function loss are decreasing for their patients.

Payers and policymakers can now influence the uptake of the new guideline by designing coverage rules that maximise effective use. This will require clear approval criteria, realistic monitoring requirements as well as equitable access to the technology in urban and rural settings for the indications for which it has been developed.

References:

https://pubmed.ncbi.nlm.nih.gov/40975564/ https://pubmed.ncbi.nlm.nih.gov/40975525/