CARI Guidelines Commentary on the KDIGO Clinical Practice Guideline for the Management of Glomerular Diseases

ABSTRACT

Aim

The KDIGO 2021 Glomerular Disease Guidelines provide updated recommendations on the management of glomerular diseases (GD), with substantial advances made in diagnosis, treatment, and improvement of outcomes for people with GD.

Methods

The Caring for Australians and New Zealanders with kidney Impairment (CARI) Guidelines commentary contextualises the updated guidelines for the Australian and New Zealand setting.

Results

Kidney biopsy remains central to diagnosis, with validated scoring systems available. However, genetic testing for suspected monogenic kidney disease is now accessible in Australia, enabling earlier diagnosis and management, particularly in situations where a kidney biopsy is considered high risk or contraindicated. The guideline emphasises timed urine collections for protein excretion over spot tests and we suggest the use of the CKiD u25 eGFR equation for people under 25. For IgA nephropathy (IgAN) and IgA vasculitis (IgAV), emerging therapies such as targeted‐release budesonide and sparsentan demonstrate promise but await approval and public subsidy in our region. For membranous nephropathy, the guideline highlights the differences in adult and paediatric management. In nephrotic syndrome, tacrolimus is used as first‐line therapy and rituximab as a second‐line agent for steroid‐dependent or frequently relapsing disease. Minimal change disease recommendations include glucocorticoid tapering after remission, while focal segmental glomerulosclerosis incorporates genetic classifications and advocates for next‐generation sequencing.

Conclusion

Our commentary underscores the need for increased participation in clinical trials to validate regional applicability and improve long‐term outcomes for people with GD in Australia and New Zealand. Clinical trials of new medications have led to more treatment options that are awaiting approval.

1. Introduction

The 2021 KDIGO Glomerular Disease Guidelines, as well as updated subtopics, provided significant, practice‐changing recommendations around the diagnosis, treatment, and outcomes of glomerular diseases (GD) [1, 2, 3, 4], as new biomarkers, genetic testing, novel treatments, and steroid‐minimisation regimens have become available. Advances in this space allow for more individualised diagnostic, treatment, and monitoring options for some conditions.

Caring for Australians and New Zealanders with Kidney Impairment (CARI) Guidelines aims to provide a commentary on the KDIGO GD guidelines, focusing on the key changes in recommendations and guidance for the management of GD and identifying aspects of management that differ in Australia and New Zealand (Table 1).

TABLE 1.

CARI Guidelines comments on differences and implementation of KDIGO GD guidelines in Australia and New Zealand.

Chapter	CARI's commentary on KDIGO glomerular diseases guidelines
General principles	CARI suggests that, depending on the practice setting, appropriate serological or genetic testing may be performed in place of or alongside kidney biopsy. CKD‐EPI formula is not validated in Aboriginal and Torres Strait Islander Peoples in Australia and Māori in New Zealand CARI supports the use of the 2021 CKiD U25 eGFR equation for patients aged < 25 years CARI has provided guidance regarding COVID 19 vaccination which was previously not discussed by KDIGO
IgAN and IgAV	The International IgA Nephropathy Prediction Tool is not validated in the Aboriginal, Torres Strait Islander, and Maori population Children with IgAN should be in shared care with paediatric nephrologist Treatment recommendation need to be updated especially to include the role of SGLT2 inhibitors, targeted release budesonide, sparsentan and atrasentan.
Membranous nephropathy	No Medicare item number available to support subsidy of Anti‐PLA2R antibodies testing in Australia. Testing to stratify membranous nephropathy, that is, urinary IgG and beta‐2 microglobulin, and selectivity index are not available in Australia and New Zealand.
Nephrotic syndrome in children	Genetic testing readily available in Australia
Minimal change disease	CARI Guidelines endorses KDIGO recommendations
Focal segmental glomerulosclerosis	Genetic testing readily available in Australia No recommendation from KDIGO regarding steroid and calcineurin inhibitor resistant focal segmental glomerulosclerosis No centralised way of identifying specialist centre in managing glomerular diseases or centres conducting clinical trials in glomerular diseases
Infection‐related glomerular diseases	Post‐streptococcal glomerulonephritis is more common among Aboriginal, Torres Strait Islander, Pasifika, and Māori Peoples than the global average, particularly in children under 14, and often follows skin (65%) or throat infections (27%)
Immunoglobulin and complement‐mediated glomerular diseases	KDIGO needs to update and give recommendation regarding iptacopan in C3‐mediated glomerular disease
ANCA‐associated vasculitis	CARI Guidelines endorses KDIGO recommendation
Lupus nephritis	Belimumab and voclosporin are not available in Australia and New Zealand for lupus nephritis
Anti‐GBM disease	CARI Guidelines endorses KDIGO recommendation

2. Methods

A Working Group of adult and paediatric nephrologists, guideline methodologists, and consumers with lived experience of GD was convened by CARI Guidelines. The Working Group reviewed the KDIGO GD Guidelines [1, 2, 3, 4] and drafted a manuscript on pertinent issues related to guidelines implementation in Australia and New Zealand. The guidelines were critically appraised by two reviewers (I.R. and D.J.T.) using the AGREE II instrument. The manuscript was reviewed by the CARI Guidelines Steering Committee and iteratively updated by the Working Group accordingly (Appendix B).

3. Commentary—Relevance to Australia and New Zealand

3.1. Critical Appraisal of Guidelines

According to the AGREE II instrument, the guidelines have been developed to a high methodological standard but have limited consumer involvement and consideration of their applicability to support their implementation in practice (Table A1).

3.2. General Principles

In this section, the 2021 guideline discusses general aspects of managing patients with GDs, including kidney biopsy, supportive care, infection and clotting risks, outcome measures, diet, and pregnancy. While it does not provide specific evidence‐based recommendations, the guidance generally applies to most forms of GD.

3.2.1. Kidney Biopsy

A kidney biopsy remains an important diagnostic and prognostic tool in the management of GD when causality is not evident. The guidelines indicate using an internationally validated scoring system when reporting kidney biopsy, such as the International Society of Nephrology and the Renal Pathology Society for lupus nephritis [5], or the Oxford MEST‐C scoring for IgA nephropathy (IgAN) [6], though this is not yet validated for IgA vasculitis (IgAV).

Increasingly, serological and genetic testing could replace kidney biopsy as a first‐line investigation in conditions such as membranous nephropathy, Alport disease, Fabry disease and familial focal segmental glomerulosclerosis. However, disease activity, chronicity, and secondary diagnoses (e.g., diabetic or hypertensive changes) may be overlooked by these methods, which are also associated with accessibility challenges in Australia and New Zealand. Therefore, CARI suggests that, depending on the practice setting, appropriate serological or genetic testing may be performed in place of or alongside kidney biopsy.

3.2.2. Assessment of Kidney Function

CARI endorses the KDIGO guidance around using a timed urine collection over random spot urine tests to assess urine protein‐to‐creatinine ratio in adult patients with marked proteinuria, as timed urine collection is associated with higher accuracy and lower variation, compared to spot urine testing. Additionally, CARI supports the routine evaluation of haematuria, especially in patients with IgAN and IgAV.

In patients with GD, assessment of eGFR using the CKD‐EPI formula is widely used in Australia and New Zealand [7] and supported by CARI Guidelines. However, this measure has not been validated in all relevant populations, including Aboriginal and Torres Strait Islander Peoples in Australia and Māori in New Zealand. Additionally, all creatinine‐based eGFR equations overestimate true GFR in patients with nephrotic syndrome and hypoalbuminemia. While the guideline does not specify which of the two CKD‐EPI formulas should be used in patients across this age range [8].

3.2.3. Management of Complications of Glomerular Disease

The guidelines focus on general principles relevant to the management of all forms of GD, providing guidance on measures to control oedema, reduce proteinuria, treat hypertension, slow kidney disease progression, and address metabolic and thromboembolic consequences of nephrotic syndrome. These supportive therapies reduce the need for immunosuppressive drugs, although some of these agents may not be necessary in certain cases. For instance, statins for dyslipidaemia or antiproteinuric agents such as angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers are not recommended for patients with steroid‐responsive minimal change disease.

The latest guideline also covered various aspects of supportive and adjunct treatment (Table A2), including vaccination coverage, but did not include COVID‐19 vaccines. The latest guidance from the Australian Technical Advisory Group on Immunisation (ATAGI) and Health New Zealand Te Whatu Ora recommends a third primary COVID vaccine of an age‐appropriate formulation that is relevant for people with GD. This includes patients receiving high doses (> 20 mg/day for > 14 days) or long‐term moderate‐dose corticosteroids (in New Zealand), mycophenolate mofetil, azathioprine, calcineurin inhibitors, cyclophosphamide, or anti‐CD20 biologic agents, as well as for patients on dialysis or planned kidney transplant [9, 10]. Ideally, the vaccine should be administered more than 2 weeks prior to immunosuppression. The current guidelines highlight the benefits of deferring vaccination by at least 6 months following treatment [9, 10].

3.2.4. Pregnancy

The updated guidelines have, for the first time, included guidance on the management of pregnancy in people with GD. The practice points focus on care before, during, and after pregnancy for managing female patients in the child‐bearing age group (Table 2) and are relevant to the Australian and New Zealand context.

TABLE 2.

Managing female patients of childbearing age with glomerular disease.

Pre‐pregnancy counselling	Discuss the risk of pregnancy for the patient, the foetus and their underlying kidney disease. Discuss the impact of kidney disease on pregnancy and the foetus Avoid teratogenic agents such as renin‐angiotensin system inhibitors and most immunosuppressive therapy. Follow safe contraception if taking any teratogenic agents. The cumulative dose should be considered when prescribing cyclophosphamide, as it could cause irreversible infertility.
During pregnancy	Patients should be managed in a multidisciplinary team including the nephrologist, obstetrician and a maternofetal medicine specialist. Renin‐angiotensin system inhibitors and some immunosuppressive therapies (e.g., MMF) are contraindicated. The choice of antihypertensive therapies during should be directed by 2023 national guidelines [11]. Consider treatment with low‐dose aspirin, calcium, and vitamin D supplements. Aim for blood pressure < 140/90 mmHg. Prophylactic anticoagulation should be considered in patients with high‐risk venous thromboembolism, such as nephrotic syndrome, previous venous thromboembolism, or high BMI. Therapeutic heparin or heparin‐derivate would be the preferred agent.
Post pregnancy	Consider screening and involvement of paediatric nephrologist where neonate is at risk of a monogenic kidney disease, for example, positive family history, known pathogenic mutation in either parent. Involve pharmacist if mother is wanting to breastfeed while taking medication that may be transmitted into breast milk. Neonates have rarely been reported to have placental transmission of anti‐body mediated disease (e.g., FSGS, MN).

Abbreviations: BMI, body mass index; FSGS, focal segmental glomerulosclerosis; MMF, mycophenolate mofetil; MN, membranous nephropathy.

3.3. IGA Nephropathy and IGA Vasculitis

Key recommendations for IgAN are summarised in Tables A3 and A4.

3.3.1. Diagnosis and Monitoring

The guidelines highlight that “The International IgA Nephropathy Prediction Tool” is useful to inform disease prognosis [12]; however, this tool is yet to be validated in the Australian and New Zealand cohort, including Aboriginal, Torres Strait Islander, and Māori populations. The international IgAN prediction tool has been updated for children to identify those at risk of progression, and suitable for clinical trial recruitment [13]. In Australia, genetic testing is now eligible for Medicare rebate for patients with suspected monogenic causes of kidney disease and can precede kidney biopsy for children with persistent isolated haematuria or steroid resistant nephrotic syndrome. CARI suggests that children with IgAN are in shared care with a Paediatric Nephrologist. CARI endorses the KDIGO 2021 practice point for a kidney biopsy for adults with IgA vasculitis (IgAV) and a typical vasculitic rash, presenting with rapidly progressive glomerulonephritis (RPGN), proteinuria > 1 g/day, and/or impaired kidney function.

3.3.2. Treatment

The guidelines recommend a 6‐month glucocorticoid course for patients at high risk of progression, that is, proteinuria > 0.75 to 1 g/day after ≥ 90 days of supportive care. For those with eGFR < 50 mL/min/1.73 m², the risk of toxicity should be evaluated against benefits, with high‐dose methylprednisolone demonstrating a higher risk of infection compared to placebo [14]. Recent trials underscore the need to update the IgAN guidelines, which is currently underway by KDIGO. The DAPA‐CKD trial demonstrated that dapagliflozin significantly reduced the risk of sustained eGFR decline, kidney failure or death, in people with CKD and no effect modification evident in people with IgAN, establishing it as a standard of care in our region. Dapagliflozin is also approved by the Therapeutic Goods Administration for this indication and is subsidised by the Pharmaceutical Benefits Scheme. CARI Guidelines have developed living guideline recommendations for SGLT2 inhibitors in people with CKD based on stage of CKD risk, including people with IgAN [15].

The NefIgArd trial showed that targeted‐release budesonide effectively reduced proteinuria and preserved eGFR, though it awaits approval in Australia and New Zealand. The Protect trial (n = 404) highlighted sparsentan's superiority over irbesartan in reducing proteinuria and slowing eGFR decline, though likewise it is unapproved for use in our region. Additionally, ongoing RCTs on endothelin A receptor antagonists [16, 17, 18], immunomodulators (atacicept, telitacicept), and complement inhibitors (avacopan, iptacopan, ravulizumab) further emphasise the importance of updating KDIGO IgAN guidelines. CARI supports the KDIGO guidance for children with IgAN, which aligns with those for adult patients.

For people with IgAV with RPGN, immunosuppression treatments could be considered following discussion of risks and benefits. Treatment should be similar to ANCA‐associated vasculitis.

3.4. Membranous Nephropathy

The 2021 guideline introduces many new recommendations on the management of adults with membranous nephropathy, with the key points summarised in Table 3. However, while these recommendations are practice‐changing, some require clarification to reflect current practice in Australia and New Zealand (Table A5). For instance, the guideline lacks recommendations on monitoring or tailoring treatment for anti‐PLA2R antibody‐negative MN patients.

TABLE 3.

Key points in the management of membranous nephropathy.

A positive anti‐PLA2R antibody can help decide treatment initiation and tailor treatment according to titres in patients with contraindications to biopsy. Anti‐PLA2R antibody titre can be used to predict or monitor for relapse and post‐transplant recurrence. Anti‐PLA2R antibody has a sensitivity of 0.78 and specificity of 0.99. Where available, tissue staining for PLA2R antigen should also be used. Anti‐PLA2R antibody alone should not be used to rule out secondary causes of MN. All patients with membranous nephropathy, regardless of presence or absence of anti‐PLAR2 antibodies and/or anti‐THSD7A antibodies should be investigated for associated conditions, including malignancy. Based on serological and clinical parameters, patients should be risk stratified into four categories: low, medium, high, and very high risk. Treatment strategies should be based on the risk category. Very high‐risk patients, defined as those with life‐threatening nephrotic syndrome or rapid regression of kidney function, should be treated with a combination of cyclophosphamide and glucocorticoid. To define relapse and resistant MN, along with proteinuria, serum albumin and anti‐PLA2R antibody should be used. Patients resistant to all conventional agents should be referred to participate in a clinical trial. In post‐transplant patients, recurrence should be monitored via observing for worsening proteinuria and hypoalbuminemia but also with anti‐PLA2R antibodies (where initially positive). There is insufficient data to support the use of anti‐THSD7A antibodies in the diagnosis of membranous nephropathy. The risk of venous thrombosis is dependent on serum albumin. Nephrologists should know how the serum albumin assay is done in their local lab when deciding on prophylactic anticoagulation. If the serum albumin is performed by bromocresol purple, serum albumin of < 20 g/L and if done by bromocresol green, serum albumin of < 25 g/L should be used to decide about anticoagulation. Bleeding risk should be considered with the help of GN tools before initiating anticoagulation. The choice of anticoagulation should be either warfarin or a combination of low‐molecular‐weight heparin with aspirin in people at high risk of venous thromboembolic events and low risk of bleeding.

Abbreviations: MN, membranous nephropathy; PLA2R, phospholipase A2 receptor.

3.4.1. Diagnosis and Monitoring

In adults with anti‐PLA2R antibody‐positive MN, CARI endorses the KDIGO 2021 recommendations regarding the routine use of anti‐PLA2R antibody testing and tailoring treatment according to the titres. In anti‐PLA2R antibody‐negative MN, kidney function and proteinuria should guide treatment. CARI endorses KDIGO's 2021 guidelines for the management of children with MN. In children, alternative pathogenic membranous antigens (e.g., semaphorin 3b) are more common causes of primary MN than anti‐PLA2R antibodies; however, testing for these alternative antigens is currently not available.

3.4.2. Treatment

CARI endorses the KDIGO 2021 recommendation that treatment should depend on the patients' risk category. It is crucial to screen for latent infection or secondary causes of MN (Hepatitis B, C, and HIV) prior to immunosuppression, particularly where risk factors are present or in endemic areas (e.g., tuberculosis, strongyloides). Most Australian children would receive 4 to 6 weeks of oral corticosteroid treatment (prior to a biopsy diagnosing MN). Otherwise, treatment is similar to that for adults.

3.5. Nephrotic Syndrome in Children

3.5.1. Steroid‐Sensitive Nephrotic Syndrome

The KDIGO 2021 guidelines have been updated in 2025 [4], which now brings KDIGO's recommendations for steroid‐sensitive nephrotic syndrome (SSNS) in children in line with the 2023 International Paediatric Nephrology Association (IPNA) guidelines for children with SSNS [19]. The guidelines now provide updated definitions for frequently relapsing and steroid‐dependent nephrotic syndrome (FRNS and SDNS, respectively), including guidance for clinical assessment and diagnostic work‐up. The IPNA guidelines provide further detail on the use of home monitoring and supportive care, managing thrombotic risk, prevention and treatment of infections, as well as dosing, monitoring, and duration [19].

3.5.1.1. Diagnosis and Monitoring

Both IPNA and KDIGO guidelines define FRNS and SDNS from a diagnostic perspective, as well as levels of adequacy of disease control in SSNS.

3.5.1.2. Treatment

Unlike KDIGO, IPNA does not suggest specific steroid‐sparing agents for FRNS or SDNS patients but recommends rituximab for those without adequate disease control following the use of at least one other steroid‐sparing agent. The routine use of ‘sick day’ steroids (steroids given at the onset of upper respiratory tract infections to prevent relapse) is no longer recommended except for children already on low‐dose alternate‐day steroids with a history of infection‐associated relapse.

Despite these guidelines, there is ongoing variability both in steroid treatment and initial steroid‐sparing agents [20]. In Australia, many centres have moved away from cyclophosphamide as a routine steroid‐sparing agent in preference to calcineurin inhibitors. Increasingly, tacrolimus is a preferred first‐line agent over ciclosporin***, while rituximab is increasingly used as a second‐line steroid‐sparing agent [21].

3.5.2. Steroid‐Resistant Nephrotic Syndrome

For children with steroid‐resistant nephrotic syndrome (SRNS), the KDIGO guidelines align with those published by IPNA in 2020 [22].

3.5.2.1. Diagnosis and Monitoring

Kidney biopsy and genetic testing continue to be indicated in all patients with initial SRNS by both IPNA and KDIGO. In children with SRNS, a clinical approach whereby negative genetic testing is required before proceeding with kidney biopsy may prove more cost‐effective and clinically relevant, as genetic testing is now available via Medicare in Australia. There remains an unmet need for additional resources, personnel (e.g., genetic counsellors), and training for nephrologists in genetic kidney medicine [22].

3.5.2.2. Treatment

Neither guideline contains information about COVID‐19 infection or vaccination. Readers are referred to the SSNS IPNA guidelines for such considerations [19].

3.6. Minimal Change Disease in Adults

3.6.1. Diagnosis and Monitoring

The updated 2021 guidelines provide guidance on the diagnosis and prognosis of minimal change disease, which is relevant to Australia and New Zealand and remains unchanged from the 2012 guidelines.

3.6.2. Treatment

Broadly, the treatment approaches in the updated guideline remain similar to the previous 2012 guideline and are appropriate to our regional setting. However, a key difference to highlight is that the previous guidelines recommended 4 weeks of high‐dose glucocorticoids after entering remission from minimal change disease. The updated guidelines now recommend tapering glucocorticoids 2 weeks after complete remission.

3.7. Focal Segmental Glomerulosclerosis in Adults

3.7.1. Diagnosis and Monitoring

The updated 2021 guidelines have provided further novel classifications (‘genetic’, ‘undetermined’) to the previous 2012 (‘primary’ and ‘secondary’) classifications for focal segmental glomerulosclerosis (FSGS). They also advise investigating secondary causes in people with sub‐nephrotic range proteinuria, or nephrotic range proteinuria with serum albumin > 30 g/L. Fortunately, in Australia, there is now access to genetic testing in patients with adult‐onset nephrotic syndrome; however, genetic testing should use next‐generation sequencing and identify a targeted gene panel [23].

3.7.2. Treatment

The guideline provides practice points guiding immunosuppressive dosing and alternatives, but no specific recommendations are made about steroid and calcineurin inhibitor‐resistant FSGS. The guidelines also recommend referring treatment‐resistant patients to specialist centres. However, in Australia and New Zealand in the section regarding identifying specialist centres conducting clinical trials in Australia and New Zealand for people with FSGS, we do not have a way of identifying specialist centres conducting clinical trials in patients with FSGS or other GDs.

3.8. Infection‐Related Glomerulonephritis

This chapter of the guidelines details bacterial, viral, and parasite‐related glomerulonephritis (GN), recommending screening for coinfections (e.g., HIV, hepatitis B, C, strongyloides) before immunosuppressive treatment where appropriate.

3.8.1. Bacterial

3.8.1.1. Diagnosis and Monitoring

The indication of kidney biopsy in cases of suspected bacterial infection‐related GN to support culture evidence, diagnosis, prognosis, and therapeutic decisions is supported. The prognosis is generally good if the infection source is controlled, except for high‐risk individuals such as the elderly, people with diabetes, and IgA‐dominant infection‐related GN [24]. Post‐streptococcal GN is more common among Aboriginal, Torres Strait Islander, Pasifika, and Māori Peoples than the global average, particularly in children under 14, and often follows skin (65%) or throat infections (27%) [25, 26].

3.8.1.2. Treatment

Antibiotics and symptom management remain the primary priorities, as the role of glucocorticoids and other immunosuppression is unproven, even in patients with crescents.

3.8.2. Viral—Hepatitis B and C

3.8.2.1. Diagnosis and Monitoring

The guidelines indicate that all patients with proteinuric GD should be tested for Hepatitis B (HBV) and C (HCV) and treated with nucleotide analogues.

3.8.2.2. Treatment

Pegylated interferon, cyclophosphamide and rituximab should be avoided due to the risk of viral replication. In cases of anti‐PLA2R antibody‐mediated MN with HBV, cyclophosphamide and rituximab should be deferred until sustained virological remission is achieved. Plasma exchange could be considered in people with HBV‐related cryoglobulinemic vasculitis.

CARI Guidelines supports adherence to the KDIGO HCV and chronic kidney disease (CKD) guideline in the management of HCV‐associated glomerular disease [27]. Patients with HCV‐related glomerular disease who have stable kidney function and/or non‐nephrotic‐range proteinuria should be treated with direct‐acting antivirals. However, patients experiencing a cryoglobulinemic flare, nephrotic syndrome, or rapidly progressive kidney failure should receive additional treatment with immunosuppressive agents, with or without plasma exchange, alongside direct‐acting antiviral therapy. In histologically active patients who are refractory to antiviral therapy, rituximab should be considered.

3.8.3. Viral—HIV‐Related Glomerulonephritis

3.8.3.1. Diagnosis and Monitoring

A kidney biopsy can guide diagnosis and treatment. HIV can lead to glomerular, interstitial, and vascular diseases. Traditional causes of kidney disease, such as diabetes and hypertension, should also be considered in the differential diagnosis of kidney disease in patients with HIV. Therefore, a kidney biopsy would help differentiate the underlying pathology.

3.8.3.2. Treatment

Antiretroviral therapy should be initiated in all patients with HIV and CKD, particularly in those with biopsy‐proven HIV‐associated nephropathy (HIVAN), regardless of the CD4 count.

3.9. Immunoglobulin and Complement‐Mediated Glomerular Disease With Membranoproliferative Glomerulonephritis Pattern of Injury

3.9.1. Diagnosis and Monitoring

Membranoproliferative glomerulonephritis (MPGN) is a pattern of injury, classified by immunofluorescence into immunofluorescence‐negative, complement‐dominant, or immunoglobulin (Figure 1). For patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), a complete evaluation for haematological malignancy or plasma cell disorders is recommended. In cases of immune complex‐mediated glomerulonephritis (ICGN), where no underlying cause has been identified, it is important to assess the likelihood and drivers of complement dysregulation, serum complement levels, autoantibodies against complement regulatory protein, and genetic testing as indicated by KDIGO.

FIGURE 1.

Pathophysiology of membranoproliferative glomerulonephritis.

3.9.2. Treatment

Although previous guidelines suggested using cyclophosphamide or mycophenolate analogues with corticosteroids in managing patients with ICGN, the disease mechanisms are now better understood. Consequently, the guidelines now suggest limited use of these treatments, tailored to kidney function and disease severity. While optimal management for several MPGN‐patterned disorders remains undefined, supportive care is advised for people with sub‐nephrotic proteinuria or eGFR < 30 mL/min/1.73 m². A limited course of glucocorticoids or calcineurin inhibitors is indicated for people with ICGN, nephrotic syndrome, and near/normal serum creatinine. For people with idiopathic ICGN, abnormal kidney function (without crescents), and active urine sediment, regardless of proteinuria, glucocorticoids alongside other immunosuppressive agents are suggested. High‐dose corticosteroids and cyclophosphamide are recommended for rapidly progressive crescentic idiopathic ICGN. Patients with idiopathic ICGN presenting with an eGFR of < 30 mL/min/1.73 m² should be treated with supportive care alone unless the kidney biopsy shows active necrotising crescentic glomerulonephritis or other reasons to support the use of immunosuppression, such as minimal interstitial fibrosis or concomitant acute tubulointerstitial nephritis.

Complement 3 (C3) glomerulopathy (C3GN) with proteinuria > 1 g/day, haematuria, or declining kidney function should be treated with mycophenolate analogue and glucocorticoid for at least 6 months. Eculizumab could be considered for patients who do not respond to this treatment.

A phase 3 double‐blind, placebo‐controlled study evaluating the efficacy and safety of iptacopan, an oral Factor B inhibitor, in 74 adults with biopsy‐confirmed C3GN with urine protein‐to‐creatinine ratio of ≥ 1 g/g and an eGFR of ≥ 30 mL/min/1.73 m² showed that after 6 months of treatment, the iptacopan group had a 35.1% reduction in proteinuria from baseline compared to the placebo group (NCT04817618). Iptacopan was recently FDA‐approved for C3GN.

In a phase 2 study, pegcetacoplan (a targeted C3/C3b inhibitor) demonstrated its efficacy, safety, and tolerability for patients with posttransplant recurrent C3GN and primary ICGN [28].

3.10. Antineutrophil Cytoplasmic Antibody‐Associated Vasculitis

3.10.1. Diagnosis and Monitoring

KDIGO guidelines for managing antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) advise that treatment should not be delayed while awaiting kidney biopsy or positive serology, especially in patients with rapidly deteriorating kidney function. The role of ANCA titre monitoring remains a challenge. The guidelines note that ANCA positivity and raising titres are not reliably predictive of relapse; therefore, treatment decisions should not rely exclusively on these levels. The disappearance of PR3 ANCA after treatment with rituximab is associated with prolonged remission [29, 30]. Conversely, changes from ANCA‐negative to positive are linked to increased risk of relapse [31].

3.10.2. Treatment

3.10.2.1. Induction of Remission

For the initial treatment of new‐onset AAV to induce remission, a combination of glucocorticoid with either cyclophosphamide or rituximab is recommended. Rituximab is preferred in children, adolescents, pre‐menopausal women, men concerned about their fertility, older adults, and those with relapsing disease or PR3‐ANCA positivity [32]. However, for severe disease with serum creatinine > 354 μmol/L, a combination of glucocorticoid and cyclophosphamide is preferred for induction therapy. Intravenous cyclophosphamide should be considered in patients with moderate cumulative dose, lower white cell counts, or adherence issues, where an infusion centre is readily available.

During treatment, pneumocystis pneumonia prophylaxis should be administered throughout the cyclophosphamide course or 6 months following rituximab infusion. Immunoglobulin G (IgG) levels should be monitored to assess hypogammaglobinaemia. To reduce corticosteroid‐related toxicity, the guidelines suggest a reduced corticosteroid dose [33], tapering to 5 mg/day by 6 months with cyclophosphamide or withdrawing prednisolone by 6 months with rituximab. Avacopan may serve as a steroid‐sparing agent or even an alternative to glucocorticoids and is now listed on the PBS for use in ANCA‐vasculitis from October 2024.

The evidence around plasma exchange in AAV is mixed [34], but CARI Guidelines endorse reserving it for specific cases as indicated by KDIGO, including diffuse alveolar haemorrhage, serum creatinine > 5.7 mg/dL (500 μmol/L) requiring dialysis, rapidly increasing serum creatinine, or comorbid AAV and anti‐glomerular basement membrane (Anti‐GBM) disease.

3.10.2.2. Maintenance of Remission, Relapsing, and Refractory Disease

KDIGO's recommendations of maintenance therapy for AAV are summarised in Figure 2 and relevant to Australia and New Zealand. The management strategies for relapsing and refractory diseases, as outlined in Figure 3, are pertinent to the treatment of AAV.

FIGURE 2.

Maintenance therapy for patients with ANCA‐associated vasculitis.

FIGURE 3.

Management of patient with relapsing and refractory ANCA‐associated vasculitis.

3.11. Lupus Nephritis

3.11.1. Diagnosis and Monitoring

The guidelines emphasise the discrepancy between proteinuria and severity of nephritis, advising holistic assessment, including clinical and laboratory parameters, for management. Treatment initiation in class III/IV lupus nephritis should be based on biopsy findings [5].

3.11.2. Treatment

3.11.2.1. Induction of Remission

Hydroxychloroquine is recommended for all patients, with corticosteroids as first‐line therapy, combined with mycophenolic acid analogues (MPAA) or low‐dose intravenous cyclophosphamide. Initial intravenous glucocorticoid pulses, followed by a lower starting dose and rapid taper, are suggested to minimise side effects of cumulative exposure to glucocorticoids. Low‐dose cyclophosphamide has fewer adverse events than the standard dose but shows similar efficacy to MPAA, according to evidence in limited populations [35]. MPAA incurs higher medication costs but lower facility costs. Initial therapy choice depends on drug availability, adherence, age, disease severity, ethnicity, and prior treatments. People with severe active lupus nephritis, including those with acute kidney injury, cellular crescents, or fibrinoid necrosis, may benefit from standard‐dose intravenous cyclophosphamide [36].

Alternative therapies include MPAA combined with calcineurin inhibitors [37], or belimumab with MPAA or low‐dose intravenous cyclophosphamide [38, 39]. However, belimumab is not yet available for lupus nephritis in Australia and New Zealand. Voclosporin is a newer option that improves response rates in people with eGFR of > 45 mL/min/1.73 m² when combined with MPAA [40], although it is also unavailable in Australia and New Zealand.

3.11.2.2. Maintenance of Remission, Relapsing, and Refractory Disease

Low‐dose glucocorticoid combined with a MPAA is recommended as first‐line maintenance therapy, with azathioprine as the second line option, followed by calcineurin inhibitor or Mizoribine (not currently available in New Zealand). Maintenance treatment should last at least 36 months, with glucocorticoids being discontinued after 12 months of complete remission. Rituximab is suggested for refractory disease or when steroid minimisation is required. The treatment of Class V lupus nephritis varies based on proteinuria, combining RAAS blockade and immunosuppression for nephrotic syndrome. KDIGO provides specific guidance in special populations, including pregnant women, children, people with lupus nephritis and thrombotic microangiopathy, as well as people with lupus and kidney failure.

3.12. Anti‐Glomerular Basement Membrane Disease

3.12.1. Diagnosis and Monitoring

KDIGO provides guidance on early diagnosis of anti‐glomerular basement membrane (anti‐GBM) disease. Key prognostic indicators include the degree of crescents in kidney biopsies and the presence of oliguria.

3.12.2. Treatment

For treatment, the guidelines detail the initiation, dosing, and duration of cyclophosphamide, glucocorticoid, and plasma exchange, as well as the requirement for dialysis at presentation. Cyclophosphamide should be administered for 2 to 3 months, and glucocorticoid for 6 months, with no maintenance therapy required due to low relapse rates (< 5%). Plasma exchange is recommended until Anti‐GBM titres are undetectable, provided sustained renal viability. However, the underlying evidence base is limited, and recommendations rely on observational studies and one small RCT, thus limiting the certainty of the guideline recommendations and practice points. For difficult cases, a conservative approach is advised, particularly for oliguric patients with advanced kidney failure and 85% to 100% crescents, excluding those with alveolar haemorrhage. In cases where patients are double positive for Anti‐GBM and ANCA, maintenance therapy should follow ANCA vasculitis protocols.

4. Conclusion

The latest KDIGO Clinical Practice guideline on managing glomerular disease provides a comprehensive overview. It adopts an evidence‐based approach to the management of GD, covering areas such as early detection and both current and emerging treatment strategies. This commentary emphasises the importance of aligning care with best practices to improve patient outcomes and maintain consistency in clinical decision‐making. Promising novel treatments are becoming available, and patients should be encouraged to participate in clinical trials.

Author Contributions

N.S.‐R. and I.R. are people with lived experience of Glomerular disease who provided intellectual input by reviewing, revising, and approving the final version of the manuscript. I.R. was also involved along with D.J.T. in appraising the guideline.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Appendix A.

TABLE A1.

Guidelines assessment according to the appraisal of Guidelines for Research and Evaluation (Agree II) instrument.

Guideline	Domain scores (%)
	Scope and purpose	Stakeholder involvement	Rigour of development	Clarity and presentation	Applicability	Editorial independence
KDIGO GD 2021 [1]	84%	66%	77%	100%	66%	100%

TABLE A2.

Supportive and adjunct therapy in the management of glomerular diseases as per the KDIGO 2021 guidelines.

Lifestyle modifications	Sodium restrictions (< 2 g/day or < 90 mmol/day) Moderate dietary protein restriction (0.8–1.9 g/kg/day) and preferably plant‐based Carbohydrate intake should be at most 35 kcal/kg ideal body weight Calories should be restricted in patients high BMI. Heart‐healthy diet Achieving ideal body weight Increased physical activity Smoking cessation Reduced alcohol intake
Blood pressure management	Achieve a target systolic blood pressure of < 120 mmHg Use renin‐angiotensin‐aldosterone system inhibitor and other antihypertensives
Oedema	Initially loop diuretics Can use combination of loop diuretics and thiazide diuretics Consider amiloride or spironolactone for patient's refractory to loop diuretics
Hyperlipidaemia	In patients with high cardiovascular risk, such as diabetes and hypertension, treat with statins
Prophylactic anticoagulation	Should be considered based on histological type, degree of proteinuria and serum albumin Use an online tool to decide which patient to anticoagulated (https://www.med.unc.edu/gntools/bleedrisk.html) Heparin or heparin derivative or warfarin are preferred anticoagulants The use of direct‐acting oral anticoagulants has yet to be studied
Vaccination and screening for infections	All patients with glomerular disease should receive pneumococcal and influenza vaccine All glomerular disease patients should be screened for tuberculosis, syphilis, hepatitis and HIV Patients treated with high‐dose corticosteroids or other immunosuppressive agents should receive Pneumocystis jirovecii pneumonia prophylaxis

Abbreviations: BMI, body mass index; GFR, glomerular filtration rate; HIV, human immunodeficiency virus.

TABLE A3.

How to manage variants of IgA nephropathy.

Patients with IgAN and nephrotic syndrome with a biopsy showing features of minimal change disease should be treated as per guidelines for minimal change disease. Patients with IgAN with nephrotic syndrome and biopsy showing features of mesangioproliferative glomerulonephritis should be treated as having a high‐risk of progression. Patients with IgAN, acute kidney injury, and biopsy showing extensive crescentic formation should be treated with cyclophosphamide and glucocorticoids, similar to treatment for ANCA‐associated vasculitis. Patients with IgAV should be managed similarly to IgAN, but the Oxford MEST‐C score is not validated in IgAV. Indication for using glucocorticoid or other immunosuppressive agents would be similar to IgAN, but extrarenal manifestation (such as pulmonary, skin and gastrointestinal) may warrant consideration of alternative immunosuppressive agents.

Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; IgAN, immunoglobulin A nephropathy; IgAV, immunoglobulin A vasculitis.

TABLE A4.

Applicability of the KDIGO recommendations in Australia and New Zealand IgA nephropathy population.

The Oxford MEST‐C scoring and the International IgA nephropathy prediction tool are not yet being validated in the Australian and New Zealand IgAN population. No easy access to enrol patients to disease registry or clinical trials especially in smaller renal units or private practices.

Abbreviation: KDIGO, Kidney Disease: Improving Global Outcomes.

TABLE A5.

Issues with the applicability of the guidelines in Australia and New Zealand membranous nephropathy population.

The guidelines recommend the routine use of an anti‐PLA2R antibody in the management of MN, but unfortunately, in Australia there is no Medicare item number for this test, which has now become the standard of care in the rest of the world, including in New Zealand. The guideline recommends using urinary IgG, urinary beta‐2 microglobulin and selectivity index in risk‐stratifying patients with MN. However, these tests are not routinely performed in Australia and New Zealand. The guideline does not have a recommendation on how to monitor or tailor treatment in anti‐PLA2R antibody‐negative MN patients. Should the clinicians use proteinuria and kidney function to make treatment decisions?

Abbreviations: MN, membranous nephropathy; PLA2R, phospholipase A2 receptor.

Appendix B. CARI Guidelines Group Steering Committee Investigators

Vincent Lee (Chair)^1,2, Emily See (Deputy Chair)^3,4, Helen Coolican⁵, Vanessa Cullen⁶, Min Jun^6,7, Rathika Krishnasamy^8,9, Kelly Lambert¹⁰, Jonathan Craig¹¹, Casey Light^12,13, Thu Nguyen¹⁴, Carla Scuderi^15,16

1. Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia

2. Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

3. Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia

4. Department of Intensive Care, Austin Health, Heidelberg, Victoria, Australia

5. Consumer Partner, Sydney, New South Wales, Australia

6. Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia

7. George Global Institute for Global Health, Sydney, New South Wales, Australia

8. Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia

9. Sunshine Coast University Hospital, Birtinya, Queensland, Australia

10. School of Medical, Indigenous and Health Sciences, The University of Wollongong, Wollongong, New South Wales, Australia

11. College of Medicine and Health, Flinders University, Adelaide, South Australia, Australia

12. School of Nursing, Curtin University, Perth, Western Australia, Australia

13. Armadale Hospital, Mount Nasura, Western Australia, Australia

14. Department of Renal Medicine, Auckland City Hospital, Auckland, New Zealand

15. School of Pharmacy, University of Queensland, Brisbane, Australia

16. Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Australia

Bose B., Carter S. A., Abdy M. E., et al., “ CARI Guidelines Commentary on the KDIGO Clinical Practice Guideline for the Management of Glomerular Diseases,” Nephrology 30, no. 9 (2025): e70119, 10.1111/nep.70119.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.