C3 glomerulopathies: dense deposit disease and C3 glomerulonephritis.

Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are types of membranoproliferative glomerulonephritis classified as C3 glomerulopathies. These conditions are characterized by an increased number of intraglomerular cells and diffuse thickening of the glomerular capillary walls, along with the deposition of C3 and minimal or absent immunoglobulin deposits. The underlying cause of both DDD and C3Gn is an abnormal activation of the alternative complement pathway, which can result from acquired or genetic alteration. In acquired forms of DDD and C3GN, the dysregulation of the alternative pathway is commonly induced by the presence of C3 nephritic factors (C3NeFs), which are autoantibodies that stabilize C3 convertase. Both DDD and C3GN can affect individuals of any age, but DDD is primarily diagnosed in children, whereas C3GN tends to be diagnosed at a significantly higher age. The presenting features of these diseases are variable and may include proteinuria, hematuria, hypertension, or kidney failure. A common finding in these diseases is low serum C3 levels with normal serum C4 levels. Chronic deterioration of renal function is commonly observed in DDD and C3GN, often leading to end-stage renal disease (ESRD), especially in DDD. Kidney transplantation outcomes in patients with these conditions are characterized by histological recurrence, which may contribute to higher rates of allograft failure.

Systemic and targeted steroids for the treatment of IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is a common glomerulonephritis partially correlated with mucosal immune system dysfunction. Progressive renal failure occurs in many patients, with about 30-50% of the patients with IgAN developing end-stage kidney disease (ESKD). Many treatments have been used for decades, despite uncertainty about their effectiveness and the ideal dose. Randomised controlled trials reported that systemic glucocorticoids can be an effective treatment for patients with persistent and significant proteinuria despite renin-angiotensin system inhibitors use possibly causing systemic side effects. The primary focus of IgAN management should be based on optimised supportive care, including renin-angiotensin system (RAS) blockade and now SGLT2 inhibitors. The novel targeted-release formulation (TRF) of budesonide has been tested to reduce the adverse events of systemic steroids by delivering the drug to the distal ileum. The local efficacy of TRF-budesonide may represent a novel and promising approach to treating IgAN. Two clinical trials showed that TRF-budesonide could significantly reduce proteinuria and haematuria and possibly preserve renal function while significantly reducing the side effects. However, the limited number of treated patients and the relatively short follow-up suggest caution before considering budesonide superior to the current six-months steroid pulses scheme. Long-term data on the efficacy and safety of TRF budesonide are awaited, together with the design of trials with a head-to-head comparison with systemic steroids before considering TRF-budesonide as the standard of care treatment for IgAN nephropathy.

Autophagy: A Silent Protagonist in Kidney Transplantation.

Autophagy is a lysosome-dependent regulated mechanism that recycles unnecessary cytoplasmic components. It is now known that autophagy dysfunction may have a pathogenic role in several human diseases and conditions, including kidney transplantation. Both defective and excessive autophagy may induce or aggravate several complications of kidney transplantation, such as ischemia-reperfusion injury, alloimmune response, and immunosuppressive treatment and side effects. Although it is still complicated to measure autophagy levels in clinical practice, more attention should be paid to the factors that may influence autophagy. In kidney transplantation, the association of low doses of a mammalian target of rapamycin inhibitor with low doses of a calcineurin inhibitor may be of benefit for autophagy modulation. However, further studies are needed to explore the role of other autophagy regulators.

Autosomal Dominant Polycystic Kidney Disease: Is There a Role for Autophagy?

Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either PKD1 or PKD2 genes, responsible for encoding polycystin 1 and polycystin 2, respectively. These proteins are primarily located within the primary cilia. The disease follows an inexorable progression, leading most patients to severe renal failure around the age of 50, and extra-renal complications are frequent. A cure for ADPKD remains elusive, but some measures can be employed to manage symptoms and slow cyst growth. Tolvaptan, a vasopressin V2 receptor antagonist, is the only drug that has been proven to attenuate ADPKD progression. Recently, autophagy, a cellular recycling system that facilitates the breakdown and reuse of aged or damaged cellular components, has emerged as a potential contributor to the pathogenesis of ADPKD. However, the precise role of autophagy in ADPKD remains a subject of investigation, displaying a potentially twofold impact. On the one hand, impaired autophagy may promote cyst formation by inducing apoptosis, while on the other hand, excessive autophagy may lead to fibrosis through epithelial to mesenchymal transition. Promising results of autophagy inducers have been observed in preclinical studies. Clinical trials are warranted to thoroughly assess the long-term safety and efficacy of a combination of autophagy inducers with metabolic and/or aquaferetic drugs. This research aims to shed light on the complex involvement of autophagy in ADPKD, explore the regulation of autophagy in disease progression, and highlight the potential of combination therapies as a promising avenue for future investigations.

Thin Basement Membrane: An Underrated Cause of End-Stage Renal Disease.

The term "thin basement membrane" (TBM) refers to a glomerular disorder characterized by diffuse uniform thinning of the glomerular basement membrane (GBM) on electron microscopy. Patients with TBM usually show an isolated hematuria with excellent renal prognosis. However, some patients can develop proteinuria and progressive kidney dysfunction in the long term. Most patients with TBM are heterozygous for pathogenic variants in genes encoding for both the α3 and α4 chains of collagen IV, a major constituent of GBM. Such variants are responsible for a wide range of clinical and histological phenotypes. The differential diagnosis between TBM and autosomal-dominant Alport syndrome and IgA nephritis (IGAN) may be difficult in some cases. Patients who progress to chronic kidney disease may show clinicopathologic features similar to those of primary focal and segmental glomerular sclerosis (FSGS). Without a shared classification of these patients, the risk of misdiagnosis and/or underestimation of the risk of progressive kidney disease is real. New efforts are needed to understand the determinants of renal prognosis and recognize the early signs of renal deterioration, allowing a custom-made diagnosis and therapeutic approach. For this purpose, a practical and simple clinical approach is supplied.

Kidney Biopsy in Pregnant Women with Glomerular Diseases: Focus on Lupus Nephritis.

Despite significant improvements of renal and obstetrical management, pregnancies in women with glomerular diseases and with lupus nephritis continue to be associated with increased complications both for the mother and the fetus as compared to those of pregnancies in healthy women. To reduce the risk of these complications, planning pregnancy in a phase of stable remission of the underlining disease is necessary. A kidney biopsy is an important event in any phase of pregnancy. A kidney biopsy can be of help during counselling before pregnancy in cases of incomplete remission of the renal manifestations. In these situations, histological data may differentiate active lesions that require the reinforcement of therapy from chronic irreversible lesions that may increase the risk of complications. In pregnant women, a kidney biopsy can identify new-onset systemic lupus erythematous (SLE) and necrotizing or primitive glomerular diseases and distinguish them from other, more common complications. Increasing proteinuria, hypertension, and the deterioration of kidney function during pregnancy may be either due to a reactivation of the underlying disease or to pre-eclampsia. The results of the kidney biopsy suggest the need to initiate an appropriate treatment, allowing the progression of the pregnancy and the fetal viability or the anticipation of delivery. Data from the literature suggest avoiding a kidney biopsy beyond 28 weeks of gestation to minimize the risks associated with the procedure vs. the risk of preterm delivery. In case of the persistence of renal manifestations after delivery in women with a diagnosis of pre-eclampsia, a renal kidney assessment allows the final diagnosis and guides the therapy.

Autophagy and podocytopathy.

Autophagy is a complex process of lysosomal-dependent degradation of unwanted cellular material. In response to endogenous or exogenous stimuli, autophagy is induced and regulated by two kinases: the AMP activated kinase and the mammalian target of rapamycin (mTOR). Cells activated by Unc-51-like kinase 1 form a double membrane complex that sequesters the cargo (phagophore) and elongates producing spherical vesicles (autophagosomes). These reach and fuse with lysosomes, which degrade the cargo (autolysosomes). The resulting macromolecules are released back and recycled in the cytosol for reuse. In the podocyte, autophagy is a homeostatic mechanism that contributes to the formation and preservation of the morphological and functional integrity of actin cytoskeleton. Podocytes, fenestrated endothelial cells and glomerular basement membrane compose the glomerular filtration barrier. Podocyte damage may cause dysfunction of the glomerular barrier, proteinuria and glomerulosclerosis in different glomerular diseases and particularly in so-called podocytopathies, namely minimal change disease and focal segmental glomerulosclerosis. Several drugs and molecules may activate autophagic function in murine models. Among them, aldosterone inhibitors, mineralocorticoid inhibitors and vitamin D3 were proven to protect podocyte from injury and reduce proteinuria in clinical studies. However, no clinical trial with autophagy regulators in podocytopathies has been conducted. Caution is needed with other autophagy activators, such as mTOR inhibitors and metformin, because of potential adverse events.

Anti-glomerular basement membrane vasculitis.

Antiglomerular basement membrane disease (anti-GBM) is a rare life-threatening autoimmune vasculitis that involves small vessels and it is characterized by circulating autoantibodies directed against type IV collagen antigens expressed in glomerular and alveolar basement membrane. The typical clinical manifestations are the rapidly progressive glomerulonephritis and the alveolar hemorrhage. The diagnosis is usually confirmed by the detection of anti-GBM circulating antibodies. If not rapidly recognized, anti-GBM disease can lead to end stage kidney disease (ESKD). An early diagnosis and prompt treatment with immunosuppressive therapies and plasmapheresis are crucial to prevent a poor outcome. In this review, we discuss the primary form of anti-GBM (the so called Goodpasture syndrome) but also cases associated with other autoimmune diseases such as antineutrophil-cytoplasmic-antibody (ANCA) vasculitis, membranous nephropathy, IgA nephritis and systemic lupus erythematosus (SLE), as well as the few cases of anti-GBM vasculitis complicating kidney transplantation in the Alport syndrome.

Glomerular diseases in pregnancy: pragmatic recommendations for clinical management.

Our understanding of the various aspects of pregnancy in women with kidney diseases has significantly improved in the last decades. Nevertheless, little is known about specific kidney diseases. Glomerular diseases are not only a frequent cause of chronic kidney disease in young women, but combine many challenges in pregnancy: immunologic diseases, hypertension, proteinuria, and kidney tissue damage. An international working group undertook the review of available current literature and elicited expert opinions on glomerular diseases in pregnancy with the aim to provide pragmatic information for nephrologists according to the present state-of-the-art knowledge. This work also highlights areas of clinical uncertainty and emphasizes the need for further collaborative studies to improve maternal and fetal health.

Renal sarcoidosis.

Sarcoidosis is a systemic inflammatory disease of unknown etiology. The pathogenesis rests on an aberrant T cell response to unidentified antigens in individuals predisposed by genetic and environmental factors. Increased expression of polarized macrophages and disequilibrium between effector and regulator T cells contribute to the formation of noncaseating granulomas, that are frequently found in affected organs. The main kidney abnormalities in sarcoidosis are granulomatous interstitial nephritis (GIN) and hypercalcemia-related disorders. The clinical diagnosis is difficult. The outcome is variable, ranging from spontaneous remission to end-stage kidney disease (ESKD). Early diagnosis and prompt treatment with corticosteroids can improve the prognosis. Hypercalcemia may be responsible for acute kidney injury (AKI) caused by vasoconstriction of afferent arterioles. Complications of persistent hypercalcemia include nephrocalcinosis and renal stones. In patients with ESKD, dialysis and transplantation can offer results comparable to those observed in patients with other causes of kidney failure. Based on a review of the literature, we present an overview of the etiopathogenesis, the renal manifestations of sarcoidosis and their complications, management and prognosis.

COVID-19 Vaccination in Kidney Transplant Candidates and Recipients.

Kidney transplant candidates and kidney transplant recipients (KTRs) are at particular risk of severe complications of COVID-19 disease. In Western countries, mortality in affected hospitalized KTRs ranges between 19% and 50%. COVID-19 vaccination remains the most important measure to prevent the severity of infection in candidates and recipients of kidney transplant. However, the uraemic condition may affect the vaccine-induced immunity in patients with advanced chronic kidney disease (CKD) and in KTRs. Retention of uraemic toxins, dysbiosis, dysmetabolism, and dialysis can diminish the normal response to vaccination, leading to dysfunction of inflammatory and immune cells. In KTRs the efficacy of vaccines may be reduced by the immunosuppressive medications, and more than half of kidney transplant recipients are unable to build an immune response even after four administrations of anti-COVID-19 vaccines. The lack of antibody response leaves these patients at high risk for SARS-CoV-2 infection and severe COVID-19 disease. The aim of the present review is to focus on the main reasons for the impaired immunological response among candidates and kidney transplant recipients and to highlight some of the present options available to solve the problem.

Delayed Graft Function in Kidney Transplant: Risk Factors, Consequences and Prevention Strategies.

BACKGROUND: Delayed graft function is a frequent complication of kidney transplantation that requires dialysis in the first week posttransplant. MATERIALS AND METHODS: We searched for the most relevant articles in the National Institutes of Health library of medicine, as well as in transplantation, pharmacologic, and nephrological journals. RESULTS: The main factors that may influence the development of delayed graft function (DGF) are ischemia-reperfusion injury, the source and the quality of the donated kidney, and the clinical management of the recipient. The pathophysiology of ischemia-reperfusion injury is complex and involves kidney hypoxia related to the duration of warm and cold ischemia, as well as the harmful effects of blood reperfusion on tubular epithelial cells and endothelial cells. Ischemia-reperfusion injury is more frequent and severe in kidneys from deceased donors than in those from living donors. Of great importance is the quality and function of the donated kidney. Kidneys from living donors and those with normal function can provide better results. In the peri-operative management of the recipient, great attention should be paid to hemodynamic stability and blood pressure; nephrotoxic medicaments should be avoided. Over time, patients with DGF may present lower graft function and survival compared to transplant recipients without DGF. Maladaptation repair, mitochondrial dysfunction, and acute rejection may explain the worse long-term outcome in patients with DGF. Many different strategies meant to prevent DGF have been evaluated, but only prolonged perfusion of dopamine and hypothermic machine perfusion have proven to be of some benefit. Whenever possible, a preemptive transplant from living donor should be preferred.

Non-Immunologic Causes of Late Death-Censored Kidney Graft Failure: A Personalized Approach.

Despite continuous advances in surgical and immunosuppressive protocols, the long-term survival of transplanted kidneys is still far from being satisfactory. Antibody-mediated rejection, recurrent autoimmune diseases, and death with functioning graft are the most frequent causes of late-kidney allograft failure. However, in addition to these complications, a number of other non-immunologic events may impair the function of transplanted kidneys and directly or indirectly lead to their failure. In this narrative review, we will list and discuss the most important nonimmune causes of late death-censored kidney graft failure, including quality of the donated kidney, adherence to prescriptions, drug toxicities, arterial hypertension, dyslipidemia, new onset diabetes mellitus, hyperuricemia, and lifestyle of the renal transplant recipient. For each of these risk factors, we will report the etiopathogenesis and the potential consequences on graft function, keeping in mind that in many cases, two or more risk factors may negatively interact together.

Predictors of increase in chronicity index and of kidney function impairment at repeat biopsy in lupus nephritis.

OBJECTIVES: Based on available data, the histological predictors of long-term outcome of lupus nephritis (LN) are not clearly defined. Aims of this retrospective study were: (i) to evaluate the change of chronicity index from the first to second kidney biopsy and to find the predictors of chronicity index increase and (ii) to detect the clinical/histological features at first and at second kidney biopsy associated with long-term kidney function impairment. METHODS: Among 203 biopsy proven LN subjects, 61 repeated kidney biopsy 49 months after the first biopsy. The reasons for repeated biopsy were: nephritic flares in 25 (41%), proteinuric flares in 21 (36%) of patients and protocol biopsy in 14 (23%) of cases. RESULTS: During 23-year follow-up, 25 patients presented a decrease in glomerular filtration rate (eGFR) ≥30%. At repeat biopsy, chronicity index increased in 44 participants (72%) and did not increase in 17 (28%). Nephritic syndrome and serum creatinine >1.6 mg/dL at presentation correlated with chronicity index increase (p=0.031, 0.027, respectively), cyclophosphamide therapy tended to protect against chronicity index increase (p=0.059). Kidney flares occurred in 53.6% of patients with vs 23.5% of those without chronicity index increase (p=0.035). Chronicity index increases of 3.5 points in patients with kidney flares vs 2 in those without flares (p=0.001). At second, but not at first kidney biopsy, two different models predicted eGFR decrease at multivariate analysis. The first included activity index >3 (OR: 3.230; p=0.013) and chronicity index >4 (OR: 2.905; p=0.010), and the second model included moderate/severe cellular/fibrocellular crescents (OR: 4.207; p=0.010) and interstitial fibrosis (OR: 2.525; p=0.025). CONCLUSION: At second biopsy, chronicity index increased in 3/4 of participants. Its increase was predicted by kidney dysfunction at presentation and occurrence of LN flares. Kidney function impairment was predicted by both activity and chronicity index and by some of their components at repeated biopsy, but not at first biopsy.

Cardiovascular Risk after Kidney Transplantation: Causes and Current Approaches to a Relevant Burden.

BACKGROUND: Cardiovascular disease is a frequent complication after kidney transplantation and represents the leading cause of mortality in this population. MATERIAL AND METHODS: We searched for the relevant articles in the National Institutes of Health library of medicine, transplant, cardiologic and nephrological journals. RESULTS: The pathogenesis of cardiovascular disease in kidney transplant is multifactorial. Apart from non-modifiable risk factors, such as age, gender, genetic predisposition and ethnicity, several traditional and non-traditional modifiable risk factors contribute to its development. Traditional factors, such as diabetes, hypertension and dyslipidemia, may be present before and may worsen after transplantation. Immunosuppressants and impaired graft function may strongly influence the exacerbation of these comorbidities. However, in the last years, several studies showed that many other cardiovascular risk factors may be involved in kidney transplantation, including hyperuricemia, inflammation, low klotho and elevated Fibroblast Growth Factor 23 levels, deficient levels of vitamin D, vascular calcifications, anemia and poor physical activity and quality of life. CONCLUSIONS: The timely and effective treatment of time-honored and recently discovered modifiable risk factors represent the basis of the prevention of cardiovascular complications in kidney transplantation. Reduction of cardiovascular risk can improve the life expectancy, the quality of life and the allograft function and survival.

Kidney Involvement in Systemic Sclerosis.

BACKGROUND: Systemic sclerosis is a chronic multisystem autoimmune disease, characterized by diffuse fibrosis and abnormalities of microcirculation and small arterioles in the skin, joints and visceral organs. MATERIAL AND METHODS: We searched for the relevant articles on systemic sclerosis and kidney involvement in systemic sclerosis in the NIH library of medicine, transplant, rheumatologic and nephrological journals. RESULTS: Half of patients with systemic sclerosis have clinical evidence of kidney involvement. Scleroderma renal crisis represents the most specific and serious renal event associated with this condition. It is characterized by an abrupt onset of moderate to marked hypertension and kidney failure. Early and aggressive treatment is mandatory to prevent irreversible organ damage and death. The advent of ACE-inhibitors revolutionized the management of scleroderma renal crisis. However, the outcomes of this serious complication are still poor, and between 20 to 50% of patients progress to end stage renal disease. CONCLUSIONS: Scleroderma renal crisis still represents a serious and life-threatening event. Thus, further studies on its prevention and on new therapeutic strategies should be encouraged.

Autophagy in lupus nephritis: A delicate balance between regulation and disease.

Autophagy is a highly regulated process wherein an unwanted cargo of damaged and dysfunctional cytoplasmic components is removed, delivered to lysosomes for degradation, and released back into the cytoplasm. Accumulating evidence suggests an important role of autophagy in the pathophysiology of systemic lupus erythematosus, with profound effects on both innate and adaptive immunity. Autophagy downregulation results in the inhibition of antigen presenting cells, reduced release of neutrophil extracellular traps and decreased activation of effector T and B cells, leading to reduced autoantibody production and attenuated type 1 interferon signaling. However, defective autophagy may accelerate the production of other inflammatory cytokines and reduce the clearance of apoptotic cells, promoting lupus development. In addition, autophagy dysfunction can concur to the pathogenesis of kidney injury in lupus nephritis. Autophagy is a pivotal mechanism to maintain podocyte integrity and endothelial cell survival. Several animal models have demonstrated that defective autophagy leads to podocyte injury and can promote an endothelial pro-inflammatory and atherogenic phenotype. Moreover, autophagy is a key homeostatic regulator of renal tubular cells, and recent evidence has pointed out that chronic autophagy deficiency may accelerate kidney fibrosis. Targeting autophagy may theoretically improve lupus nephritis outcomes, but novel, non-invasive methods to measure and monitor autophagic activity are urgently needed. In addition, the extent and timing of autophagy inhibition still require additional studies before clinical translation may be attempted. In this review, we will also discuss the effect of several clinically available drugs that can regulate the autophagic flux and their effect in lupus nephritis patients.

The Impact of Preeclampsia in Lupus Nephritis.

INTRODUCTION: Women with systemic lupus erythematosus (SLE), particularly those with lupus nephritis (LN), remain at high risk for adverse pregnancy outcome. Although in the last decades maternal and fetal outcomes have improved dramatically, preeclampsia remains a major cause of maternal and perinatal morbidity and mortality. AREAS COVERED: A narrative review of literature was conducted, underlying the importance of pre-conception counseling, and focusing on the correlation between preeclampsia and LN. The clinical characteristics of preeclampsia were described, with emphasis on risk factors in LN and the differential diagnosis between preeclampsia and lupus flares. Additionally, the prevention and treatment of preeclampsia were discussed, as well as the management of short-term and long-term consequences of preeclampsia. We highlight the importance of a pre-pregnancy counseling from a multidisciplinary team to plan pregnancy during inactive SLE and LN. EXPERT OPINION: Further studies are needed to evaluate the long-term consequences of pregnancy in LN. Considering that preeclamptic patients can be at high risk for long-term renal failure, we suggest renal checkup for at least 6-12 months after delivery in all patients.

Beyond ISN/RPS Lupus Nephritis Classification: Adding Chronicity Index to Clinical Variables Predicts Kidney Survival.

Background: A renewed interest for activity and chronicity indices as predictors of lupus nephritis (LN) outcome has emerged. Revised National Institutes of Health activity and chronicity indices have been proposed to classify LN lesions, but they should be validated by future studies. The aims of this study were (1) to detect the histologic features associated with the development of kidney function impairment (KFI), and (2) to identify the best clinical-histologic model to predict KFI at time of kidney biopsy. Methods: Patients with LN who had more than ten glomeruli per kidney biopsy specimen were admitted to the study. Univariate and multivariate logistic regression and Cox proportional hazards models were used to investigate whether activity and chronicity indices could predict KFI development. Results: Among 203 participants with LN followed for 14 years, correlations were found between the activity index, and its components, and clinical-laboratory signs of active LN at baseline. The chronicity index was correlated with serum creatinine. Thus, serum creatinine was significantly and directly correlated with both activity and chronicity indices. In the multivariate analysis, glomerulosclerosis (OR, 3.05; 95% CI, 1.17 to 7.91; P=0.02) and fibrous crescents (OR, 6.84; 95% CI, 3.22 to 14.52; P<0.001) associated with either moderate/severe tubular atrophy (OR, 3.17; 95% CI, 1.04 to 9.64; P=0.04), or with interstitial fibrosis (OR, 2.36; 95% CI, 1.05 to 5.32; P=0.04), predicted KFI. Considering both clinical and histologic features, serum creatinine (OR, 1.68; 95% CI, 1.31 to 2.15; P<0.001), arterial hypertension (OR, 4.64; 95% CI, 1.90 to 11.32; P<0.001), glomerulosclerosis (OR, 2.12; 95% CI, 1.00 to 4.50; P=0.05), and fibrous crescents (OR, 5.18; 95% CI, 2.43 to 11.04; P<0.001) independently predicted KFI. Older age (P<0.001) and longer delay between clinical onset of LN and kidney biopsy (P<0.001) were significantly correlated with baseline chronicity index. Conclusions: The chronicity index and its components, but not the activity index, were significantly associated with an impairment of kidney function. The Cox model showed that serum creatinine, arterial hypertension, chronic glomerular lesions, and delay in kidney biopsy predicted KFI. These data reinforce the importance of timely kidney biopsy in LN.

Therapies for Membranous Nephropathy: A Tale From the Old and New Millennia.

Primary Membranous Nephropathy (PMN) is the most frequent cause of nephrotic syndrome in adults. If untreated, PMN can lead to end-stage renal disease; moreover, affected patients are at increased risk of complications typical of nephrotic syndrome such as fluid overload, deep vein thrombosis and infection. The association of PMN with HLA-DQA1 and the identification in around 70% of cases of circulating autoantibodies, mainly directed towards the phospholipase A2 receptor, supports the autoimmune nature of the disease. In patients not achieving spontaneous remission or in the ones with deteriorating kidney function and severe nephrotic syndrome, immunosuppression is required to increase the chances of achieving remission. The aim of this review is to discuss the evidence base for the different immunosuppressive regimens used for PMN in studies published so far; the manuscript also includes a section where the authors propose, based upon current evidence, their recommendations regarding immunosuppression in the disease, while highlighting the still significant knowledge gaps and uncertainties.