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.

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.

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.

Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial.

BACKGROUND: A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. METHODS: We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. RESULTS: At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. CONCLUSIONS: This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.

The inflammatory state is a risk factor for cardiovascular disease and graft fibrosis in kidney transplantation.

Several factors, such as donor brain death, ischemia-reperfusion injury, rejection, infection, and chronic allograft dysfunction, may induce an inflammatory state in kidney transplantation. Furthermore, inflammatory cells, cytokines, growth factors, complement and coagulation cascade create an unbalanced interaction with innate and adaptive immunity, which are both heavily involved in atherogenesis. The crosstalk between inflammation and thrombosis may lead to a prothrombotic state and impaired fibrinolysis in kidney transplant recipients increasing the risk of cardiovascular disease. Inflammation is also associated with elevated levels of fibroblast growth factor 23 and low levels of Klotho, which contribute to major adverse cardiovascular events. Hyperuricemia, glucose intolerance, arterial hypertension, dyslipidemia, and physical inactivity may create a condition called metaflammation that concurs in atherogenesis. Another major consequence of the inflammatory state is the development of chronic hypoxia that through the mediation of interleukins 1 and 6, angiotensin II, and transforming growth factor beta can result in excessive accumulation of extracellular matrix, which can disrupt and replace functional parenchyma, leading to interstitial fibrosis and chronic allograft dysfunction. Lifestyle and regular physical activity may reduce inflammation. Several drugs have been proposed to control the graft inflammatory state, including low-dose aspirin, statins, renin-angiotensin inhibitors, xanthine-oxidase inhibitors, vitamin D supplements, and interleukin-6 blockade. However, no prospective controlled trial with these measures has been conducted in kidney transplantation.

The evolution of the therapeutic approach to membranous nephropathy.

Primary membranous nephropathy (MN) is a frequent cause of nephrotic syndrome (NS) in adults. In untreated patients, the outcome is variable, with one-third of the patients entering remission while the remaining ones show persisting proteinuria or progression to end-stage renal disease. Randomized clinical trials reported the efficacy of a 6-month regimen alternating intravenous and oral glucocorticoids with an alkylating agent every other month. The potential side effects of this regimen were limited by the fact that the use of glucocorticoids and alkylating agent did not exceed 3 months each. Two randomized trials with follow-ups (FU) up to 10 years provided assurance about the long-term efficacy and safety of this cyclical therapy. Calcineurin inhibitors have also been used successfully. However, in most responders, NS relapsed after the drug was withdrawn. Conflicting results have been reported with mycophenolate salts and adrenocorticotropic hormone. Observational studies reported good results with rituximab (RTX). Two controlled trials demonstrated the superiority of RTX over antiproteinuric therapy alone and cyclosporine. However, the FUs were relatively short and no randomized trial has been published against cyclical therapy. The available results, together with the discovery that most patients with MN have circulating antibodies against the phospholipase A2 receptor 1, support the use of cytotoxic drugs or RTX in MN. It is difficult to choose between these two different treatments. RTX is easier to use, but the FUs of the available studies are short, thus doubts remain about the long-term risk of relapses and the safety of repeated administrations of RTX.

New-Onset Diabetes after Kidney Transplantation.

New-onset diabetes mellitus after transplantation (NODAT) is a frequent complication in kidney allograft recipients. It may be caused by modifiable and non-modifiable factors. The non-modifiable factors are the same that may lead to the development of type 2 diabetes in the general population, whilst the modifiable factors include peri-operative stress, hepatitis C or cytomegalovirus infection, vitamin D deficiency, hypomagnesemia, and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors (tacrolimus more than cyclosporine), and mTOR inhibitors. The most worrying complication of NODAT are major adverse cardiovascular events which represent a leading cause of morbidity and mortality in transplanted patients. However, NODAT may also result in progressive diabetic kidney disease and is frequently associated with microvascular complications, eventually determining blindness or amputation. Preventive measures for NODAT include a careful assessment of glucose tolerance before transplantation, loss of over-weight, lifestyle modification, reduced caloric intake, and physical exercise. Concomitant measures include aggressive control of systemic blood pressure and lipids levels to reduce the risk of cardiovascular events. Hypomagnesemia and low levels of vitamin D should be corrected. Immunosuppressive strategies limiting the use of diabetogenic drugs are encouraged. Many hypoglycemic drugs are available and may be used in combination with metformin in difficult cases. In patients requiring insulin treatment, the dose and type of insulin should be decided on an individual basis as insulin requirements depend on the patient's diet, amount of exercise, and renal function.

Hyperuricemia as a trigger of immune response in hypertension and chronic kidney disease.

Accumulating evidence indicates that asymptomatic hyperuricemia is involved in the development of hypertension and chronic kidney disease. A 2-hit model has been proposed to explain the role of urate in hypertension. The first hit entails activation of the renin-angiotensin system and inhibition of nitric oxide synthesis, which promote endothelial dysfunction, proliferation of vascular smooth muscle cells, and sodium reabsorption, leading to a moderate but consistent increase in systemic blood pressure. The second hit involves the immune system. Uric acid released in response to hypertension-induced damage can be recognized as a danger molecule by pattern-recognition receptors, the sentinels of the innate immunity. Downstream signaling from these receptors leads to dendritic cell maturation and activation of resting T cells, but it can also trigger the inflammasome and induce the secretion of proinflammatory cytokines. This proinflammatory milieu concurs in expanding the extracellular fluid volume and in increasing vascular resistances, which further promote systemic hypertension. Through similar mechanisms, hyperuricemia may also cause vascular and tubulointerstitial lesions that favor the development and progression of chronic kidney disease. To counteract these actions, xanthine oxidase inhibitors and uricosuric agents have been advocated as logical candidates to decrease the serum levels of uric acid. However, despite a clear rationale for using hypouricemic drugs in patients with chronic kidney disease, there is currently a lack of robust evidence that lowering uric acid may slow the progression of renal disease.

Is preeclampsia a risk for end-stage renal disease?

Little information is available about the risk of end-stage renal disease (ESRD) after preeclampsia. The review of Covella et al. demonstrated that former preeclamptic women have a significant risk of ESRD in the medium term. However, it is still unknown which preeclamptic woman are at higher risk for progressive kidney disease. After delivery, women who had preeclampsia, particularly those with persistent hypertension, symptomatic proteinuria, or microalbuminuria, should receive a regular checkup for kidney disease.

Causes of late transplant failure in cyclosporine-treated kidney allograft recipients.

BACKGROUND: There is little information about very long-term outcomes of kidney allograft recipients exposed to calcineurin inhibitors. METHODS: In this single-centre retrospective study with 20-year follow-up, we analyzed data from 644 patients who underwent primary renal transplantation between 1983 and 1993. Participants were treated with a cyclosporine-based immunosuppressive scheme and had allograft function at 1 year. RESULTS: After 20 years, 15.2% patients died, 39.7% experienced allograft loss, 26.8% were alive with a functioning transplant, and 18.2% were lost to follow-up. Cardiovascular disease (30.8%), malignancy (26.6%) and infection (17.0%) were the main causes of death. Age, new-onset proteinuria > 1 g/day, major acute cardiovascular event (MACE), and malignancy were independent predictors of mortality at time-dependent multivariate analysis. Chronic rejection (63.3%), recurrent glomerulonephritis (14.0%), and nonspecific interstitial fibrosis/tubular atrophy (13.2%) were the leading cause of allograft loss. Basal disease, hepatitis C, difference between 1 year and nadir serum creatinine, new-onset proteinuria > 1 g/day, and MACE were independent predictors of transplant failure. Among patients with 20-year allograft function, we recorded the following complications: hypertension (85%), malignancy (13%), diabetes (9%), and cardiovascular disease (9%). Median serum creatinine and proteinuria were 1.4 mg/dL and 0.6 g/day, respectively. CONCLUSIONS: Prolonged use of cyclosporine may expose to several dose-related adverse events and may contribute to the development of allograft dysfunction but it does not necessarily cause relentless, progressive transplant failure if patients are carefully and consistently monitored during the follow-up.

Thrombospondin immune regulation and the kidney.

Most therapeutic attempts to prevent the progression of kidney diseases have been based on interventions to inhibit the production of transforming growth factor-ß (TGF-ß). Thrombospondins (TSPs) play an important role in activating TGF-ß. In the healthy kidney, two TSPs are expressed, TSP1 and TSP2, which exert contrasting effects. While TSP1 is a major activator of TGF-ß in renal cells and exerts pro-inflammatory effects both in vitro and in vivo, TSP2 lacks the ability for TGF-ß activation but regulates matrix remodeling and inflammation in experimental kidney disease. The effects of TSPs in the kidney have been mostly investigated by using the murine model of unilateral ureteral obstruction. In this model, TSP1 expression is increased along with the development of interstitial fibrosis and TGF-ß. Relief of the obstruction gradually improves renal function and decreases the expression in TSP1 and TGF-ß1. Several inhibitors of TSP1 prevented progressive interstitial fibrosis in murine models of ureteral obstruction, suggesting that control of latent TGF-ß activation by inhibiting TSP1 might represent a novel potential target for preventing renal interstitial fibrosis. However, further studies are needed to assess whether TSP1-mediated TGF-ß activation can be safely used in humans. In fact, TSPs normally act to suppress tumors in vivo. Moreover, TGF-ß can exert a pivotal function in the immune system, as it may induce the production of regulatory T cells and suppress B cell responses. Knowledge of the molecular mechanisms involved in TGF-ß regulation may help in finding effective treatments of tissue fibrosis, cancer and autoimmune disease.

Lupus nephritis: When and how often to biopsy and what does it mean?

Renal disease is a frequent complication of SLE which can lead to significant illness and even death. Today, a baseline renal biopsy is highly recommended for all subjects with evidence of lupus nephritis. Biopsy allows the clinician to recognize and classify different forms of autoimmune lupus glomerulonephritis, and to detect other glomerular diseases with variable pathogenesis which are not directly related to autoimmune reactivity, such as lupus podocytopathy. Moreover, not only glomerular diseases, but other severe forms of renal involvement, such as tubulo-interstitial nephritis or thrombotic microangiopathy may be detected by biopsy in lupus patients. Thus, an accurate definition of the nature and severity of renal involvement is mandatory to assess the possible risk of progression and to establish an appropriate treatment. The indications to repeat biopsy are more controversial. Some physicians recommend protocol biopsies to recognize the possible transformation from one class to another one, or to identify silent progression of renal disease, others feel that good clinical monitoring is sufficient to assess prognosis and to make therapeutic decisions. At any rate, although any decision should always be taken by considering the clinical conditions of the patient, there are no doubts that repeat renal biopsy may represent a useful tool in difficult cases to evaluate the response to therapy, to modulate the intensity of treatment, and to predict the long-term renal outcome both in quiescent lupus and in flares of activity.

The Renal Connexome and Possible Roles of Connexins in Kidney Diseases.

Connexins are membrane-spanning proteins that allow for the formation of cell-to-cell channels and cell-to-extracellular space hemichannels. Many connexin subtypes are expressed in kidney cells. Some mutations in connexin genes have been linked to various human pathologies, including cardiovascular, neurodegenerative, lung, and skin diseases, but the exact role of connexins in kidney disease remains unclear. Some hypotheses about a connection between genetic mutations, endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) in kidney pathology have been explored. The potential relationship of kidney disease to abnormal production of connexin proteins, mutations in their genes together with ER stress, or the UPR is still a matter of debate. In this scenario, it is tantalizing to speculate about a possible role of connexins in the setting of kidney pathologies that are thought to be caused by a deregulated podocyte protein expression, the so-called podocytopathies. In this article, we give examples of the roles of connexins in kidney (patho)physiology and propose avenues for further research concerning connexins, ER stress, and UPR in podocytopathies that may ultimately help refine drug treatment.

The impact of cold ischemia time on renal transplant outcome.

Cold ischemia triggers a cascade of noxious effects, which are amplified by restoration of blood supply reperfusion. These injuries generate inflammatory and immune responses that may potentially result in delayed graft function, enhanced alloimmune reactivity, and development of progressive pathological changes. Debout et al. outline the clinical importance of cold ischemia time in renal transplantation by demonstrating that each additional hour of cold ischemia can increase the risk of allograft failure and death.

Ischaemia-reperfusion injury: a major protagonist in kidney transplantation.

Ischaemia-reperfusion injury (IRI) is a frequent event in kidney transplantation, particularly when the kidney comes from a deceased donor. The brain death is usually associated with generalized ischaemia due to a hyperactivity of the sympathetic system. In spite of this, most donors have profound hypotension and require administration of vasoconstrictor agents. Warm ischaemia after kidney vessels clamping and the cold ischaemia after refrigeration also reduce oxygen and nutrients supply to tissues. The reperfusion further aggravates the state of oxidation and inflammation created by ischaemia. IRI first attacks endothelial cells and tubular epithelial cells. The lesions may be so severe that they lead to acute kidney injury (AKI) and delayed graft function (DGF), which can impair the graft survival. The unfavourable impact of DGF is worse when DGF is associated with acute rejection. Another consequence of IRI is the activation of the innate immunity. Danger signals released by dying cells alarm Toll-like receptors that, through adapter molecules and a chain of kinases, transmit the signal to transcription factors which encode the genes regulating inflammatory cells and mediators. In the inflammatory environment, dendritic cells (DCs) intercept the antigen, migrate to lymph nodes and present the antigen to immunocompetent cells, so activating the adaptive immunity and favouring rejection. Attempts to prevent IRI include optimal management of donor and recipient. Calcium-channel blockers, l-arginine and N-acetylcysteine could obtain a small reduction in the incidence of post-transplant DGF. Fenoldopam, Atrial Natriuretic Peptide, Brain Natriuretic Peptide and Dopamine proved to be helpful in reducing the risk of AKI in experimental models, but there is no controlled evidence that these agents may be of benefit in preventing DGF in kidney transplant recipients. Other antioxidants have been successfully used in experimental models of AKI but only a few studies of poor quality have been made in clinical transplantation with a few of these agents and we still lack of unambiguous demonstration that pre-treatment with these antioxidants can attenuate the impact of IRI in kidney transplantation. Interference with the signals leading to activation of innate immunity, inactivation of complement or manipulation of DCs is a promising therapeutic option for the near future.

The dialysis scenario in patients with systemic lupus erythematosus.

Although prognosis of lupus nephritis has improved over time, a substantial amount of lupus patients still reach end-stage renal disease and require dialysis. Treatment of these patients can be challenging, since the disease poses a number of problems that can portend a poor prognosis, such as infections, lupus reactivations, vascular access thrombosis and cardiovascular complications. Consensus is lacking among investigators about the real incidence of these complications and related diagnosis and treatment. Moreover, the choice of the type of dialysis treatment and the overall prognosis are still a matter of debate. In this paper, we have reviewed the currently available literature in an attempt to answer the most controversial issues about the topic.

Anti-C1q antibodies: a biomarker for diagnosis and management of lupus nephritis. A narrative review.

Nephritis is a frequent and severe complication of Systemic Lupus Erythematous (SLE). The clinical course of lupus nephritis (LN) is usually characterized by alternating phases of remission and exacerbation. Flares of LN can lead to deterioration of kidney function, necessitating timely diagnosis and therapy. The presence of autoantibodies against C1q (anti-C1qAb) in the sera of SLE patients has been reported in various studies. Some research suggests that the presence and changes in the titer of anti-C1qAb may be associated with the development of LN, as well as with LN activity and renal flares. However, the exact role of anti-C1qAb in LN remains a subject of debate. Despite variability in the results of published studies, anti-C1qAb hold promise as noninvasive markers for assessing LN activity in SLE patients. Measuring anti-C1qAb levels could aid in diagnosing and managing LN during periods of both inactive disease and renal flares. Nevertheless, larger controlled trials with standardized laboratory assays are necessary to further establish the utility of anti-C1qAb in predicting the reactivation and remission of LN and guiding treatment strategies.