Clinical Queries: Nephrology最新文献

Background

Pulmonary Renal Syndromes are heterogeneous group of disorders characterized by co-occurrence of rapidly progressive glomerulonephritis (RPGN) and alveolar hemorrhage due to an autoimmune etiology. This condition many a times presents as an emergency and can be rapidly fatal. A high index of suspicion is required to identify PRS early because appropriate diagnosis and timely institution of treatment is necessary for favorable results. The most common causes of PRS include anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), anti-glomerular basement membrane (Anti-GBM) disease and systemic lupus erythematosus (SLE) which are responsible for almost 80% of the cases. All these condition share similar clinical presentation however there are some salient features which differentiate them in terms of prognosis and management.

Methods

This is a narrative review using the search terms; “pulmonary renal syndrome, granulomatosis with polyangiitis; eosinophilic granulomatosis with polyangiitis; microscopic polyangiitis; anti-GBM disease and systemic lupus erythematosus.

Results

The most common causes of PRS include anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), anti-glomerular basement membrane (Anti-GBM) disease and systemic lupus erythematosus (SLE) which are responsible for almost 80% of the cases. All these condition share similar clinical presentation however there are some salient features which differentiate them in terms of prognosis and management. The response to immunosuppressive therapy and long term prognosis also differs because of distinguishing features in pathogenesis of these disorders. There is no consensus about the management protocols of pulmonary renal syndromes however, various immunological societies have laid down treatment protocols with variable success rates.

Conclusion

The syndrome of PRS has a high short-term mortality (20–40%). The rates of remission are >90% with current protocols and effective second line therapies exist for those who don't attain remission. Relapse rates are about 15% at 18 months and are higher with patients having PR3-ANCA and a diagnosis of GPA. A high index of suspicion is required to identify PRS early because treatment delays may be rapidly fatal.

The prevalence of CKD is increasing worldwide. There is tremendous imbalance in organ supply and demand worldwide. India is having mainly living donor (up to 90%) kidney transplantation program. Majority (up to 45%) of the living donors, although healthy and willing, are rejected due to ABO incompatibility. Deceased donation contributes to <10% of KT in India. Kidney paired donation, ABO incompatible KT, desensitization protocols, and marginal living donors are the ways to expand the living donor pool. The age at time of CKD reporting is less as compared to western stand and economic constraints are the most important hurdle in access to renal replacement therapy. The best long-term patient and graft survival is seen in KPD, which is cost effective and can be performed in all transplant centers. KPD has potential to expand the KT rate by 25%. The state and national KPD program will increase the donor pool and it increases the transplant rate in KPD. The harmony and co-ordination in different transplant centers, uniform guidelines to accept donor and patients for transplantation and computer software are required for the national KPD program.

Diabetic nephropathy is the most frequent cause of end stage renal disease (ESRD) worldwide. Current treatments consisting of glycaemic and blood pressure control, and efficient anti-proteinuric effects of RAS blockade are not sufficient to prevent progression of ESRD in a substantial proportion of patients. This finding is consistent with the hypothesis that key pathogenic mechanisms leading to progression of renal disease in diabetic patients are not modified or inactivated by current therapeutic approaches. Despite extensive research in molecular signalling mechanism and a number of high-profile clinical trials of potentially nephroprotective agents, the pathogenetic mechanisms underlying the diabetic nephropathy are not fully understood. Currently, only one trial (atrasentan) that seems to have a potentially renoprotective effect is underway. Further research into the potential nephroprotective effects of novel glucose lowering agents is needed.

Focal Segmental Glomerulosclerosis (FSGS) participates in different clinical presentations therefore involved in underlying pathophysiological etiologies. Numerous reports have proposed that vulnerability to develop FSGS has an important genetic component. These studies comprise familial aggregation, differences in the incidence of FSGS between different ethnic groups, and segregation analysis. Genetic methods have been used to classify genes that contribute towards genetic predisposition. Various studies revealed the precise role of “candidate genes”, which may cause FSGS with different pathogenesis. New studies to assess the role of associated genes have shown contradictory results. These results may be due to the fact that some of the previously reported genes may play only a moderate role. Presently genome wide studies have been carried out and these studies have contributed in finding out the location chromosomal positions. Interestingly novel, unrecognized genes to FSGS have been found. We have focused on different genetic studies including exact role and function of these genes on FSGS and have discussed the strength and weaknesses of these studies. Understanding of the development of FSGS may track future therapies and outcomes.

Diabetic nephropathy (DN) is characterized by albuminuria, which is usually accompanied by hypertension, progressive rise in proteinuria. There are several approaches to delay progression of diabetic nephropathy towards end stage renal failure (ESRD). Current approaches include a) control of blood glucose; b) low-protein diet; c) control of hypertension; restriction of dietary salt, phosphorus and potassium in advanced cases d) control of hyperfiltration, usually through angiotensin-converting enzyme inhibitors or angiotensin-receptor blocking agents. Nutrition management is fundamental for the prevention of diabetic nephropathy to ESRD.

Zebrafish (Danio rerio) has emerged as a potential vertebrate model for high throughput screening in drug discovery and development process. Easy breeding, short maturation time, transparent embryos for easy observation, good regeneration capability, well characterization of developmental stages, low maintenance cost, high productivity, less ethical constrains, etc. are a few unique characteristics which make zebrafish an attractive model for biomedical research. Apart from these, zebrafish possesses many anatomical, physiological and genetical similarities with higher mammals. Many pathological disorders have been successfully studied in zebrafish like cancer, cardiovascular, renal diseases, immunological, hematological disorders, etc. The pronephros of zebrafish imitates mammalian kidney at structural, functional and cellular level and thus allows informative nephrological research. The present review highlights the use of zebrafish as a model to screen nephroprotective molecules, to enable better understanding of nephrotoxicity and thus to target new therapies.

Minimal change disease is the commonest cause of nephrotic syndrome in children and third most common cause in adults. There are new insights in the pathogenesis of disease, and it is now considered a podocyte disorder. New biomarkers have been identified to explain the pathogenesis. The treatment in children is almost standardised, however in adults, the evidence is not so robust and treatment is mostly extrapolated from randomized trials in children and uncontrolled or retrospective studies in adults. The long term prognosis of disease is excellent in children and steroid sensitive patients. Steroid resistance is a marker of poor prognosis. Genetic studies are helpful in detecting patients with mutations, as, they do not respond to immunosuppressive drugs. The therapeutic armamentarium of treatment of MCD has widened with discovery of new immunosuppressive drugs like tacrolimus, mycophenolate mofetil and rituximab, which are helpful in treatment of steroids resistant and steroid dependent nephrotic syndrome.

Systemic lupus erythematosus is associated with renal involvement in almost 50–80% of cases. Although proliferative lupus nephritis is the most common form, isolated membranous lupus nephritis (MLN or class V lupus nephritis) accounts for 11–20% of cases while mixed proliferative and MLN (Class III + V/IV + V) can be seen in another 21–30%. MLN can present as either sub-nephrotic or nephrotic proteinuria with or without microscopic hematuria or renal dysfunction. These patients are at high risk of cardiovascular and cerebrovascular complications due to thrombotic tendency, dyslipidemia and hypertension. Uniform evidence regarding prognostic factors, outcome and therapy of MLN are still elusive. Systematic analysis of several studies have shown that sustained nephrotic proteinuria, failure to achieve complete remission and associated proliferative lesions denotes poor prognosis. In general, the long term renal survival rate is 50–90%, while end stage renal disease occurs in 12–22% cases. Transformation to proliferative nephritis is also well known, thus a close follow up is warranted in all pure MLN cases. Those with persistent nephrotic proteinuria, renal dysfunction and mixed histology should be treated aggressively with immunosuppressive agent while less severe cases can be managed with adjunctive therapies.

Pauciimmune vasculitis encompasses a group of systemic necrotizing vasculitis with paucity of immune complex deposition on microscopic examination. All these diseases have anti-neutrophil cytoplasmic antibody (ANCA) positivity, hence, also termed as ANCA associated vasculitides. It encompasses a spectrum of small vessel vasculitis; granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Activated neutrophils (and eosinophils in EGPA) resulting from known and unknown environmental influences on a susceptible genetic background cause vascular injury in various organ systems. The spectrum of disease extends from involvement of upper and lower respiratory tracts to life threatening renal and nervous system involvement. High index of suspicion and early diagnosis and initiation of immunosuppression therapy is crucial for minimizing the risk of morbidity and mortality.