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Glomerulonephritis in Paramedic Pharmacology Essay


Pathophysiology of Glomerulonephritis

Glomerulonephritis (GN), nephritis, or Bright’s disease is an acute inflammatory condition of the renal system that affects the glomerular capillary vessels (Couser, 2016). GN pathophysiology has an immunological basis where circulating antibody-antigen complexes, immunoglobulins (IgAs), and proteins resulting from an immune response become entrapped in the kidney glomerular tuft and peri-tubular capillary walls branching from the efferent arterioles. The trapping of these deposits induces an immune response via the classical pathway and elevated production of leucocytes and platelets, which produce proteases and cytokines (Couser, 2016). The proteases and chemical mediators produced induce inflammatory responses that cause acute glomerular tissue injury. The inflammatory response affects glomerular ultra-filtration, capillary wall permeability to red blood cells and proteins, and impaired renal salt balance (Couser, 2016). The disturbances manifest as edema, proteinuria, haematuria, and elevated blood pressure in patients.

Typically, GN appears following an allergic reaction or infectious disease. Protein components are resulting from an atopic allergy lodge in the glomerulus, triggering an immune response. It is also suggested that initial glomerular inflammation may cause the malpighian body to acquire antigenic properties and induce post-infectious GN (Wilhelmus et al., 2015). Infection-related GN follows recurrent streptococcal infections, especially β-hemolytic streptococcal pharyngeal and skin infections (Couser, 2016). Other pathogenic agents, e.g., viruses, and certain drugs (corticosteroids) also induce progressive impairment of glomerular function. Exposure to aetiologic/external agents activates the adaptive immune response via molecular mimicry or other mechanisms, resulting in the release of immune reactants that end up being entrapped in the glomerulus (Couser, 2016). Thus, infection and autoimmunity precipitate the acute lesions/inflammations underlying GN syndrome pathogenesis.

Current Pharmacological Research and Pharmacological Management of GN

Current guidelines recommend ACE/ARB inhibitors and corticosteroid agents for the pharmacological management of GN subtypes – post-infectious GN, nephritic syndrome, IgA neuropathy, and lupus nephritis. KDIGO (2012) recommends a 12-week course of corticosteroid therapy of prednisone/Prednisolone (20mg–60mg/day) for pediatric patients with steroid-sensitive GN and calcineurin inhibitor for steroid-resistant GN. In contrast, adults should receive high-dose corticosteroids (80mg-120mg/day prednisone/Prednisolone) for 4-12 weeks for steroid-sensitive GN and cyclosporine (3mg/kg/d) for the resistant form (KDIGO, 2012).

With regard to post-streptococcal GN or PSGN, symptom remission has been achieved with Eculizumab therapy in patients exhibiting steroid-resistance (Levart, Ferluga, Vizjak, Mraz, & Kojc, 2016). The drug is a recombinant monoclonal antibody that suppresses complement component 5 or C5 activity to curb the progression of glomerular inflammation (Levart et al., 2016). It targets and represses the complement system (immunity) involved in the destruction of external agents or particles. Complement proteins cause tissue/cell damage in the glomeruli, leading to GN symptoms. By inhibiting C5, Eculizamab interrupts the inflammatory processes underlying GN. Therefore, therapeutic interventions for PSGN involve complementary inhibitors to curb inflammation progression.

Other potential treatments for GN used in clinical trials include the ACE inhibitors/ARB blockers. Rauen et al. (2015) found that effective blood pressure management and proteinuria treatment with ACE and ARB agents could reduce IgA-GN symptoms. In particular, an oral corticosteroid course for a patient with “GFRs >30ml/min and proteinuria >750 mg/day” following a six-month ACE/ARB treatment can reduce GN symptom progression (Rauen et al., 2015, p. 2231). Further evidence also indicates that steroid therapy involving slow-release drugs, e.g., budesonide, can decrease proteinuria and GN symptoms (Rauen et al., 2015). The KDIGO (2012) guidelines recommend ACE/ARB therapy to manage hypertension and decrease proteinuria. Further, immune regulating agents such as hydroxychloroquine have been shown to achieve a rapid reduction in protein excretion and GFRs (<50 ml/min) (Rauen et al., 2015). Clinical trials involving drugs that induce immunosuppression show promising results.

Immunosuppressive regimens have been shown to decrease proteinuria and improve renal function, especially in acute GN cases. Zwiech (2015) evaluated the impact of immunosuppressive therapy on serum macrophage migration inhibitory factor (MIF), a biomarker of inflammation in GN. The study found that steroids-cyclophosphamide combination therapy significantly decreases MIF levels in serum and urine, an indication of symptom remission. The recommendations for corticosteroid therapy initiation entails Class II condition and protein excretion of >3g/day based on symptom severity (KDIGO, 2012). The initiation of steroid drugs is normally pulsed methyl-prednisone. Its posology involves a three-day course of 500-1000 mg/day administered alternately followed by “oral prednisone, 1mg/kg/day, stepping down to 5-10mg/day” for 12 consecutive weeks (KDIGO, 2012, p. 145). With this regimen, complete symptom remission can be achieved without the administration of immunosuppressive agents.

IV cyclophosphamide shows significant efficacy in lowering the immune response to curb GN progression and manage exacerbations in combination with corticosteroids. The most common cyclophosphamide formulation is the Euro-lupus regimen that uses “500mg of cyclophosphamide administered twice-weekly” at an initial dosage of 3.5mg six times a day (Zwiech, 2015). Subsequently, the patient is put under azathioprine maintenance therapy to avoid cyclophosphamide toxicity. However, for severe GN symptoms, a high-dose regimen of 500-1000 mg/month is recommended (KDIGO, 2012).

To develop less toxic drugs than the current generation of immunosuppressive agents, researchers have examined mycophenolate mofetil or MMF. Sundel, Solomons, Lisk, and Aspreva (2012) found that MMF has equal efficacy, but lower side effects compared to cyclophosphamide. MMF therapy was shown to prevent balding and bone marrow toxicity seen with cyclophosphamide administration (Sundel et al., 2012). In addition, low-dose MMF (2.5 mg/day) had the same efficacy (up to 60%) as cyclophosphamide in relation to curbing symptom progression. The main downside to MMF is that relapse rates are high. As a result, treatment guidelines recommend a starting regimen of corticosteroids/cyclophosphamide-based on the Euro-Lupus protocol to initiate symptom abatement before beginning an MMF course in Caucasian patients (KDIGO, 2012). In contrast, MMF shows a high efficacy as an initial treatment for mild lupus nephritis and certain populations – Blacks, Asians, and steroid-resistant patients (Mok et al., 2016). Therefore, complete symptom remission can be achieved with proper patient/drug choice for initiation and maintenance.

Another drug with similar pharmacokinetics and pharmacodynamics as MMF is Tacrolimus. The drug has been shown to have similar efficacy as MMF; however, the relapse rate is high (Mok et al., 2016). Thus, patients exhibiting MMF or cyclophosphamide resistance can be given Tacrolimus. GN treatment occurs in two stages: initiation and maintenance. Corticosteroids are the preferred treatments for maintenance to avoid symptom remission. A low maintenance dose is recommended to achieve symptom remission. The inclusion of cyclophosphamide in steroid therapy has been shown to give better outcomes compared to a steroid monotherapy (Mok et al., 2016). An initiation steroid-cyclophosphamide therapy can give reduce symptoms by 80% in patients (Walsh et al., 2012). Attempts to reduce the adverse effects of cyclophosphamide have focused on low dosages and the use of other immunosuppressive agents.

A recent clinical trial involving a comparison of Rituximab and IV cyclophosphamide initiation in patients with severe symptoms found that the former has fewer side effects but comparable efficacy to the latter (Specks et al., 2013). IV Rituximab was given at a dose of 500-1000mg, 4xweek for four weeks. The results showed improved symptom remission and lower relapse rates. As a result, Rituximab is a first-line therapy for treating relapses or mild GN cases. It is also used with patients exhibiting cyclophosphamide resistance or presenting with malignant growths. In one study, Rituximab was used as an induction therapy after a 500mg IV corticosteroid initiation therapy and maintenance achieved through MMF administration (Condon et al., 2013). The results indicated that 86% of the patients achieved full symptom remission with only 24% relapsing to lupus nephritis within 12 months. The results were comparable to those obtained with cyclophosphamide initiation therapy.

The high relapse rate is a problem in the pharmacological management of GN. Therefore, the efficacy of a drug is determined by the relapse rate after achieving complete remission. Dooley et al. (2012) follow-up study compared patients who received “steroid/cyclophosphamide therapy” with those given steroid/MMF initiation regimen (p. 1894). They established that MMF is a better maintenance drug than other immunosuppressive agents – cyclophosphamide and azathioprine – for the Caucasian patients. The study further found that the relapse rate significantly reduces when the maintenance therapy lasts for > 1 year. The KDIGO (2012) guidelines also suggest that the maintenance therapy (immunosuppressive agents) be given for over a year following full symptom remission. Therefore, an appropriate maintenance therapy with immunosuppressive drugs continued for over a year is required to achieve full recovery and prevent relapse.

Potential Relevance of the Findings to Paramedical Practice

The pathophysiological mechanisms underlying GN and the associated adverse events such as protenuria have implications for paramedical practice. The infection-related and autoimmune processes indicated in GN pathogenesis may manifest as acute GN symptoms requiring appropriate corticosteroid posologies for induction or emergency interventions for elevated blood pressure or abnormal protenuria (>1g/day). In addition, understanding the clinical parameters for diagnosis/prognosis is crucial in addressing the adverse events that may precipitate renal failure. An emergency therapy with ACE/ARB blockers can help in hypertension and proteinuria control in most patients (KDIGO, 2012). The aim is to achieve complement system inhibition to stop the inflammation progression before the cyclophosphamide maintenance therapy.

For patients presenting to the ED with severe GN symptoms, pharmacological research evidence shows that steroid induction therapy can achieve full symptom remission and prevent relapse. A high-dose three-day course of pulse prednisone (500-1000 mg/daily) offered in alternating days and a subsequent oral prednisone stepped down from 5mg to 10mg/day can attain complete/partial symptom remission (Wilhelmus et al., 2015).

Other pharmacological agents relevant to paramedic practice are the immunosuppressive drugs. GN is an immune-related disorder. Immunosuppressive agents, such as mycophenolate mofetil, cyclophosphamide, Eculizamab, and azathioprine, can help stop the inflammation progression by inhibiting the complements that induce acute inflammatory responses. However, their efficacy differs depending on genetics and symptom severity, among others. Therefore, appropriate patient or drug selection is required to achieve optimal patient outcomes and safety. An assessment of the patient’s response, toxicity levels, and symptom severity during the induction therapy would help achieve better long-term treatment outcomes. Supportive care at the ED should include effective blood pressure and protenuria control to reduce the comorbidity associated with GN. In addition, for GN whose aetiology is linked to infectious agents, antibiotic administration can help treat the underlying pathological causes.

References

Condon, M., Ashby, D., Pepper, R., Cook, H., Levy, J., Griffith, M.,… Lightstone, L.

(2013). Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Annals of Rheumatic Disease, 72, 1280-1286. Web.

Couser, W. (2016). Pathogenesis and treatment of glomerulonephritis: An update. The Jornal Brasileiro de Nefrologia, 38(1), 107-122. Web.

Dooley, M., Jayne, D., Ginzler, E., Isenberg, D., Olsen, N., Wofsy, D.,… Solomons, N. (2012). Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. New England Journal of Medicine, 365, 1886-1895. Web.

Kidney Disease: Improving Global Outcomes [KDIGO]. (2012). KDIGO clinical practice guideline for glomerulonephritis. Kidney International Supplements, 2, 139-274. Web.

Levart, T., Ferluga, D., Vizjak, A., Mraz, J., & Kojc, N. (2016). Severe active C3 glomerulonephritis triggered by immune complexes and inactivated after eculizumab therapy. Diagnostic Pathology, 11, 94-102. Web.

Mok, C., Ying, K., Yim, C., Siu, Y., Tong, K., To, C. & Nq, W. (2016). Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: A randomised controlled trial and long-term follow-up. Annals of Rheumatic Diseases, 75(1), 30-36. Web.

Rauen, T., Eitner, F., Fitzner, C., Sommerer, C., Zeier, M., Otte, B.,…Floege, J. (2015). Intensive supportive care plus immunosuppression in IgA nephropathy. New England Journal of Medicine, 373, 2225-36. Web.

Specks, U., Merkel, P., Seo, P., Spiera, R., Langford, C., Hoffman, G.,…Stone, J. (2013). Efficacy of remission-induction regimens for ANCA-associated vasculitis. New England Journal of Medicine, 369, 417-27. Web.

Sundel, R., Solomons, N., Lisk, L., & Aspreva, L. (2012). Efficacy of mycophenolate mofetil in adolescent patients with lupus nephritis: Evidence from a two-phase, prospective randomized trial. Lupus, 21, 1433-43. Web.

Walsh, M., Flossmann, O., Berden, A., Westman, K., Hoglund, P., Steeman, C., & Jayn, D. (2012). Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis & Rheumatology, 64, 542-548. Web.

Wilhelmus, S., Bajema, I., Bertsias, G., Boumpas, D., Gordon, C., Lightstone, L.,…Jayn, D. (2015). Lupus nephritis management guidelines compared. Nephrology, Dialysis, Transplantation, 31(6), 904-913. Web.

Zwiech, R. (2015). Macrophage migration inhibitory factor urinary excretion revisited –MIF a potent predictor of the immunosuppressive treatment outcomes in patients with proliferative primary glomerulonephritis. BMC Immunology, 16(1), 1-9. Web.

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