Chapter Outline
THE GLOBAL IMPACT AND CHALLENGES, 1161
OUTCOME MEASURES AND CLINICAL TRIALS IN GLOMERULONEPHRITIS, 1163
QUANTIFICATION OF THE BENEFITS OF PROTEINURIA REDUCTION, 1163
Membranous Glomerulonephritis, 1164
Focal Segmental Glomerulosclerosis, 1164
Immunoglobulin A Nephropathy, 1164
Remission in Lupus Nephritis and Vasculitis, 1165
INDIVIDUALIZING THERAPY: MECHANISM OF ACTION AND TOXICITIES OF THERAPY, 1166
Corticosteroids, 1166
Calcineurin Inhibitors, 1167
Alkylating Agents, 1168
Azathioprine, 1170
Mycophenolate Mofetil, 1170
Rituximab and Ocrelizumab, 1171
Eculizumab, 1171
Adrenocorticotropic Hormone, 1171
Treatment Algorithms and Considerations, 1172
CONCLUSION, 1173
The Global Impact and Challenges
The societal burden of glomerulonephritis (GN) to both the individual and the health care system is grossly underappreciated and the costs underestimated due to the lack of national or international registries of GN at the level of renal pathologic processes. The full disease impact is also substantially discounted if assessed solely from figures derived from end-stage kidney disease (ESKD) registries, as GN is not only a common cause of ESKD that can affect patients at any age, but also treatment strategies for the disease are chronic and not without significant morbidity and mortality even in patients who never reach ESKD.
With respect to ESKD, there are significant global variations in the percentage of incident and prevalent patients secondary to GN. According to the United States Renal Data System, GN accounts for approximately 30% of the cases receiving pre-ESKD care and 10% to 20% of incident patients undergoing dialysis. Very similar data have been reported from the Canadian Organ Replacement Registry, wherein GN accounted for 11% of ESKD cases, ranking second among identifiable causes behind diabetes. In the countries belonging to the European Renal Association–European Dialysis and Transplant Association ESKD Registry, significant variations are noted with much higher GN incidence rates in Eastern European countries, ranging from 8.6% in Denmark to 19.6% in Romania, wherein GN is the most common identifiable cause of ESKD. In the past, GN had dominated causation of ESKD in the Australia and New Zealand Registry, but current reports suggest the same trends as those observed in North American databases, wherein GN is now behind diabetes as a cause of ESKD (27% versus 30%, respectively). In registries from Pacific Asian regions, however, GN continues to account for the majority of cases of incident ESKD. These differences have been attributed to various factors, including genetic background as well as environmental and infectious exposures, but additional factors such as differences in health care policies and disparities in access to ESKD programs may also exist. In contrast to data describing incident ESKD populations, GN dominates as the cause of ESKD among prevalent patients on renal replacement therapy or with a functioning renal transplant, but these numbers are likely to be biased, reflecting the younger age on average as well as the enhanced survival of the patient population with GN compared to patients with diabetes. Regardless, the full burden of GN as an incident or prevalent cause of ESKD remains underestimated in ESKD registries due to the high likelihood that cases of ESKD categorized as “hypertensive nephrosclerosis” or “unknown” may very likely also represent undiagnosed GN given the often-asymptomatic course in many patients.
As a significant number of patients will live with GN for many years before they ultimately progress to dialysis or will die before reaching that stage, an estimate of the global extent of these diseases may therefore be better approximated by imputing incidence rates from countrywide registries of renal pathologic conditions. Further, these broadly inclusive local registries based on pathologic processes that capture all biopsies performed in a large and defined geographic region can provide important insights regarding potential shifts in the distribution of histologic subtypes of GN. Such a registry from Finland, for example, reported an incidence of GN that ranged from 8.7 to 25.4 per 100,000 population in the central hospitals and the university center, respectively, which was remarkably higher than the rates reported by European biopsy registries (between 1 and 6.9). Such variations are seen throughout the world, undoubtedly biased by biopsy practice patterns. However, if one were to assume an average crude incidence of GN to be between 100 and 200 per million population, this would indicate an annual incident rate of GN in North America (population 400 million) of between 40,000 and 80,000 cases.
Data from our own linked clinical and pathology regional registry that have captured GN cases from the greater Toronto area since 1975 have noted that the annual absolute number of biopsy-proven cases of GN has not substantially changed, but shifts within the specific histologic groups have occurred ( Table 34.1 ). There has been a 2- to 3-fold increase in immunoglobulin A (IgA) nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS), a 2-fold reduction in idiopathic membranoproliferative GN (MPGN), and virtually no change in the incidence of membranous glomerulonephritis (MGN) over the past 3 decades. Although similar shifts over time have been reported from other large North American centers, it is not entirely clear if this represents true changes in incidence patterns, variations in biopsy practice patterns or reporting, and/or changes to the ethnic composition of the study population through immigration. Geographic and ethnic variation clearly influences diagnostic patterns. In a large retrospective review of 600 biopsies from China, IgAN accounted for 40% of all diagnoses and was three times more common than FSGS and 30 times more common than membranous nephropathy. The recognition of “new” treatable causative factors, such as hepatitis C virus producing the injury pattern of MPGN, is another possible explanation for variation and changes in histologic subtypes. Still, changes in histologic subtypes of GN, if real, may reflect fundamental shifts in biologic and environmental factors underlying the pathogenesis of these diseases and is another substantive reason for the creation of national and international GN registries.
| 1975-79 | 1980-84 | 1985-90 | 1990-94 | 1995-99 | 2000-04 | Total | |
|---|---|---|---|---|---|---|---|
| IgA | 129 | 215 | 227 | 262 | 309 | 356 | 1498 |
| FSGS | 141 | 164 | 163 | 239 | 311 | 271 | 1289 |
| Membranous | 134 | 172 | 171 | 164 | 129 | 143 | 913 |
| MPGN | 90 | 67 | 33 | 46 | 37 | 31 | 304 |
| Lupus | 170 | 191 | 143 | 174 | 136 | 100 | 914 |
| Vasculitis | 29 | 66 | 76 | 93 | 76 | 68 | 408 |
| Total | 693 | 875 | 813 | 978 | 998 | 969 | 5326 |
These crude estimates of the population incidence of GN are not informative with respect to describing the natural history of these disorders over the critical period between biopsy and registration as an ESKD statistic. Despite this limitation, during the past decade there have been important changes in our approach to the treatment of patients with GN driven by prospectively collected natural history data and therapeutic studies. There has also been an important shift in the treatment of GN to a more evidence-based approach with the publication of a new set of evidence-based recommendations for management of patients with GN developed under the auspices of Kidney Disease: Improving Global Outcomes (KDIGO). Although this endeavor will assist with the standardization of practice, the paucity of high quality (level 1) evidence remains a significant obstacle in the treatment of glomerular disease.
The randomized controlled trial remains the gold standard for the assessment of therapeutic efficacy, but there are important limitations to both the interpretation and execution of such studies in patients with GN. Even the currently available clinical trials have limitations in regard to their generalizability, with existing trials excluding many patients such as those with atypical presentations and comorbid conditions, and often represent a skewed ethnic composition given that most are small single-center experiences. Furthermore, major changes in nonspecific treatment (such as introduction of inhibitors of the renin angiotensin aldosterone system for blood pressure control) and in our understanding of the pathogenesis of these diseases (such as the recognition of the causal link between MPGN and hepatitis C), have reduced the external validity of previously completed trials even though they may have been well-designed, randomized controlled studies. Larger randomized controlled trials in GN are not appealing to funding agencies (either in the private or public sector), as the target population is relatively small and the cost of such studies is high. Part of the financial burden relates to the size and duration of studies required to demonstrate “clinical benefit” in patients with GN. A major disincentive for the development of such studies is a lack of consensus regarding the clinical relevance of surrogate outcome measures. In general, only “hard outcomes” such as patient and/or renal survival are acceptable to granting agencies, government policy regulators, and the pharmaceutical industry. Since the great majority of patients with GN, regardless of the specific subtype, will have slowly progressive disease, this limits the capacity to organize, fund, or even properly interpret clinical trials.
Assessment and follow-up of large cohorts of patients with GN during the trajectory of their chronic kidney disease though has yielded new and important information that has influenced patient management and altered how we assess treatment benefit. These efforts have allowed a more accurate identification of modifiable predictors of clinical outcome, thus allowing physicians to alter the course of the patient’s disease. Although renal and patient survival remains the gold standard of benefit in the treatment of GN, surrogate markers of these end points have emerged during the past decade, and a significant contribution to this domain of practice has been a better understanding of the importance of proteinuria on renal injury and the recognition that its reduction has a substantial impact on both the rate of progression of kidney disease and ultimately on renal survival. It is generally accepted that complete remission of proteinuria does lead to significant improvement in quality of life (e.g., improvement of edema), as well as in renal survival. A quantitative assessment of the value of proteinuria reduction is also emerging and will be a crucial element in the decision making of nephrologists in terms of balancing the risks and benefits of treatment. However, the quantitative impact of a partial remission in proteinuria, including its definition and duration on renal survival, requires further clarification before its universal acceptance as a surrogate indicator of long-term survival.
A series of publications on the most common primary and secondary progressive GNs has provided a more comprehensive framework focused on a more uniform definition and an improved estimate of the benefits of achieving a partial remission of proteinuria. This body of literature is described later. This should provide practicing nephrologists with a critical piece of information to assist them in both their therapeutic decisions and patient counseling. The capacity to translate proteinuria reduction into a semiquantifiable estimate of improvement in long-term outcome provides an important element of the benefit in the risk/benefit equation, not only in terms of whether to initiate treatment, but more commonly today to provide help in the decision about prolonging treatment or retreating a patient to maintain or reestablish a partial remission.
Outcome Measures and Clinical Trials in Glomerulonephritis
During the past decade there have been important changes in our approach to the treatment of patients with GN driven by prospectively collected natural history data, therapeutic studies, and the evolution toward a more evidence-based approach to clinical care. Central to this process is the identification of surrogate outcomes of kidney disease progression that indicate risk for kidney failure and morbidity attributable to kidney disease. This process is not only critical for design of clinical trials and regulatory drug approval processes, but also essential for defining treatment goals for patients.
A significant contribution to this domain of practice has been a better understanding of the importance of proteinuria in renal injury and the recognition that its reduction has a substantial impact on both the rate of progression of kidney disease and ultimately on renal survival. Although this has significantly improved our capacity to assess the benefits of treatment, our evaluation of risks of therapy requires further refinement. Furthermore, while complete remission of proteinuria is accepted as a surrogate marker of favorable patient and kidney outcome in patients with GN, the relationship between partial remission of proteinuria in GN and reduction of kidney failure and mortality appears to be highly clinically relevant but requires further validation and refinement.
The shift in the treatment of GN to a more evidence-based approach is supported by the publication of clinical practice guidelines to help the nephrologist in the management of patients with these disorders. While the randomized controlled trial remains the gold standard for the assessment of therapeutic efficacy, there are important limitations to both the execution and interpretation of such studies in patients with GN. Randomized controlled trials in GN are not appealing to funding agencies (either in the private or public sector), as the target population is relatively small and the diseases are most often slowly progressive, requiring longer observation periods to reach hard end points such as kidney failure, and therefore the cost of such studies is high. The lack of consensus regarding the clinical relevance of surrogate outcome measures limits design and feasibility of randomized controlled studies in GN.
The currently available clinical trials have limitations in regard to their generalizability. To design statistically and financially viable studies, investigators must select a relatively homogeneous population to ensure that the required sample size is achievable and that the study can be completed within an acceptable time frame. A homogeneous population, by definition, excludes many patients, such as those with atypical presentations and comorbid conditions, and often represents a skewed ethnic composition due to language fluency requirements for participation. Furthermore, major changes in nonspecific treatment (such as introduction of inhibitors of the renin angiotensin aldosterone system for blood pressure control) and in our understanding of the pathogenesis of these diseases (e.g., the causal link between MPGN and hepatitis C) have reduced the external validity of previously completed trials, even though they may have been well-designed, randomized controlled studies.
Quantification of the Benefits of Proteinuria Reduction
Renal and patient survival remain the gold standard of measurement of benefit in the treatment of GN; however, few clinical trials in GN consider these definitive end points directly. The rare nature and relatively slow rate of progression of these diseases make the identification of surrogate end points of hard outcomes a necessity. A series of publications has focused on estimating the benefits of achieving a partial remission of proteinuria. This provides nephrologists with a critical piece of information to assist them in both their therapeutic decisions and patient counseling. The capacity to translate proteinuria reduction into a semiquantifiable estimate of improvement in long-term outcome remains a challenge; however, these studies suggest strongly that proteinuria should inform decisions regarding initiation and duration of immunosuppressive treatment.
Membranous Glomerulonephritis
Natural history studies in MGN have demonstrated the value of complete remission of proteinuria and the unfavorable outcome in patients with persistent high-grade proteinuria. Although a variety of definitions of partial remission have been applied to membranous nephropathy over the past 25 years, the great majority of studies required reduction to subnephrotic-range proteinuria (<3.5 g/day). A study of a prospective cohort of 348 nephrotic patients with MGN assessed the benefit of a complete or partial remission of proteinuria on both renal survival and rate of progression. Partial remission required both a reduction to less than 3.5 g/day and a 50% decrease from peak proteinuria. Over a median follow-up of 60 months, 30% of patients had a complete remission, 40% had a partial remission, and the remaining 30% had no remission. At 10 years, renal survival in those with a complete remission was 100% with little disease progression over the same time frame as measured by the slope of the creatinine clearance (−1 mL/min/yr). Those achieving a partial remission had a 90% renal survival at 10 years and a more rapid rate of progression compared to those with complete remission, although still limited to a loss of −2 mL/min/yr of creatinine clearance. In comparison, those with no remission had a renal survival of only 50% at 10 years and a very significant increase in progression rate that was five times the rate seen in the partial remission group (−10 mL/min/yr). Achieving a partial remission was an independent predictor both of renal survival and rate of progression. Kidney survival from renal failure for partial remission was significantly improved (hazard ratio [HR] for ESKD compared to the reference group of no remission, 0.08; 95% confidence interval [CI], 0.03 to 0.19; P < 0.001). In addition, the value of a partial remission was also analyzed using time-dependent variables to ensure attribution of any benefit on survival to the time after partial remission has been achieved. Indeed the adjusted hazard ratio for the risk for ESKD in patients achieving a partial remission (expressed as a time-dependent variable) was 0.17 in comparison to those not achieving a remission of proteinuria (95% CI, 0.09 to 0.33; P < 0.001). Additional important information gleaned from the study included the observation that treatment-induced partial remissions had the same favorable long-term outcome as those acquired spontaneously, and although the rate of relapse was high (47%), the relapses were often reversible with repeat treatment. These data strongly support the contention that partial remission is an important therapeutic target in patients with membranous GN with measurable and clinically relevant benefits for both progression rate and renal survival. This study did not identify the intervention required for achievement of partial remission of proteinuria; partial remission of proteinuria is also associated with favorable outcome when achieved spontaneously. Nonetheless, the findings allow a better assessment of treatment benefits by attributing a quantitative value to partial remission. This in turn facilitates the assessment of the balance between benefits and risk of treatment of patients with MGN.
Focal Segmental Glomerulosclerosis
The same estimates of benefit of proteinuria reduction in regard to the long-term outcome are available for patients with FSGS. It has been appreciated for some time that complete remission of proteinuria is the best predictor of favorable renal survival. However, a standardized definition of partial remission and an assessment of its benefit would improve the physician’s ability to balance the benefits of intense immunosuppressive treatment versus the well-recognized risks of the current available treatment regimens for FSGS. Factors that have been previously associated with a poor outcome in FSGS have included the severity of initial proteinuria, the initial creatinine clearance, and the extent of tubulointerstitial disease on histologic examination. Histologic variant is an important consideration; however, reduction of proteinuria is likely an independent determinant of outcome.
The impact of proteinuria reduction on disease course was addressed in a long-term cohort study of 281 nephrotic patients with biopsy-proven primary FSGS followed over an average of 65 months. A partial remission, defined by both a reduction of proteinuria to subnephrotic range (<3.5 g/day) and a 50% reduction from peak proteinuria, provided the best discrimination among the patients in terms of both renal survival and progression rate. During the observation period 55 patients had a complete remission, 117 patients achieved a partial remission, and 109 had no remission of proteinuria. Partial remission was independently predictive of both renal survival and rate of decline in renal function by multivariate analysis and was associated with more favorable outcome even in the context of a future disease relapse. Partial remission was associated with improved renal survival with a time-adjusted hazard ratio of 0.48 (95% CI, 0.24 to 0.96; P = 0.04). Ten-year renal survival was 75% in the partial remission group compared to 35% in those with no remission. Similar to MGN, this information on the quantitative benefits of partial remission is important in the assessment of the FSGS patient because it provides equipoise to the risks of treatment.
Immunoglobulin a Nephropathy
The importance of proteinuria in IgAN has been long recognized, but its relative value compared to FSGS and membranous nephropathy is quite distinct. There are important quantitative differences in the impact of proteinuria in patients with IgAN compared with those with FSGS and MGN. Proteinuria, at far lower levels compared to MGN and FSGS, is tightly correlated with renal outcome.
Treatment studies and observational data support the importance of proteinuria reduction in mitigating risk for progressive disease in IgAN. Analyzing patients with IgAN enrolled in a series of randomized controlled trials of fish oils, Donadio and associates demonstrated an association between proteinuria reduction and both improved renal survival and prolonged time to doubling of serum creatinine clearance. A study of a prospectively enrolled cohort of more than 500 patients with primary IgAN followed for an average of 78 months evaluated the clinical relevance of achieving a partial remission of proteinuria to less than 1 g/day. In the almost 200 patients who achieved and sustained partial remission of proteinuria (either spontaneously or through treatment), the mean rate of decline in renal function was only 10% of the rate in those who did not. Furthermore, regardless of the level of presenting proteinuria, those who attained a partial remission had the same long-term prognosis and slow rate of disease progression as those subjects whose peak proteinuria never exceeded 1 g/day. Although there were other modifiable factors identified in the multivariate analysis associated with kidney function decline (time-averaged mean arterial pressure and exposure to agents that blocked the renin angiotensin aldosterone system), the level of sustained proteinuria was the dominant modifiable risk. The differential in both progression rate and renal failure risk was dramatic, and understanding the impact of even a small but sustained improvement in proteinuria is extremely valuable information for the practicing physician. Occasionally IgAN presents with the nephrotic syndrome and preserved renal function. In this subset of patients, partial or complete remission of the nephrotic syndrome is also associated with a favorable outcome.
Proteinuria has strong links to cardiovascular mortality in patients without GN. A longitudinal study of nearly 1400 patients with IgAN followed in Korea suggested that this disease—particularly when associated with proteinuria of less than 1 g/day—may be associated with a higher standardized mortality rate. The potential independent benefit of proteinuria reduction on mortality certainly merits further study.
Remission in Lupus Nephritis and Vasculitis
Similar to the primary progressive variants of GN, complete absence of active renal disease has been associated with excellent long-term renal survival in systemic lupus erythematosus (SLE), although even this status does not guarantee freedom from ever developing chronic kidney disease. Quantitation of the effect of partial remission of proteinuria on long-term outcome has been estimated in a long-term observational study of 86 patients with biopsy-proven diffuse proliferative lupus nephritis followed for a decade. The authors defined complete remission as absence of significant proteinuria and a serum creatinine of less than 1.4 mg/dL and a partial remission as a 50% reduction in baseline proteinuria with a nadir in proteinuria of less than 1.5 g/day and no more than a 25% rise in baseline serum creatinine clearance. Patient and renal survival were strongly influenced by whether the patient achieved a complete remission, partial remission, or no remission in proteinuria. At 10 years the patient survival and renal survival in subjects achieving a complete remission were 95% and 94%, respectively; in those reaching a partial remission, they were 76% and 45%; and, in those who never met criteria for a partial or complete remission, they were only 46% and 13%. The clinical value of a reduction in proteinuria in terms of amelioration of long-term outcome was confirmed in a 10-year follow-up of a clinical trial comparing immunosuppressive regimens and in pediatric and adolescent patients with SLE.
Studies have indicated that long-term evaluation of proteinuria reduction and remission statistics is important for purposes of prognostication. At 6 months of evaluation, less than half of patients with severe lupus nephritis enrolled in therapeutic trials will have reached a complete remission. A review of long-term outcomes of patients with severe lupus nephritis treated in a prior randomized controlled study indicated that halving of proteinuria at 6 months was an important predictor of both long-term renal and patient survival. The finding of an association between polymorphic kidney disease risk variants at the apolipoprotein 1 gene ( APOL1 ) and more rapid progression to ESKD in sub-Saharan African ancestry populations may lead to genetically guided individualization of therapies, and certainly future clinical studies that include populations of African ancestry will need to take this variable into account.
Rapid deterioration in renal function is a severe and relatively common manifestation of vasculitis, a systemic disorder that commonly terminates in ESKD or death of the patient without appropriate therapy. The rapidity of kidney disease progression and the significant risk for either disease-associated or drug-related mortality distinguish vasculitis from the previously described primary GNs. The significant benefits in terms of both kidney and patient survival with treatment compared to no treatment is countered by the current potent drug regimens required that have their own significant life-threatening consequences; significant adverse effects are described in up to 90% of treated patients. This confluence of severe disease and toxic therapy is aggravated by the more advanced average age at presentation of vasculitis compared to other types of GN. This further emphasizes the importance of accurate and early assessment of the predictive markers of outcome for both patient and renal survival. The need for considering both risk and benefits was demonstrated in a review of 100 patients with vasculitis, whose presenting creatinine clearance was above 500 µmol/L (5.6 mg/dL). Fifty-five percent of the deaths were attributed to the adverse effects of treatment, almost exclusively related to opportunistic infections, including Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia and cytomegalovirus infections. In contrast, only 25% of the deaths were attributed to active uncontrolled vasculitic disease, with the remaining 25% related to the underlying advanced age and/or comorbid conditions of the patients. The authors determined that in patients presenting with vasculitis and severe renal failure, predictors of the need for permanent renal replacement therapy were limited. The only indicators identified were age at onset of the disease and pathologic process, the degree of arteriosclerosis, and the proportion of segmental crescents and/or eosinophilic infiltrates. No clinical parameters were independently predictive of death. Even within these limited predictive indices, the variation was wide and the sensitivity low.
In a prospective study in patients with mild to moderate renal involvement at presentation (i.e., serum creatinine concentration <500 µmol/L), the authors noted that the level of renal function at onset and renal pathologic lesions suggestive of chronicity were indicators of a poor prognosis. In contrast, the presence of active lesions such as crescents and necrosis was the only indicator that predicted a treatment response and improved renal outcome at 18 months. A semiquantitative assessment of prognosis based on any one individual factor or a combination of them was not performed, likely related to the acuity of the condition and the wide deviations in these predictive indices. A systematic review of studies in vasculitis, including patients with minimal renal involvement, identified similar predictors of outcome in regard to remission, relapse, and renal and overall patient survival.
Against this background, a heightened awareness of the risks of our current therapies needs to be considered in every patient by the practicing nephrologist. The real dangers associated with these therapies mandate repeated reviews of the patient, including a critical analysis of the response likelihood versus the accumulating risks of ongoing therapy. This assessment should include the possibility of a repeat renal biopsy to assess activity versus irreversible chronic damage. In addition, when evaluating potential benefit of immunosuppressive therapy, improvement in organ and patient survival should still be paramount, but the integration of the benefits of proteinuria reduction and improved quality of life should now also be counted. Often not considered in this balance of risks and benefits of treatment is the risk of inadequate treatment of the GN, forgetting that renal replacement modalities (i.e., dialysis or transplantation) have their own attendant high rate of morbidity and mortality.
Individualizing Therapy: Mechanism of Action and Toxicities of Therapy
With every one of the immunosuppressive agents used in the treatment of GN, the risks of treatment versus potential benefits must be assessed on the basis of drug exposure (a composite of dose and duration) and individual patient factors, including gender, age, and comorbid conditions such as obesity, diabetes mellitus, and cardiac disease. Further, there is not universal availability of many of the newer drugs and biologic agents due to the paucity of controlled data and the high costs of many of these agents. Thus careful attention must be paid to potential side effects from the therapeutic choices made by practicing clinicians with side effect profiles often dominating the choice of therapy.
Corticosteroids
Glucocorticoids are the most common antiinflammatory and immunosuppressive drugs used in the treatment of both primary and secondary GN. They have protean effects on immune responses mediated by T and B cells, including reversibly blocking T cell and antigen-presenting cell–derived cytokine and cytokine-receptor expression. Their hydrophobic structure permits them to easily diffuse into cells and bind to specific cytoplasmic proteins, facilitating translocation of these proteins into the cell nucleus, where they bind to a highly conserved glucocorticoid receptor DNA-binding domain (the glucocorticoid response element) and modulate gene transcription. Some of the downstream effects accounting for the antiinflammatory activity of glucocorticoids include the inhibition of synthesis of proinflammatory cytokines implicated in glomerular and tubulointerstitial injury, such as interleukin-2, interleukin-6, interleukin-8, and tumor necrosis factor. Glucocorticoids also exert a host of nontranscriptional immunomodulatory effects on immune effector cells, including alteration of leukocyte trafficking and chemotactic properties and modulation of endothelial function, vasodilation, and vascular permeability. Evidence suggests a potential role in modulating production of putative leukocyte-derived permeability factors that contribute to proteinuria.
Major Adverse Effects
Infection is a potential risk common to all immunosuppressant medications. Pronounced suppression of cell-mediated immunity results from the protean effects of corticosteroids on the immune system. Glucocorticoid exposure poses a significant short- and long-term risk for infection, particularly in older patients. A nested case-control analysis indicated a rate of serious infection as high as 46% with 6 months of continuous use of greater than 5 mg/day in patients with rheumatoid arthritis. In addition to the potential to cause infection, glucocorticoids have widespread systemic side effects, including, but not limited to, impaired glucose tolerance, cardiovascular and gastrointestinal toxicity, and potentially severe musculoskeletal damage, as well as a large array of cosmetic, ophthalmologic, and psychiatric side effects.
Glucocorticoids affect glucose metabolism by increasing hepatic gluconeogenesis and decreasing peripheral tissue insulin sensitivity. These changes in glucose homeostasis may be ameliorated by dose reduction. However, the metabolic effects of these drugs may not be completely reversible, even when the dose is reduced to physiologic range or discontinued entirely. While higher doses of glucocorticoids are associated with a higher risk for hyperglycemia, additional risk factors for steroid-induced hyperglycemia include African American and Hispanic ancestry, obesity (defined as a body mass index > 30 kg/m 2 ), older age, a family history of diabetes, and the presence of other components of the metabolic syndrome.
Given the elevated risk for cardiovascular disease in patients with kidney disease, the added cardiovascular toxicity of glucocorticoids is also an important consideration. A large cohort study of 68,781 glucocorticoid users demonstrated that high-dose steroids are independently associated with cardiovascular events after adjustment for other traditional risk factors, including hypertension, glucose intolerance, and obesity. Gastrointestinal effects of glucocorticoids include induction of gastritis and gastrointestinal bleeding.
Glucocorticoids have important musculoskeletal effects. Muscle injury associated with chronic steroid treatment with glucocorticoid produces a pattern of proximal weakness, atrophy, and myalgia. The ideal management includes discontinuation of steroid administration, although recovery can take weeks or months. Steroid myopathy is more common when the patient has been exposed to the potent fluorinated steroids (dexamethasone, betamethasone, triamcinolone), but similar patterns of muscle injury have been described with the nonfluorinated steroids such as prednisone. Osteopenia is commonly seen in patients with chronic steroid exposure. A retrospective study of a quarter of a million oral corticosteroid users over 18 years of age suggested relative rate of nonvertebral fracture during oral corticosteroid treatment increased even at doses as low as 2.5 to 7.5 mg/day. Fracture risk rapidly declined toward baseline after stopping treatment. The European League Against Rheumatism released recommendations regarding chronic prednisone dosing and avoidance of loss of bone density. Avascular necrosis is a different type of bone injury. It is a devastating condition associated with destruction of the head of the femur or other long bones. The relationship between development of avascular necrosis and dose of prednisone is less clear.
Vision may be affected by cataract formation and increased intraocular pressure. Thinning of the skin, easy bruising, development of striae, and impaired wound healing may also be potentiated by glucocorticoids. Mood lability and insomnia induced by glucocorticoids also contribute to their relatively poor patient tolerance.
Strategies for Reducing Toxicity
There are several strategies available for minimizing steroid exposure. In minimal change disease and some cases of FSGS, for instance, alternate-day prednisone therapy may be considered in lieu of daily regimens. This alternate-day approach is, however, not supported with evidence suggesting equal efficacy in adults with the nephrotic syndrome. An alternate strategy is shortening the course and/or a more rapid taper of the prednisone, and this approach is currently being investigated in the context of vasculitis (Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody (ANCA)–Associated Vasculitis [PEXIVAS] study, www.clinicaltrials.gov ). More commonly, a second nonglucocorticoid immunosuppressive agent is introduced for its “steroid-sparing” potential. The introduction of these agents has allowed the total exposure to corticosteroids in many of these disorders to be limited by allowing a shorter initial total exposure to the drug.
Alternate strategies specifically focus on reducing or preventing the complications related to corticosteroid treatment. Such prophylactic strategies include the use of antibiotics such as trimethoprim-sulfamethoxazole to prevent P. jirovecii pneumonia. Retrospective studies indicate that a corticosteroid dose equivalent to 16 mg of prednisone for a period of 8 weeks was associated with a significant risk for pneumocystis pneumonia. Ongoing surveillance for diabetes is required along with regular eye examinations. Antihypertensive regimens may require adjustment while on high-dose therapy, and gastric protection in the form of a proton pump inhibitor should be prescribed. In relationship to the risk for fracture, if daily corticosteroids (0.5 to 1 mg/kg) are expected to be used in excess of 8 to 12 weeks in adults, consideration should be given to adding vitamin D 1000 U/day and 1 g/day of calcium, or consider the addition of bisphosphonate therapy while on the steroids. Other high-risk indicators for fractures should also trigger preventive treatment such as previously documented osteoporosis, advanced age, or likelihood of inactivity/immobility during the use of steroids. Bisphosphonates may have more potent effects to prevent reduction in bone density during corticosteroid use; however, it is important to note that bisphosphonates remain in mineralized bone for months to years, posing a theoretical risk for teratogenicity when administered to women of childbearing potential.
Calcineurin Inhibitors
Cyclosporine and tacrolimus are calcineurin inhibitors (CNIs) that suppress the immune response by downregulating T cell activation. They specifically block calcium-dependent T cell receptor signaling transduction, thereby inhibiting the transcription of interleukin-2, as well as other proinflammatory cytokines, in both T cells and antigen-presenting cells. Interleukin-2 serves as the major activation factor for T cells and a key modulator of both T and B cell activity in numerous immunologic processes. Tacrolimus and cyclosporine have a common mechanism of action (i.e., inhibition of calcineurin phosphatase), though they bind different intracellular proteins. These intracellular proteins belong to the immunophilin family with cyclosporine binding cyclophilin and tacrolimus binding FKBP12. The role of differential immunophilin binding in the mechanism of toxicity is not clear, but it may allow for the unique side effect profile of each of these drugs. An alternative mechanism of action of these agents has been suggested relating to their capacity to stabilize the internal cytoskeletal structure of the glomerular podocyte. This is an intriguing possibility and may help explain the efficacy of CNI therapy in some of the glomerular-based diseases at lower drug levels compared to those required in solid organ transplantation.
Major Adverse Effects
The CNI agents have significant adverse effects with the most concerning being their nephrotoxicity. This is particularly relevant when prolonged therapy is being contemplated. These longer treatment courses are usually given to prevent or modify the well-recognized risk for relapse of nephrotic syndrome that does occur upon treatment withdrawal. CNI-associated nephrotoxicity can be severe, and reports indicate a significant risk for chronic kidney disease if the drug is given in high doses for prolonged periods, such as occurred in early recipients of nonrenal solid organ transplants. However, the cyclosporine dose and duration used in these studies are no longer considered appropriate, and lower doses in the glomerular-based diseases versus solid organ transplantation are currently advocated. In addition, modifications have occurred in drug formulation of cyclosporine, which have resulted in more consistent and predictable pharmacokinetics, allowing at least potentially even lower drug exposure regimens.
New-onset or worsening of hypertension is another important and common dose-dependent adverse effect of CNI use and likely contributes to their long-term nephrotoxic potential. The reported incidence of hypertension in patients with glomerular diseases treated with CNIs varies from 10% to 30%. An additional significant adverse effect is the induction of glucose intolerance and even overt diabetes. This seems to be specific to CNIs and is somewhat more common with tacrolimus. The transplantation literature highlights the potential contributions of CNIs to development of hyperglycemia, which is thought to be a result of both impaired insulin secretion and increased insulin resistance. The higher rate of hyperglycemia associated with tacrolimus use may reflect differential effects on pancreatic β-cell insulin transcription and release. Even when CNIs are used as monotherapy, the risk for new-onset diabetes has been reported to be as high as 4%.
As with all immunosuppressive agents, CNIs affect immune surveillance and are associated with an increased rate of infections and malignancy. The incidence of malignancy induced by CNIs in the glomerular diseases is very hard to determine from the literature. Very few of the GN treatment studies have been long enough to assess CNI exposure as an independent risk factor. Cyclosporine, however, has been used in the long-term management of other autoimmune diseases, including rheumatoid arthritis and psoriasis. When patients with rheumatoid arthritis treated with cyclosporine were compared to control patients (who received placebo, d -penicillamine, or chloroquine), an increased cancer risk was not seen. A review of patients with psoriasis did find an increase in the standardized incidence ratio of cancer in patients treated with cyclosporine compared to the general population. However, when examined more closely and skin malignancies, known to be more common in patients with psoriasis, were excluded, the incidence was not significantly higher in the CNI-treated patients. As such, though not well described, the incidence of drug-associated malignancy specifically in the context of GN therapy is considered to be relatively low. The underlying risks for infection associated with untreated nephrotic syndrome and the potential for malignancy associated with membranous nephropathy further complicate the assessment of risk for these complications with CNI treatment.
Other common adverse effects of CNIs are cosmetic and include gum hypertrophy and hypertrichosis (less frequent with tacrolimus than cyclosporine). The excess hair growth can be severe and can contribute to poor drug adherence. A cohort of approximately 200 pediatric nephrotic patients treated with cyclosporine for an average of 22 months was reviewed; reported side effects of such prolonged therapy included hypertrichosis (52.3%), gum hyperplasia (25.4%), hypertension (18.8%), and renal impairment (9.1%). Close examination of the subgroup of patients with renal impairment in this study is revealing. In the small number (n = 18 patients) that demonstrated renal impairment, 12 recovered completely after the cyclosporine was stopped, 3 experienced stable but continued renal impairment, and only 3 (1.5% of the total number exposed) had slow progression of their renal disease. On multivariate analysis, resistance to the cyclosporine treatment was the only factor predictive of renal impairment
Strategies for Reducing Toxicity
In contrast to transplantation, long-term low-dose therapy with cyclosporine (1.0 to 2 mg/kg/day) with or without low-dose steroids, has been shown to be both safe and effective at maintaining remission. The lower toxicity of CNIs in patients with GN is at least in part related to the lower daily maintenance dose required and the capacity to gradually increase the dose over days or weeks to achieve a therapeutic effect versus the need for a much more rapid dose escalation following solid organ transplantation. Although higher doses of cyclosporine may be required for the induction phase in membranous nephropathy, the initial dose can usually be reduced during the maintenance phase. In renal transplant patients, CNI dose has been safely reduced after the first year with renal function remaining stable even after 20 years of exposure to this agent. Nevertheless, nephrotoxicity is a risk with this therapy, and careful monitoring of drug levels, a constant awareness of drug interactions (which may either increase or decrease drug levels), and frequent monitoring of renal function are mandatory.
One of the mechanisms of the nephrotoxicity that is attributable to these agents is their renal vasoconstrictive properties. This hemodynamic effect is both dose dependent and reversible but may still result in dangerous episodes of acute kidney injury. Therefore patients should be cautioned as to what to do in the event of unanticipated volume contraction secondary to dehydration. The more delayed chronic damage in the tubulointerstitial compartment and the small arterioles is less well understood but may also be ameliorated at least in part by a dose reduction or discontinuation of the agent. Toxicity may be more evident when CNIs are used in patients with more advanced renal impairment and/or those with significant tubulointerstitial and/or vascular changes noted on histologic evaluation. However, with careful monitoring and the slow escalation of dosage, even patients with significant renal dysfunction can be safely treated with CNIs.
The hypertension that commonly accompanies treatment with CNIs is another adverse effect that requires attention. However, the adjustments in antihypertensive medication are usually straightforward, and the presence of hypertension does not generally preclude or limit CNI usage. The vasoconstrictive effects of cyclosporine, in addition to their effects on renal potassium secretion, may limit the ability to use higher doses of inhibitors of the renin angiotensin aldosterone system to control blood pressure in patients on cyclosporine. With respect to the risk for diabetes, ongoing vigilance by the prescribing physician is required. In patients at highest risk for developing glucose intolerance, including obese individuals, those with a strong family history of diabetes, older adults, and those with metabolic syndrome, strategies for preventing this adverse effect include preferential use of cyclosporine over tacrolimus and/or the use of CNI monotherapy, thereby at least avoiding the additive risk of corticosteroid exposure.
Alkylating Agents
Cyclophosphamide is the most common alkylating agent used in the treatment of GN. It is a cytotoxic agent that acts largely through the alkylation of purine bases. This DNA damage induces apoptosis or altered function of both B cells and T cells. Chlorambucil is the other drug of this class that is used, although less commonly than cyclophosphamide because of significant differences in both the short- and long-term adverse effect profile and drug tolerability.
Major Adverse Effects
Infertility in both men and women has been reported with these agents, most commonly following cyclophosphamide, and is likely the most concerning long-term side effect given the often younger age of patients with glomerular disease. This effect is closely related to total exposure but is also strongly impacted by the age of the patient. One early series indicated that the rate of permanent ovarian failure was 26% in those who received between 10 and 20 g of cyclophosphamide but was greater than 70% in those whose cumulative dose was more than 30 g. This effect is of particular concern in women during the later part of their reproductive life. It has been estimated that women who receive a single course of cyclophosphamide therapy (10 to 20 g exposure) before the age of 25 years are at significantly less risk for permanent sterility (0% to 15% risk) compared to the same exposure after the age of 30 (30% to 40% risk). An even higher risk has been estimated by Ioannidis and colleagues, who calculated the risk for permanent ovarian failure for a standard dose of 12 g/m 2 to be 90% in women when treated after the age of 32. This combined effect of age and exposure on fertility can be expressed as an odds ratio. These authors suggest an odds ratio for permanent ovarian failure of 1.48 per 100 mg/kg of cumulative dose and 1.07 per patient-year of age. Although more difficult to estimate, there is certainly a substantial risk for infertility in men as well. However, the age effect has not been as clearly demonstrated as in women. Studies have indicated that long-term gonadal toxicity was not evident until the cumulative exposure to cyclophosphamide was greater than 300 mg/kg, but later information suggests a substantial risk at a cumulative dose of less than 168 mg/kg (equivalent to 12 g for a 70-kg patient), and gonadal toxicity, as indicated by a reduction in sperm count, has been documented with exposures as low as 100 mg/kg. Various approaches have been examined to preempt loss of ovarian function and to preserve fertility during exposure to cytotoxic agents. Among these, the use of gonadotropin-releasing hormone agonists to induce a prepubertal state during exposure has been examined with promising effects, but no universal consensus.
The other major adverse effect is the risk for malignancy. It is suspected that this has been underestimated in the past at least in part due to the delay between exposure to the drug and the appearance of the cancer. This latent period may be many years. Data from an epidemiologic study of 293 Danish patients with antineutrophil cytoplasmic antibody–associated vasculitis treated with cyclophosphamide suggested a much lower safety limit for exposure than previously indicated. The authors concluded that patients who received a cumulative dose of more than 36 g of cyclophosphamide (equivalent to 2 mg/kg for 8 months in a 70-kg patient) had a substantial increased risk for the development of a malignancy compared to the normal age- and sex-controlled population. Their standardized incidence ratio of acute myelocytic leukemia was 59.0, bladder cancer was 9.5, and nonmelanoma skin cancer was 5.2 above this cumulative cyclophosphamide exposure. They also confirmed the substantial delay between exposure and malignancies with a latent period of 6.9 to 18.5 years. This exposure of 36 g is a much lower threshold for these serious complications than previously estimated and needs to be validated in an independent data set. In the meantime, however, the potential for toxicity at much lower exposure limit should be kept in mind when considering the more prolonged course of cyclophosphamide as a treatment option in membranous nephropathy, lupus nephritis, or vasculitis.
An additional well-recognized, short-term adverse effect of the alkylating agents is bone marrow suppression, particularly the white cell line. A meta-analysis reported significant leukopenia in 25% of patients with lupus nephritis who were treated with cyclophosphamide. Another short-term adverse effect of cyclophosphamide is an increased susceptibility to infections. These infections can be severe and resistant to therapy and in combination with leukopenia can be overwhelming. Additional less serious but disconcerting side effects that can affect compliance include alopecia and hemorrhagic cystitis. This long list of potentially serious complications makes monitoring, for both short-term and long-term effects of these agents, a critical and necessary component of management.
Chlorambucil is an alternative alkylating agent used in the treatment of membranous nephropathy. The original regimen developed by Ponticelli and coworkers with this agent cycled it monthly with corticosteroids over 6 months. The adverse effects of chlorambucil are similar to cyclophosphamide, although it has not been associated with the bladder toxicity with associated gross hematuria. Even so, chlorambucil may be less well tolerated overall than cyclophosphamide and has the added associated risk for acute myelogenous leukemia.
Strategies for Reducing Toxicity
Strategies to limit exposure focus on limiting duration of therapy rather than modifying the dose. The exception to this is the use of intravenous cyclophosphamide in lupus and vasculitis, wherein less frequent and smaller doses of intravenous cyclophosphamide appear to be as effective as the earlier higher-dose regimens with fewer adverse events. A shorter-duration regimen of exposure is an established option in membranous nephropathy. The two published effective regimens vary dramatically in terms of cyclophosphamide exposure (see earlier chapters). In the original classic 6-month regimen, for example, cyclophosphamide exposure is limited to 3 months compared to the later-published routine that employs a full year of exposure.
Substitution of other agents less toxic than cyclophosphamide is another option. Mycophenolate mofetil (MMF) or azathioprine for maintenance therapy in lupus nephritis are well-established options and appear to have similar efficacy with significantly fewer adverse effects. Data from a randomized controlled trial in patients with diffuse proliferative lupus nephritis confirmed that MMF (3 g/day) was associated with fewer pyogenic infections than a cyclophosphamide-based regimen (relative risk, 0.36). Similarly, long-term therapy with azathioprine has been proven to be as efficacious as cyclophosphamide in the maintenance phase of vasculitis, with less toxicity. Similar results in terms of complete and partial remissions were obtained when MMF was substituted for the year of cyclophosphamide in membranous nephropathy, but a significantly lower incidence of serious side effects was observed. This study was not a randomized controlled trial since the cyclophosphamide-treated patients were a historical control group. Unfortunately, the relapse rate was very much higher than in the cyclophosphamide group. Replacement of the cyclophosphamide with CNIs is another option. This substitution strategy could be employed when initial therapy with cyclophosphamide has failed, in the situation where the patient has relapsed, and/or when repeated exposure to alkylating agents was being considered. This strategy can be used in the management of patients with membranous nephropathy, lupus nephritis, or FSGS.
Monitoring the other potential adverse effects of cyclophosphamide by frequent blood counts and adjusting the dose relative to degree of renal impairment, age, and other comorbid conditions are additional tools to minimize cyclophosphamide toxicity. The likelihood of inducing opportunistic infections such as P. jirovecii pneumonia and/or cytomegalovirus can also be reduced by the use of prophylactic antibiotics or antivirals as described earlier in the discussion of corticosteroids. With respect to the potential to cause infertility in young patients, young men might consider sperm banking, while there are also data to suggest a gonadotropin-releasing hormone analog may provide ovarian protection, decreasing the rates of premature ovarian failure from 30% to 5% in one study.
Azathioprine
Azathioprine is an inhibitor of inosine monophosphate dehydrogenase, a critical enzyme involved in de novo purine synthesis, required for lymphocyte division resulting in depressed levels of both B and T lymphocytes as well as immunoglobulin synthesis. Its metabolite 6-Thio-GTP causes immunosuppression by blockade of GTPase activation in T lymphocytes specifically by blocking activation of Rac proteins.
Major Adverse Effects
Gastrointestinal side effects, including nausea and vomiting, are common and remain the primary reason for treatment interruptions. Liver toxicity with a significant increase in serum transaminase levels has also been described as has pancreatitis. Dose-related bone marrow suppression primarily affects white blood cells but can affect all cell lines and can be severe in patients with low levels of thiopurine methyltransferase. This genetic abnormality affects approximately 0.3% of the population, in whom the enzyme is lacking, while 11% of individuals are heterozygous for a variant low-activity allele with intermediate activity, causing diminished azathioprine metabolism. Similarly, allopurinol causes drug accumulation and can result in severe myelosuppression. As with all immunosuppressive agents, bacterial and viral infections do occur, particularly in the setting of leukopenia, and increased rates of malignancies, in particular skin cancers, have been noted.
Strategies for Reducing Toxicity
There is no consensus among physicians treating glomerular disease with respect to the assessment for thiopurine methyltransferase deficiency. Both genetic testing and functional assays are available, but it is common practice to simply slowly escalate the dose while surveying for toxicity. Myelosuppression will typically improve with dose reductions, and allopurinol should be avoided.
Mycophenolate Mofetil
MMF is a relatively new immunosuppressive agent. It is hydrolyzed into mycophenolic acid, the active moiety of the drug. Similar to azathioprine, MMF is a reversible inhibitor of inosine monophosphate dehydrogenase, a critical enzyme involved in de novo purine synthesis, required for lymphocyte division. Several factors contribute to the lymphocyte-specific effects of MMF on purine metabolism. First, unlike other cells, lymphocytes are uniquely dependent upon de novo purine synthesis to generate RNA and DNA since they do not have a salvage pathway for purine generation. Inhibition of this pathway by MMF therefore predominantly affects lymphocyte metabolism. MMF also is a highly potent inhibitor of the isoform of inosine monophosphate dehydrogenase that is expressed in activated lymphocytes (the type II isoform), contributing to its specificity. The selectivity of MMF for inhibiting lymphocyte proliferation is the concept that underlies the reduced toxicity of MMF compared to other alkylating agents that affect all dividing cells. In addition to its effects on T and B cells, MMF may also affect fibroblast proliferation or activity and endothelial function.
Major Adverse Effects
The principal adverse effects of MMF relate to gastrointestinal symptoms, including both upper gastrointestinal irritation with nausea and vomiting and lower tract involvement with diarrhea. This is more common with MMF than with cyclophosphamide. These symptoms tend to occur early in the course of treatment and can improve over time.
As with all antimetabolites, MMF can cause hematologic complications, including leukopenia and anemia. The myelosuppressive effects of MMF contribute to the risk for infection associated with its use, and, while some data suggest a lower infection risk than with cyclophosphamide in lupus nephritis, several studies indicate similar risk for serious infection, and serious infections have been reported. Furthermore, the transplantation literature suggests an increased risk for viral infections with MMF, particularly in the context of multidrug regimens. It is too early to determine whether there is a difference with respect to risks for late-onset malignancy with MMF when used for the treatment of lupus or other variants of GN.
Although there is no fertility impact, MMF has now clearly emerged as a human teratogen with an identifiable pattern of malformations—craniofacial (microtia or anotia, absent auditory canal, cleft palate, hypertelorism) and limb anomalies. In women who become pregnant while on MMF, manufacturer’s data notes a 33% increased miscarriage rate and a 22% rate of teratogenicity. Therefore some informed women may elect to terminate the pregnancy.
Strategies for Reducing Toxicity
Unlike the transplantation context, the dose of MMF can frequently be titrated up over the course of days to weeks to minimize development of gastrointestinal symptoms. Splitting the dosage into four times per day versus the standard two doses per day also reduces gastrointestinal problems. Temporarily reducing the dose also may be tried. The predominant effect on the bone marrow is leukopenia and is usually corrected by a temporary dose reduction. If the full dose is still not tolerated, the addition of MMF-sparing agents such as a low dose of steroid or a CNI may be considered. Sexually active women initiating MMF should have a negative pregnancy test before initiating the therapy, and those who desire pregnancy should be off MMF at least 6 weeks before conception.
Rituximab and Ocrelizumab
Rituximab is a genetically engineered, chimeric, murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant pre-B and mature B cells. The CD20 antigen is not expressed on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. Thus it has an impressive safety record when compared to classic cytotoxic agents. The precise mechanism of action of anti-CD20 antibodies in autoimmune disease and in particular GN is unclear. It is known that B cells play an important role as immunoregulatory cells by both antigen presentation and cytokine release. Their elimination could have dampening effects on other immune cells such as T lymphocytes, dendritic cells, and macrophages. In vitro studies have demonstrated that the Fc portion of rituximab binds human complement and can lead to cell lysis of the targeted cell through complement-dependent cytotoxicity, and it has been demonstrated that rituximab mediates antibody-dependent cellular cytotoxicity. Rituximab has been shown to be effective in the treatment of idiopathic membranous nephropathy and may work at least in part by depletion of the autoantibody to the podocyte-located antigen phospholipase A 2 receptor. Further, rituximab may have a direct podocyte-modulating effect via cross reactivity with sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulation of acid sphingomyelinase essential for the lipid-raft compartmentalization of the podocyte plasma membrane, as well as for the organization and signaling of podocytes in general. This potential direct effect on podocytes independent of its known effect on selective depletion of the B cell clone may make it a very effective option to consider for the treatment of idiopathic glomerular diseases.
Ocrelizumab is a genetically engineered, fully humanized monoclonal antibody directed against the same CD20 antigen found on the surface of normal B cells, with the same mode of action as rituximab. Due to its fully humanized nature, this anti-CD20 antibody can be infused more rapidly and has less immediate infusion-related reactions than rituximab. In addition, due to the fully humanized construct, formation of autoantibodies directed against the drug are unlikely, thereby enhancing the potential efficacy and safety of repeated treatments.
Major Adverse Effects
Acute infusion-related reactions can vary from minor symptoms to severe life-threatening reactions. Minor reactions occur in up to 10% of exposed individuals and include skin rash, pruritus, flushing, nausea, vomiting, fatigue, headache, flulike symptoms, dizziness, hypertension, and/or runny nose. Anaphylaxis and shock can occur but are fortunately rare (<1%). Other rare side effects that have been seen with the use of rituximab include anemia, cardiac arrhythmias, respiratory failure, and acute kidney injury (occurring in <0.1.%). The latter severe reactions have been seen primarily—though not exclusively—with the use of ocrelizumab in the treatment of hematologic malignancies where the tumor cell burden is high and an acute tumor lysis syndrome can develop. More delayed adverse effects include serum sickness and an increased incidence of infection, including reactivation of latent viral infections, including hepatitis B and several cases of pneumocystis pneumonia. There have been several reports of the development of progressive multifocal leukoencephalopathy in patients treated with this agent. This devastating syndrome is due to the activation of latent JC polyomavirus and is associated with progressive neurologic impairment and ultimately death within months of diagnosis. In the majority of reported cases, progressive multifocal leukoencephalopathy developed when rituximab was used in combination with chemotherapy. Given the impact of rituximab on antibody formation, vaccinations that contain live organisms should be avoided during treatment with rituximab.
Formation of human antichimeric antibodies (HACAs) does occur, although their clinical significance is unclear. Despite the appearance of HACAs in patients treated with rituximab and their theoretical consequences, these sequelae have not been uniformly observed in the small studies in GN. The new fully humanized version of the anti-CD20 agent should either ameliorate or eliminate the problem of HACA formation.
Strategies for Reducing Toxicity
The precise dose and/or regimen to use in patients with autoimmune disorders are unknown. Although the relationship between peripheral CD20-positive cell depletion and response is poor, it has been suggested that a single dose, in membranous nephropathy, is adequate for B cell depletion and provides a similar response in proteinuria as multiple doses of the agent.
Eculizumab
Eculizumab is an anti-C5 monoclonal antibody designed for use in diseases characterized by functional impairment of endogenous inhibitors of the activation of the alternative complement pathway. The activation of this cascade has classically been implicated in atypical hemolytic uremic syndrome, thus providing a potential rationale for this agent in these diseases. Emerging evidence suggests that complement dysregulation may be a critical contributor to many forms of progressive glomerular injury traditionally attributed to classical or lectin-activated complement pathways. Activation of these pathways and their potential inhibition by eculizumab may have relevance in the context of MPGN, SLE, and other forms of GN.
Major Adverse Effects
Overall eculizumab is well tolerated, but there is the potential for an increased risk for Neisseria meningitidis infections associated with blocking the alternate complement pathway. Therefore vaccination and careful surveillance are recommended based on its use in patients with paroxysmal nocturnal hemoglobinuria.
Strategies for Reducing Toxicity
The precise dose and/or regimen to use in patients with glomerular diseases is presently unknown.
Adrenocorticotropic Hormone
Synthetic formulations of adrenocorticotropic hormone (ACTH) have previously proven effective in patients with nephrotic syndrome, and the use of ACTH for the treatment of elevated cholesterol and proteinuria dates back many decades. In Europe the synthetic formulation of ACTH, tetracosactide (Synacthen), which is not available in North America, has proven similarly effective in both uncontrolled series and a small randomized controlled trial in which it was compared to cytotoxic therapy. To date there are limited data to also suggest natural ACTH (H.P. Acthar Gel), which is currently the only available ACTH preparation in North America, may also have a beneficial effect in patients with nephrotic syndrome by lowering proteinuria and improving serum albumin and cholesterol profiles.
The active ingredients of H.P. Acthar Gel are part of the family of structurally related peptides known as melanocortin peptides. Melanocortin peptides, which include ACTH and the α-, β-, and γ-melanocyte-stimulating hormones, are derived from the natural protein pro-opiomelanocortin, which binds to the cell surface G protein–coupled receptors known as melanocortin receptors (MCRs). To date, five forms of MCRs have been cloned, each with different tissue distributions, affinities, and physiologic roles. As such, their potential therapeutic mechanisms are numerous and complex. Potential renoprotective mechanisms include corticosteroid-mediated systemic immunosuppression and antiinflammatory actions subsequent to ACTH-induced steroidogenesis through MC2R interaction, as well as direct MCR-mediated immunomodulation and antiinflammatory effects (MC1R, MC3R, and MC5R). Correction of dyslipidemia mediated by MC1R and MC5R on hepatic cells and neurogenic antiinflammatory effects mediated by MC3R and MC4R expressed in the central nervous system are likely also beneficial to the kidneys. Finally, a direct MCR-mediated protective effect on kidney cells, particularly the podocytes, has been described. MCRs are expressed in glomerular podocytes, and receptor stimulation has been demonstrated to reduce oxidative stress and improve glomerular morphology by diminishing podocyte apoptosis, injury, and loss in the remnant kidney animal model.
Major Adverse Effects
In a pilot study, side effects were noted to be dose dependent. Reported side effects associated with the use of ACTH include steroid-like effects, including a cushingoid appearance, weight gain, and worsening of edema or bloating. Potential skin changes include acne, flushing, and bronzing. With respect to potential psychologic effects of the treatment, increased irritability, depression, and improved mood have been noted, along with transient insomnia, tremulousness, dizziness, muscle aches or pain, headaches, gastrointestinal symptoms, and blurred vision, as well as generalized weakness or fatigue. Glucose intolerance and frank diabetes are also potential rare side effects that tend to improve with the cessation of treatment.
Strategies for Reducing Toxicity
The precise dose and/or regimen to use in patients with glomerular diseases is presently unknown.
Treatment Algorithms and Considerations
Treatment recommendations are reviewed in other chapters of this book. A rigorous effort to promote evidence-based therapy for GN has been published by the KDIGO group. This has been an outstanding addition to guide nephrologists regarding therapeutic algorithms. The purpose of these guidelines is to assist in decision making and to highlight the evidence underlying each therapeutic algorithm. However, guidelines cannot account for all of the variations in patient comorbid conditions or individual nuances in potential treatment toxicity (e.g., desire to preserve fertility). Therefore application of these guidelines to the individual patient requires careful consideration. In practice, we consider the following questions before making guideline-based treatment recommendations:
- 1.
What is the risk for progression to kidney failure in this individual patient?
The critical question is whether the risks of the medication outweigh the risks of progression of the kidney disease. Complementary considerations are the morbidity and mortality associated with dialysis or with transplantation, where many of the same medications will be used to prevent rejection.
Proteinuria is one of our main considerations when we decide whether or not there is an advantage to addition of immunomodulatory treatment to conservative therapy for treatment of patients with primary idiopathic GN. While the threshold of proteinuria associated with highest risk for disease progression varies according to disease ( Figure 34.1 ), this measure is a more important contributor to our treatment decisions than histologic diagnosis. For example, membranous nephropathy may be a lesion that is very amenable to immunologic therapy. However, patients with membranous GN with persistent subnephrotic-range proteinuria have an excellent long-term prognosis. The added advantage of immunotherapy versus conservative therapy alone is not established in this subpopulation. Renal insufficiency at presentation and progression of renal insufficiency during observation should also be considered. While this may argue for a more aggressive approach to care, side effects of immunosuppressive therapy are often more frequent in patients with impaired clearance and additional susceptibility to infections. Pathologic indices of kidney injury, in particular tubulointerstitial fibrosis, are also informative to address chronicity and prognosis. Indeed, a common clinical error is to put patients with irreversible kidney injury at risk with little chance of benefit. Advanced tissue injury with impaired clearance may change the risk/benefit ratio of immunotherapy.
