Treatment Of Severe Immune Suppression Of Tumor Grade IgA Nephropathy

BackgroundIgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. It has a wide spectrum of clinical presentations and the prevalence rate varies across different geographical regions. Immunological factors could be partially responsible for disease progression. Key to therapeutic decision making is assessment of the individual’s prognosis. Clinical parameters (such as renal function, pathology stage, proteinuria and hypertension) are used to predict prognosis and risk of progression. More severe clinical and pathological manifestations in progressive IgAN patients are associated with a worse renal prognosis and higher incidence of end-stage renal disease. In this case, active immunosuppressive therapy should be considered in order to block or even reverse the progression of this disease. Furthermore, close relationship between clinical remission initially achieved after immunosuppressive therapy and the long-term renal outcome of IgAN has been reported, however it is more likely to be seen in early pathology stages and has not been clarified in individuals with severe pathology stages. Moreover, treatment options for progressive IgAN is still largely based on opinion or weak evidence. Consequently, the recent Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Glomerulonephritis have assigned low levels of evidence for almost all recommendations and suggestions related to the disease. The immunosuppressive therapy for IgAN is still a controversial issue because of scepticism regarding expected results and concerns about possible side effects. Currently, only a few studies have evaluated the indication, efficacy and side effects (especially for infection like severe pneumonia) of immunosuppressive therapy for progressive IgAN.Objectives1. Investigating the relationship between proteinuria, blood pressure, initial renal function and prognosis, and further explore relationship between clinical remission achieved after initial therapy, recurrence after initial remission and prognosis;2. Analyzing common and important side effects associated with immunosuppressive therapy in IgAN patients with severe pathology stages, and taking a further research on the clinical features, treatment and prognosis of PneumoCystis (jirovecii) Pneumonia (PCP) infection in IgAN patients under immunosuppressive therapy in Peking Union Medical College Hospital (PUCMH).3. Evaluating the treatment options for IgAN patients with severe pathology stages in PUMCH, and further evaluating the administration and efficacy of corticosteroids plus cyclophosphamide (CTX).Methods We enrolled99patients who were diagnosed as IgAN with Class IV or higher pathology stages according to the Lee classification by renal biopsy result in PUMCH, and regularly followed up for at least1year between March2006and March2010, with intact clinical and pathological data. Patients with cirrhosis, HIV infection, or other secondary forms of IgAN or rheumatological disease such as lupus nephritis are ruled out for final analysis. Baseline features, follow-up records, treatment and prognosis were reviewed and analyzed retrospectively.Results1. There are99patients enrolled with the onset age of32(13-70), Mean arterial pressure (MAP) of onset105.12±18.77mmHg, estimated glomerular filtration rate (eGFR [CKD-EPI formula])67.65±27.85ml/min/1.73m2,24h urinary protein (24hUP)2.43(0.25-25.00)g/d. The mean follow-up time was41(12-84) months with total time-average proteinuria (TA-UP)1.29±1.20g/d, total time-average mean arterial blood pressure (TA-MAP)93.22±12.44mmHg, eGFR decline rate0.1143±1.3600ml/min/1.73m2/month. Total TA-UP (P<0.001) and total TA-MAP (P=0.002) levels were discovered to be strongly correlated with serum creatinine (SCr) change rate. The renal function decline rate was lower in TA-UP<1g/d group compared with TA-UP≥1g/d group.2. Comparing to the initial non-remission group, the initial remission group had lower renal function deterioration rate during follow-up, lower total TA-UP (P=0.008), and higher proportion of corticosteroids monotherapy (P=0.031). Comparing to patients who had non-recurrence (non-recurrence group) within2years after initial remission (n=9), the recurrence group (n=8) had higher deterioration rate of renal function and lower remission rate (P=0.009) at the end of the follow-up duration.3. Infection risk group (n=13) had higher renal function deterioration rate, higher average daily steriod dose in combination therapy (P=0.001), more immunosuppressants use (P=0.011), more endpoint events (P=0.035). Of11patients (25.0%) with menstrual abnormalities,3presented as permanent menopause,5presented as short-term menopause.4. Of10patients clinically diagnosed as PCP in PUMCH,7(70%) developed PCP within4months of the diagnosis of IgAN.9patients (90%) had chronic renal dysfunction impairment (eGFR<60ml/min/1.73m2, mean eGFR34.7±13.8ml/min/1.73m) at onset of PCP, The mean duration of symptoms before specific medication for PCP was9.50±3.89days after2007.8patients had achieved clinical remission and average duration of hospitalization was32.8±23.1days.5. For the patients with severe pathology stage IgAN in PUMCH, most patients (78.8%) received combinated immunosuppressive therapy.88.5%of them received corticosteroids plus cyclophosphamide. The remission rate at initial6months,1,2, and>2year were55.2%,59.3%,67.2%,50.0%, respectively.6(6.1%) patients developed serious side effects.6(6.1%) reached end-point events.Conclusions1. In IgAN patients with severe pathology stages, the total TA-UP and total TA-MAP levels had strong correlation with deterioration rate of renal function; Patients with initial remission have a slower decline of renal function and a better prognosis. Recurrence within2years after initial remission is associated with renal functional deterioration and poor prognosis.2. The infection risk is probably related to the progression of the disease and poor prognosis, The daily steriod dose and the number of immunosuppressive agents affect the risk of infection in combined immunosuppressive therapy.3. High risk of PCP develops in the first half year after intensive immunosuppressive therapy. Chronically impaired renal function in IgAN might be a risk factor for PCP infection, Significant deterioration of renal function during potent immunosuppressive therapy requires special attention on the side effect of PCP infection. Early suspection and proper treatment of PCP in IgAN patients under immunosuppressive therapy are important to improve prognoses.4. PUMCH positively supplies immunosuppressive therapy to severe pathology stage IgAN patients, and combined immunosuppressive therapy occupies a high proportion. Combined corticosteroids and cyclophosphamide therapy, as the most common option, has a high remission rate, a low incidence of serious side effects. Renal disease progression and side effects risk are well balanced in the treatment strategy.