Short term outcome of patients attending a renal-immunology clinic in central IndiaM Atlani1, NK Kapoor2, D Joshi2, R Sutar3, T Sharma2, A Joshi4
1 Department of Nephrology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
2 Department of Pathology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
3 Department of Psychiatry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
4 Department of Community and Family Medicine, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_1320_20
Source of Support: None, Conflict of Interest: None
Keywords: Glomerular diseases, IgA nephropathy, membranous nephropathy, monoclonal gammopathy of renal significance
Glomerular diseases (GDs) are the most common form of immunologically mediated renal diseases. It is also a common cause of the end-stage renal disease (ESRD) worldwide. Patients with primary and secondary GDs have mortality rates 2.7- and 3.9-fold higher than the general population, respectively. Other types of immunologically mediated disorders include interstitial diseases i.e., acute interstitial nephritis.
GD outcomes have been reported by surrogate biochemical endpoints outcomes e.g., ESRD and mortality.
As GDs and other renal immune diseases have long remitting-relapsing course and need close follow-up, many have systemic components and treatment-related morbidity as well, in a view to providing a single point of service for such patients, they are followed up at a renal immunology clinic (RIC) at our center, which is run in collaboration of nephrologist, pathologist, rheumatologist, and liaison psychiatrist.
Clinical outcomes and predictors for ESRD and mortality in GDs have not been reported for Indian patients. Long-term outcomes of GDs has been reported in studies from the USA and Asia, which did not include Indian patients.,, The present study was conducted to determine short-term outcome of patients and their renal outcome of biopsy-proven renal-immunologic diseases of various types in light of current management strategies from renal immunology clinic at a tertiary care center in central India.
This is a longitudinal follow-up study of subjects attending RIC. The study was approved by AIIMS, Bhopal human ethics committee. Patients were enrolled for the study from April 2018 till December 2019. Consecutive patients of either gender registered under RIC were asked to participate in this study. Consent was obtained from all patients. Those registered were closely followed up by a team as mentioned above. The patients were followed up biweekly for 1st month, then monthly for 3 months, and at the 6th month. The primary endpoint for the analysis was the incidence of ESRD or loss of >50%eGFR and patient survival at 6 months. Secondary outcomes evaluated were the rate of complete and partial remission of proteinuria demography, the incidence of various glomerular diseases, and infective complications of therapy.
The data collected from subjects were entered in an excel file and secured within the office of nephrology. Data included pertained to demography, clinical renal syndrome, blood pressure, blood chemistry, urine protein to creatinine ratio (uPCR) and serology, genetic analysis, serum electrophoresis, and immunofixation, free light chain assays, complement levels, histopathology, treatment, and follow up.
Tissue for histopathologic diagnoses was obtained by renal biopsies performed by a nephrologist in a craniocaudal manner under real-time ultrasonography (USG) guidance with an 18-gauge automatic renal biopsy gun. Tissue was obtained for light microscopic analysis and immunofluorescence. All standard procedures were followed for staining the kidney tissue. It was analyzed by SPSS 16.
Descriptive statistics were presented for central tendency and measure of dispersion by the median and interquartile range (IQR). Appropriate nonparametric statistical tests (Wilcoxon rank-sum test; Chi-square test of independence) were applied in order to check for the statistical association between groups categorized on the basis of composite renal outcome (ESRD/eGFR fall ->50%) with a 95% confidence interval (CI) level.
Seventy-eight subjects were included in the study out of ninety-two. Fourteen were excluded due to nonimmune pathology on renal biopsy i.e., extensive glomerulosclerosis or diabetic nephropathy. Four (5.1%) patients lost to follow-up during the study period. The mean age of the patient was 37 years (SD = 13.89) and males 40 (51%) outnumbered females marginally 38 (49%).
The most common primary renal diagnosis (n = 51) received among various glomerular diseases included [Figure 1]. Membranous nephropathy (MN) 20 (25.6%) followed by, IgA nephropathy 13 (16.6%), focal segmental glomerulosclerosis 11 (14.1%), minimal change disease (MCD) 5 (6.4%) membranoproliferative glomerulonephritis (MPGN) 2 (2.5).
Among the secondary glomerular diseases, (n = 27) lupus nephritis (LN) 8 (10.2%), monoclonal gammopathy of renal significance (MGRS) 4 (5.1%), cast nephropathy (Cast N) 5 (6.1%), systemic amyloidosis (Sys Amy) 5 (6.4%), postinfectious glomerulonephritis (PIGN) 4 (5.1%), and rapidly progressive glomerulonephritis (RPGN) (Wegner's granulomatosis) 1 (1.2%). This is depicted in [Figure 1].
Overall, 12.8% (10) patients reached the renal endpoint of ESRD or >50% fall in eGFR. Three patients (two with IgA nephropathy and one patient with cast nephropathy) developed new ESRD and seven patients (two with MN, one with IgA nephropathy, and three with steroid-resistant FSGS and one with systemic amyloidosis) suffered loss of more than 50% of eGFR [Table 1].
Thirty patients (33.3%) achieved complete remission of proteinuria, whereas 24 (30.7%) achieved partial remission. Twenty-four (30.7%) patients were resistant to disease-specific therapies.
Three (5.8%) patients succumbed (one with MN and two with MCD) to various causes.
Univariate analysis identified three investigated factors as significant (P < 0.001) predictors of composite renal outcome of ESRD/Fall of eGFR >n50%. These include the presence of hypertension, the severity of hypertension (Systolic BP >160 mm Hg), and resistance to proteinuria remission, and this ominous association was detected statistically significant at 95% CI. [Table 2].
Details of patients with membranous nephropathy are shown in [Table 3].
Three (15%) were hypertensive, six had hypothyroidism (30%), and two patients had chronic kidney disease (10%) [Table 3].
All patients met high-risk criteria of disease progression to renal failure and were started immunosuppressive therapy. All patients received conservative treatment with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and atorvastatin. The overall response rate of mPR was 93.7%. None of the patients developed ESRD. Two patients developed a 50% fall in eGFR at 6 months.
Details of patients with IgA nephropathy are given in [Table 4].
Thirteen patients (14%) had IgA nephropathy [Table 4].
In all, 84% of the patients had nephrotic range proteinuria, and 50% had hypertension. All but two patients had MEST-C scores available, and in one patient, it was not possible to assess it because of extensive glomerulosclerosis. Thirty-three percent each had M1 and E1, 100% patients had S1, 44.4% had T1, and 55.5% had C-1. All patients were treated according to the kidney disease outcomes quality initiative (KDOQI) guidelines. At 6 months, nine (69.2%) patients had stable eGFR. ARBs, discontinued in 33% of the patients due to hyperkalemia. Two patients (16%) had associated thrombotic microangiopathy (TMA). Two patients presented with nephrotic syndrome during early pregnancy.
Focal segmental glomerulosclerosis
Eleven (14.1%) patients had FSGS on biopsy. The other details of these patients are shown in [Table 5].
All patients had primary FSGS and had not otherwise specified (FSGS -NOS) variant on kidney biopsy. Six (55%) were hypertensive. All patients other than two had full-blown abrupt onset of nephrotic syndrome. Eight patients had >10 gm/day proteinuria, two had more than 5 gm/day, and the rest two had <5 gm/day proteinuria. Two out of five steroid- resistant patients underwent genetic analysis; one patient had mutations in gene ANLN (+) (Anillin, actin-binding protein) exon 2 on chromosome 7 with variant c.21A > G and FAT (-1) in exon 2 with variant c. 1616G>A. The other patient was found to have a mutation in gene CRB2 (+) at Exon 7.
All patients had survived at 6 months follow-up.
Minimal change disease
Details are summarized in [Table 6]. None of the patients developed a fall in eGFR or ESRD, but two patients succumbed due to infective causes. One patient developed nocardia chest infection following steroid therapy [Table 6].
Membrano proliferative glomerulonephritis
Two patients with a membranoproliferative pattern on kidney biopsy were treated with a 6-month course of steroid with mycophenolate mofetil and achieved complete remission of proteinuria. None developed ESRD or fall in eGFR.
All patients with Class III and IV had impaired eGFR (severe lupus nephritis) at presentation, which improved with treatment. None of the patients developed ESRD or eGFR loss of >50% at 6 month. All patients were surviving at 6 months [Table 7].
All patients with lupus nephritis received hydroxychloroquine (HCQ) and angiotensin II receptor blockers (ARB) as supportive therapy. Patients of class III and IV presented with nephrotic syndrome, whereas one patient of Class IV had nephrotic -nephritic syndrome. Class V patient had nephrotic syndrome. All but one patient was female.
Monoclonal gammopathy (MG) associated renal involvement
Renal involvement and outcome were as shown in [Table 8].
Amongst the MGRS, two patients lost to follow up both were resistant till follow-up. Amongst two others, one patient had TMA, he became dialysis free and regained 50% of renal functions after treatment with chemotherapy.
One patient of kappa light chain amyloidosis had chronic HCV genotype-1b infection with active viral proliferation but no evidence for chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Antiviral treatment with daclatasvir and sofosbuvir did not reduce proteinuria.
Post-infectious glomerulonephritis (PIGN)
All patients achieved complete remission and recovery of renal functions. Two patients (50%) were treated with steroid (one had crescent on biopsy), whereas one patient (25%) with mild derangements of renal function was managed conservatively, one patient (25%) lost to follow up. All presented with nephrotic- nephritic syndrome.
One patient developed a 50% fall in eGFR, whereas one patient with AKI succumbed due to noncompliance with dialysis. None of the patients developed complete or partial remission of proteinuria. Patients were treated with conservative treatment only.
Four (80%) out of five patients had a past history of tuberculosis, and one (20%) had poorly managed rheumatoid arthritis. Three patients had nephrotic syndrome, one patient had AKI with nephrotic syndrome, whereas one patient presented with ESRD.
Rapidly progressive glomerulonephritis
Only one patient with RPGN secondary to Wegener's granulomatosis and angiomatosis was found. She had a severe renal failure on presentation with eGFR 14 mL/mt/1.73 m2. She received standard induction therapy with IV cyclophosphamide and glucocorticoids without the use of rituximab or plasmapheresis with a successful outcome of recovery of eGFR to 39 mL and proteinuria remission.
Our study showed in short terms 94.9% of patients survived. Higher number of patients died under the category of benign disease like MCD. The deaths were not directly attributed to renal failure but to the infectious complications of treatment [Table 6] or to malignancy [Table 3].
Initial long-term studies of proteinuric diseases also showed deaths in benign diseases like MCD, but deaths were not attributable to renal failure similar to our study. However, mortality rates were higher in patients with proliferative diseases with either epithelial or endothelial proliferations, varying between 30% and100%).
In our study, 87.2% of patients had good renal survival. The renal outcome was worst for patients with FSGS, chiefly in terms of fall in eGFR of >50%, whereas a greater number of patients with IgA nephropathy reached ESRD. Similar results were reported by previous studies. A Korean study showed 325 (16.7%) patients progressed to ESRD and 164 (8.4%) patients out of 1943 died during the median follow-up of 90 months. Patients with minimal change disease exhibited the best renal and patient outcomes, whereas those with membranoproliferative GN had the worst. IgA nephropathy patients appeared to have a good survival rate in spite of their considerable progression to ESRD, and focal segmental glomerulosclerosis patients showed poor renal and patient outcomes. Another study found FSGS as the most powerful predictor for ESRD. Our study shows that in short term as well as compared to the long term results of other studies, primary GDs FSGS and IgA nephropathy runs in close parallel as the leading cause of the poor renal outcome. Though our univariate analysis for factors of renal survival primary diagnosis type did not reach statistical significance, it may be due to a small cohort size. No such data are available for Indian patients to the best of our knowledge.
On univariate analysis, factors that reached statistical significance for renal outcome were hypertension as well as the severity of hypertension (Systolic BP > 160 mm Hg) and resistance to achieve remission of proteinuria.
Previous studies have also shown that among patients with CKD in the modification of diet in renal disease (MDRD) study, higher baseline mean arterial pressure independently predicted a greater rate of eGFR decline. Patients were followed up for 3.5 years in the MDRD study, our study suggests hypertension and its severity affects renal survival even in the short term of 6 months as well.
It is well established that the enhanced susceptibility for an adverse renal outcome to high blood pressure levels in the renal disease population is a consequence of an impairment of the mechanism of renal autoregulation that normally attenuates the transmission of elevated systemic pressures to the glomeruli in uncomplicated hypertension.
Resistance to achieving either complete or partial remission of proteinuria was strongly associated with poor renal outcome in short term. These results are similar in line with other reports which showed the extent of “residual proteinuria” that persists despite optimal treatment with an angiotensin receptor blocker or ACEI also predicts renal prognosis.
Reduction in proteinuria percentage over the first 3 months, as well as the absolute level of proteinuria at 3 months, was strong independent predictors of the subsequent rate of fall in eGFR in the secondary analysis of REIN study.
In the irbesartan diabetic nephropathy trial (IDNT), at 12 months, a higher reduction in proteinuria was associated with a higher reduction in the risk of ESRD (HR 0.44; 95% CI 0.40–0.49 for each halving of baseline proteinuria.
In the African American study of kidney disease and hypertension study (AASK Trial), study change in proteinuria from baseline to 6 months predicted subsequent progression.
A meta-analysis of data from 1860 patients with nondiabetic CKD showed that during antihypertensive treatment, the current level of proteinuria was a powerful predictor of the combined endpoint of doubling of baseline serum creatinine or onset of ESRD (RR 5.56; 95% CI 3.87–7.98 for each 1.0 g/day increase in proteinuria.
Recently, in a study reaching either a complete or partial remission, using a novel or conventional definition was associated with better long-term outcomes in patients with FSGS.
The association of nonresponsive proteinuria with the poor renal outcome can be explained by excessive filtered proteins in tubules leads to increased absorption in tubules, which causes the release of vasoactive and inflammatory proteins, which lead to tubular cell apoptosis, monocyte infiltration and accumulation in the interstitium of extracellular matrix, and ultimately scarring and eGFR loss.
Similar to MDRD study results baseline eGFR was not found associated with renal outcome. However, patients who suffered poor renal outcomes (ESRD/50% fall in eGFR) had higher grades of CKD at presentation.
We also did not find an association with baseline proteinuria (urine PCR), whereas baseline proteinuria was a strong predictor of eGFR decline in MDRD study, our results may be due to the small cohort and small number of patients achieving primary endpoint of composite renal outcome. Also, small difference in the level of proteinuria patients who developed and did not develop composite renal outcomes may be responsible. Many other trials i.e. AASK REIN have shown higher baseline proteinuria was strongly associated with rapid fall in eGFR.
Another study has found female sex or lower hemoglobin as a contributor of progression. We did not find an association of gender with the renal outcome, but we did not look for an association with hemoglobin.
One of the studies of GDs found responsiveness to the therapy was higher in primary glomerular diseases (PGD) than in the secondary glomerular diseases (SGD) group (P < 0.001). Mortality rates were 2.27% in the PGD group and 18.3% in the SGD group. The presence of SGD (odds ratio 7.74) was independent risk factor for patient death (P < 0.001). Results were mainly driven by the presence of systemic amyloidosis, (55%) as the most common SGD, which is resistant to most therapies. Complete remission rates of SGD's were higher in our series and were mainly attributed to LN and PIGN. The difference in our results may be due to the nature of diseases and available therapies.
This small study from a cohort of Indian renal immune disease patients shows FSGS and IgA nephropathy have poor renal outcome in short term also. Benign diseases like MCD may have high mortality which was driven by complications of therapy. Hypertension, its severity, and resistance to achieve proteinuria remission are significantly associated with poor renal outcomes in short term. Newer therapies are needed to improve the outcome of renal immune diseases.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]