Contrary to popular belief, even though crescentic glomerulonephritis is the most severe form of renal disease it may not manifest as rapidly loss of renal function. Normal renal function and minor urinary abnormality does not necessarily rule out this entity9,11–14,19. Any urinary abnormalities in these patients have to be addressed and managed expeditiously. Clinicians should have a high index of suspicion for renal involvement in patients with urinary abnormalities alone. Timely initiation of appropriate therapy can reduce the likelihood of progression to chronic kidney disease. The aim of this study was to highlight the occurrence of these cases and to define their clinical characteristics and outcomes at our center.
We presented unusual case series of patients who presented with normal renal function but renal biopsy showed diffuse proliferative crescentic nephritis. This is the largest, most comprehensive and detailed case series of patients with biopsy proven Crescentic GN presented with minimal disturbance of biochemical renal function. Tissue diagnosis with renal biopsy should remain the gold standard for diagnosis when urinary abnormalities are present in these patients. A review of the literature for the prevalence and the possible reasons of the normal renal function in this clinical setting are compared in our research as shown in Table 4.
Table 4
Comparing our findings to other reports on CrGN with normal renal function
| Stephen P. McAdoo[9] | Hironari Hanaoka[14] | Chwee Ang[13] | Vibhanshu Gupta[12] | Sandhya Manohar[11] | This paper |
Adapted from | Rheumatol2015 | Clin Rheumatol 2016 | Nephrol Dial Transplant 1998 | Saudi J Kid Dis and Trans2010 | Future Sci2015 | -2024 |
Study type | retrospective review | retrospective review | Case series | Case report | Case report | retrospective review |
n | 38 | 15vs12 impaired | 5vs9 impaired | 1 | 1 | 98vs300 impaired |
year | 1995–2011 | 1999–2010 | 1976–1996 | 2012 | 2015 | 2010–2021 |
Disease type | crescentic GN | AAV | anti-GBM | LN | LN | crescentic GN |
Mean age | 57 (17–78) | 60.4 ± 20.8 | 22(18–79) | 18 | 47 | 28.9 ± 11.5 |
Male rate | 31.6 | 66.7 | 60 | female | male | 23.3 |
Baseline SCr (umol/l) | 84 (52–115) | 61.8 ± 17.7 | 44.2 | 106.1 | 88 | 79.6(61.0-97.2) |
Proteinuria (g/d) | 1.32 (0-1.7) | 0.4 ± 0.4 | 1.6 | 3.9 | 3.6 | 2.9(1.9–4.8) |
Positive ANCA% | 68.4 | 100 | 0 | - | - | 6.5 |
Positive anti-GBM% | - | - | 40 | - | - | 0 |
Cr-last follow-up(umol/l) | 82(52–147) | eGFR50 | - | normal | - | 120.1(53.0-79.6) |
require dialysis at last % | 5.2 | 0 | 0 | 0 | - | 7.8 |
Crescents% | 21 (0-100) | 12.1 ± 9.2 | 15 | 60 | 8–10 | 56.3(51.8–62.7) |
Sclerotic glomeruli% | 4 (0–33) | 7.5 ± 8.8 | 10 | - | 79–83 | 0(0-4.7) |
Abbreviations: AAV: ANCA-associated vasculitis; LN: lupus nephritis |
A retrospective review from London9 observed 38 patients presented with preserved biochemical renal function despite demonstrating histopathological features of severe GN on renal biopsy. Clinicopathological diagnoses were ANCA-associated GN (74%), LN (18%), anti-GBM disease (5%) and HSPN (3%). All patients received immunosuppression and most had good long-term renal outcomes, although two (5.2%) progressed to end-stage renal disease within 3 years, which is consistent with our result.
An Australian research13 reported a prevalence of 36% of patients with anti-GBM disease have normal renal function. Other studies have found that 15%-35%20–24 of patients with anti-GBM disease have normal renal function. All five patients with normal renal function are alive, and the serum creatinine is less than 0.2 mmol/l in all (100%), hematuria persists in one (20%), and proteinuria > l g/day in two (40%). The less renal damage might be the result of lower levels of circulating anti GBM antibodies and less glomerular complement deposition.
Tang et al19. noted the serum creatinine was > 1.4 mg/dl in approximately 76% of their patients with diffuse crescentic glomerulonephritis and the remaining (~ 34%) were in the normal range. Manohar et al11. presented an unusual case of a patient who presented with nephrotic range proteinuria and a normal renal function but renal biopsy showed diffuse proliferative crescentic lupus nephritis. This patient had an atypical presentation of Class IV lupus nephritis with no RBC casts or elevated serum creatinine. Thus concluded that Renal biopsy is a valuable tool to guide therapy and should strongly be considered in patients with suspected kidney disease with SLE. Another research from India12presented an interesting case of crescentic Diffuse Proliferative Lupus Nephritis with remarkably preserved renal function, nephrotic range proteinuria and more than 60% crescents on biopsy. The preserved renal function of this case may be attributed to the presence of only a moderate chronic tubulointerstitial nephritis, the promising prognosis may be resulted from the timely initiation of immunosuppression to reverse the cellular crescents.
Hanaoka et al14. investigated the clinicopathological features and prognosis of ANCA-associated crescentic glomerulonephritis in 12 patients (ratio of 44.4%) with normal eGFR at diagnosis. They observed significantly higher eGFR during follow up in patients who received intensified therapy such as initial IVCY treatment than in those who did not, supporting that patients with normal renal function had a poor renal outcome and may still require standard intensive treatment to prevent damage accrual.
There have been some theories proposed to explain the normal renal function in patients with crescentic glomerulonephritis. Some11 have attributed this to a sampling error, resulting in histology that is not representative of the overall picture. Some evidence supports that patients with severe tubular lesions are likely to have abnormal renal function25,26. Factors that have been predicted to affect the renal function are evidence of chronicity like glomerular sclerosis, fibrous crescents (unlike fibro cellular which are more active lesions), tubular atrophy and interstitial fibrosis26. Our patients had significantly lower involvement of the tubular injury, lower proportions of glomerular sclerosis and fibrous crescents in normal eGFR group and supporting that this may have played a role in their relatively preserved renal function. Indeed 50% of renal function may be lost before serum creatinine is elevated and therefore a relatively normal serum creatinine does not exclude RPGN27. Findings of proteinuria and hematuria are not specific for RPGN but are more sensitive than serum creatinine in early stages of the disease27. Last, in our study more severe hypocomplementemia, higher titers of ANA, ds-DNA and higher intensity of peripheral capillary IgG, IgA, IgM, C3 and C1q deposition by Immunofluorescence were observed in normal eGFR group, consistent with previous opinions that cell-mediated immunity plays a key role in crescent formation, with the increasing rate of crescent and uremia state, humoral immunity response may be relatively suppressed, which could be proved by increasing levels of complement, immunoglobulin, cryoglobulins and CD20 + cells, thus resulting in less mature B cells and less autoantibodies production, as well as less immune complex deposit in renal tissues1,28–33.
What are the clinical clues for the possibility of severe renal pathology like necrotizing and crescentic GN, alerting nephrologists and especially non-nephrologists timely renal biopsy and intensive immunosuppressive therapy? Apart from urinary abnormality, anemia, hypoalbuminemia, we observed gross hematuria, hypertension, severe hypocomplementemia, high titers and positive rates of ANA, ds-DNA, ANCA and GBM, multisystem injury involvement in Crescentic GN with normal renal function but renal biopsy showed diffuse proliferative crescentic nephritis. Patients had extrarenal manifestations of multisystem autoimmune disease that facilitated early detection of asymptomatic GN9, and our observations suggest that this may have improved long-term outcomes. These patients are at high risk of progression to fulminant RPGN that may result in progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy, particularly in patients who are anti-MPO and GBM antibody positive [22]
Even with normal renal function, the aggressive pathological findings warranted timely initiation of appropriate therapy of steroids and immunosuppressants and improved renal prognosis9,12–14. With immunosuppressive treatment, the majority of these patients have a good renal prognosis, normal eGFR group had an median creatinine of 79.6(61.0-97.2) umol/L, and eGFR of 99.6(72.8-124.3) ml/min/1.73 m2 by the end of follow-up. 88.9% of them keep normal renal function, although a small number are at risk of progressing to ESRD.
Our study has obvious limitations: It is a single-center, retrospective, uncontrolled design with small sample size, and it includes a cohort of patients who have received somewhat heterogeneous treatment. Secondly, the study spans a relatively short observational period, possibly because 89% of this cohort had normal renal function during follow up and no longer regularly come to hospital. We hope to propose a larger size, longer follow-up, multi-center study in the future to further confirm this study. In conclusion, crescentic GN may present in patients with no or only minor disturbance of renal function and mild urinary abnormalities, which have poor renal outcomes and may require standard intensive immunosuppressive treatment to prevent accrual of damage. This often occurs in patients with abnormal immunological indicators and underlying systemic autoimmune disease, regular performance of urinalysis, renal function tests and shorter time from onset to biopsy may affect timely management and improve long-term outcomes in these cases. Renal biopsy remains the diagnostic gold standard when urinary abnormalities are present in nephritis.