Introduction
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in India and several other countries in the world.[1] The clinical course of proteinuric DN is well understood and is characterized by progressive increase in proteinuria and decline in glomerular filtration rate. Thirty-five percent to 45% of both type-1 and type-2 diabetic patients patients progress to ESRD in 20–35 years.[1] Various forms of nondiabetic kidney disease (NDKD) may occur alone or can be superimposed on DN, which may alter the management and prognosis. The commonly encountered NDKDs are focal segmental glomerulosclerosis (FSGS), idiopathic membranous glomerulopathy, acute poststreptococcal glomerulonephritis, minimal change disease, lupus nephritis, and chronic glomerulonephritis.[2,3] The development of collapsing glomerulopathy (CG) in DN as a cause of proteinuria is rare and has not been widely reported.
CG has now been recognized as a common, distinct pattern of proliferative parenchymal injury that portends a rapid loss of renal function and a poor response to empiric therapy.[4] The pathological appearance is characterized by segmental/global collapse of glomerular capillary tuft, with wrinkling and retraction of capillary walls, overlaid by epithelial cell proliferation in the bowman space.[5,6,7] CG is now regarded as podocytopathy.[8] Till date, one large case series by Salvatore et al,[9] has described CG in association with DN. We report a case series of seven cases of CG superimposed on DN.
Methodology
All patients of diabetes mellitus (DM), who were suspected to have an underlying NDKD, underwent renal biopsy. There were a total of seven cases of CG superimposed on DN in the last five years. CG was defined by Columbia Classification – at least one glomerulus with global or segmental collapse of capillary tuft, wrinkling of the basement membrane, and hyperplasia of the overlying epithelial cells usually containing protein droplets/vacuolization. Vascular sclerosis and hyalinosis were noted. Demographic, clinical, laboratory, and serological findings were obtained and correlated with renal biopsy findings.
Results
We had a total of seven cases of CG superimposed on DN in the last five years. The average age of our patients was 55 years (range: 39–76 years). All were of type-2 DM. Six patients had a history of long-standing DM (average of 15 years). Only one patient had a short duration of diabetes for two years. They were not on regular follow-up. Their sugars were poorly controlled. Out of seven patients, three were on insulin at the time of diagnosis. Baseline serum creatinine (SCr) was known only in three of them and was in the range of 1.8–3.5 mg/dL. All patients had nephrotic range proteinuria, average of 8 g/day (Range: 4–12 g/day). Only two patients had urinary active sediments. All had diabetic retinopathy. Four patients had a severe renal failure at presentation with average SCr of 8 mg/dL (range: 6–13 mg/dL) and were initiated on hemodialysis (HD). The other three patients were suspected to have acute kidney injury on chronic kidney disease (CKD), with an average SCr of 2 mg/dL (Table 1).
;)
Table 1: Data of seven patients in our case series of collapsing glomerulopathy superimposed on diabetic nephropathy.
Clinical presentation and indications for renal biopsy were as follows:
- Two patients presented with volume overload, pulmonary edema and rapidly worsening renal failure requiring mechanical ventilation and intensive care unit care
- Three patients had worsening edema and uncontrolled blood pressure and worsening renal functions
- Two patients had new onset pedal edema, accelerated hypertension, and worsening renal functions.
Renal biopsy showed CG superimposed on DN in all seven cases. All specimens had more than 10 glomeruli. Four patients had class IV DN, two had class III DN and one had class IIb DN. Three biopsies showed interstitial fibrosis and tubular atrophy (IFTA) >50%. All biopsies showed arteriolar hyalinosis and sclerosis (Figure 1). Immunofluorescence had shown linear positivity for IgG and albumin. All the serologies [human immunodeficiency virus (HIV), hepatitis B and hepatitis C] were negative. Antinuclear antibodies, antineutrophil cytoplasmic antibodies were negative. None of the patients were suspected to have any malignancy, viral infections, or any other drug abuse. Electron microscopy was not done as the diagnosis was evident on light microscopy.
Figure 1: Collapsing glomerulopathy superimposed on diabetic nephropathy.
Four patients, who had presented with severe renal failure, became dialysis dependent. Two patients were in CKD-stage 3 at presentation, progressed to ESRD within two years, and later underwent renal transplantation. One patient is being followed up for the last eight months, currently is in CKD-stage 3b and is being managed with diabetes and blood pressure control, along with anti-proteinuric measures. None of these patients were instituted on any immunosuppressive therapy.
Discussion
DN is always presumed in a patient who has a long-standing DM associated with a slow increase in proteinuria and gradual worsening of renal dysfunction. Various forms of the glomerular disease may superimpose on DN. The development of CG in the background of DN is a very rare phenomenon and it has a unique pathology.
CG is a distinct pathological entity, characterized by segmental or global collapse affecting at least one glomerulus with overlying hypertrophy/hyperplasia of visceral epithelial cells (pseudo cresents) and tubulointerstitial disease (sometimes with microcystic transformation).[10] CG was considered as a subtype of FSGS under Columbia classification. CG is now considered separately from FSGS under the spectrum of podocytopathies. CG and FSGS are characterized by podocyte injury, which leads to podocyte dedifferentiation and proliferation in the former, and podocyte depletion in the latter.[11]
Clinically, CG usually presents as massive proteinuria, hypertension, and renal insufficiency with rapid progression to ESRD. It was first identified among the HIV afflicted patients as HIV-associated nephropathy. Later, various other etiologies have been identified as mentioned in Table 2. CG may occur concurrently with other glomerular diseases.[11]
Table 2: Etiologies and classification of collapsing glomerulopathy.
[ 10 ]On reviewing the literature, we came across only one large case series of CG superimposed on DN. This was a retrospective study done by Salvatore et al[9] on 534 patients with biopsy-proven DN, 26 patients (5.3%) had CG on DN. Ninety percent of these 26 patients had nephrotic range proteinuria and the mean SCr of 3.8 mg/dL. Twelve out of 26 had class IV DN, eight had class III DN and six had class II DN in biopsy. Extensive arteriolar hyalinosis and arteriosclerosis were seen in most cases. On follow-up, 77% (13 out of 17 patients followed up) developed ESRD within seven months, while the remaining four had stable proteinuria and renal functions at follow-up.
A case report of CG superimposed on DN has been reported in the Indian Journal of Nephrology[10] in a 56-year-old man with long-standing DM, with CKD for five years (baseline SCr: 2.1 mg/dL). He had presented with complaints of worsening pedal edema and oliguria for two weeks. He was diagnosed with worsening of renal functions and proteinuria (SCr: 5.4 mg/dL and urine albumin 4+). Renal biopsy showed advanced DN, severe IFTA, arteriolar hyalinosis, and sclerosis with superimposed CG. He progressed to ESRD over 15 days and was initiated on maintenance HD.
Our case series of seven patients of type-2 DM, who had biopsy-proven CG superimposed on DN. Six patients progressed to ESRD and dialysis-dependent state (4 of them at presentation and 2 of them progressed to ESRD over a period of 2–3 years). All had nephrotic range proteinuria. Four had class IV DN, two had class III DN and one had class II DN on biopsy. All biopsies showed severe arteriolar hyalinosis and arteriosclerosis. Two of our patients underwent living donor renal transplantation and are doing well (2 years’ posttransplant), with stable renal functions and no proteinuria.
The pathogenesis of CG involves visceral epithelial cell injury leading to cell cycle dysregulation and proliferative phenotype. Salvatore et al[9] have postulated that ischemic podocyte injury secondary to severe obliterative microvascular diseases such as arteriolar hyalinosis and arteriosclerosis play an important role. The development of CG in DN has a unique pathology (Figure 2).
Figure 2: Pathogenesis of development of collapsing glomerulopathy in diabetes mellitus.
Unlike other podocytopathies, the podocyte injury in CG is characterized by a marked dysregulation of quiescent podocyte phenotype. The diseased podocytes exhibit a loss of markers of differentiation and a gain of markers of proliferation. The markers of proliferation (e.g., podocalyxin, synaptopodin, and WT-1), and markers of differentiation on the surface of the podocytes (e.g., cyclin D1 and cyclin E). The podocytes have been described to “transdifferentiate” toward amacrophage-like cell. Thus, in CG, there is a distinct pattern of proliferative parenchymal injury. In the study by Salvatore et al, the markers of mature podocytes (WT-1, synaptopodin, and podocalyxin) were variably absent in the glomerulus in the segments of collapse.[9] Immunohistochemistry was not done in our study.
In DN, renal dysfunction may result primarily from progressive glomerulosclerosis, which may be a cause or a consequence of concomitant hypertension and obesity. Vascular compromise may lead to glomerular and podocyte ischemia in DN in a similar mechanism as in other secondary forms of CG. CG is often focal and could be easily missed on biopsy. Since the presentation of proteinuria is a shared manifestation of underlying diabetic process as well as CG, it may be clinically overlooked by the treating nephrologist.
Conclusion
Severe podocyte injury and development of CG contribute to an increased level or new onset proteinuria in DN. Significant hyaline vascular disease, commonly observed in DN, could contribute to ischemic insult to podocytes. The diagnosis of CG superimposed on DN is of prognostic significance, and it signifies poor prognosis.
Conflict of interest:
None declare
REFERENCES
1. Reutens AT. Epidemiology of diabetic kidney disease. Med Clin North Am 2013;97:1–18
2. Kasinath BS, Mujais SK, Spargo BH, Katz AI. Nondiabetic renal disease in patients with diabetes mellitus. Am J Med 1983;75:613–7
3. Amoah E, Glickman JL, Malchoff CD, Sturgill BC, Kaiser DL, Bolton WK. Clinical identification of nondiabetic renal disease in diabetic patients with type I and type II disease presenting with renal dysfunction. Am J Nephrol 1988;8:204–11
4. Albaqumi M, Soos TJ, Barisoni L, Nelson PJ. Collapsing glomerulopathy. J Am Soc Nephrol 2006;17:2854–63
5. D'Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic classification of focal segmental glomerulosclerosis: A working proposal. Am J Kidney Dis 2004;43:368–82
6. Laurinavicius A, Hurwitz S, Rennke HG. Collapsing glomerulopathy in HIV and non-HIV patients: A clinicopathological and follow-up study. Kidney Int 1999;56:2203–13
7. Valeri A, Barisoni L, Appel GB, Seigle R, D’Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: A clinicopathologic study. Kidney Int 1996;50:1734–46
8. Wiggins RC. The spectrum of podocytopathies: A unifying view of glomerular diseases. Kidney Int 2007;71:1205–14
9. Salvatore SP, Reddi AS, Chandran CB, Chevalier JM, Okechukwu CN, Seshan SV. Collapsing glomerulopathy superimposed on diabetic nephropathy: Insights into etiology of an under-recognized, severe pattern of glomerular injury. Nephrol Dial Transplant 2014;29:392–9
10. Etta PK, Rao MV, Gowrishankar S. Collapsing glomerulopathy superimposed on diabetic nephropathy. Indian J Nephrol 2019;29:207–10
11. Barisoni L, Schnaper HW, Kopp JB. A proposed taxonomy for the podocytopathies: A reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol 2007;2:529–42
