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Resolution of C1q deposition but not of the clinical nephrotic syndrome after immunomodulating therapy in focal sclerosis.

Tibor Fülöp T, Csongrádi É, Lerant AA, Lewin M, Lewin JR - J Nephropathol (2015)

Bottom Line: The biopsy revealed focal sclerosis but no C1q deposition.Second, histological diagnoses may evolve over time, especially in a patient receiving active and powerful immune-modulating treatment.In our case, the clinical nephrosis did not change with immunosuppressive therapy while C1q deposition ceased, making this latter entity likely the immunologically mediated process.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, University of Mississippi Medical Center, Jackson, MS, USA.

ABSTRACT

Background: The natural evolution of C1q nephropathy (C1qNP) during immunosuppressive treatment is relatively little studied or understood.

Case presentation: A 30 year-old Caucasian female was referred to us for further management of biopsy-proven C1qNP and severe nephrotic syndrome. Serologic work-up remained negative, including complement C3 and C4 levels and repeated testing for antinuclear antibodies. A renal biopsy revealed minimal change nephropathy vs. focal sclerosis on light microscopy and C1qNP on immunopathology. She has failed trials of high-dose oral prednisone, mycophenolate mofetil 1,500 mg twice a day and a subsequent regimen of monthly IV cyclophosphamide 750 mg × 9 cycles. She also received the maximum tolerated angiotensin-converting enzyme inhibitor and spironolactone therapy. Random urine protein-to-creatinine (UPC) ratio predicted proteinuria in the range between 5-35 gm/day, while serum creatinine rose progressively from 1.0 mg/dL to 1.4 mg/dL (to convert to μmol/L, multiply by 88.4). A decision was made to repeat renal biopsy to reassess the underlying histology. The biopsy revealed focal sclerosis but no C1q deposition.

Conclusions: Our case illustrates at least two points: first, an established pathologic diagnosis does not obviate the need for repeated renal biopsy later on, should diagnostic uncertainty persist. Second, histological diagnoses may evolve over time, especially in a patient receiving active and powerful immune-modulating treatment. In our case, the clinical nephrosis did not change with immunosuppressive therapy while C1q deposition ceased, making this latter entity likely the immunologically mediated process.

No MeSH data available.


Related in: MedlinePlus

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Mentions: A 30 year-old Caucasian female has been referred to our medical center with a diagnosis of biopsy-proven C1qNP for further management. She had profound nephritic syndrome with serum albumin 1.2-2 g/dL (to convert to g/L, multiple by 10), with co-morbid stage III chronic kidney disease, high blood pressure, untreated obstructive sleep apnea (OSA), hyperlipemia, depression, obesity and electrolyte problems (persisting metabolic alkalosis and hypokalemia). She presented initially to an outside nephrologist with clinical nephrosis 10 months after childbirth with Cesarean delivery. Initial serologic work-up was entirely unremarkable, including serum complement C3 and C4 levels and testing for antinuclear antibodies. One month later (09/2006) she received a renal biopsy revealing minimal change nephropathy versus focal segmental glomerulosclerosis (FSG) on light microscopy and C1qNP on immunopathology. The light microscopy specimen had 10 glomeruli (one of them globally sclerosed) but no fibrosis or crescent formation. Immunofluorescence was also positive for IgG in selected glomerular areas but none was detected for complement C3, C4, albumin or fibrinogen. Electron microscopy described mesangial dense deposits in the glomeruli and an extensive effacement of the visceral epithelial cell foot processes (Figures 1- 3). Thereafter, she received repeated trials of high-dose glucocorticoids (1 mg/kg per os prednisone) via her local nephrologist, but achieved only partial remission (predicted proteinuria range 20-30 g/day) and immediate flares of profound clinical nephrosis, once withdrawal of steroids was attempted. At this point, her primary nephrologist requested a second opinion with our medical center. During her first visit with us (06/2007), she had normal blood pressure of 123/81 mmHg but had severe, 3+ bilateral pitting edema. She has weighed 105 kg and her body mass index calculated at 40 kg/m2. Serum albumin was 1.4 gm/dL with random urine protein/creatinine (UPC) concentrations of 4800 and 133 mg/dL (predicted proteinuria 36 gm/day); serum electrolytes were remarkable for serum potassium 3 mM/L and bicarbonate 31 mM/L. A repeated serologic workup with us also remained entirely negative. At that point of time, her medical therapy has been revised with escalation of potassium-sparing diuretics and sleep medicine consultation was initiated for a suspected OSA. Her immuno-modulating therapy was also revised. Her initial regimen was a combination of mycophenolate mofetil 1500 mg twice a day and prednison 40 mg once a day for 14 months, thereafter, we switched to monthly IV cyclophosphamide 750 mg × 9 cycles. Her clinical response to these therapies was only marginal with only mild and transient improvement of nephritic syndrome and subjective well-being. Her care was further complicated by the cessation of compliance with continuous positive airway pressure (CPAP) for OSA and occasional lapses of compliance with medical therapy and follow-up. Altogether, over this period her serum albumin varied from 1.2 to 2.8 mg/dL and predicted proteinuria based on random UPC ranged 5-35 g/day, while creatinine rose progressively from 1.0 mg/dL to 1.4 mg/dL (to convert to μmol/L, multiply by 88.4). However, with a regimen of “triple diuretics” (furosemide, metolazone, spironalactone) we have been able to control clinical nephrosis and peripheral edema to an acceptable degree. Approximately 2 years after her initial visit with us we faced the clinical dilemma of ongoing nephritis-range proteinuria failing maximized and multifaceted medical therapy. While she claimed that she felt better on IV Cyclophosphamide, she did not achieve meaningful remission of nephrosis on any of the attempted immune-modulating therapy, along with maximally tolerated doses of ACE inhibitor and spironolactone. Therefore, a decision was made to proceed with a repeated renal biopsy to reassess the underlying histology. Her medical therapy at this point included furosemide 80 mg once in the morning and once at noon, spironolactone 400 mg daily, amiloride 5 mg daily, metolazone 5 mg daily, lisinopril 40 mg daily, esomeprazole 40 mg daily, paroxetine 40 mg daily, combined estrogen/progesterone hormone preparation for birth control and as needed trazodone at bedtime. A repeated renal biopsy (07/2009) was a limited specimen without overt interstitial fibrosis, but 1 of the 6 recovered glomeruli showed focal sclerosis; however, no C1q deposition was observed (Figures 4-5). Additionally, immunofluorescence of the specimen was negative for C4 and fibrinogen and had only a very sparse staining for glomerular C3 and tubular IgG. Once again, diffuse podocyte foot process effacement was noted on the electron microscopy specimen but no electron dense deposit. Based on this biopsy, further immunosuppressant medical therapy has been abandoned and she was treated with continuing antihypertensive therapy only, including ACE inhibitors and potassium-sparing diuretics.


Resolution of C1q deposition but not of the clinical nephrotic syndrome after immunomodulating therapy in focal sclerosis.

Tibor Fülöp T, Csongrádi É, Lerant AA, Lewin M, Lewin JR - J Nephropathol (2015)

© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4417671&req=5

Mentions: A 30 year-old Caucasian female has been referred to our medical center with a diagnosis of biopsy-proven C1qNP for further management. She had profound nephritic syndrome with serum albumin 1.2-2 g/dL (to convert to g/L, multiple by 10), with co-morbid stage III chronic kidney disease, high blood pressure, untreated obstructive sleep apnea (OSA), hyperlipemia, depression, obesity and electrolyte problems (persisting metabolic alkalosis and hypokalemia). She presented initially to an outside nephrologist with clinical nephrosis 10 months after childbirth with Cesarean delivery. Initial serologic work-up was entirely unremarkable, including serum complement C3 and C4 levels and testing for antinuclear antibodies. One month later (09/2006) she received a renal biopsy revealing minimal change nephropathy versus focal segmental glomerulosclerosis (FSG) on light microscopy and C1qNP on immunopathology. The light microscopy specimen had 10 glomeruli (one of them globally sclerosed) but no fibrosis or crescent formation. Immunofluorescence was also positive for IgG in selected glomerular areas but none was detected for complement C3, C4, albumin or fibrinogen. Electron microscopy described mesangial dense deposits in the glomeruli and an extensive effacement of the visceral epithelial cell foot processes (Figures 1- 3). Thereafter, she received repeated trials of high-dose glucocorticoids (1 mg/kg per os prednisone) via her local nephrologist, but achieved only partial remission (predicted proteinuria range 20-30 g/day) and immediate flares of profound clinical nephrosis, once withdrawal of steroids was attempted. At this point, her primary nephrologist requested a second opinion with our medical center. During her first visit with us (06/2007), she had normal blood pressure of 123/81 mmHg but had severe, 3+ bilateral pitting edema. She has weighed 105 kg and her body mass index calculated at 40 kg/m2. Serum albumin was 1.4 gm/dL with random urine protein/creatinine (UPC) concentrations of 4800 and 133 mg/dL (predicted proteinuria 36 gm/day); serum electrolytes were remarkable for serum potassium 3 mM/L and bicarbonate 31 mM/L. A repeated serologic workup with us also remained entirely negative. At that point of time, her medical therapy has been revised with escalation of potassium-sparing diuretics and sleep medicine consultation was initiated for a suspected OSA. Her immuno-modulating therapy was also revised. Her initial regimen was a combination of mycophenolate mofetil 1500 mg twice a day and prednison 40 mg once a day for 14 months, thereafter, we switched to monthly IV cyclophosphamide 750 mg × 9 cycles. Her clinical response to these therapies was only marginal with only mild and transient improvement of nephritic syndrome and subjective well-being. Her care was further complicated by the cessation of compliance with continuous positive airway pressure (CPAP) for OSA and occasional lapses of compliance with medical therapy and follow-up. Altogether, over this period her serum albumin varied from 1.2 to 2.8 mg/dL and predicted proteinuria based on random UPC ranged 5-35 g/day, while creatinine rose progressively from 1.0 mg/dL to 1.4 mg/dL (to convert to μmol/L, multiply by 88.4). However, with a regimen of “triple diuretics” (furosemide, metolazone, spironalactone) we have been able to control clinical nephrosis and peripheral edema to an acceptable degree. Approximately 2 years after her initial visit with us we faced the clinical dilemma of ongoing nephritis-range proteinuria failing maximized and multifaceted medical therapy. While she claimed that she felt better on IV Cyclophosphamide, she did not achieve meaningful remission of nephrosis on any of the attempted immune-modulating therapy, along with maximally tolerated doses of ACE inhibitor and spironolactone. Therefore, a decision was made to proceed with a repeated renal biopsy to reassess the underlying histology. Her medical therapy at this point included furosemide 80 mg once in the morning and once at noon, spironolactone 400 mg daily, amiloride 5 mg daily, metolazone 5 mg daily, lisinopril 40 mg daily, esomeprazole 40 mg daily, paroxetine 40 mg daily, combined estrogen/progesterone hormone preparation for birth control and as needed trazodone at bedtime. A repeated renal biopsy (07/2009) was a limited specimen without overt interstitial fibrosis, but 1 of the 6 recovered glomeruli showed focal sclerosis; however, no C1q deposition was observed (Figures 4-5). Additionally, immunofluorescence of the specimen was negative for C4 and fibrinogen and had only a very sparse staining for glomerular C3 and tubular IgG. Once again, diffuse podocyte foot process effacement was noted on the electron microscopy specimen but no electron dense deposit. Based on this biopsy, further immunosuppressant medical therapy has been abandoned and she was treated with continuing antihypertensive therapy only, including ACE inhibitors and potassium-sparing diuretics.

Bottom Line: The biopsy revealed focal sclerosis but no C1q deposition.Second, histological diagnoses may evolve over time, especially in a patient receiving active and powerful immune-modulating treatment.In our case, the clinical nephrosis did not change with immunosuppressive therapy while C1q deposition ceased, making this latter entity likely the immunologically mediated process.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, University of Mississippi Medical Center, Jackson, MS, USA.

ABSTRACT

Background: The natural evolution of C1q nephropathy (C1qNP) during immunosuppressive treatment is relatively little studied or understood.

Case presentation: A 30 year-old Caucasian female was referred to us for further management of biopsy-proven C1qNP and severe nephrotic syndrome. Serologic work-up remained negative, including complement C3 and C4 levels and repeated testing for antinuclear antibodies. A renal biopsy revealed minimal change nephropathy vs. focal sclerosis on light microscopy and C1qNP on immunopathology. She has failed trials of high-dose oral prednisone, mycophenolate mofetil 1,500 mg twice a day and a subsequent regimen of monthly IV cyclophosphamide 750 mg × 9 cycles. She also received the maximum tolerated angiotensin-converting enzyme inhibitor and spironolactone therapy. Random urine protein-to-creatinine (UPC) ratio predicted proteinuria in the range between 5-35 gm/day, while serum creatinine rose progressively from 1.0 mg/dL to 1.4 mg/dL (to convert to μmol/L, multiply by 88.4). A decision was made to repeat renal biopsy to reassess the underlying histology. The biopsy revealed focal sclerosis but no C1q deposition.

Conclusions: Our case illustrates at least two points: first, an established pathologic diagnosis does not obviate the need for repeated renal biopsy later on, should diagnostic uncertainty persist. Second, histological diagnoses may evolve over time, especially in a patient receiving active and powerful immune-modulating treatment. In our case, the clinical nephrosis did not change with immunosuppressive therapy while C1q deposition ceased, making this latter entity likely the immunologically mediated process.

No MeSH data available.


Related in: MedlinePlus