|Year : 2016 | Volume
| Issue : 4 | Page : 144-148
Nondiabetic renal disease: a conclusive renal biopsy can overcome diagnosis delay
Mohamed O Ezwaie1, Sahar J Kharraz2, Jebril S Alabidi2, Aisha A Jazwee2
1 Nephrology and Hemodialysis Division, Department of Medicine, Benghazi Medical Center; Department of Medicine, Faculty of Medicine, Benghazi University, Benghazi, Libya
2 Nephrology and Hemodialysis Division, Department of Medicine, Benghazi Medical Center, Benghazi, Libya
|Date of Submission||29-Feb-2016|
|Date of Acceptance||15-Nov-2016|
|Date of Web Publication||20-Feb-2017|
Mohamed O Ezwaie
Nephrology and Hemodialysis Division, Benghazi Medical Center, Benghazi University, Benghazi
Source of Support: None, Conflict of Interest: None
Diabetic patients are at risk of developing renal dysfunction as part of microvascular complications of diabetes mellitus, but they could develop renal dysfunction because of nondiabetic renal diseases as a result of glomerulopathy, either in primary or secondary forms (glomerulonephritis or vasculitis), or as part of tubulointerstitial involvement because of paraproteinemia. Here, we report on two diabetic patients who had different clinical profiles in terms of their diabetes type, clinical presentation, and decrease in renal dysfunction from the time of diagnosis of diabetes mellitus. A clinical scenario resulted in a delay in diagnosis and management, until a conclusive renal biopsy reported a definitive diagnosis, with implementation of therapeutic protocols and satisfactory outcomes in both patients.
Keywords: diffuse alveolar hemorrhage, focal segmental glomerulosclerosis, heavy proteinuria, Henoch–Schönlein purpura, nondiabetic renal disease
|How to cite this article:|
Ezwaie MO, Kharraz SJ, Alabidi JS, Jazwee AA. Nondiabetic renal disease: a conclusive renal biopsy can overcome diagnosis delay. J Egypt Soc Nephrol Transplant 2016;16:144-8
|How to cite this URL:|
Ezwaie MO, Kharraz SJ, Alabidi JS, Jazwee AA. Nondiabetic renal disease: a conclusive renal biopsy can overcome diagnosis delay. J Egypt Soc Nephrol Transplant [serial online] 2016 [cited 2017 Dec 17];16:144-8. Available from: http://www.jesnt.eg.net/text.asp?2016/16/4/144/200352
| Introduction|| |
The overall incidence of diabetic nephropathy (DN) in type 1 diabetes mellitus (DM) is in the range of 30–45%, with peak onset 10–15 years after the diagnosis of diabetes. This diabetic complication tends to occur in a somewhat predictable manner in type 1 than in type 2 DM. The current diagnosis of DN is mostly made on the basis of clinical findings and supported by persistent proteinuria without hematuria, in conjunction with a slowly progressive decrease in renal function. However, diabetic patients are at risk of developing nondiabetic renal disease (NDRD) ,, which should be suspected when renal dysfunction occurs in a rapidly progressive form or overt proteinuria is diagnosed in patients with a relatively shorter duration of DM, associated with active urinary sediment findings. NDRD is common in type 2 DM (22% in European patients vs. 26.7% in Asian patients) , whereas NDRD is rare in patients with type 1 DM, accounting for 2–3% of unselected diabetic patients with proteinuria . Our first patient had a juvenile form of DM for two decades; the rapid onset of renal dysfunction along with systemic involvement led us to suspect the presence of NDRD, until a second renal biopsy was performed, which indicated mesangial IgA deposition; thus, a diagnosis of Henoch–Schönlein purpura-related nephritis was made. The second patient was a middle-aged woman with type 2 DM of 8 years, who presented with poorly controlled hypertension and heavy proteinuria without significant retinopathy, associated with active urinary sediment, a negative autoimmune profile (AIP), and subsequent renal biopsy that indicated a focal segmental glomerulosclerosis pathology.
| Case presentation|| |
A 30-year-old woman presented to us; she had type 1 DM since 1993, gravida 5, para 4, with one abortion, and all her deliveries were performed by elective cesarean section because of large-size babies. Despite long-standing DM (20 years), there was no clinical evidence of microvascular or macrovascular complications, no history suggestive of pre-eclampsia during her pregnancies, and no history of photosensitivity, arthralgia, mouth ulcers, or deep vein thrombosis.
In May 2013 (4 weeks after delivery), she was admitted to the hospital in a critical state (for 10 days) with generalized anasarca, respiratory distress with hemoptysis, and purpuric skin rash ([Figure 1]). She was treated with loop diuretics, steroids, and multiple blood transfusions, and required respiratory support. Her renal function was marginally deteriorated (serum creatinine 1.8 mg/dl), but with significant proteinuria (4–5 g/day) chest x-ray (CXR), bilateral lung infiltrations ([Figure 2]); her coagulation profile was normal and her diabetes was managed with insulin infusion. A provisional diagnosis of systemic lupus with vasculitis was made, although she did not fulfill any definite clinical or serological criteria for systemic lupus erythematosus. In June 2013, she was discovered to have positive hepatitis C virus (HCV) serology and her autoimmune profile (AIP) was negative for cytoplasmic antinuclear cytoplasmic antibody (c-ANCA) and perinuclear antinuclear cytoplasmic antibody (p-ANCA).
In August 2013, she underwent evaluation for her persistent nephrotic syndrome, hemoptysis, and vasculitic purpuric rash. Chest computed tomography showed upper and lower pneumonic infiltrates mainly on the right side, AIP was negative for anti double strand DNA (anti-dsDNA), anticulear antibody (ANA), p-ANCA, c-ANCA, antiphospholipid antibodies, and C3 and C4 were normal, and there was no cryoglobulinemia. A diagnosis of ANCA-negative vasculitis was made rather than HCV-related nephritis, and she was started on pulse methylprednisolone therapy 1 g for 4 days, followed by prednisolone 60 mg/day and azathioprine 50 mg/day. Her proteinuria level became less than 2 g/day and renal function (serum creatinine 0.8 mg/dl) improved.
In October 2013, the patient was grossly cushingoid hypertensive, still had a recurrent purpuric skin rash, episodes of nondysenteric diarrhea, bilateral loin pain, and ankle edema with microscopic hematuria and moderate proteinuria despite being on immunosuppressive therapy, prednisolone, and azathioprine.
In December 2013, repeat renal biopsy with light microscopy (L/M), immunofluorescence (IF), and electron microscope (E/M) indicated membranoproliferativeglomerulonephritis (MPGN) with classical IgA mesangial deposition ([Figure 3]). A final diagnosis of Henoch–Schönlein purpura with renal and lung involvement was made. She was a candidate for induction therapy, with four pulses of intravenous methylprednisolone (1 g each), to control her severe systemic vasculitis, followed by cyclosporine, with maintenance azathioprine as a steroid-sparing agent (to limit her cushingoid features).
In July 2015, her current therapy included cyclosporine 75 mg twice daily, azathioprine 50 mg once daily (OD), candesartan 16 mg OD, and furosemide 40 mg as needed; there were no purpuric eruptions and no edema. Her blood pressure (BP) was 120/80 mmHg. Her recent laboratory data were as follows: serum creatinine was 1.3 mg/dl, proteinuria reduced to 600 mg/24 h, there was no microscopic hematuria, creatinine clearance was 62.8 ml/min, and HbA1C was 6.6%.
A 59-year-old Libyan woman with a history of type 2 DM for 8 years presented (July 2014) with bilateral leg swelling and exertional dyspnea II for 2 weeks. There was no orthopnea or paroxysmal nocturnal dyspnea (PND), no oliguria or hematuria, and no features of connective tissue disease (CTD) (skin rash, alopecia, ulcerations, arthropathy, and Raynaud’s phenomenon). The patient was shifted 2 years ago from oral hypoglycemic agent (OHA) to a Mixtard regimen plus metformin, with relatively adequate glycemic control (HbA1C 6.5–7.2%), but her lipid profile required initiation of statin therapy (rosuvastatin 20 mg daily). She had been hypertensive for the last 2 years, which had become difficult to control over the last 6 months despite combined enalapril and metoprolol therapy.
Physical on examination (O/E): she was relatively obese (BMI 29.3 kg/m2) and her BP was 160/90 mmHg. She had pitting edema lower limbs (LL) (++), but jugular venous pulse (JVP) was normal. There was no goiter, palpable cervical lymph node (LN): left side (chronic gingivitis), breast O/E: normal, chest bilateral: basal stony dullness. There were regular heart sounds, with ejection systolic murmur (ESM) at the base of the heart, no organomegaly of the abdomen, and no shifting dullness. Neurologically, the cranial nerves were normal, and there was no motor or sensory deficit, or delayed ankle jerks.
Laboratory data were as follows: blood urea 30 mg/dl, serum creatinine 1.7 mg/dl, K 4.3 mmol/lm serum albumin 2.4 g/dl, aspartate aminotransferase (AST) 25 IU/l, alanine aminotransterase (ALT) 18 IU/l, FBG 123 mg/dl, HbA1C 7.1%, cholesterol 388 mg/dl, low density cholesterol (LDL) 284 mg/dl, high density cholesterol (HDL) 43 mg/dl, triglyceride (TG) 202 mg/dl serum Ca 8.9 mg/dl, and serum PO4 3.6 mg/dl. Peripheral blood film indicated normocytic normochromic anemia, no blast cells, and erythrocyte sedmintation rate (ESR) 42 mm/h; HCV, HIV, and HbsAg were all negative. Urine examination indicated red blood cell (RBC) 10–12/high power field (HPF), with few granular casts, total protein 7.4 g/24 h, protein–creatinine ratio 5.1 (normal<0.2 mg), and creatinine clearance 72.6 ml/min/1.73 m2. On serum protein electrophoresis, there was no paraprotein band. Her AIP was negative for anti-dsDNA, c-ANCA, and p-ANCA, with normal complement components.
Imaging studies of the neck showed multiple cervical LNs, the largest being 1.2 cm in size, in the left submandibular region (chronic gingivitis, which responded to a 10-day course of amoxicillin). Chest and mediastinum studies showed that lung parenchyma was normal, there was no hilar or mediastinal LNs, but with evidence of pleural effusion bilateral. Studies of the abdomen and pelvis showed that liver parenchyma was normal and both kidneys were normal in size, with a simple small cortical cyst in right. Studies of the kidney showed no para aortic LN, and adnexa were normal.
Case review: a middle-aged obese woman with type 2 DM (8 years) presented with the following:
- Severe nephrotic syndrome (overt proteinuria 7.4 g/24 h).
- Uncontrolled hypertension.
- Hyperlipidemia (despite normal HbA1C).
- No clinical evidence of microvascular complications.
- No clinical features of CTD.
- Negative AIP.
- Negative infectious serology.
| Discussion|| |
The functional structure of the nephron, particularly the glomerular components, glomerular basement membrane, and the mesangium, are potential targets for immune complex deposition, which is triggered by a variety of systemic vasculitic processes . In addition, kidneys receive 25% of cardiac output, resulting in a high (proteins and immune complexes) filtration pressure.
Henoch-Scholein purpura (HSP) is a nonthrombocytopenic small-vessel vasculitis, characterized by tissue deposition of IgA-containing immune complexes. It is a disease that occurs mainly in children and young adults (<20 years of age), with an estimated incidence of 14–20 per 100 000 population, whereas the incidence in adults varies between 3.4 and 14.3 per million population. For this reason, only a few reports of HSP in adults are available in the literature . Infectious etiology (parvovirus B19 and streptococci) has been implicated in the development of HSP, but it is not a prerequisite for the occurrence of the disease . HSP usually runs a benign course in children, but in adults, presentation can be more dramatic and severe, and relapses are more frequent. In the absence of renal disease, complete recovery is observed in 94% in children, whereas in adults, complete recovery is observed in 89% of cases and the disease lasts 4–6 weeks. However, recurrence occurs in approximately one-third of patients with nephritis, with 11% becoming dialysis dependent after 15 years of follow-up ,.
Furthermore, diabetic patients are susceptible to infectious (pneumonia) and noninfectious (nephropathy) complications. In our case, her vasculitic presentation was preceded by severe pneumonia, which was complicated by diabetic ketoacidosis during the last trimester of her last pregnancy; this infection episode probably triggered her postpartum systemic vasculitis.
Until 1990, the American College of Rheumatology criteria for HSP were the most commonly used criteria for diagnosis. This classification has been superseded by the European League Against Rheumatism (EULAR, 2008) criteria for the classification of vasculitis . Our patient fulfilled three criteria (cutaneous and renal), including biopsy-proven IgA deposition.
The first presentation of our patient was highly suggestive of an NDRD, as part of systemic vasculitis, as she presented with nonthrombocytopenic purpura, respiratory distress associated with rapidly declining hemoglobin, and the requirement for multiple blood transfusions highly suggestive of diffuse alveolar hemorrhage, and nephrotic syndrome with deterioration of renal function (serum creatinine 2 mg/dl). At that time, her AIP was negative for lupus autoantibodies and ANCA antibodies and anti-GBM antibodies were not assessed; she was managed in more conservative way using oral steroids.
Upon further evaluation, she was found to have positive HCV serology, and on the basis of the first renal biopsy report, this was interpreted on light microscopy finding of membranoproliferative glomerulonephritis, with an assumption of HCV-related nephropathy, despite the fact that her HCV infection was of recent onset and there was no evidence of cryoglobulinemia. She was started on hepatitis C virus eradication therapy, on rather empiric basis, which was stopped after 6 months, because of severe pancytopenia, and her clinical course showed a poor response as she had recurrent episodes of purpuric skin rash and evidence of persistent nephritis .
When she was referred to us 12 months from onset, we believed that her NDRD was most likely because of ANCA-negative vasculitis on the basis of multisystem involvement and a negative AIP. However, for an etiological diagnosis, we decided to perform a second renal biopsy, which clearly showed MPGN with mesangial IgA deposition, with no extracapillary proliferation or interstitial involvement ; thus, a final diagnosis of Henoch–Schönlein purpura was made. Diffuse alveolar hemorrhage is exceedingly rare in HSP, but can occur, as in our patient , and an induction therapy using four pulses of methylprednisolone, followed by cyclosporine at 100 mg twice daily and azathioprine at 75 mg daily (started as steroid-sparing adjuvant therapy), was effective, and the patient achieved good clinical remission within 6 weeks ,.
A wide spectrum of NDRD has been reported in type 2 DM by many studies . The most common NDRD found in type 2 DM include acute tubulointerstitial nephritis, membranous nephropathy, IgA nephropathy, crescentic glomerulonephritis, and focal segmental glomerulosclerosis . Our patient, an elderly obese woman with type 2 DM (8 years), presented with severe nephrotic syndrome (overt proteinuria, 7.4 g/24 h); three predisposing factors influence the occurrence of focal segmental glomerulosclerosis rather than DN: obesity, short duration of DM, and absence of retinopathy ,.
The patient was started on nephropathy conservative therapy: salt and protein restriction (0.8 g/kg/day), loop diuretics, triple antihypertensive regimen, enalapril, bisoprolol, and diltiazem. Rosuvastatin was increased to 40 mg OD dalteparin prophylaxis subcutaneous (S/C) 3500 U on a daily basis. The patient responded well (6 weeks): proteinuria reduced to 5.6 g/day, serum albumin 3.1 g/dl. Renal function worsened (serum creatinine 2.5 mg/dl), with persistent microscopic hematuria, despite good control of BP (120/80 mmHg).
On the basis of the persistent nephrotic syndrome and worsening renal function, a computed tomography-scan guided kidney biopsy (September 2014, [Figure 4]) was performed: L/M: 12 glomeruli, 2 sclerotic, and 5 focal segmental sclerosis, the rest of the glomeruli showed normal mesangial cellularity with normal glomerular basement membrane (GBM) thickness. Interstitium showed normal cellularity, with a mild degree of tubular atrophy, and no tubulitis or tubular necrosis. Arterioles showed mild intimal proliferation and moderately thickened media IF: IgM mesangial deposits; there was no IgA deposition.
|Figure 4: (a) Early focal segmental changes at the periphery of the glomerulus (H&E stain). (b) Focal segmental glomerulosclerosis with IgM nonlinear immunofluorescence deposits.|
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For the postmenopausal diabetic patient (risk of osteoporosis), biopsy showed no interstitial damage, but there was mild renal dysfunction; cyclosporine 125 mg twice daily was started, with prednisolone 10 mg daily for 3–4 months to achieve remission. Her last laboratory data (January 2016) were as follows: serum creatinine 0.9 mg/dl, serum albumin 3.7 g/dl, HbA1C 7.1%, no microscopic hematuria, urine protein 180 mg/24 h, and creatinine clearance 89 ml/min/1.73 m2.
| Conclusion|| |
Diabetic patients are prone to NDRD (glomerulopathy and vasculitis). Henoch–Schönlein purpura is not always a benign vasculitis, particularly in adults, where nephritis and relapses are more frequent, and can be associated with severe complications such as diffuse alveolar hemorrhage. Evidence suggests that glucocorticoids increase the rate of resolution of the arthritis and abdominal pain, but when used alone, do not appear to prevent recurrent disease or decrease the likelihood of progression of renal disease, mandating the use of cytotoxic (cyclophosphamide/cyclosporine) therapy. The duration of diabetes (<10 years) is one of the strongest predictors of NDRD, particularly in type 2 DM. Although retinopathy is less frequent in type 2 DM in comparison with type 1 DM, the absence of retinopathy favors NDRD in type 2 DM, but still does not exclude the occurrence of DN in patients with subnephrotic proteinuria. To confirm the diagnosis in type 2 DM with proteinuria, a full AIP and a conclusive renal biopsy are necessary to define the nature of nephropathy to implement the appropriate therapeutic protocol and the renal outcomes of NDRD in diabetic patients depend on the nature of the nondiabetic lesion.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]