What is the appropriate workup and treatment for a patient with hematuria and a history of renal transplant, who is currently on immunosuppressive therapy?

Workup and Management of Hematuria in Renal Transplant Recipients

In a renal transplant recipient with hematuria, immediately obtain an allograft biopsy when there is unexplained hematuria, particularly if the patient has a history of potentially treatable recurrent primary kidney disease such as IgA nephropathy, MPGN, anti-GBM disease, or ANCA-associated vasculitis. 1, 2, 3

Initial Diagnostic Approach

Determine the Source and Etiology

First, establish whether hematuria is microscopic or gross, and identify the most likely source:

• Evaluate for recurrent glomerulonephritis if the patient's original kidney disease was IgA nephropathy, MPGN, anti-GBM disease, or ANCA-associated vasculitis, as these conditions commonly recur and present with microhematuria 1
• Assess for thrombotic microangiopathy (TMA) if the original disease was HUS, particularly during episodes of graft dysfunction 1, 4
• Consider graft intolerance syndrome if gross hematuria is accompanied by allograft tenderness, fever, or constitutional symptoms 1
• Rule out malignancy in the transplanted kidney, bladder, or native kidneys, as immunosuppression increases cancer risk 1, 5
• Evaluate for infectious causes including BK virus nephropathy, particularly if there is concurrent graft dysfunction 1
• Consider vascular complications such as pseudoaneurysm at the anastomotic site, especially if there is gross hematuria 6

Essential Laboratory and Imaging Studies

Obtain the following tests immediately:

• Urinalysis with microscopy to quantify hematuria and assess for proteinuria, casts, and dysmorphic red blood cells 1, 2
• Urine protein-to-creatinine ratio to quantify proteinuria 1, 2
• Serum creatinine to assess for graft dysfunction 1, 2
• Complete blood count with peripheral smear to evaluate for schistocytes if TMA is suspected 1, 4
• Lactate dehydrogenase, haptoglobin, and indirect bilirubin if hemolysis/TMA is suspected 1, 4
• ADAMTS13 activity level and inhibitor titer if TTP is in the differential 4
• BK virus quantitative plasma PCR if viral nephropathy is suspected 1
• ANCA, anti-GBM antibodies, complement levels if recurrent vasculitis or glomerulonephritis is suspected 3

Imaging considerations:

• Renal ultrasound with Doppler of the transplanted kidney to assess for structural abnormalities, masses, or vascular complications 5, 6
• CT urography if urothelial malignancy is suspected, though contrast administration should be carefully considered given transplant status 1
• Cystoscopy if bladder pathology (malignancy, infection) is suspected 1, 5

When to Perform Allograft Biopsy

Proceed immediately to allograft biopsy in the following scenarios:

• Unexplained proteinuria >3.0 g/day 2, 3
• Persistent unexplained increase in serum creatinine 1, 2, 3
• New onset proteinuria with hematuria in patients with primary diseases prone to recurrence 1, 2
• Microhematuria in patients with IgA nephropathy, MPGN, anti-GBM disease, or ANCA vasculitis as original disease 1, 3

The biopsy is critical because recurrent disease can occur as early as 19 days post-transplant and requires specific treatment 2. Do not delay biopsy when clinical indicators are present, as early intervention improves outcomes 2, 3.

Treatment Based on Etiology

Recurrent Glomerulonephritis (IgA Nephropathy, MPGN)

If biopsy confirms recurrent glomerulonephritis with proteinuria:

• Initiate ACE inhibitor or ARB at maximum tolerated dose for proteinuria >0.5 g/day 1, 2, 3
• Target blood pressure <130/80 mmHg if proteinuria <1 g/day, or <125/75 mmHg if proteinuria >1 g/day 2
• Consider corticosteroid therapy (6-month course) if proteinuria remains >0.75-1 g/day after at least 90 days of optimized supportive care and eGFR >50 ml/min/1.73 m² 2
• Avoid corticosteroids if eGFR <30 ml/min/1.73 m² unless there is crescentic disease with rapidly deteriorating function 2, 3

Recurrent ANCA Vasculitis or Anti-GBM Disease

If biopsy shows recurrent rapidly progressive glomerulonephritis:

• Immediately initiate high-dose corticosteroids (methylprednisolone pulses followed by oral prednisone taper for at least 6 months) 1, 3
• Add cyclophosphamide (oral daily for 3 months) 1, 3
• For anti-GBM disease specifically, add plasma exchange for 14 days or until anti-GBM antibodies become undetectable 3
• Consider rituximab as alternative or addition for severe ANCA vasculitis 3

Thrombotic Microangiopathy/HUS-TTP

If clinical and laboratory findings suggest TMA:

• Initiate therapeutic plasma exchange immediately with fresh frozen plasma if ADAMTS13 activity is severely reduced or life-threatening consequences exist 4
• Administer methylprednisolone 1 gram IV daily for 3 days, with first dose after first plasma exchange 4
• Consider rituximab (375 mg/m² weekly for 4 weeks) for acquired TTP with ADAMTS13 activity <10% 4
• Monitor platelet count, hemoglobin, and LDH daily to assess response 4
• Avoid platelet transfusion unless life-threatening bleeding, as it may worsen TMA 4

Graft Intolerance Syndrome

If gross hematuria with allograft tenderness and fever:

• Treat with pulse steroids followed by steroid taper 1
• If recurrent episodes occur despite medical management, proceed to graft nephrectomy or embolization 1

Malignancy

If imaging or cystoscopy reveals malignancy:

• Reduce immunosuppressive medications considering cancer stage, whether cancer is exacerbated by immunosuppression, and available therapies 1
• Refer to oncology for definitive cancer treatment 1

Immunosuppression Management During Workup and Treatment

Maintain baseline immunosuppression carefully:

• Continue calcineurin inhibitor at therapeutic levels to prevent rejection and minimize donor-specific antibodies 2
• Continue mycophenolate mofetil if tolerated, as antimetabolites are not implicated in most recurrent disease pathogenesis 4
• Maintain corticosteroids as part of baseline immunosuppression 4
• Do not excessively reduce maintenance immunosuppression, as this may trigger rejection 3

Critical Pitfalls to Avoid

• Do not delay biopsy when unexplained proteinuria >3.0 g/day or persistent creatinine increase occurs 2, 3
• Do not initiate immunosuppressive therapy for recurrent glomerulonephritis without first ensuring at least 90 days of optimized supportive care with maximally tolerated ACE inhibitor/ARB 2
• Do not treat with immunosuppression if eGFR <30 ml/min/1.73 m² unless crescentic disease with rapid deterioration 2, 3
• Do not transfuse platelets in suspected TMA unless life-threatening bleeding 4
• Do not ignore the native kidneys as potential bleeding sources if transplant evaluation is unrevealing 5

Ongoing Monitoring

After initial treatment, establish surveillance:

• Monitor proteinuria (decrease ≥40% indicates treatment success) 3
• Monitor serum creatinine regularly 2, 3
• Continue screening for microhematuria every 3 months during first year, then annually in patients with recurrence-prone primary diseases 1
• Monitor for relapse with weekly hemoglobin and platelet counts until steroid taper complete in TMA cases 4