Clinico-Histological Features of Thrombotic Microangiopathy in Renal Biopsies: A Retrospective Study
Niraimathi MANICKAM1, Vinita AGRAWAL2, Pallavi PRASAD2, Manoj JAIN2, Narayan PRASAD3
1Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research Karaikal, PUDUCHERRY, INDIA
2Department of Pathology and 3Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, UTTAR PRADESH, INDIA
Keywords: Thrombotic microangiopathy, Malignant hypertension, Hemolytic Uremic Syndrome , Lupus nephritis
Thrombotic microangiopathy (TMA) is often first detected on a renal biopsy performed for renal manifestations. Apart from
hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura, there are various secondary conditions associated with TMA.
This study analyzes the clinico-pathological spectrum, etiological factors and renal outcome of TMA diagnosed on renal biopsy.
Material and Method: A retrospective evaluation of renal biopsies for TMA over 5.5 years was performed. Clinical and laboratory data was
collected from patient records.
Results: A total of 40 biopsies from 39 patients showed TMA comprising 33 native and 7 transplant biopsies. Malignant hypertension (n=13) was
the most common etiology in native biopsies followed by postpartum TMA (n=7), atypical HUS (aHUS) (n=7), and lupus nephritis (n=6). TMA
in transplant biopsies was due to acute rejection (n=4) and CNI toxicity (n=3). Serum creatinine was high in most patients (mean 5.6 + 2.5 mg/
dl). aHUS showed the highest mean LDH levels and the lowest average platelet counts. Renal biopsies in malignant hypertension and postpartum
TMA showed isolated arterial changes while aHUS and lupus nephritis showed both glomerular and arterial involvement. Postpartum TMA and
aHUS had poor renal outcome requiring renal replacement therapy.
Conclusion: Most postpartum TMA and aHUS had systemic features of TMA while malignant hypertension and lupus nephritis showed ‘isolated
renal TMA’. This emphasizes the importance of careful evaluation of renal biopsies even in the absence of systemic features of TMA.
Thrombotic microangiopathy (TMA) is a group of
systemic disorders characterized by microvascular injury
in the form of endothelial swelling, denudation, fibrinoid
necrosis and/or fibrin thrombi in capillaries and in other
small sized blood vessels. It affects multiple organs;
however, the kidney is predominantly involved. TMA has
a wide spectrum with diverse etiologies and overlapping
clinical manifestations. Apart from the characteristic
causes of TMA like Hemolytic uremic syndrome (HUS)
and Thrombotic Thrombocytopenic Purpura (TTP), the
various secondary causes include infection, malignant
hypertension, pregnancy, pre-eclampsia/ eclampsia, the
HELLP (hemolytic anemia, elevated liver enzymes, low
platelets) syndrome, autoimmune disorders, malignancy,
hematopoietic stem cell transplantation, drug toxicity, etc.,
(1, 2). In graft kidney, TMA is associated with rejection,
calcineurin drug toxicity, viral infection, and recurrence
of HUS or atypical HUS (1). Both in native and allograft
kidney, TMA-associated renal injury is associated with
high mortality and end stage renal disease (ESRD).
Renal biopsies are not routinely performed for classical
cases of diarrhea positive (D+) HUS and TTP-associated
TMA. Atypical presentations and secondary causes of
TMA require renal biopsy for confirmation. However,
at times, TMA on a renal biopsy is identified without
clinical suspicion. Only a few studies have investigated the
spectrum of TMA on renal biopsies (1, 3).
The aim of this study is to analyze the etiological factors of
TMA in native and graft renal biopsies and evaluate their
clinical features and implications in the management and
This retrospective study evaluates clinical, laboratory and
pathological features of TMA in all native and transplant
biopsies done over a period of 5.5 years (January 2012 to
June 2017) in the Sanjay Gandhi Postgraduate Institute of
Medical Sciences (SGPGIMS), Lucknow. The Institutional
Ethics Committee approved the study (IEC Code:
2019-28-IP-EXP-7). Histochemical stains viz. Hematoxylin
& Eosin (H&E), Periodic Acid Schiff (PAS), Periodic acid Silver Methanamine (PSM) and Masson’s Trichrome (MT)
were performed as routine in all biopsies. Serial sections
were taken wherever indicated.
All biopsies of acute TMA with presence of fibrin thrombi
and/or fibrinoid necrosis in glomerular capillaries,
arterioles and/or interlobular arteries confirmed on MT
stain were included in the study. Renal biopsies with
ANCA-associated vasculitis, crescentic glomerulonephritis
and lupus nephritis with fibrinoid loop necrosis due to
disease activity were not included. Clinically suspected
TMA with non-diagnostic histological features was also not
included. Changes of chronic TMA were noted. Clinical
and laboratory data was collected from the Hospital
information system (HIS). Laboratory parameters included
Hemoglobin levels, complete blood counts and peripheral
smear evaluation for fragmented RBCs; serum creatinine,
serum protein, serum albumin, serum LDH, 24-hour
urinary protein estimation, and urinalysis.
All patients with biopsy-proven TMA in this study (n=40)
were grouped into five etiological categories based on the
following clinical and laboratory features:-
a) ‘Malignant hypertension’ when patients present with
high blood pressure on admission (diastolic BP > 120
mmHg) or show rapid rise in blood pressure with
ocular changes (retinal hemorrhages, exudates or
papilledema) and renal dysfunction (rise in serum urea,
creatinine, proteinuria) with or without hypertensive
encephalopathy or left ventricular hypertrophy
b) ‘Pregnancy/Postpartum TMA’ if patient presents
with acute kidney injury either during the course of
pregnancy or in the postpartum period with or without
hypertension, microangiopathic hemolytic anemia or
c) ’Lupus nephritis’ when renal biopsy shows TMA features
in known SLE patients who fulfilled adequate clinical
and immunological criteria along with histological &
immunofluorescence features of lupus nephritis
d) TMA cases of any cause in renal graft biopsy with
graft dysfunction, anytime after transplantation were
grouped into ‘Graft TMA’
e) ‘aHUS’ cases were categorized based on clinical suspicion
when a patient presents with hemolytic anemia and
thrombocytopenia following prodromal symptoms like
fever but without diarrhea, unlike classical HUS.
The etiological categorizations were based on the
predominant clinical presentation/diagnosis. Except for complement studies and ADAMTS13 assay, all relevant
laboratory work-up was done to rule out various other
possible etiologies of TMA.
During the 5.5 years’ study period, 40 renal biopsies
(33-native, 7-allograft) from 39 patients had histological
features of TMA. The mean age at presentation was 31+12
years (range 7 to 65) with a male:female ratio of 2:3.
Oliguria (n=23) and fever (n=13) were the most common
presentations. The mean serum creatinine was 5.6 + 2.5
mg/dl (0.3 to 9.6 mg/dl). Most (92.5%, n=37) patients had
variable degree of proteinuria (1+ to 4+) and microscopic
hematuria (n=22, 55%). The mean 24-hour urine protein
(n=17) was 1.9 + 1.3 g/day. Mean serum LDH was 1421 +
1293 u/l (393 to 5392 u/l), mean hemoglobin and platelet
counts were 8.1+ 2.5 g/dl (3.7 to 14.9 g/dl) and 148x103+
76.6 x103/mm3 (33 to 333x103/mm3) respectively. Table
1 shows the clinical and laboratory findings in TMA
according to etiology.
Malignant hypertension (n=13; 39%) was the commonest
etiology of TMA in native biopsies followed by pregnancyrelated
TMA (n=7; 21%), atypical Hemolytic uremic
syndrome (aHUS) (n=7; 21%) and lupus nephritis (n=6;
18%). Patients of aHUS, pregnancy-related TMA presented
with short duration of illness (days to weeks) while
malignant hypertension and lupus nephritis had prolonged
illness (months to years). In graft renal biopsies, rejection
(n=4; 57%) was the commonest transplant-associated
TMA followed by calcineurin inhibitor (CNI) induced
drug toxicity (n=3; 43%).
Patients of malignant hypertension were predominantly
males (11/13; 85%) with blood pressure (BP) ranging from
140/100 to 210/130 mmHg. Three patients had associated
IgA nephropathy and one showed immunoglobulinmediated
Patients with pregnancy-related TMA presented in
immediate postpartum (1 to 6 days) as acute kidney injury
(AKI) after lower segment caesarian section (LSCS); except
for one, in post-abortion with induction at 10 weeks due to
uncontrolled malignant hypertension. The majority (6/7)
was a second pregnancy with oliguria and high BP. Cortical
necrosis was seen in five biopsies.
In seven patients of aHUS, clinical suspicion was raised
due to low platelet counts, hemoglobin concentration, and
high LDH following a prodromal infection in the absence
of diarrhea (D-). Majority were females (n=6) with fever and oligo-anuria. Genetic analysis for abnormalities
in complement pathway or ADAMTS assay was not
performed. However, a wide array of investigations was
done to rule out other possible causes like infections,
autoimmune disorders, and coagulation abnormalities.
Lupus Nephritis-associated TMA (n=6) were all previously
diagnosed young females on treatment. Two had SLEassociated
co-morbidities including endocarditis, serositis
and CNS vasculitis. Anti-phospholipid antibody (APLA)
panel was negative in all. Five of the six biopsies were of
class IV and one was class III of ISN/RPS classification.
One class IV Lupus Nephritis has associated Class V lesions
and two had fibrocellular crescents.
Seven biopsies from six renal allograft recipients showed
features of TMA. All six patients were young males with
live-related donor transplantation and four being ABO
incompatible. Biopsy proven native kidney disease was
available in one with IgA Nephropathy. Of seven biopsies,
four had evidence of rejection including antibodymediated
rejection (n=2), acute T-cell mediated rejection
(n=1), and combined antibody and T-cell mediated acute
rejection (n=1). Three biopsies showed features of CNIinduced
TMA, all receiving tacrolimus with high blood
TAC levels. Immunofluorescence showed positive C4d in
peritubular capillaries (ptc) in antibody-mediated (n=2)
and combined antibody and cellular rejection (n=1). Three patients underwent graft nephrectomy for severe antibodymediated
rejection (n=2) and non-responding severe acute
T-cell mediated rejection (n=1).
One of the patients who underwent biopsy twice for
persistent graft dysfunction showed features of TMA in
both. First biopsy showed CNI-drug toxicity changes and
tacrolimus was changed to cyclosporine. Second biopsy, 20
days later, showed combined antibody and cell mediated
rejection with C4d positive in 20% ptc.
There was a statistically significant difference in the
average serum LDH levels, hemoglobin concentration, and
serum albumin values among various categories. aHUS
had significantly higher mean serum LDH levels and
lower average platelet counts. Lupus nephritis showed the
lowest average hemoglobin and serum albumin values. The
mean serum creatinine was higher in postpartum TMA.
Fragmented RBCs were seen in only five patients (12.5%)
Click Here to Zoom
|Table I: Clinical and laboratory features in various etiologies of renal TMA
Table II shows histological features in various etiologies of
acute TMA. Fibrinoid necrosis of arterioles and/arteries
was seen in all categories of TMA. Fibrin thrombi in glomeruli were uncommon (12.5%), seen only in aHUS
(3/7) (Figure 1A,B) and in Lupus Nephritis (2/6) (Figure
1C). Both arteriolar and arterial changes were seen in
malignant hypertension. Arterial fibrinoid necrosis was
seen in all patients of postpartum-TMA (Figure 1D) and
six (85.7%) of seven transplant-related TMA. Malignant
hypertension in addition showed arterial changes like
mucoid intimal change, fibro-intimal hyperplasia, and
splitting of internal elastic lamina along with arteriolar
changes like hyalinosis. Cortical necrosis was common in
postpartum-related TMA (5/7) followed by aHUS (3/7)
and antibody-mediated rejection (3/7). Chronic TMA
changes associated with acute changes manifesting as focal
multilamellation and splitting of GBM were seen most
commonly in aHUS. Crescents were seen in eight biopsies,
which included all four glomerulonephritis (3 IgA and one
MPGN) with malignant hypertension along with lupus
nephritis (n=2), aHUS (n=1) and postpartum TMA (n=1)
Click Here to Zoom
|Figure 1: Renal biopsies in
(TMA) due to aHUS showing
A) fibrin thrombi in glomeruli
(H&E; x200). B) glomerular
mesangiolysis (H&E; x400).
Lupus Nephritis displaying.
C) fuschinophilic fibrin thrombi
within glomerular capillary loops
with involvement of the hilar
arteriole (Mason Trichrome;
x400). D) postpartum renal
biopsy shows partial arterial
occlusion due to marked
expansion of intima by mucoid
edema and fuschinophilic
fibrinoid material with luminal
blood clot (Mason Trichrome;
Click Here to Zoom
|Table II: Histopathological features in various etiologies of renal TMA
Of all categories of TMA in native renal biopsies, isolated
blood vessel changes were common with malignant
hypertension and postpartum TMA while both glomerular and blood vessel changes were common in aHUS and
lupus nephritis. In graft biopsies, blood vessel changes
predominated with arteries involved more than arterioles.
Of 33 with native renal biopsy, 15 (45.5%) patients
received plasmapheresis with hemodialysis in 21(63.6%).
Supportive therapy and treatment for specific etiology e.g.
anti-hypertensives were also administered. 18 of 31 patients
(58%) were dialysis dependent requiring renal replacement
therapy at presentation. Many of the postpartum TMA
(n=6) and aHUS (n=5) patients were dialysis dependent
while lupus nephritis patients were mostly dialysis
Follow-up data was available for 23 of 33 patients (69.7%)
varying from 7 days to 2.5 years (8.8 months ± 13). A 62-
year old patient of malignant hypertension-associated
TMA presenting with ESRD died of sepsis at one year of follow up. Of 13 who had thrombocytopenia (7.7-142 x103/
mm3) at presentation, platelet counts normalized (150-
317x103/mm3) in nine patients on follow-up (7 days to 2.5
years). Of 22 patients with low hemoglobin concentration
(5.1 to 12.4 g/dl) at presentation, 13 showed a rise in levels
at follow-up (7.3 to 14.5).
Of 22 with high serum creatinine at presentation, complete
remission was seen only in four (serum creatinine 0.9 to 1.2
mg/dl) and partial remission in eight (serum creatinine 1.7
to 3 mg/dl) patients. Ten patients continued to have high
serum creatinine levels (5.4 to 11.5 mg/dl) and were dialysis
dependent at follow up. Comparing mean serum creatinine
values on follow up with levels at diagnosis, malignant
hypertension patients showed no remission while
postpartum TMA and aHUS showed partial remission.
Lupus nephritis showed near complete remission in follow
up (Table I).
Two of six-transplant patients received plasmapheresis
and three received hemodialysis. Three underwent graft
nephrectomy, one of whom died of sepsis in the immediate
post-operative period. Two of the remaining three patients
showed complete remission on follow up.
TMA is a histological diagnosis representing microvascular
injury resulting from varied etiologies with differing
prognosis. Though it involves multiple organs, kidney is
the most commonly involved organ (3). In this study, we
retrospectively analyzed various etiologies of renal biopsy
proven TMA with clinical, laboratory and pathological
correlation. Malignant hypertension was the common
cause of TMA in native kidney biopsies followed by
postpartum-TMA, aHUS, and lupus nephritis. This is
similar to the large Chinese cohort study of 109 patients,
where malignant hypertension followed by connective
tissue disorders, pregnancy related-TMA and aHUS were
the common etiologies of TMA (3).
Most of the malignant hypertension patients in this study
presented with anemia, high serum creatinine, proteinuria
with mildly elevated LDH, and near normal platelet counts.
Liang et al. who described TMA-like changes in eight
(61.5%) of the 13 biopsies of malignant hypertension also
reported similar lower incidence of thrombocytopenia and
LDH elevation, which he attributed to the antihypertensive
therapies in these patients. The thrombocytopenia resolved
within 3-5 days of control of blood pressure (4). We also
found thrombocytopenia (3/13; 23%) only in a few patients
with malignant hypertension who were referred to our
center after initial management.
TMA is one of the major causes of pregnancy-related AKI
after reduction in prevalence of sepsis and hypotension
in developing countries (5-7). The spectrum of TMA in
pregnancy includes pre-eclampsia (PE)/HELLP, HUS/TTP,
aHUS, and lupus nephritis/APLA syndrome (5). Acute
kidney injury in second and third trimester of pregnancy
could be due to pre-eclampsia/ HELLP or HUS/TTP
while in the post-partum period aHUS is the commonest
etiology (5, 6). Studies show that most of the pregnancyrelated
aHUS occurs in the second pregnancy and has a
poor outcome resulting in renal failure requiring dialysis,
while pregnancy-related TTP has a better renal outcome
(1). In our study, most postpartum TMA occurred in the
second pregnancy and remained dialysis-dependent on
follow up. Pregnancy acts as a trigger to the manifestation
of underlying etiologies including genetic complement
abnormalities and ADAMTS 13 deficiency (1, 7). In a
study by Thoenes and John, postpartum renal failure was associated with severe obliterative changes predominating
in interlobular arteries when compared to glomeruli and
arterioles (8). We also observed fibrinoid necrosis of
arteries with organized thrombi causing luminal occlusion,
none of which involved the glomerular capillaries. Most of
the pregnancy-related TMA (5 of 7) in this study showed
cortical necrosis, which leaves only a small portion of viable
biopsy available for examination. Fibrin thrombi formed in
the glomeruli could move into arterioles and arteries and
vice versa; therefore, arterial or glomerular involvements
are hypothesized to be dependent on the time of renal
biopsy or duration of ongoing TMA (8).
Lupus nephritis-related TMA is often diagnosed only on
renal biopsies, which is important for timely management.
The prevalence of TMA in lupus nephritis ranges from
0.5% to 24.3% (9, 10). In various studies, patients with
TMA had higher disease activity, serum creatinine,
proteinuria levels, blood pressure, and class IV lesions
(ISN/RPS classification) than lupus nephritis without
TMA (10, 11). Our study also had similar findings. Class
IV was predominantly involved (5 out of 6 biopsies). In
addition, the mean hemoglobin and serum albumin levels
were the least when compared to other categories, probably
reflecting the chronicity of SLE disease. The causes of TMA
in lupus nephritis are multifactorial including HUS/TTP,
APLA syndrome, malignant hypertension, scleroderma,
drugs etc., though ‘isolated renal TMA’ is the commonest
(10). Histologically, lupus vasculopathy (LV) and noninflammatory
necrotizing vasculopathy closely resembles
TMA. Features of glomerular fibrin thrombi, fragmented
RBCs and mucoid edematous changes in interlobular
arteries are suggestive of lupus nephritis-associated TMA
(1). We found TMA-associated lesions in both glomerular
capillaries (fibrin thrombi) and interlobular arteries, but
more commonly in arteries while excluding glomerular
loop necrosis that was part of disease activity.
aHUS accounts for 5% to 12% of all HUS and affects
both children and adults with marked proteinuria and
hypertension. aHUS is a term commonly used in the
absence of typical features of (D+) HUS (12, 13). Yu et al.
have reported aHUS with highest serum creatinine and
pregnancy-associated TMA with highest LDH level while
both these groups had lower platelet counts than other
etiologies of TMA (3). We found higher serum creatinine
levels in pregnancy-associated TMA, while LDH was highest
in aHUS. Both of these groups had low platelet counts with
lowest in aHUS. The limitation of our study is that genetic/
biochemical analysis for abnormalities in complement
pathway or ADAMTS assay were not performed.
Histologically, isolated glomerular and isolated arterial
TMA were noted in three biopsies each of aHUS. Other
studies have shown that both glomerular and blood vessel
changes were common in aHUS and postpartum TMA
while interstitial blood vessels are involved in malignant
hypertension (3). In another study by Thoenes and John,
predominant glomerular changes were seen in children
with HUS while predominant arterial changes were seen
in malignant hypertension, postpartum TMA (8). Both
glomerular and blood vessel changes were seen in older
children (14). The prognosis in aHUS is generally poor
with 50% developing ESRD (15). Four of our patients
developed ESRD requiring dialysis with no benefit from
TMA in graft biopsies can be ‘de novo’ or recurrent with
‘de novo’ being more common, usually occurring in early
post-transplant period (first 6 months) (16). In this study,
all seven graft biopsies with TMA were in immediate posttransplantation
(1 day to few weeks) period. In a six-year
study by Satoskar et al., 55% of ‘de novo TMA’ showed
antibody-mediated rejection, which was the commonest
cause of TMA in graft biopsies (16). Risk factors for de
novo TMA include younger recipient age, older donor age
with 50% survival rate at 3 years (17, 18). We also found
rejection (n=4) as the commonest cause.
Both cyclosporine and tacrolimus are known to cause
TMA in varying proportions (1 to 14%). The mechanism
of drug-induced TMA are variable, the important being
the direct toxicity on endothelium with release of various
pro-coagulants along with its vasoconstrictor effect (19).
In our study, all patients with suspected CNI induced
TMA were on tacrolimus with high blood levels. The
usual treatment includes drug withdrawal, dose reduction,
and switching over to other CNI (20). However, this can
lead to development of rejection. In one of our patients,
tacrolimus was changed to cyclosporine following the
suspicion of tacrolimus-induced TMA in the first biopsy
which later showed features of combined rejection in
the second biopsy (20). Another possibility is underlying
C4d negative antibody-mediated rejection with subtle
histological changes in the first biopsy, which manifested
as combined rejection (C4d positive and DSA positive in
subsequent follow up) in the second biopsy.
Histological features of TMA post-transplant may not be
associated with systemic signs of TMA (16). This highlights
the importance of graft biopsy in diagnosis of TMA, which
are mostly renal-limited rather than systemic (21).
To conclude, TMA on renal biopsies has a wide clinicopathological
spectrum and etiological factors with varying prognosis. Although this study has a limitation of not
representing the entire spectrum of renal TMA as many
classic forms are seldom biopsied, it emphasizes the need
for renal biopsies even in the absence of systemic features
of TMA for early diagnosis and management. Most
postpartum patients and aHUS had systemic features of
TMA while malignant hypertension and lupus nephritis
present as ‘isolated renal TMA’ without systemic signs and
laboratory findings of TMA. Histologically, TMA involving
arteries and arterioles predominated in the postpartum and
malignant hypertension category respectively while mixed
glomerular and blood vessels changes were seen in aHUS
and lupus nephritis. Knowledge of various histopathological
features of TMA in a renal biopsy is necessary not only for
the diagnosis but also for the correct identification of the
CONFLICT of INTEREST
The authors declare no conflict of interest.
Concept: NM, VA, Design: NM, VA, PP, MJ, Data collection
or processing: NM, NP, Analysis or Interpretation: NM,
VA, MJ, NP, Literature search: NM, PP, Writing: NM, VA,
Approval: NM, VA, PP, MJ, NP.
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