Reviews

Kidney complications of parasitic

diseases
Elizabeth De Francesco Daher 1 ✉, Geraldo Bezerra da Silva Junior1,2, Mayuri Trivedi 3
,
Tarek Fayad 4, Nattachai Srisawat5, Sanjeev Nair 6, Padet Siriyasatien 7,
Marcus Vinícius Guimarães de Lacerda8, Maria Alice Sperto Ferreira Baptista9,
Mahesha Vankalakunti10 and Vivekanand Jha 11,12,13
Abstract | Parasitic agents have been known to cause human disease since ancient times and
are endemic in tropical and subtropical regions. Complications of parasitic diseases, including
kidney involvement, are associated with worse outcomes. Chagas disease, filariasis, leishmaniasis,
malaria and schistosomiasis are important parasitic diseases that can damage the kidney.
These diseases affect millions of people worldwide, primarily in Africa, Asia and Latin America,
and kidney involvement is associated with increased mortality. The most common kidney
complications of parasitic diseases are acute kidney injury, glomerulonephritis and tubular
dysfunction. The mechanisms that underlie parasitic disease-​associated kidney injury include
direct parasite damage; immunological phenomena, including immune complex deposition and
inflammation; and systemic manifestations such as haemolysis, haemorrhage and rhabdomyolysis.
In addition, use of nephrotoxic drugs to treat parasitic infections is associated with acute kidney
injury. Early diagnosis of kidney involvement and adequate management is crucial to prevent
progression of kidney disease and optimize patient recovery.

Anthropozoonosis
A disease that is transmitted
from animals to humans.
✉e-​mail: ef.daher@uol.com.br
https://doi.org/10.1038/
s41581-022-00558-​z
Parasitic diseases are a global public health problem
owing to the large number of affected individuals and
their associated morbidity and mortality. The WHO’s list
of 20 neglected tropical diseases includes 11 parasitic dis-
eases1 of which four — Chagas disease, filariasis, leish-
maniasis and schistosomiasis — are often associated with
kidney damage. Malaria also commonly causes kidney
complications, including acute kidney injury (AKI).
The prevalence of parasitic diseases is highest in trop-
ical and subtropical regions, particularly those with high
levels of poverty, poor sanitation and exposure to the
transmitting agents (Supplementary Figure 1). The bur-
den of these diseases is particularly high in Africa, which
accounts for more than 90% of cases of malaria and schis-
tosomiasis worldwide2, and in Latin America, particu-
larly in Brazil, which has a high prevalence of parasitic
diseases in more than 40% of municipalities3. Increases
in human migration, tourism and business-​related
travel have led to an increasing prevalence of parasitic
diseases in non-​endemic regions, including high-​income
countries4. Knowledge of these diseases is therefore
important to the global medical community and should
not be restricted to those in endemic regions5.
Access to health care is not equal worldwide and most
parasitic diseases affect the populations of low- and
middle-​income countries, where adequate treatment
and particularly kidney care, including dialysis and
transplantation, is often not available or is prohibitively
expensive for the majority of patients6–8. Prevention and
treatment of parasitic diseases is crucial for avoiding
or minimizing complications, including AKI and pro-
gression to CKD and/or kidney failure. Some parasitic
diseases, such as leishmaniasis and schistosomiasis, are
associated with the development of kidney complica-
tions that can be asymptomatic, including glomerulo-
nephritis (Table 1). Kidney function should be evaluated
in all patients with these diseases. Novel biomarkers of
kidney function, endothelial injury and inflammation
could aid the identification of subclinical abnormali-
ties for early detection of kidney injury and might also
provide insights into the pathophysiology of kidney
involvement in parasitic diseases9.
In this Review, we focus on kidney involvement in
Chagas disease, filariasis, leishmaniasis, malaria and
schistosomiasis. We describe the epidemiology, clin-
ical features, mechanisms of kidney injury and renal
pathological aspects of these diseases.
Chagas disease
Chagas disease (also known as American trypanoso-
miasis) is an anthropozoonosis caused by the protozoan
Trypanosoma cruzi, which is transmitted via contact

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Key points
• Parasitic diseases are a major public health problem worldwide and are associated
with multiple complications, including kidney injury.
• The highest incidence of parasitic diseases is in tropical regions; however, they are
increasingly observed in high-​income countries, mainly among immigrant
populations.
• Kidney involvement is common in Chagas disease, filariasis, leishmaniasis, malaria and
schistosomiasis.
• Kidney injury in these diseases is mediated by immunological phenomena, systemic
manifestations of the parasitic infection, direct damage caused by the parasites and
use of nephrotoxic medications.
• Acute kidney injury, glomerulonephritis and tubular dysfunction are the most
frequently observed kidney abnormalities in patients with parasitic diseases.
• Early detection of kidney impairment in these patients is essential to enable adequate
management and prevent progression to chronic kidney disease and/or kidney failure.
Haematophagous
with the faeces of infected haematophagous insects of
Feeding on blood. the genus Triatominae10. Chagas disease is widely dis-
tributed in the Americas, from the USA to Argentina10.
‘Mega’ organs The WHO estimates that approximately 8 million
Highly disproportionate
people are infected with T. cruzi worldwide and Chagas
enlargement of organs,
which is typically seen in disease results in >10,000 deaths per year11. In Brazil,
Chagas disease. a national program for Chagas disease control that was
implemented in 1950 has virtually eliminated the main
Dyskinesias species of the disease vector, Triatoma infestans, from
Movement disorders
characterized by involuntary
the country10.
muscle movements. T. cruzi is able to parasitize a wide variety of cell types,
including kidney cells12. The parasites invade the blood
Amastigote and lymphatic vessels, from which they can disseminate
Rounded cells of protozoa
to any organ and tissue in the body. The development
without flagella, especially used
to describe Leishmania spp. of heart disease, including epicarditis, myocarditis and
endocarditis is frequently observed. In the chronic
form of Chagas disease, heart disease is characterized
by progressive, fibrous, chronic myocarditis, which can
be asymptomatic or present with congestive syndrome
or alterations in the heart rhythm and conduction of
the electrical stimulus. Lesions in the digestive tract are
found mainly in the muscular layers and in the intramu-
ral nervous plexuses of the hollow viscera10. The chronic
digestive form manifests as alterations in the secretion,
motility, absorption and dilation of the hollow viscera,
resulting in ‘mega’ organs such as mega-​oesophagus and
Author addresses
1
School of Medicine, Federal University of Ceara, Fortaleza, Ceara, Brazil.
2
School of Medicine, University of Fortaleza, Fortaleza, Ceara, Brazil.
3
Department of Nephrology, Lokmanya Tilak Government Medical College and Hospital,
Mumbai, India.
4
Faculty of Medicine, Cairo University, Cairo, Egypt.
5
Division of Nephrology, Chulalongkorn University, Bangkok, Thailand.
6
Department of Nephrology, Saveetha Medical College and Hospital, Thandalam,
Chennai, India.
7
Vector Biology and Vector Borne Disease Research Unit, Chulalongkorn University,
Bangkok, Thailand.
8
Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Amazonas State University,
Manaus, Amazonas, Brazil.
9
São José do Rio Preto Medical School. São José do Rio Preto, São Paulo, Brazil.
10
Manipal Hospitals, Bangalore, India.
11
The George Institute for Global Health India, New Delhi, India.
12
Faculty of Medicine, Imperial College London, London, UK.
13
University of New South Wales, Sydney, Australia.
nATuRe RevIeWS | NEPHroloGy
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megacolon10. Other characteristic features of Chagas dis-
ease include autonomic denervation, cardiomyopathy,
dyskinesias, lack of coordination of the ureter and blad-
der, and urinary stasis and reflux, which may predispose
to secondary bacterial infections of the urinary tract10,12.
The disease can result in urinary incontinence, mainly
because of bladder overactivity, detrusor overactivity
and moderate bladder hypocontractility13. Tubular dys-
function, which manifests as an inability to concentrate
urine, has also been described10.
Evidence from experimental studies suggests that
heart and kidney involvement in Chagas disease are
connected12 (Fig. 1). Acute cardiac manifestations of
Chagas disease, such as myocarditis, pericarditis and
electrical conduction disturbances, can result in cardio­
renal syndrome type 1, defined as acute heart failure
leading to AKI14. Cardiorenal syndrome type I occurs
in 20–30% of patients with Chagas disease admitted with
heart failure14,15. A Brazilian study reported mild kidney
disease in 27.3% and moderate to severe kidney disease
in 30.5% of patients with Chagas cardiomyopathy16.
T. cruzi infection can lead to functional and struc-
tural alterations of the kidney that are associated with
decreased renal blood flow or damage to proximal
tubule cells as well as substantial interstitial inflamma-
tory infiltrate10. Loss of kidney function is associated
with high parasite loads17 and autoimmune phenomena
have also been described. A study of rats infected with
T. cruzi showed that the glomerular deposits in Chagas
disease consist of immune complexes containing parasite
antigens and autoantibodies (that is, rheumatoid factor
and antinuclear antibodies)18. Membranoproliferative
glomerulonephritis in Chagas disease is also likely asso-
ciated with immune complex deposition19. Glomerular
deposits of IgM, predominantly in the mesangium, occur
in the early stages of infection and are associated with
an inflammatory response and ischaemia–reperfusion
injury, which lead to AKI20,21. In addition, membra-
nous nephropathy with expression of the target antigen
phospholipase A2 receptor (PLA2R) has been reported
in kidney biopsy samples22. Interstitial nephritis and
amastigote forms of T. cruzi have been observed in a
renal allograft biopsy sample23.
As Chagas disease can be transmitted from organ
donors to transplant recipients, screening of all donors
has been implemented in endemic areas of Latin America,
such as Brazil and Argentina24. The risk of such transmis-
sion is lower for kidney transplantation (10–20%) than
for heart transplantation (75%)24. An autopsy study of a
patient with acute Chagas disease transmitted via kidney
transplantation identified T. cruzi antigens in the glomer-
ulus, renal interstitium and smooth muscle of the blad-
der wall, suggesting direct injury as a result of the acute
infection25. Reactivation of Chagas disease in infected
recipients has also been described following heart26 and
kidney transplantation27. This reactivation could be
attributed to the immunosuppressed state of the patients.
Filariasis
Filariasis is caused by parasites of the order Spirurida,
superfamily Filarioidea and family Onchocercidae,
which are usually called ‘filarial worms’ or ‘filariae’,
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Table 1 | Kidney lesions in parasitic diseases

Disease Glomerular Tubular Amyloidosis Acute Post- Pathophysiology of kidney Extra-​renal
lesions lesions kidney transplant injury manifestations
injury disease
Chagas MPGN, No Rare Yes Yes Immune complex deposition, Bladder overactivity, urinary
disease membranous interstitial nephritis incontinency, inability to
nephropathy, concentrate urine, heart and
MesPGN gastrointestinal disease.
Filariasis MPGN, Yes Yes No No Lymphatic vessel obstruction, Chyluria, lymphadenopathy,
membranous immune complex deposition lower limb oedema.
nephropathy
Leishmaniasis MPGN, FSGS Yes Yes Yes Yes Immune complex deposition, Prolonged fever,
inflammatory response, drug hepatosplenomegaly,
toxicity, tubular injury pancytopenia.
Malaria MPGN, FSGS, Yes Rare Yes Yes Haemodynamic factors, Episodes of high fever, chills,
MesPGN, TMA erythrocyte parasitaemia, haemolysis, jaundice.
immunological phenomena
Schistosomiasis MPGN, FSGS, Yes Yes Yes Yes Immune complex deposition, Hepatosplenomegaly,
membranous inflammatory response ascites, ureteral stricture,
nephropathy, urinary obstruction
IgA nephropathy
FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; MesPGN, mesangial proliferative glomerulonephritis; TMA, thrombotic
microangiopathy.

Chyluria
The presence of chyle (lymph
laden with fat) in the urine,
resulting in a milky white
colour.
Dysuria
Pain or discomfort during
urination.
Haematochyluria
The presence of blood and
chyle or lymph in the urine.
that are transmitted by the mosquito vector Culex
quinquefasciatus28. The species that can cause disease in
humans are Wuchereria bancrofti, Brugia malayi, Brugia
timori, Loa loa, Onchocerca volvulus, Mansonella ozzardi,
Mansonella perstans and Mansonella streptocerca28. The
adult forms parasitize the lymphatic system, the connec-
tive, cutaneous, adipose and muscular tissues and the
serous cavities of the vertebrate hosts.
Filariasis is highly prevalent in South and South-​East
Asia, where the disease in endemic in nine countries:
India, Indonesia, Myanmar, Bangladesh, Nepal, Sri Lanka,
Timor-​Leste, Thailand and Maldives29. The WHO esti-
mates that 1.4 billion people live in risk areas, which
are distributed throughout 73 countries in Asia, Africa,
America and the Pacific Islands, in almost all hot and
humid regions, with 120 million infected individuals,
of whom approximately 15 million have lymphoedema
or elephantiasis28,30. Lymphatic filariasis accounts for
2.8 million disability-​adjusted life years (DALYs)30 and
parasitic chyluria is endemic in South Asia and in some
parts of Australia and Africa31. The incidence of lym-
phatic filariasis has decreased substantially since 2000,
with the greatest decrease in the Americas, mainly as a
result of community-​based public health interventions32.
Filariasis has varied clinical manifestations depending
on the stage of the parasite, the immune response of the
host and the number and location of the worms28.
The predilection of filariasis parasites for the lymphatic
system is the cause of the main clinical manifestations
observed in humans. Adult worms cause damage to the
lymphatic vessels, whereas microfilariae are responsi-
ble for extralymphatic manifestations. Depending on
the location of the worm, lymphadenitis or lymphang-
itis can occur. Acute filarial lymphangitis can result in
a moderate systemic reaction, with fever, headache,
asthenia and myalgia. The usually painless infarction
of compromised lymph nodes, most commonly in
the inguinal, epitrochlear and axillary regions, causes
lymphadeno­pathy. Episodes of acute lymphangitis can
be followed by hydrocele and lymphoedema, which
result from obstruction of the lymphatic vessel owing to
inflammatory reactions triggered by the disintegration
of adult worms28. Obstruction of the lymphatic system
by parasites results in increased pressure and retrograde
flow of chylous fluid through the renal lymphatic ves-
sels, which become varicose and rupture into the uri-
nary tract29,33. The resulting chyluria is associated with
urinary symptoms such as dysuria, urinary retention and
flank pain33.
Haematochyluria is more frequent than isolated haema-
turia in filariasis, with the most likely mechanism being
the rupture of small blood vessels into the enlarged lym-
phatic capillaries or diapedesis of blood corpuscles into
the lymphatic channels28. Haematuria is normally micro-
scopic and is observed in associ­ation with microfilarae-
mia independent of the paras­itic load. Kidney injury and
haematuria might be caused by the formation of immune
complexes triggered by parasitaemia and their depo-
sition in the glomerular basement membrane28 (Fig. 2).
Erythrocyte casts34,35 and nephrotic-​range proteinuria
have also been reported36.
Patients with filariasis can develop membranous
glomerulonephritis, mesangioproliferative glomerulon­
ephritis and membranoproliferative glomerulonephri-
tis with complement consumption28. Microfilaria can
be detected in the glomeruli of patients with filariasis-
associated proteinuria and deposits of IgM are observed
in the mesangial region37,38. Proliferative glomerulone-
phritis is associated with nephrotic-​range proteinuria38,39.
Chronic W. bancrofti infection can lead to AA-​type renal
amyloidosis, which manifests with intense proteinuria
and can remit with anti-​filarial treatment40. A study of
patients from an area with endemic W. bancrofti filaria-
sis reported a prevalence of proteinuria of 20% and the
presence of filarial antigen in immune complex deposits
in kidney biopsy samples41. Other filarial species, such as

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Loa loa, have also been associated with kidney damage,
with cases of asymptomatic proteinuria associated with
microscopic haematuria28. The microfilariae could reach
the renal tubule through the glomerular capillaries or
through the rupture of the renal lymphatic vessels28.
Leishmaniasis
Leishmaniasis is a group of parasitic diseases caused
by species of the genus Leishmania that can manifest
as visceral and cutaneous or mucocutaneous forms42.
Transmission occurs through the bites of female sand-
flies (genus Phlebotomus in Old World countries and
Lutzomyia in New World countries)43,44. Visceral leish-
maniasis affects 1–2 million people annually worldwide,
with approximately 500,000 new cases a year, predom-
inantly on the Indian subcontinent, in East Africa and
in Latin America, mainly Brazil43,45. Repeated epidemics
of visceral leishmaniasis have been reported in African
countries, including Ethiopia, Kenya, South Sudan and
Sudan42, and of cutaneous leishmaniasis in various
parts of Afghanistan and the Syrian Arab Republic46. In
Thailand, most of the cases of leishmaniasis reported
before 1999 were in Thai workers who had returned from
Middle Eastern countries such as Saudi Arabia, Iraq and
Libya47. Leishmaniasis then became autochthonous in
Thailand and a new species, Leishmania siamensis, was
identified48. Both cutaneous and visceral leishmaniasis
have been reported in Thailand48.
Visceral leishmaniasis causes systemic disease and
is characterized by immune dysfunction owing to the
parasitism of macrophages43. Abnormalities in immune
responses in infected patients include increased circulat-
ing levels of TGF-​β and IL-10, which is associated with
B cell activation43. Cases vary from asymptomatic infec-
tion, which occurs in most people who are infected in
endemic areas, to the complete syndrome or kala-​azar,
which is a chronic disease of prolonged evolution45.
Infection of the reticuloendothelial tissues — liver,
spleen, bone marrow, lymph nodes and digestive system
— results in a wide spectrum of clinical manifestations.
Symptoms range from irregular and recurrent fever to
pancytopenia, haemorrhage and hepatosplenomegaly43,44.
Triatominae
T. cruzi
Fig. 1 | Kidney involvement in Chagas disease. Chagas disease is caused by T. cruzi, which is transmitted via contact
with the faeces of infected haematophagous Triatominae insects. Both acute and chronic forms of Chagas disease can
cause cardiovascular dysfunction, such as cardiomyopathy and heart failure, that leads to kidney hypoperfusion and the
development of cardiorenal syndrome. Immune complexes containing parasite antigens and autoantibodies deposit in
the glomeruli, leading to glomerulonephritis. Some patients develop acute kidney injury, which can progress to chronic
kidney disease. C3, complement C3.
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Kidney involvement in visceral leishmaniasis is associ-
ated with increased mortality and is one of the strong-
est prognostic factors for death, followed by advanced
age, jaundice, other associated infections, oedema and
platelet count <50,000 per mm3 blood.
Kidney damage in visceral leishmaniasis mainly
results from immunological phenomena, such as the
deposition of immune complexes, activation of T cells,
upregulation of adhesion molecules, inflammatory pro-
cesses and the presence of parasite antigens in the kidney
tissue, which can trigger glomerulonephritis and inter-
stitial nephritis45,49 (Fig. 3). AKI occurs in up to 46% of
patients with visceral leishmaniasis and is associated with
the use of nephrotoxic drugs, such as amphotericin B,
secondary infections, haemodynamic abnormalities and
systemic inflammatory responses45,50. In most patients,
leishmaniasis-​associated AKI does not require dial-
ysis and kidney function recovers following parasite
treatment51,52.
Clinical manifestations of kidney damage in patients
with visceral leishmaniasis, including proteinuria, hae-
maturia, leukocyturia and electrolyte disturbances
(hyponatraemia, hypokalaemia, hypochloraemia, hypo­
calcaemia, hypomagnesaemia), increased the excretion
fraction of several electrolytes and defects in urinary
acidification45. The electrolyte disturbances might be
explained by renal tubular damage caused by Leishmania
infection. A study in 37 patients with cutaneous leishma-
niasis, of whom 27 had a urinary concentrating defect,
reported overexpression of the tubular transporters Na/H
exchanger (NHE3), H+-​ATPase and pendrin and signif-
icantly reduced levels of aquaporin 2 compared with
healthy individuals53.
Novel biomarkers might be helpful for early detection
of kidney abnormalities in patients with visceral leish-
maniasis. Increased serum and urinary levels of neutro-
phil gelatinase-​associated lipocalin (NGAL) and urinary
levels of kidney injury molecule-1 (KIM1) and monocyte
chemotactic protein-1 (MCP1) have been reported in
patients with visceral leishmaniasis-​associated AKI50.
In one study, serum NGAL was independently associ-
ated with AKI development and was the most reliable
Parasite
Chagas disease antigen
Antibody
Cardiovascular dysfunction Immune complex formation
Kidney hypoperfusion Glomerular deposits
of IgM, IgG and C3
Cardiorenal syndrome Glomerulonephritis
Acute kidney injury
Chronic kidney disease
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biomarker for prediction of AKI development in these
patients50. Urinary NGAL was also reported to be an ear-
lier biomarker of amphotericin B nephrotoxicity than
serum creatinine54.
In patients with leishmaniasis-​associated glomer-
ular disease, the most common lesion is characterized
by a mesangial proliferative pattern, with deposition
of immunocomplexes43. Rapidly progressive glomer-
ulonephritis can also occur, with a rapid decrease in
kidney function55. Other histological patterns include
membranoproliferative glomerulonephritis, focal seg-
mental glomerulosclerosis (FSGS), amyloid deposits and
global sclerosis (in cases of advanced kidney disease).
Tubulointerstitial injuries are also frequent, includ-
ing tubulointerstitial nephritis, interstitial fibrosis and
tubular atrophy43,45. Amyloid deposits can occur in
chronic disease43. In endemic areas, co-​infection with
visceral leishmaniasis and Chagas disease can result in
severe kidney involvement, including rapidly progressive
glomerulonephritis49.
Visceral leishmaniasis has been reported in kid-
ney transplant recipients and specific treatment with
nephrotoxic drugs, such as amphotericin B, can worsen
allograft function56. Transmission of visceral leishma-
niasis via kidney transplantation might be possible but
has not been proven. A more accepted theory is that
patients from endemic areas can manifest visceral
leishmaniasis after transplantation owing to immuno­
suppression56. Screening at-​risk kidney transplant can-
didates for Leishmania infection is recommended, but
the ideal serological or molecular test remains to be
established57.
Other conditions that result in immunosuppression,
such as HIV infection, have been reported in association
with visceral leishmaniasis; in these cases, Leishmania
could be considered an opportunistic infection58–60.
The most frequent histological patterns in patients
with kidney disease associated with visceral leishma-
niasis and HIV infection are membranoproliferative
glomerulonephritis and interstitial nephritis59.
Malaria
Malaria is an endemic parasitic disease caused by agents
of the genus Plasmodium, which are subdivided into five
species: P. vivax, P. falciparum, P. malariae, P. ovale and
P. knowlesi61–63. The parasites are transmitted through
the bites of infected female Anopheles mosquitoes.
P. falciparum infections usually have a more severe clin-
ical picture, whereas P. vivax infections are often consid-
ered to have a benign course; however, this parasite can
also cause severe malaria64,65. P. vivax is the most widely
distributed agent66.
In 2020, approximately 241 million cases of malaria
and 627,000 associated deaths were reported world-
wide67. Approximately two-​thirds of annual global deaths
attributed to malaria are of children under 5 years of
age68. Malaria has been reported in more than 100 coun-
tries worldwide, with more than 90% of cases occurring
in tropical Africa. The disease is endemic in Africa,
Asia and Latin America and has a higher incidence in
low-​income countries, in regions where there are armed
conflicts, illegal trade of goods and migratory move-
ment of workers or refugees and in endemic countries
that have not developed disease control programs61.
In the Americas, the majority of cases of malaria are in
the Amazon region of Brazil69.
The clinical manifestations of malaria depend on
the species of Plasmodium and the immunity of the
infected individual64,65. AKI and cerebral malaria are
the most severe complications and are associated with
increased mortality70. AKI has been described in patients
with severe P. falciparum, P. vivax and P. malariae
infections61. The incidence of Plasmodium knowlesi
malaria is increasing in South-​East Asia and this disease

a Parasite antigen b c
Filariasis
Filarial
worms
Antibody
Invasion of Microfilaraemia Immune complex
lymphatic system formation

Glomerular deposits d e
Culex Lymphadenopathy
of IgM, IgG and C3
mosquitos

Chyluria Glomerulonephritis

Chronic kidney disease

Fig. 2 | Kidney involvement in filariasis. a | Filariasis is caused by infection
with filarial worms that are transmitted through the bites of Culex
mosquitoes. The most common manifestation of filariasis is chyluria, which
is caused by invasion and obstruction of the lymphatic system by parasites,
which leads to rupture of the renal lymphatic vessels into the urinary tract.
Microfilaraemia seems to have a key role in triggering the formation of
immune complexes, which deposit in the glomeruli. The resulting
glomerulonephritis can progress to chronic kidney disease. b | Microfilaria
(arrow) in the glomerular capillary lumen of a 47-​y ear-​o ld man
who presented with painless gross haematuria, subnephrotic proteinuria
and normal kidney function. (Periodic acid-​reactive Schiff stain;
×100 magnification). c | Acute tubular injury with interstitial oedema and
inflammatory cell infiltrates rich in eosinophils in a biopsy sample from a
42-​year old man who presented with moderate proteinuria, chyluria and an
estimated glomerular filtration rate of 42 ml/min/1.73 m2 (haematoxylin
and eosin (H&E) stain; ×40 magnification). d | Diffuse and global
endocapillary hypercellularity with a predominance of neutrophilic
infiltrates and rarely eosinophils in a biopsy sample from a 38-​year-​old man
who presented with severe azotaemia. Urinalysis showed 1+ proteinuria
and microhaematuria. (H&E; ×40 magnification). e | The larval form of
microfilaria (arrows) in the peritubular capillary lumina of the same patient
(H&E stain; ×100 magnification).

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a b
Visceral leishmaniasis
Leishmania Antibody
Parasite
antigen
• Kidney hypoperfusion
Lutzomyia or Immune-mediated mechanisms • Treatment with
Phebotomus • Immune complex formation nephrotoxic drugs
sandflies • Inflammation • Kidney tubular injury

• Acute interstitial nephritis Acute kidney injury

• Glomerulonephritis

Chronic kidney disease

Fig. 3 | Kidney involvement in visceral leishmaniasis. a | Leishmaniasis is
caused by infection with Leishmania parasites that are transmitted through
the bites of female sandflies. Acute kidney injury, chronic kidney disease
and tubular damage have been reported in patients with the complete
syndrome of visceral leishmaniasis (that is, kala-​azar). The deposition of
immune complexes in the glomeruli, kidney hypoperfusion, tubular injury,
acute interstitial nephritis and treatment with nephrotoxic drugs have
roles in the development of kidney injury. Glomerulonephritis and
acute kidney injury can progress to chronic kidney disease. In addition,
interstitial involvement and associated tubular damage can persist after
specific treatment, resulting in chronic kidney dysfunction. b | Kidney
biopsy sample from a 46-​year-​old male kidney transplant recipient
showing acute tubulointerstitial nephritis. The patient presented
with weight loss, pancytopenia and hepatosplenomegaly and was
diagnosed with visceral leishmaniasis (haematoxylin and eosin stain;
×400 magnification).

Oliguria
Reduced urine output, usually
defined as <500 ml in 24 h.
Rhabdomyolysis
A clinical condition caused by
muscle injury with release of
intracellular content, including
myoglobin, creatine kinase,
lactate dehydrogenase and
electrolytes. These substances
are harmful to the kidney.
is also associated with AKI63,71. The risk of developing
AKI was similar in patients with P. knowlesi infection to
those with P. vivax or P. falciparum63.
Approximately 40% of patients with malaria develop
AKI72. A study of patients with malarial AKI in India
reported that around 36% required dialysis and around
10% died in hospital73. Older age, higher leucocyte count
and thrombocytopenia were associated with the devel-
opment of AKI and higher serum lactate dehydrogenase
and liver enzyme levels, lower haemoglobin levels and
cerebral involvement were associated with mortality in
these patients.
Children are also at an increased risk of severe
malaria-​associated complications68. AKI is estimated to
occur in 20–59% of children with malaria68,74–76 and is
associated with high mortality (>25%)74,77. A study car-
ried out at a tertiary-​care centre in India identified dis-
seminated intravascular coagulation, jaundice and high
parasite density in peripheral blood smears as risk factors
for death among children with malaria-​associated AKI74.
Other severe complications, such as cerebral malaria, are
also associated with an increased risk of death among
paediatric patients74,77. Children with malaria are at an
increased risk of mortality after hospital discharge and
of neurocognitive development problems68.
Severe malaria can cause disease in the glomeruli,
tubules and interstitial region. In general, kidney dam-
age is severe and causes oliguria; mild proteinuria has also
been reported61. Non-​oliguric AKI is not common in
patients with malaria and is suggestive of tubular injury as
is the case for other parasitic diseases. Malaria-associated
AKI also presents with metabolic acidosis, which is usu-
ally severe, and electrolyte disturbances, most frequently
hyponatraemia (30–50% of patients) and hypercalcae-
mia, which is associated with haemolysis, rhabdomyolysis
and acidosis61,69. Chronic proteinuria has been reported
in patients with malaria caused by P. malariae, particu-
larly in children61. In these patients, kidney injury is
mediated by immune complexes and does not normally
respond to antimalarial therapy.
Kidney injury in malaria is the result of factors
including hypovolaemia, central and peripheral vaso-
constriction, intravascular haemolysis, haemoglobinu-
ria, deposition of immune complexes and intravascular
coagulation61 (Fig. 4). Evidence exists of direct injury by
all Plasmodium species in the kidneys, including mixed
infections71. The main pathophysiological mechanism
of malarial nephropathy is probably erythrocyte parasit-
ism, which causes vascular damage and haemodynamic
abnormalities61,69. Parasitized red cells tend to adhere
to healthy erythrocytes, blood platelets and capillary
endothelium, leading to the formation of rosettes and
clumps, which impair the microcirculation. These events
in association with haemodynamic instability likely
contribute to kidney injury.
Malaria nephropathy is associated with increased
production of cytokines including TNF-​α, IL-1α, IL-6,
IL-10 and granulocyte–macrophage colony-​stimulating
factor (GM–CSF), which are thought to have a role in the
pathophysiological process of tissue injury69. In Ugandan
children hospitalized with severe malaria, levels of the
glycoprotein chitinase-3-​like 1 (CHI3L1) were increased
and associated with increased risk of in-​h ospital
death and all-​cause 6-​month mortality76. CHI3L1 is
highly expressed in healthy kidney tissue, secreted by
activated kidney macrophages upon stress or dam-
age and by activated macrophages, neutrophils, fibro-
blasts and other cell types in response to inflammation,
and freely filtered by the glomerulus76.
Systemic phenomena such as decrease in effective
circulating volume, vasoconstrictive events, haemol-
ysis, erythrocyte parasitaemia, deposition of immune
complexes in glomeruli and rhabdomyolysis also con-
tribute to the development of malaria-​associated kidney
disease61,69. Auto-​antibodies, including anti-​DNA and
anti-​phosphatidylserine, have been identified in children
with severe malaria and associated with AKI78.
Oxidative stress and cell-​free haemoglobin derived
from haemolyzed parasitized red blood cells were asso-
ciated with a future need for haemodialysis among

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a b c
Malaria
Plasmodium
Immunological Cytoadherence
phenomena Erythrocyte
of parasitized
• Immune complex parasitism
cells
deposition
• Autoantibodies
Cytokines and
Tissue
Anopheles • Hypovolaemia inflammatory
hypoperfusion
mosquito • Haemolysis mediators d e
• Rhabdomyolysis
• Hyperviscosity Reduced kidney blood flow
• Jaundice
• Hyperbilirubinaemia
• Intravascular Acute tubular necrosis
coagulation
• Hepatorenal
syndrome Acute kidney injury

Glomerulonephritis Chronic kidney disease

Fig. 4 | Kidney involvement in malaria. a | Malaria is cause by Plasmodium
parasites, which are transmitted via the bites of infected female Anopheles
mosquitoes. Erythrocyte parasitism and immunological phenomena are the
key causes of organ damage. Cytoadherence of parasitized erythrocytes
leads to tissue hypoperfusion and ischaemic kidney injury. Multifactorial
events, including immunological phenomena, hypovolaemia, haemolysis,
rhabdomyolysis, hyperbilirubinaemia and microangiopathic thrombotic
disturbances also contribute to malaria-​associated kidney injury. b–d | Kidney
histology in a 24-​year-​old man with P. vivax malaria who presented with fever,
active haemolysis and Kidney Disease Improving Global Outcomes stage 3
acute kidney injury. b | Kidney biopsy sample showing P. vivax malarial
parasites (arrows; haematoxylin and eosin (H&E) stain). c | Kidney biopsy
sample showing clumps of red blood cell casts with acute tubular injury and
coarse brownish pigment in the epithelial cytoplasm of the proximal tubule
(Masson’s trichrome stain) d | Prussian blue stain (arrow) confirming that the
pigment is iron. e | Kidney biopsy sample from a 45-​year old man with malaria
showing diffuse cortical necrosis with ghost outlines of all compartments. The
patient presented with fever, rapidly developing anaemia, thrombocytopenia
and kidney failure. The fever resolved with antimalarial therapy but he
remained anuric (H&E stain). All histology images (b–d) are ×40 magnification.

Hyperparasitaemia
A high parasite load in the
bloodstream.
patients with severe falciparum malaria in Bangladesh79.
Biomarkers of sequestered parasite burden (plasma
P. falciparum histidine rich protein 2 (PfHRP2)) and
immune activation (plasma soluble urokinase-​type
plasminogen activator receptor (suPAR)) were also
associated with AKI severity in patients with severe fal-
ciparum malaria, and both plasma suPAR and PfHRP2
concentrations at hospital admission were associated
with later requirement for dialysis 80. Haemolysis-
mediated endothelial activation was associated with
organ dysfunction in patients with severe malaria owing
to P. knowlesi infection62. Angiopoietin-2 and osteo­
protegerin were independent risk factors for AKI in
these patients, suggesting that endothelial activation
is a key mediator of haemolysis-​induced end organ
damage62.
The pathophysiology of the glomerular lesion asso-
ciated with P. vivax infection is not completely under-
stood. Hyperparasitaemia likely results in increased
cytoadherence of parasitized erythrocytes to the vascular
endothelium62. Endothelial damage evidenced by release
of Weibel–Palade body constituents, such as osteopro-
tegerin, is an important factor that contributes to organ
dysfunction in malaria. AKI is attributed mainly to intra-
vascular haemolysis and ischaemic injury62. Severe fal-
ciparum malaria is associated with reduced levels of the
von Willebrand factor-​cleaving protease ADAMTS13
(ref. 81) . The resulting reduction in von Willebrand
factor cleavage likely increases the risk of coagulation
and thrombotic events, which have a key role in the
pathophysiology of malaria-​associated AKI.
Nephrotic syndrome has been observed in some
patients with malaria, with findings of mesangiopro-
liferative glomerulonephritis, chronic proliferative
glomerulonephritis with capillary wall thickening,
segmental sclerosis and tubular atrophy82–84. Collapsing
FSGS and acute interstitial nephritis have also been
described82,85.
Histopathological findings in kidney biopsy samples
from patients with malaria-​associated AKI include acute
cortical necrosis, acute tubular injury or acute tubular
necrosis, thrombotic microangiopathy (TMA), intersti-
tial fibrosis and tubular atrophy71. TMA in patients with
malaria should be suspected when AKI is prolonged
and associated with anaemia and thrombocytopenia.
Elevated levels of thrombomodulin, ICAM1, E-​selectin
and VCAM1, in the acute stages of P. vivax infection, are
associated with the development of TMA61. However, the
mechanism by which malaria causes TMA remains to be
fully elucidated86.
The most common histological finding in patients
with kidney injury owing to P. malariae infection is acute
tubular necrosis. The most frequent glomerular lesion
is membranoproliferative glomerulonephritis, with
the eventual formation of crescents, tubular atrophy
and lymphomononuclear infiltrate in the endothelial
compartment61. In patients with P. vivax malaria, cases
of benign or severe post-​infectious glomerulonephritis
with nephritic syndrome and transient hypocomplemen-
taemia have been reported61. Membranoproliferative glo-
merulonephritis and crescentic glomerulonephritis have
also been observed in these patients61. Histopathological
findings in the kidney of patients infected by P. vivax
who develop AKI include casts associated with red blood
cell clumps and cortical necrosis.
Schistosomiasis
Schistosomiasis is caused by trematodes of the genus
Schistosoma that reproduce in freshwater snails and
are transmitted via contact with contaminated water.

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S. mansoni, S. japonicum, S. haematobium, S. intercalatum
and S. mekongi are associated with human disease87.
S. mansoni is found in South America and the Caribbean
region, S. haematobium in Africa and the Middle East,
and S. japonicum and S. mekongi in South-​East Asia87.
Schistosomiasis transmission is reported in 78 coun-
tries, and the disease is endemic in 52 countries where
there is moderate-​to-​high transmission88. Estimates
suggest that in 2018, more than 290 million people
worldwide required preventive treatment for schistoso-
miasis and more than 97 million received treatment88.
Genitourinary schistosomiasis caused by S. haematobium
is endemic in North and Central African countries
and is associated with an increased risk of bladder
malignancy89.
Schistosomiasis presents with a wide range of man-
ifestations, from asymptomatic to severe disease. The
infection can be divided into acute and chronic phases.
In general, the acute phase has abrupt onset with fever,
chills, headache, asthenia, anorexia, myalgia, cough
and diarrhoea. Patients with chronic hepatosplenic
schistosomiasis develop portal hypertension. The
main clinical symptoms and signs of this disease are
ascites (86.7%), splenomegaly (80%) and hepatomegaly
(63.3%)87. In the severe form, digestive haemorrhage and
haematemesis can occur87.
Chronic S. haematobium infection can also cause
anatomical abnormalities in the urinary tract, such as
ureteral stricture and consequent urinary obstructive
complications90. Ureteral stricture has been described in
a kidney transplant recipient91 and severe urinary tract
obstruction in African children with S. haematobium
infection92. Urinary symptoms, including haematuria,
are also observed in patients with S. haematobium93. The
eggs of the parasite cause a granulomatous inflammatory
process, which favours a pro-​oncogenic environment,
generating hyperplasia, dysplasia, squamous metapla-
sia and, consequently, bladder neoplasia89. Urodynamic
abnormalities have also been described in patients with
neuroschistosomiasis caused by S. mansoni94.
A study in a cohort of 60 patients with hepatos-
plenic schistosomiasis in Brazil reported AKI in 43.3%
of patients95. AKI was associated with use of diuretics,
including furosemide and spironolactone, ascites and
elevated levels of aspartate aminotransferase. The levels
of MCP1 were increased and correlated with albuminu-
ria in patients with S. mansoni infection96. Similarly,
MCP1 levels were higher in patients with hepatosplenic
schistosomiasis owing to S. mansoni infection than in
healthy controls97.
The clinical manifestations of kidney injury in schisto-
somiasis vary but nephrotic syndrome is the most fre­quent

a
Schistosomiasis
Schistosoma
Circulating schistosomal Unknown
antigens from eggs mechanisms
and digestive tract
Snail

Immune Deposition of • Amyloidosis

complex schistosomal • IgA nephropathy
formation antigens in • Membranous nephropathy
glomeruli • Focal segmental
glomerulosclerosis
Parasite
antigen Glomerulonephritis
Antibody
Acute kidney injury Chronic kidney disease

b c d

Fig. 5 | Kidney involvement in schistosomiasis. a | Schistosomiasis is caused by Schistosoma parasites that are released
by freshwater snails and transmitted to humans via contact with contaminated water. Circulating schistosomal antigens
from the eggs and digestive tract of the parasites result in the formation of immune complexes. Deposition of these
antigens and immune complexes in the glomeruli lead to glomerulonephritis. A broad range of histopathological changes
in the kidneys have been reported, including amyloidosis, IgA nephropathy, membranous nephropathy and focal
segmental glomerulosclerosis. However, the exact pathophysiology is unknown. b | Kidney biopsy sample from a patient
with schistosomiasis who presented with oedema, proteinuria (5.8 g per 24 h) and serum creatinine 1.9 mg/dl. The sample
shows membranous nephropathy associated with schistosomiasis, with globally fibrosed glomeruli (haematoxylin and
eosin stain, ×400 magnification). c | Silver methenamine stain of the biopsy sample showing thickening of the glomerular
basement membrane (×400 magnification). d | Anti-​C3 stain of the biopsy sample showing complement activation
consistent with immune-​mediated disease (×100 magnification).

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Table 2 | African Association of Nephrology classification of schistosomal glomerulonephritis

Class Histology Immuno­ Aetiological Prevalence Manifestations Treatment
fluorescence agent
I Mesangioproliferative IgM, C3, S. haematobium, 27–60% Microhaematuria, proteinuria Antiparasitic
schistosomal S. mansoni asymptomatic, treatment
gut antigens 10–40% with kidney
disease
II Diffuse proliferative C3, salmonella S. haematobium, Unknown Acute nephritic syndrome, Combined
antigens S. mansoni, toxaemia antiparasitic and
Salmonella anti-​salmonella
treatment
III Membranoproliferative IgG, IgA, C3, S. haematobium, 7–20% asympto- Hepatosplenomegaly, nephrotic None effective
schistosomal S. mansoni matic, 80% with syndrome, hypertension,
gut antigensa kidney disease progressive CKD
IV Focal segmental IgM, IgG, IgAa S. mansoni 11–38% Hepatosplenomegaly, nephrotic None effective
glomerulosclerosis syndrome, hypertension,
progressive CKD
V Amyloid Amyloid A S. haematobium, 16–39% Hepatosplenomegaly, nephrotic None effective
protein S. mansoni syndrome, hypertension,
progressive CKD
VI Cryoglobulinaemic IgM, C3, fibrin, S. mansoni, HCV Unknown Cirrhosis, splenomegaly, Interferon
amyloid A nephrotic syndrome, plus ribavirin,
protein purpura, vasculitis, arthritis, corticosteroids,
hypertension, progressive CKD immunosuppression
and plasmapheresis
C3, complement component 3; CKD, chronic kidney disease; HCV, hepatitis C virus. aNot always present. Adapted with permission from Barsoum82, Elsevier.

presentation87. Non-​nephrotic proteinuria is present
in up to 25% of patients with the hepatosplenic form and
5% of those with the hepatointestinal form of S. mansoni
schistosomiasis87. Other clinical manifestations of schis-
tosomal glomerulopathy include nephrotic–nephritic
syndrome, haematuria and hypertension98.
Urinary specific gravity is increased in patients with
schistosomiasis, is higher in those with S. haematobium
than in those with S. mansoni infection, and can reflect a
urinary concentration defect99. A Brazilian study reported
a urinary acidification deficit in 45% of patients and a uri-
nary concentration deficit in 85% of patients with hepat-
osplenic schistosomiasis97. Solute-​free water reabsorption
was also lower in these patients than in healthy individ-
uals. The expression of aquaporin-2 was decreased and
expression of the Na-​K-2Cl co-​transporter (NKCC2) was
increased in patients with hepatosplenic schistosomia-
sis compared with healthy individuals100. These altera-
tions, which seem to be mediated by immuno­logical
mechanisms, such as immune complex deposition and
associated tubular damage, might underlie the urinary
concentration defect seen in these patients100.
Approximately 10–15% of patients with schistoso-
miasis develop glomerular disease101 and one-​third of
patients with schistosomiasis-​associated glomerulopa-
thy progress to kidney failure98. The urine of patients
with hepatosplenic schistosomiasis and glomerulopathy
showed significantly increased levels of the chemokines
CCL2, CCL11, CCL5 and CCL3 compared with urine
from healthy individuals102. This finding provides evi-
dence of a role of inflammation in the pathogenesis of
schistosomal glomerulopathy, as these chemokines have
been associated with macrophage accumulation and
kidney injury in animal models of kidney disease102.
The intensity of parasitaemia seems to influence the
severity of the glomerular lesion in schistosomiasis.
An experimental study showed that animals infected
with a high number of parasites but not those with a
low number of parasites showed substantial proteinuria,
hypoalbuminaemia and hypercholesterolaemia103. These
pathological alterations correlated significantly with the
duration of infection by S. mansoni. Recently, a study
with 152 patients with S. mansoni infection in north-
east Brazil have found elevated levels of urinary VEGF
and nephrin, evidencing podocyte injury, and it was
independently of parasitic load104.
Immune complex deposition may be the main mech-
anism that underlies the development of schistosomiasis
glomerulopathy (Fig. 5). In patients with S. mansoni infec-
tion, immune complex formation is triggered by circu-
lating antigens that originate from the digestive tract of
the parasites87,100. The circulating anodic antigen (CAA)
and the circulating cathodic antigen (CCA) of S. mansoni
were identified in glomerular deposits in humans and
in experimental studies98. Soluble antigens from the
S. mansoni egg might also be involved in the patho-
genesis of glomerulonephritis87. Hepatic involvement
resulting in portal hypertension with collateral circula-
tion facilitates the passage of schistosomal antigens that
bind to antibodies in the circulation and subsequently
deposit in the glomeruli87. Immune complex deposition
might therefore be increased by portal hypertension105.
Autoimmunity also has an important role in the patho-
genesis of schistosomiasis-​associated glomerular dis-
ease and some patients with S. mansoni infection show
persistent abnormalities, such as proteinuria, even after
specific antiparasitic treatment101.
Kidney histopathological findings in schistosomiasis
include mesangial injury, with mesangial expansion and
cell proliferation. Duplication of the glomerular base-
ment membrane has also been reported106. Six classes
of glomerulopathy caused by schistosomiasis have been

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described: mesangioproliferative glomerulonephri- Conclusions

tis associated with deposition of immune complexes
containing schistosomal antigens, IgM and C3; dif-
fuse proliferative glomerulonephritis characterized by
neutrophils, monocytes and eosinophils invading the
mesangium, C3 subendothelial and mesangial deposits
associated with IgG and IgM; membranoproliferative
glomerulonephritis; FSGS; amyloid and cryoglobuli-
naemic forms87,107 (Table 2). Mesangioproliferative glo-
merulonephritis may be the most prevalent form of
schistosomal glomerulopathy105. Membranous nephro­
pathy has also been described with S. mansoni eggs caus-
ing tubulointerstitial nephritis detected in kidney biopsy
samples108. IgA nephropathy is less frequently associated
with schistosomiasis109.
Treatment
No specific treatments exist for parasite-​associated kid-
ney diseases or their complications. Immune suppres-
sion for specific types of glomerulonephritis associated
with parasitic diseases should be prescribed on an indi-
vidual patient basis. Kidney biopsy is generally indicated
in the case of nephrotic proteinuria or progressive loss of
kidney function that does not respond to treatment. In
general, treatment of the parasitic disease is associated
with improvement in kidney function.
Parasitic diseases affect a large number of people
worldwide and are associated with organ dysfunction,
including kidney disease. Common features of the
pathogenesis of kidney injury in these diseases include
immunological phenomena, systemic manifestations
and direct damage caused by the parasites. Correct
diagnosis of the parasitic disease and early identification
of kidney injury is crucial for successful management of
patients. Novel biomarkers of kidney injury can help cli-
nicians to detect early kidney involvement and provide
adequate treatment. However, the best biomarker for
each disease and its application in the different clinical
setting is yet to be determined.
A high burden of parasitic diseases is associated with
poverty and other socio-​economic factors that need to
be addressed to achieve adequate control of these dis-
eases. In addition, many of the drugs that are used to
treat parasitic diseases have important toxicities, includ-
ing nephrotoxicity. More effective and less toxic drugs
are urgently needed. Further studies of the pathogenesis
of these diseases and the identification of specific bio-
markers might lead to the discovery of novel therapeutic
targets.
Published online 28 March 2022

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Acknowledgements
The authors thank all health care workers who dedicate their
careers to the treatment of infectious and parasitic diseases,
especially those in Brazil, Egypt, India and Thailand. E.F.D.
and G.B.S.J. have received grants from the Brazilian Research
Council — Conselho Nacional de Desenvolvimento Científico
e Tecnológico, CNPq (protocol numbers 302017/2018-6 and
310974/2020-8).
Author contributions
E.D.F.D., G.B.S.J., M.T., N.S., P.S., S.N., T.F., M.A.S.F.B., M.V.
and V.J. researched the data for the article. E.D.F.D., G.B.S.J.,
M.T., N.S., P.S., S.N. and T.F. wrote the text. E.D.F.D.,
G.B.S.J., M.V.G.L., T.F., M.A.S.F.B. and M.V. made substantial
contributions to discussion of the content. All authors
reviewed and/or edited the manuscript before submission.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Nephrology thanks A. Bagga, who
co-reviewed with V. Mahesh; R. Claure-​Del Granado; and
the other, anonymous, reviewer(s) for their contribution to the
peer review of this work.
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Supplementary information
The online version contains supplementary material available
at https://doi.org/10.1038/s41581-022-00558-​z.
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