Objectives: In many countries of sub-Saharan Africa, the most common causes of end-stage kidney disease are hypertension, chronic glomerulonephritis, and diabetes mellitus. So far, literature on recurrent focal segmental glomerulosclerosis in sub-Saharan African populations is limited. With the intention of providing guidance for best practices in sub-Saharan Africa, we reviewed available evidence for African Americans, a population with a similar genetic background. We chose this population as a pseudo-population to show how similar genetic backgrounds can predict disease occurrence in similar populations residing in different continents.
Materials and Methods: Our extended PubMed and Scopus literature search used these key words: “focal segmental glomerulosclerosis in African Americans” (search 1), “recurrent focal segmental glomerulosclerosis after kidney transplantation” (search 2), “risk factors for recurrent focal segmental glomerulosclerosis” (search 3); and “APOL1 gene and kidney transplantation” (search 4).
Results/Conclusions: Search 1 yielded 4 articles, search 2 yielded 44 articles, search 3 yielded 6 articles, and search 4 yielded 8 articles. African Americans were shown to be disproportionately predisposed to end-stage kidney disease, traceable to focal segmental glomerulosclerosis (the most common cause of glomerulonephritis leading to end-stage kidney disease). Apolipoprotein L1 presence in 22% of African Americans explained the odds ratio of 17 in developing focal segmental glomerulosclerosis and 8 times lifetime risk of end-stage kidney disease. Focal segmental glomerulosclerosis recurred in 30% of kidney transplant recipients; risk factors included young age, rapid progression to end-stage kidney disease, and White race recipient. Circulating permeability factors played a central role in primary and recurrent focal segmental glomerulosclerosis. For recurrent cases, transplant biopsy has remained the gold standard for diagnosis, with treatment involving a multi-modal approach, often resulting in partial or complete remission of proteinuria; allograft loss can occur if treatment is not successful. More randomized clinical trials are needed to chart the way forward for prolonged allograft function.
Key words : Apolipoprotein L1, End-stage kidney disease, Glomerulonephritis, Nephrotic syndrome, Sub-Saharan Africa
Kidney transplantation is the preferred option for treatment of end-stage kidney disease (ESKD).1 In many countries of sub-Saharan Africa (SSA), the most common causes of ESKD are hypertension, chronic glomerulonephritis, and diabetes mellitus.2 The cost of both dialysis and kidney transplantation is unaffordable for most patients in SSA due to absence of health insurance.2 To make kidney transplantation an attractive option, it is important to define the primary renal disease responsible for ESKD. The literature and data available for SSA populations are very limited. With the intention of providing guidance for best practices and research for ESKD patients in these geographical areas, we applied a literature review equivalent to the statistical practice of using a pseudo-population. These same risk factors for ESKD are observable among African Americans (AA), a population who shares a genetic background with people of SSA. These similarities are the result of the trans-Atlantic slave activity between the 16th and 19th centuries, during which millions of people from West Africa were transported as slaves to the Americas and Caribbean, and the more recent large influx of black African immigrants into the United States.
The goal of kidney transplantation is to improve quality of life.3 Kidney transplantation is more cost effective than dialysis.3 The frequency of hospital visits declines remarkably for transplant recipients compared with patients undergoing in-center hemodialysis.3
Kidney transplant recipients have a survival advantage over ESKD patients on dialysis.3 Despite benefits of kidney transplant, every recipient needs to be aware of the potential of disease recurrence.1 Although this information may not be well received by recipients, it helps them make an informed decision about kidney transplant. This will enable patients to understand that kidney transplant is not a cure but one of the treatment options for ESKD.
Focal segmental glomerulosclerosis (FSGS) is a disease of the podocyte (podocytopathy) that has various clinico-pathologic manifestations like massive proteinuria of >3.5 g/day in adults, hypoalbuminemia of <3.5 g/dL, generalized edema, and hypercholesterolemia >200 mg/dL.4 In children, the corresponding figures are proteinuria of >1 g/m2 of body surface area/day, hypoalbuminemia <2.5 g/dl, hypercholesterolemia >200 mg/dL, and gross edema.4 Clinical features vary from asymptomatic proteinuria to nephrotic range proteinuria.4
Podocytes play a central role in maintaining the architecture of the glomerulus. Podocytes form foot processes on the outer surface of the glomerular basement membrane, and the endothelial cells of the glomerular capillary form the innermost layer of the glomerular filtration barrier.4 Focal segmental glomerulosclerosis is sometimes referred to as a variant of minimal change disease, and both conditions are podocytopathies.4 The major distinction between FSGS and minimal change disease is that some 40% to 70% of patients with FSGS and persistent proteinuria will progress to ESKD over a period of 10 to 20 years.
Focal segmental glomerulosclerosis is the most common cause of nephrotic syndrome among adults in the United States; it accounts for about 40% of cases, and prevalence is approximately 7 per million population.4 Among children, FSGS constitutes 20% of nephrotic syndrome.4 Of the common causes of ESKD in the United States, chronic glomerulonephritis ranks third, and about 4% of ESKD cases are secondary to FSGS.4 The risk of developing FSGS is 3 to 4 times higher among AA compared with White populations.5 Progression of FSGS to ESKD among AA also tends to be faster compared with that shown in other racial groups.5 A study of glomerular diseases in Nigeria found FSGS to be the most common lesion, accounting for 48% of cases.6
Focal segmental glomerulosclerosis is classified into primary (idiopathic), when no etiological agent is linked to it, and secondary, when etiology is known.7 The histological Columbia classification describes 5 types, which include the following: tip lesion, not otherwise specified lesion, collapsing variant, perihilar variant, and cellular variant.8 This classification helps determine the prognosis of FSGS, with tip lesion considered benign or steroid sensitive and collapsing variant carrying the worst prognosis.8 The secondary form of FSGS can be subclassified into virus-associated FSGS (HIV, parvovirus B19), genetic/familial forms of FSGS, adaptive forms of FSGS (obesity, sickle cell disease), medication-associated FSGS (lithium, bisphosphonate), and mutations of the apolipoprotein L1 (APOL1) gene FSGS.4
Genetic factors play a vital role in both FSGS and recurrent FSGS (rFSGS) in children.4 The various components of the podocyte-like podocin and nephrin constitute the proteins affected by most genetic mutations.4 Early childhood onset of genetic FSGS is autosomal recessive, whereas autosomal dominant FSGS occurs in late adulthood.4 Focal segmental glomerulosclerosis due to the autosomal recessive mode of inheritance includes mutations in nephrin, podocin, MYO1E, PLCE1 (phospholipase C epsilon 1 gene), and CD2AP; these present in early childhood.4 Focal segmental glomerulosclerosis arising from the autosomal dominant mode of inheritance includes the TRPC6 gene (transient receptor potential cation 6 gene), the INF2 gene (inverted formin 2 gene), and the ACTN4 gene (α-actinin-4 gene).4 These genes code for the podocyte and the structures around it that control the slit diaphragm, which regulates filtering of protein into the Bowman space from the glomerular capillaries. Recurrent FSGS tends to be less common in genetic forms of FSGS compared with primary FSGS.4
Although over 50 genetic mutations have been linked to genetic FSGS, a few of them cause more than 60% of the common clinical forms encountered.9 The NPHS1 gene is located on chromosome 19q13.1; it codes for nephrin, which forms a vital part of the slit diaphragm.9 Mutations in the NPHS1 gene are responsible for Finnish-type nephrotic syndrome, which presents at birth with massive proteinuria and is usually resistant to steroid therapy (termed steroid-resistant nephrotic syndrome [SRNS]).10 The NPHS2 gene is located on chromosome 1q25.2, and it produces podocin, a transmembrane protein responsible for recruiting nephrin to the slit diaphragm.9 Nephrotic syndrome in NPHS2 gene mutations occurs between 3 months and 6 years of life with rapid progression to ESKD before the age of 10 years.10 The MYO1E gene is on chromosome 15q22.2 and produces nonmuscle myosin 1e, which facilitates intracellular movement and membrane trafficking.9 The PLCE1 gene is located on chromosome 10q23.33 and elaborates the phospholipase Cε1 signaling protein, which interacts with nephrin.9 The CD2AP gene is localized to chromosome 6p12 and produces the CD2-associated protein, which acts as a scaffolding molecule between the slit diaphragm and actin cytoskeleton.9 All of these genes are transmitted by the autosomal recessive mode of inheritance, causing childhood nephrotic syndrome, which is often SRNS.10
The TRPC6 gene is located on chromosome 11q22.1 and produces the transient receptor potential cation channel 6 protein; which is a receptor-activated calcium channel localized at the foot process membrane that interacts with podocin and nephrin.9 The INF2 gene is located on chromosome 14q32.33, its protein product is inverted formin 2, and it is a member of the formin family, functioning in depolymerization and polymerization of actin filaments.9 The ACTN4 gene is on chromosome 19q13, and it elaborates α-actinin-4, a member of the spectrin gene superfamily and cytoskeletal protein important for maintaining the structural integrity of the slit diaphragm.9 All of these genes are inherited through the autosomal dominant mode, and mutations in them cause nephrotic syndrome in adults.10
A significant proportion of FSGS cases are AA patients whose risk of developing ESKD has been linked to APOL1 gene mutations.5 This may be the reason for the 8.2 time lifetime risk of ESKD in AA patients, who constitute 33% of those in the United States with ESKD and who have poorer graft outcomes after kidney transplant.5 About 30% of patients with FSGS who undergo kidney transplant develop rFSGS; this contributes significantly to long-term graft outcomes.5 Prospective transplant recipients whose native kidney disease is as a result of FSGS should know about the risk of rFSGS following kidney transplant.7 Because AA share the same geographic background as Blacks in West Africa, it can be extrapolated that their genome is likely to be the same. This has been alluded to by the similarly high frequency of APOL1 gene mutations, which occurs in 22% of AA, 45% of Yoruba in South Western Nigeria, and 30% of Ibos in South Eastern Nigeria.11
The APOL1 G1 allele is made up of 2 missense variants (S342G and I384M), whereas the APOL1 G2 allele is a 6-base pair in-frame deletion (N388del/Y389del).11 Both G1 and G2 occur on the same chromosome 22.11 The APOL1 gene was an evolutionary means of preventing the development of human African trypanosomiasis (sleeping sickness) among people of SSA descent.5 The APOL1 gene produces a lytic protein that lyses the trypanosome in the blood of infected individuals.5
The APOL1 protein, as shown in Figure 1, consists of 3 regions. The C-terminal harbors the serum resistance-associated protein interacting domain, the N-terminal is the site of the pore-forming protein, and sandwiched between both is the membrane-addressing protein.11
Recurrence of FSGS can present in both children and adults.8 Factors linked to rFSGS include early age of onset (<6 years old), rapid progression of FSGS to ESKD, having a living related donor kidney, and bilateral nephrectomy before transplant.8,12 Other risk factors implicated include elderly donor, first graft loss from rFSGS, and White recipient of AA deceased donor graft.7
Primary FSGS and rFSGS have been linked to the presence of circulating permeability factors in their etiopathogenesis. The circulating permeability factors include soluble urokinase plasminogen activator receptor (suPAR), anti-CD40 antibodies, and cardiotrophin-like cytokine 1.13
Some other glomerular diseases known to recur posttransplant, like membranous nephropathy (MN), are associated with the presence of anti-phospholipase A2 receptor antibody. Anti-phospholipase A2 receptor antibody occurs in over 80% of primary MN, and its presence in serum of transplant recipients has been strongly linked to risk of recurrent MN.14 Other glomerular diseases known to recur after transplant include immunoglobulin A nephropathy (IgAN), membranoproliferative glomerulonephritis, and atypical hemolytic uremic syndrome.14
The diagnosis of rFSGS is based on nephrotic range proteinuria occurring after transplant.4 Heavy proteinuria pretransplant is known to predispose to early rFSGS.4 Two types of recurrence are recognized: early recurrence (within a few hours to a few days) or late recurrence (usually after several months to years).4 Late rFSGS is less aggressive than early rFSGS and may be linked to calcineurin inhibitor toxicity.4 The main diagnostic criterium for rFSGS is performing an allograft biopsy. An allograft biopsy finding would show podocyte effacement in the early stage, which then progresses to segmental sclerosis after a while.4 Childhood rFSGS usually does not have genetic mutations in slit diaphragm like NPHS1 and NPHS2 mutations.15
The presence of APOL1 gene renal risk variants (RRVs) in potential donors may lead to early rFSGS in the recipient.16 The proposal for genetic testing for the APOL1 gene may then have a strong argument for such to be part of routine work-up of kidney donors in the future, especially among Africans.16 Furthermore, the presence of the APOL1 gene RRV could make living donors have a higher risk of developing FSGS and ESKD several years after kidney donation.16
Making a diagnosis of recurrent glomerular disease can be challenging in most patients because of no histological diagnosis of native kidney disease before development of ESKD.17 Hence, the concept of protocol biopsies may help to detect early recurrence.17
Treatment of rFSGS is as challenging as treatment of FSGS in native kidneys. This is partly because of the various pathogenic mechanisms that have been proposed as the cause of rFSGS.14 Therapies like plasmapheresis, immunoadsorption, intravenous cyclosporin, methylprednisolone, and rituximab have been used with varying degrees of success.14 The use of intravenous cyclosporin has received much attention as its antiproteinuric effect is attributable to stabilization of the actin cytoskeleton in podocytes and the ability to inhibit T-cell proliferation.18 There are also emerging therapies, including abatacept, belatacept, galactose, and adrenocorticotropic hormone (ACTH).19-22
Materials and Methods
We conducted a systematic literature search using Scopus and PubMed from 2009 to 2019 for publications in the English language. The search guideline used was PRISMA, with the PRISMA flow diagram used to screen the searched articles and eventually allow for full article review. The following keywords were used: “FSGS in African Americans” (search 1), “recurrent FSGS after kidney transplantation” (search 2), “risk factors for recurrent FSGS” (search 3), and “APOL1 gene and kidney transplantation” (search 4). The abstracts from search 1 through to search 4 were retrieved. All studies on animal models, HIV-related studies, and other renal diseases, as well as all review articles, were excluded. Inclusion criteria were articles containing case reports, case series, case controls, retrospective studies, and randomized clinical trials. We retrieved 382 full articles, and these were reviewed to ascertain their relevance. After eliminating articles that did not meet the inclusion criteria, we had a total of 62 articles.
Prevalence of focal segmental glomerulosclerosis among end-stage kidney disease and African American patients
Glomerulonephritis is the third leading cause of ESKD in the United States, after diabetes mellitus and hypertension, with FSGS being the most common cause of glomerulonephritis leading to ESKD. Population prevalence of FSGS among the general population is difficult to ascertain as not every patient with a glomerular disorder undergoes a kidney biopsy.
A large-scale study comprising 29 nephropathology centers from 4 continents surveyed the frequency of glomerular diseases from kidney biopsies.23 Of 60 340 biopsies with a specific diagnosis, 42 603 had glomerular diseases. The study population included 53% Whites, 19% Blacks, 14% Latinos, and 10% Asians.23 In North America, FSGS and diabetic glomerulosclerosis both had a prevalence of 19.1%, and both were the most frequent diagnoses. In Europe, FSGS made up 15%, which was second to IgAN at 22%. In South America, lupus nephritis was predominant with 38%, whereas FSGS was second with 16%. In Asia, FSGS was the fifth most common with 6.9%, and IgAN was the most common.23 This study was unique in attempting to get a uniform criterion for studying glomerular diseases worldwide. Some of the limitations were omission of Africa and Australia, missing data of racial classification amounting to 43%, fewer centers from Asia and South America, and the retrospective nature of the study, which may have included misdiagnoses of some glomerular lesions.23 Although the study tried to find a link between genetic, environmental, and epigenetic factors influencing the frequency of glomerular diseases in different races from 4 continents, further studies are needed to fully explain these disparities.23
In a single-center retrospective study from Sim and associates,24 the electronic health records of patients who underwent kidney biopsies over a 12-year period (2000-2011) were assessed. The study was done at the Kaiser Permanente Southern California health system and consisted of a racially and ethnically diverse US population. Of 2501 patients diagnosed with primary glomerulonephropathy, AA constituted 17.4% (the third largest ethnicity group in the study).24 Among all racial groups, FSGS was the most common histologic pattern identified, making up 38.9% of the study population. In the AA group, FSGS accounted for the largest proportion of all the biopsies (49.8%). For rate of disease occurrence, FSGS showed the highest rise in rate over time, from 1.6 cases per 100 000 person-years in 2000 to 5.3 cases per 100 000 person-years in 2011. Patients with FSGS had higher average serum creatinine levels compared with those with other glomerulonephropathies, which may lead to early progression to ESKD.24
Murugapandian and colleagues,25 in a single-center study conducted in Southern Arizona, retrospectively analyzed kidney biopsy records between 2004 and 2014, with 710 specimens included. The third most frequent racial group was the AA population, accounting for 7.32%. Of 710 patients with glomerulonephritis in this retrospective study, FSGS accounted for 158 cases (22.25%) and was the most common pattern of glomerulonephritis.25
The temporal trend in glomerular diseases over a 30-year period was the focus of the study from O’Shaughnessy and associates.26 This cross-sectional study reviewed all native kidney biopsies referred to the Division of Nephropathology at the University of North Carolina. Of 21 374 patients, AA patients (38.3%) were the most predominant after White patients (56.8%). Focal segmental glomerulosclerosis was the most common glomerular disease of all the 18 subtypes, with White patients accounting for 50.6% and AA patients accounting for 45.4%. The temporal trend showed that the frequency of FSGS continued to increase from 22.6% (1986-1995) to 27.2% (1996-2005) and plateaued at 24.7% (2006-2015).26
One constant denominator in these studies was the high prevalence of FSGS both worldwide as well as among AA individuals. The high frequency of FSGS among AA patients is linked to the APOL1 gene RRVs. This may explain why FSGS ranks as the leading cause of glomerulonephritis in ESKD patients in the United States.
Genetic risk factors for focal segmental glomerulosclerosis among African Americans
Genetics plays an important role in the pathogenesis of many diseases, with kidney disease among the AA population being one that continues to intrigue researchers.
The risk of FSGS among the AA population has been linked to the presence of the APOL1 gene mutation. In 2010, Genovese and colleagues27 linked APOL1 found exclusively among AA to the development of FSGS and hypertension-attributed ESKD.5,27 The discovery of 2 APOL1 gene variants (G1 and G2) in 2010 has revolutionized the approach to the study of kidney disease among AA. Both of the APOL1 gene variants are located on chromosome 22. The finding of the MYH9 gene in close proximity to the APOL1 gene on chromosome 22 explains the reason why some researchers had previously linked the MYH9 gene to the increased risk of kidney disease among AA.27 In their genome-wide association study of 56 and 61 FSGS patients from AA and European American ethnic backgrounds, respectively, and a control population composed of 1759 AA and 1531 European Americans, there was complete absence of the APOL1 gene among the European Americans and strong association of FSGS with APOL1 gene among AA.27
Kopp and colleagues28 conducted a genetic analysis of the APOL1 RRVs among patients with FSGS and HIV-associated nephropathy (HIVAN) and a control group in AA and European Americans. This case control study on the APOL1 genotype included 1378 participants: 217 primary FSGS AA, 168 primary FSGS European Americans, 54 HIVAN AA, and 939 matched controls. The presence of 2 renal risk gene (G1 and G2) or 2 copies of G1 or 2 copies of G2 led to an odds ratio of 17 for primary FSGS among AA and odds ratio of 29 for HIVAN among AA. Among European Americans, the APOL1 gene was very rare.28
In another study, Papeta and colleagues29 studied AA patients who had biopsy-proven FSGS, HIVAN, and IgAN; most of the FSGS and HIVAN patients had APOL1 risk variants. However, APOL1 risk variants were not present in IgAN patients. The role of the APOL1 risk variant in the etiology of FSGS rather than the MYH9 gene was confirmed by these studies.27-29
The concept of “second hit” hypothesis in relation to APOL1-related kidney diseases has also been proposed from the finding that renal disease does not develop in all AA with the APOL1 gene RRVs (G1 and G2 alleles). The role of the NPHS2 gene in conjunction with APOL1 risk variants was studied by Bostrom and colleagues.30 This genome-wide association study found significant interactions between APOL1 and NPHS2 genes among AA who had developed ESKD from FSGS and hypertension-attributed nephropathy. On the other hand, the ACTN4 gene was not found to contribute to APOL1-related kidney diseases among AA.31 Hence, HIV infection and the NPHS2 gene have been proposed to be possible “second hits” for the full development of APOL1-related kidney diseases.28,30
Other genetic mutations linked to FSGS, especially in childhood, include NPHS1 (nephrin gene), NPHS2 (podocin gene), TRPC6, ACTN4, INF2, and PLCE1.32 The NPHS1, NPHS2, and PLCE1 genes cause SRNS; these genes are transmitted by autosomal recessive inheritance.32 The TRPC6, ACTN4, and INF2 genes cause SRNS inherited by autosomal dominant transmission.32 Among AA children with FSGS, these gene mutations were absent, as seen in studies by Chernin and associates33 and Laurin and associates.32
The impact of APOL1 gene RRVs was further evaluated by Ng and associates34; this was to ascertain the role of APOL1 in AA children with chronic kidney disease and nephrotic syndrome. The study population included the Nephrotic Syndrome Study Network (NEPTUNE) and Chronic Kidney Disease in Children (CKiD) cohort; both enrolled children with glomerular diseases. A high risk APOL1 gene was found in a significant proportion of children with FSGS: in 89% of the CKiD cohort and in 67% of the NEPTUNE cohort.34 The APOL1 risk variant plays a vital role in the FSGS among both children and adults of AA racial background. Areas of further research include finding the genetic cause of AA patients whose FSGS is not linked to the APOL1 risk variant gene.
Risk factors for recurrent focal segmental glomerulosclerosis
Because rFSGS affects about 30% of FSGS patients posttransplant, knowledge of the risk factors is vital for optimum patient care.
Children and younger adults who develop FSGS with rapid progression to ESKD within a period of 10 years are prone to have rFSGS posttransplant.35-37 As a result of proteinuria being an early finding in rFSGS, some patients undergo pretransplant nephrectomies of the native kidneys; this has also increased the rate of rFSGS.35,36
Living donation often ensures a better long-term renal allograft survival; however, as a result of close relatives being donors for most children, rFSGS tends to be more rampant in recipients of living donors.35,36 On the other hand, Nehus and colleagues37 did not find any relationship between living donation and increased risk of rFSGS.
Significant proteinuria (>7 g/day) and hypoalbuminemia (<2.8 g/dL) pretransplant may also portend a high risk for rFSGS.36,38 Another risk factor is female sex, and this may suggest the role of autoimmune or endocrine factors in rFSGS.36
Recipient race also plays some role in rFSGS. Schachter and colleagues39 reported rate of 13% among AA patients compared with 29% among White patients in a single-center study. In their patient cohort, Nehus and colleagues37 showed a preponderance of White patients affected by rFSGS compared with AA patients.37
The type of immunosuppressive drug used to treat the native FSGS or the ones used posttransplant have been shown to not influence the rate of rFSGS.36,39
Although Columbia histology classification is considered a clue to the aggressiveness of native FSGS, it may not necessarily recur as the same type in the allograft; hence, disease severity in rFSGS will depend on the histology pattern in the allograft.39
In a retrospective study by Francis and associates,40 data from the Australia and New Zealand dialysis and transplant (ANZDATA) registry over a 20-year period showed that younger age, non-White ethnicity, and living donation were factors associated with rFSGS. Despite the risk of living donation contributing to rFSGS, these allografts still had a survival advantage over deceased donors.40 Results from 30-year data from ANZDATA, which compared allografts that developed recurrent glomerulonephritis posttransplant, showed that younger age was a risk factor for rFSGS.17 Table 1 summarizes the risk factors for rFSGS.
Role of genetic factors in focal segmental glomerulosclerosis recurrence
The NPHS2 mutation causes the hereditary forms of FSGS and SRNS in children.41 In a retrospective study from the European FSGS Transplantation Study group, 83 patients with biopsy-confirmed FSGS were recruited,41 with 53 patients undergoing genetic analysis for NPHS2 gene mutation. Recurrence of FSGS occurred in 30 of the 83 patients, whereas, among the 53 patients who had genotyping for NPHS2 mutation, 17 had rFSGS. The NPHS2 mutation was found in 15 patients, and none of these patients had rFSGS. The authors concluded that the presence of NPHS2 mutation prevented rFSGS.41 Another study by Sun and associates42 found 2 genetic mutations that prevented recurrence of FSGS. In the study, NPHS1 and TRPC6 gene mutations were studied in a family, and a family member who developed FSGS and later ESKD had both mutations. A sibling who donated at the age of 35 years had heterozygous TRPC6 mutation. At 20 years after kidney transplant, both the donor and recipient have remained free of proteinuria.42 Mutations in NPHS1, NPHS2, ACTN4, and TRPC6 genes have all been reported to reduce the rate of FSGS recurrence.38,39,41
Role of APOL1 gene in recurrent focal segmental glomerulosclerosis
Because APOL1 gene has been implicated in the etiology of FSGS in native kidneys, an important question to ask is the role of the APOL1 gene in rFSGS. Callender and colleagues43 documented the reduced long-term survival of grafts from AA deceased donors. Although the reason for this was not known, the work by Reeves-Daniel and associates44 linked APOL1 gene mutations to be responsible in a single-center study of 106 AA deceased donors to assess APOL1 risk variants between 1998 and 2009. In their study, 136 kidney transplant recipients who were followed for 26 months showed significantly reduced graft survival among recipients of deceased donors with 2 APOL1 risk variants versus survival in recipients of deceased donors with less than 2 APOL1 risk variants. There were 8 graft losses among recipients of 2 APOL1 risk variants from AA deceased donors. The lesions found on transplant biopsies were linked to APOL1 nephropathy in 75% of the cases (FSGS was found in 1 case, the FSGS collapsing variant was found in 2 cases, and arteriosclerosis was found in 3 cases). A multivariate analysis showed that, compared with HLA antibody mismatches, cold ischaemia time, and recipient age, an APOL1 risk variant was the strongest predictor of graft failure.44 This finding was validated in a multicenter study of 55 centers in the United States involving APOL1 genotyping of 657 deceased donors of AA ethnicity.45 Despite early graft failure recorded in APOL1 2-risk alleles, the long-term survival was 89.3% at 1 year, 73.0% at 5 years, and 54.5% at 10 years posttransplant.45
Permeability factors affecting recurrent focal segmental glomerulosclerosis
One of the reasons why a circulating permeability factor is suspected in FSGS is based on a case reported by Gallon and colleagues.46 The group reported the case of a 27-year-old man who had ESKD secondary to FSGS and received a living related kidney transplant from his sister who was 24 years old. The recipient developed heavy proteinuria (urinary protein of 10 g/day) by day 2 posttransplant. This was despite pretransplant and posttransplant treatment with plasmapheresis and triple immunosuppressive therapy. A transplant biopsy done by day 6 posttransplant showed recurrence of FSGS. The failing allograft was retransplanted into a 66-year-old patient with ESKD secondary to diabetic nephropathy. After this retransplant, the allograft function improved, with serum creatinine reduced from 5.27 to 1.84 mg/dL and proteinuria reduced from 25 to 1.2 g/day. A transplant biopsy showed reversal of effacement of podocytes. At 8 months posttransplant, proteinuria was 0.27 g/day and estimated glomerular filtration rate was 90 mL/min. Such a case brings to bear the likelihood of a circulating permeability factor as a cause of rFSGS.46
The circulating permeability factor that has received much scientific scrutiny is the urokinase plasminogen activator receptor (uPAR). This receptor is a 3-domain protein (D1, D2, and D3) held to the cell membrane by glycosylphosphatidylinositol.13 Although it is primarily a urokinase receptor, it also forms complexes with transmembrane proteins like vitronectin, caveolin, integrins, and G-protein-coupled receptors.13 When uPAR is cleaved from the cell membrane, it becomes suPAR, and its molecular weight can range from 20 to 50 kDa. The molecular weight will depend on whether it exists as D1, D2, D3 or as D2, D3, as shown in Figure 2. In the kidneys, uPAR is localized to the podocytes and tubular epithelial cells. It is also expressed on several other cells. The functions of uPAR are cell proliferation, migration, and survival. Wei and associates47 were the first investigators to describe suPAR as a circulating permeability factor in FSGS and rFSGS. In about two-thirds of FSGS patients, they found serum levels of suPAR to be elevated.
The serum suPAR level was measured in a cohort study, and median suPAR serum levels were highest for the FSGS group.48 The median suPAR levels were significantly higher in primary FSGS and rFSGS. The authors concluded that suPAR is a circulating permeability factor that can cause primary FSGS and rFSGS.48
Another study by Franco Palacios and colleagues49 reported that urinary suPAR was more diagnostic of rFSGS than elevated serum suPAR. The group demonstrated elevation of suPAR in all patients studied who developed ESKD from primary FSGS, diabetic nephropathy, IgAN, autosomal dominant polycystic kidney disease, and MN. Serum and urinary suPAR were also noted to correlate positively with proteinuria and albuminuria in all ESKD patients. The group concluded that, because serum suPAR was elevated in all classes of ESKD patients irrespective of etiology, elevated urinary suPAR was predictive of rFSGS.49
Diagnostic criteria of recurrent focal segmental glomerulosclerosis
A biopsy of the native kidney must be done to diagnose FSGS; likewise, the cornerstone of diagnosing rFSGS is transplant biopsy. The Columbia histologic classification of FSGS seen in transplant biopsy may mimic that shown in the native kidneys. In a study from Ijpelaar and colleagues,50 81% of those with certain FSGS variant in native kidneys had recurrence in the transplant biopsy. The group found 3 types of recurrences. This may indicate that the FSGS variant may determine likelihood of rFSGS. Variable degrees of proteinuria, ranging from subnephrotic to nephrotic range, will often herald the onset of rFSGS.38 The median time of occurrence of proteinuria was 1 to 6 days, and delayed graft function occurs in about 25% to 42% of cases of rFSGS.38 Also, more acute rejection episodes (54% to 75%) were seen in rFSGS, and reduced allograft survival, with a 5-year survival of 50%, was shown to be a feature of rFSGS.38 Recently, developed cell-based tests may help predict rFSGS.51
Evaluating the role of APOL1 genetic screening for kidney donors
Recent literature highlights the risk of living kidney donors to develop chronic kidney disease and ESKD after donation. One of the concerns stems from AA donors carrying the 2 APOL1 gene RRVs. There is still some controversy on whether AA donors should undergo APOL1 gene screening. Two case reports of living related donors of African ancestry have demonstrated that presence of APOL1 RRVs can predisposed to chronic kidney disease 7 years after donation.52,53 A retrospective analysis of AA donors with 2, 1, and 0 APOL1 RRVs showed marked differences in allograft survival.54 Donors with 2 APOL1 RRVs showed reduced survival compared with those with 1 and 0 APOL1 RRVs. In a new ongoing prospective study to evaluate the role of 2 APOL1 RRVs in both donors and recipients in long-term renal allograft outcome (the APOL1 Long-Term Kidney Transplantation Outcomes Network),55 it is hoped that the question on the relevance of APOL1 genetic screening in AA donors can be answered.
Role of protocol biopsies in management of recurrent focal segmental glomerulosclerosis
A transplant biopsy can be done based on allograft dysfunction or a surveillance biopsy can be done in the context of graft monitoring for development of subclinical rFSGS. Biopsies allow clinical teams to obtain an early diagnosis and early start of treatment. In a case report, Sakai and associates56 studied protocol biopsy timing, with the first a few hours posttransplant, the second 3 months posttransplant, and the third 1 year posttransplant. The first and second transplant biopsies revealed rFSGS, which allowed early treatment, forestalling allograft dysfunction. By the third biopsy, the histologic changes had reversed.56 The risk of complications like bleeding following biopsy may limit acceptance of this to monitor recurrence. The American Society of Transplantation has recommended the use of serial urinary albumin-creatinine ratio (UACR) in spot urine to monitor rFSGS,57 with UACR done daily for 1 week, weekly for 4 weeks, every 3 months for 1 year, and then annually. With this strategy, proteinuria can be detected early and rFSGS can be confirmed by allograft biopsy.
Strategies to prevent and treat recurrent focal segmental glomerulosclerosis
Treatment of rFSGS with a multimodal approach involving the use of several therapies has been shown to achieve remission in many patients. Circulating permeability factors as the etiopathogenesis of rFSGS have led to use of plasmapheresis, which can reduce serum levels of circulating permeability factors. In addition to plasmapheresis, treatment includes immunoadsorption, high-dose cyclosporin, methylprednisolone, rituximab, abatacept, belatacept, ACTH, galactose, and blockers of the renin angiotensin system.
For FSGS patients undergoing their first kidney transplant, there is no benefit of administering plasmapheresis during transplant.35,58,59 For FSGS patients undergoing a subsequent transplant after an initial rFSGS (frequency of rFSGS approaches 80% in subsequent transplant), peritransplant plasmapheresis may be beneficial.58 Other studies have demonstrated no benefit of adding rituximab therapy to plasmapheresis in pretransplant prophylaxis against rFSGS.60,61
Treatment of rFSGS with plasmapheresis and other modalities (ie, high-dose cyclosporin and/or methylprednisolone and rituximab) has been shown to result in complete remission in 42% to 63% of cases, partial remission in 8% to 50% of cases, and no remission in 8% to 29% of cases.62,63 The combination of plasmapheresis and rituximab yielded up to 66% to 87% response rate with reduced cases of allograft loss when treatment was started early.61,64 Rituximab was helpful for achieving remission in patients who were dependent on plasmapheresis to prevent rFSGS for several months.64 In a study by Straatmann and associates,65 among a pediatric population who were treated with intensive plasmapheresis (sole therapy), 100% remission was achieved in 7 patients.
In a systematic review and meta-analysis of rFSGS treatment utilizing plasmapheresis that evaluated 77 case reports and case series, the achieved remission rate was 71%, with rates of remission similar in children and adults.66
Immunoadsorption, a form of apheresis treatment (similar to plasmapheresis), is sometimes favored beyond plasmapheresis because it is not associated with bleeding complication. Immunoadsorption in combination with other therapies was able to achieve complete remission in 58% to 66% and partial remission in 16% to 42% in some case series.67,68
Abatacept (cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin fusion protein) acts by blocking the B7-1 molecule (CD80) through costimulatory inhibition. Podocytes exhibit the B7-1 molecule, and their inhibition reduces proteinuria from proteinuric kidney disease. Abatacept achieved remission of proteinuria in 100% of patients who had conventional rFSGS treatment failure using plasmapheresis and rituximab.19,69 Abatacept was of no benefit in other case series of patients with rFSGS who did not respond to conventional therapies.70,71 Belatacept is a B7-1 blocker that binds to CD80; it was shown to be of no benefit in reducing proteinuria among patients with rFSGS.19 A well-designed randomized clinical trial may be able to answer the question of their relevance for treatment of rFSGS.
Adrenocorticotropic hormone has been used for treatment of glomerulonephritis and acts through the melanocortin 1 receptor.22 The use of ACTH for rFSGS was first described by Mittal and colleagues in a case report of a patient of rFSGS who did not respond to plasmapheresis and rituximab. However, when the patient was started on subcutaneous ACTH gel 80 U/ml (given twice weekly for 6 weeks), proteinuria resolved.72 Another case series showed remission of proteinuria among 20 patients who did not respond to plasmapheresis, rituximab, and blockers of the renin angiotensin system.22 They received subcutaneous ACTH 80 units twice weekly for 6 months.22 Further studies are needed to ascertain the benefit of using ACTH for treatment of rFSGS.
Renin angiotensin system blockage with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (ARB), and direct renin inhibitors is used to treat hypertension with a peculiar effect in reducing proteinuria. In a case report of use of ramipril (an angiotensin-converting enzyme inhibitor) 10 mg daily, candesartan (an ARB) 64 mg daily, and aliskiren (a direct renin inhibitor) 300 mg daily, partial remission was achieved in a patient with rFSGS who did not respond to plasmapheresis and rituximab.73 Another case report highlighted the use of telmisartan (an ARB) 120 mg daily along with prednisolone 30 mg daily to achieve remission of rFSGS.74 These case reports show the versatility of treatments available for rFSGS; however, further studies are needed to confirm their validity.
Oral galactose, a simple sugar-like glucose, is among the plethora of options that can be of relevance in rFSGS treatment. Galactose works by binding to the circulating permeability factor in serum of patients with rFSGS. The benefit of using galactose along with other therapies like plasmapheresis and rituximab, when there was no appreciable response to conventional therapies, was shown in several case report.21,75 Because these are case reports, further studies are needed to elucidate on the role of galactose in treatment of rFSGS.
A cursory look at the above treatment modalities shows that they can be replicated in the SSA population. However, making a diagnosis early still requires a transplant biopsy before appropriate therapy can be utilized to improve allograft outcome. There is also a need to conduct randomized clinical trials to show which of these combination therapies will have the best outcome.
The AA population was chosen as a pseudo-population to show how similar genetic backgrounds can help predict disease occurrence in similar populations residing in different continents. Recurrent FSGS is known to affect about 30% of patients with primary FSGS following their first transplant, and this approaches 80% in second and subsequent transplants. As a result of FSGS recurrence, the life span of many allografts is shortened to less than 50% survival by 5 years posttransplant. Recognized risk factors may play some role in recurrence, especially presence of the APOL1 gene RRVs among AA donors. In workup of living donors for kidney transplant in SSA, APOL1 genotyping may be required to help prognosticate the outcome of the allograft in the recipient. APOL1 genotyping will also help to identify donors who may be at risk of developing proteinuria and ESKD years after donation. Diagnosis of rFSGS is based on transplant biopsy, whereas monitoring of UACR enables early noninvasive diagnosis. The treatment of rFSGS has remained elusive as it is based on multimodal therapy; about 30% of patients have no response and ultimately graft loss. However, with newer emerging therapies, it is expected that these will bring hope at the end of the tunnel in the management of rFSGS. With increased knowledge among nephrologists in SSA, better care of transplant recipients will be guaranteed.
DOI : 10.6002/ect.2020.0542
From the 1Department of Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos State, Nigeria; and the 2Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Umeizudike I. Theophilus, 1-5 Oba Akinjobi Road, GRA Ikeja, Lagos State, Nigeria
Figure 1. Apolipoprotein L1 Lytic Protein Structure
Table 1. Risk Factors for Focal Segmental Glomerulosclerosis Recurrence
Figure 2. Urokinase Plasminogen Activator Receptor Attached to Cell membrane, Showing That It Can Be Cleaved From the Membrane to Exist as D1 and D2-D3