Monogenic Kidney Diseases in Kidney Transplantation

Abstract

Monogenic kidney diseases are involved in up to 15% of end-stage kidney diseases (ESKDs) in adults, and in 70 % of pediatric patients. When these disorders lead to kidney failure (KF), kidney transplantation (KT) is the preferred mode of replacement therapy. KT requires specific considerations depending on the nature of the genetic disorder, the potential oncological risk, the risk of recurrence in the graft, the possibility of specific complications of immunosuppression, and the issue of living donation. The availability of genetic testing should play an increasing role in the evaluation of patients or related living donor candidates before transplantation, relevant for the pretransplantation and posttransplantation management.

At least 10% to 15% of adults and 70% of children with ESKDs have an inherited kidney disease.^1,2 Early age of onset, familial history of kidney diseases, congenital or cystic disease, and association with syndromic and extrarenal features are classically associated with a higher probability of genetic kidney diseases (GKDs).^3,4 The increasing availability of genetic testing and reference databases implies that a molecular diagnosis can be obtained more readily, usually before patients are considered for KT.

Considering that KT is the preferred option for most patients with GKD and KF, important issues should be considered both before and after transplantation. Genetic testing has a direct clinical utility, by influencing disease surveillance and management, and guiding specific therapies. Some kidney diseases of genetic origin may recur on the kidney graft or present an increased risk of cancer or systemic manifestations, requiring early diagnosis and specific management in terms of immunosuppression and follow-up. In addition, the availability of genetic testing has practical implications for the selection of related living donor candidates.5, 6, 7

Here, we address the specificities of genetic testing in KT; discuss the risk of recurrence in the transplant and of oncological transformation associated with certain GKD; review specific features of the most frequent inherited disorders and those with multisystemic complications; discuss the influence of immunosuppression on disease courses and living donation; and list unmet needs and perspectives in the field.

Genetic Testing in Kidney Transplant Candidates

Diagnostic Yield of Genetic Testing in Kidney Transplant Candidates

In daily practice, about 15% of chronic kidney diseases (CKDs) are of unknown origin.³ Currently, there is no strong recommendation for the systematic use of genetic testing in such cases. An increased likelihood of a genetic diagnosis is associated with positive family history, young age of onset, structural or cystic abnormalities of the kidneys, unknown etiology of CKD, and extrarenal manifestations (Figure 1). The studies of Groopman et al.⁵ demonstrated that exome sequencing yielded a genetic diagnosis in approximately 10% of cases in 2 cohorts totaling 3315 adult patients with advanced CKDs (and among them 2144 with ESKDs) reaching 17% in patients with CKDs of unknown origin. A recent extensive literature survey of diagnostic yield across and within kidney phenotype groups reviewed 5 studies reporting on ESKD populations that were waitlisted for transplant surgery or had received a kidney transplant. A diagnostic yield was extrapolated ranging from 12.5% to 24.6%.⁸ The authors report that positive family history, consanguinity, extrarenal features, and young age of onset of ESKD positively influenced the diagnostic yield.⁸ However, it is important to state that ESKD onset at adult age should not prevent from pursuing a genetic diagnosis because typical childhood-onset diseases can be diagnosed at adult age. A prominent example is the rather common recurrent 290kb NPHP1 deletion that was detected in homozygous state in 0.5% of an adult cohort of 5606 patients with ESKDs. The authors concluded that nephronophthisis is a relatively frequent monogenic cause of adult-onset ESKDs.⁹

Figure 1.

Genetic testing in kidney transplantation: predictive factors, modalities, actionable genes, and impact. aHUS, atypical hemolytic and uremic syndrome; CGH, comparative genomic hybridization; CKD, chronic kidney disease; CNV, copy number variation; GNC3, C3 glomerulopathy; MLPA, multiplex ligation-dependent probe amplification; MPS, massive parallel sequencing; PH1, primary hyperoxaluria; SNP, small nucleotide polymorphism; WES, whole exome sequencing; WGS, whole genome sequencing.

Impact of Identifying a Genetic Origin to KF

Identifying the genetic origin of KF has important clinical implications for the patient, including pretransplant and posttransplant management, because some GKDs have extrarenal metabolic, vascular, or oncologic manifestations; and for living donation (Table 1). However, genetic tests are expensive, and the cost-effectiveness of a systematic genetic testing strategy is not established.¹ In particular, the identification of multiple variants of unknown significance raises the issue of specificity and the need for filtering parameters. Social, professional, and psychological consequences of a genetic diagnosis for the patient and relatives deserve careful management (Figure 1). In any case, patients and families must be carefully informed about the implications of genetic testing.³

Table 1.

Screening for genetic kidney diseases with implications for kidney transplantation

Type of disease	Clinical features
Complement mediated diseases	•Atypical HUS •GNC3 •KFUO suggesting TMA (preeclampsia, malignant hypertension, secondary TMA)
Crystalline nephropathies	•Primary hyperoxaluria •KFUO with a history of lithiasis and/or nephrocalcinosis •KFUO with an interstitial nephritis pattern (bland sediment, low proteinuria) •KFUO with a proximal tubulopathy pattern
Glomerular diseases	•Steroid-resistant nephrotic syndrome •FSGS lesions on kidney biopsy •KFUO with a glomerular pattern (hematuria, glomerular proteinuria)
Cystic diseases	•ADPKD (family history, enlarged kidneys, liver cysts) •ADTKD (bland sediment, normal-sized kidneys, early hyperuricemia/gout)

ADPKD, autosomal dominant polycystic kidney disease; ADTKD, autosomal dominant tubulointerstitial kidney disease; FSGS, focal segmental glomerulosclerosis; HUS, hemolytic and uremic syndrome; KFUO, kidney failure of unknown origin; TMA, thrombotic microangiopathy; GNC3, C3 glomerulopathy.

Genetic testing in the context of KT has the capacity to identify GKDs at risk of recurrence in the kidney graft or associated with a risk that could be modified by the transplant management. In line, both Kidney Disease: Improving Global Outcomes¹⁰ and Kidney Disease Outcomes Quality Initiative¹¹ recommend performing genetic testing in patients with a clinical course consistent with genetic focal segmental glomerulosclerosis, C3 glomerulopathy (C3G), atypical hemolytic and uremic syndrome (aHUS), and primary hyperoxaluria (PH) (Tables 1 and 2).

Table 2.

Genetic kidney diseases at risk of recurrence after kidney transplantation

Disease (Inheritance)	Risk of recurrence	Management
Atypical HUS (AD/AR)	High-risk, moderate-risk, low-risk stratificationa	Eculizumab prophylaxis in high-risk and moderate-risk
C3 glomerulopathy (AD)	67%–84 % independent of the type of mutations	Consider eculizumab in early and severe case of recurrence.
Primary hyperoxaluria (AR)	Not quantified	Before transplantation -Early initiation of conservative measures after diagnosis (hyperhydration, potassium-sodium citrate, vitamin B6) -Consider early initiation of RNAi (if available) During and after transplantation -Consider isolated kidney transplantation combined with RNAib -Consider isolated kidney transplantation in highly-selected vitamin B6 responders -Consider dual liver-kidney transplantationc -In patients not on chronic dialysis: consider early transplantation (before occurrence of systemic oxalosis) -In patients on chronic dialysis: consider transplantation when predialysis POx <30–35 mmol/ld
APRT deficiency (AR)	Not quantified	XO inhibitors at high doses to initiate early after diagnosis and continue after transplantation.

AD, autosomal dominant; APRT, adenosine phosphoribosyl transferase; AR, autosomal recessive; HUS, hemolytic and uremic syndrome; KT, kidney transplantation; PH, primary hyperoxaluria; Pox, plasma oxalate; RNAi, RNA interference agents; XO, xanthine oxidase.

^aHigh risk: history of recurrence with a previous allograft and/or pathogenic variant of the CFH/C3/CFB genes; moderate risk: negative complement screening result or pathogenic variant in the CFI gene or detectable circulating anti-CFH antibody; low risk: isolated pathogenic variants in MCP or DGKE genes or anti-CFH antibodies no longer detected at the time of transplantation.

^bUnder investigation, only in countries where RNAi are available.

^cIf RNAi not available or have demonstrated their inefficacy in decreasing hepatic oxalate production.

^dOr if demonstration of the absence of systemic oxalosis.

Genetic Testing Techniques

The modalities for genetic testing have been reviewed in detail recently.^3,6,12 In Table 3, we summarize the commercially available methods, with their indications, limits, advantages, and examples where the tests are most appropriate. Most genetic laboratories currently use massive parallel sequencing-based exome sequencing with data analysis restricted to virtual panels based on genes known to be linked to a given phenotype or group of diseases (Figure 1). Panels have the benefit of excluding incidental findings in genes not linked to the observed phenotype; if targeted panels are used (i.e., only genes of interest sequenced as opposed to whole exome sequencing [WES]) they need however to be updated frequently due to the discovery of new genes. WES allows retrospective expansion of analysis when no pathogenic variants are found in the initial panel, for example when new genes have been associated with the phenotype. However, WES has in general less deep sequence coverage than targeted gene panels and some genes need to be evaluated with specific techniques, including long-range polymerase chain reaction or capture-based panels (e.g., PKD1) or variable number tandem repeat sequencing approach coupled with a spectrometry-based probe extension assay (e.g., MUC1). Coverage of WES is limited to exonic regions and misses deep intronic variants, variants in regulatory regions, and variants in intergenic regions as recently described in Gitelman disease¹³ or Alport syndrome (AS).¹⁴ These variants can be captured by whole genome sequencing.

Table 3.

Different genetic testing modalities and their indications, advantages, and limitations

Test	Application	Indications	Advantages	Limitations	Examples
Sanger sequencing	Detection of SNVs and small indels	- Validation of MPS results - Targeted specific gene(s), e.g., phenotypes with little genetic heterogeneity - MPS-refractory regions	- Fast and cost effective for low number of genes - No incidental findings	- Limited number of genes analyzable - No detection of large structural variants - Low sensitivity for low-level mosaicism	- APOL1 genotyping - Specific phenotypes (Fabry disease, tuberous sclerosis)
Chromosomal microarray	Copy number variants (unbalanced genomic rearrangements)	- Multiple congenital anomalies - recognizable phenotypes associated with CNV (e.g., del 17q12)	- Good resolution (∼200kb) - Untargeted/genome-wide - SNP array able to detect uniparental disomy	- No detection of SNVs, small indels, and CNV under the resolution threshold - No detection of balanced chromosomal rearrangements - Limited detection of low-grade mosaicism - Inaccuracies in some chromosomic regions (e.g., telomeres)	- 17q12 recurrent deletion syndrome - 22q11.2 deletion syndrome
Multiplex ligation-dependent probe amplification	Small copy number variants (e.g., exon-level CNV) and/or assessment of methylation status	- Analysis of genes where exon deletions or duplications or aberrant methylation are a known mechanism of disease - Confirm/refine deletions/duplications suspected on MPS analysis	- Fast and cost effective - High throughput (multiplex) - Sensible to methylation	- No detection of unknown SNVs, may miss small indels - Not readily available for all targets - Limited detection of low-grade mosaicism - Susceptible to polymorphisms	Suspicion of kidney disease linked to HNF1B (prenatal hyperechogenic kidneys or a multisystemic presentation with e.g., MODY, hypoMg2+ and GU abnormalities)
Targeted MPS gene panel	Phenotype driven detection of SNV and indels in genes of interest (Targeted panel sequencing or virtual panels from exome or genome sequencing)	Phenotype(s) or group of disorders with defined spectrum of genes involved	- No incidental findings - Can be optimized to reach high coverage for CNV calling (includes exon-level) and detection of mosaicism (targeted panels) - Analysis can be extended to exome or genome (virtual panels)	- Frequent update with redesign and validation of the assay may be necessary (targeted panels) - No detection of large CNV and structural variants	- Cystic kidney disease gene panel - Gene panel for COL4A3, COL4A4, and COL4A5 for suspected Alport syndrome
Exome sequencing	Detection of SNVs and indels within coding regions of the genome	- Genetically heterogeneous or nonspecific phenotypes, e.g., CKD of unknown etiology - Syndromic diseases without “spot diagnosis” and/or after negative targeted panel	- Unbiased analysis of coding region - Cost-efficient because most patients with monogenic disease harbor variants in coding regions - Discovery of novel genes - Allows incidental findings in actionable genes	- Lower per-base coverage and limited coverage of certain regions - Limitations in CNV calling - Incidental findings	- CKD of unknown etiology after routine clinical workup - Multiple congenital anomalies with normal chromosomal microarray
Genome sequencing	Detection of SNVs, indels and CNV within coding and non-coding regions	- Idem Exome sequencing - Soon first line test due to genome-wide detection of SNV, indels, CNV and balanced rearrangements?	- Coding and non-coding region, i.e., deep intronic variants - Improved sensibility of CNV detection (uniform coverage) - Detection of balanced rearrangements -Superior to overcomes pseudogene homology	- Challenges in interpreting noncoding variants - Interpretation bottleneck due to large amounts of data, increased turnaround time - Incidental findings	- Detection of second intronic variant in recessive diseases (e.g., Gitelman or Alport syndromes) - Complex genes with pseudogenes (e.g., PKD1)

APOL1, apolipoprotein 1; CKD, chronic kidney disease; GU, genitourinary; indels, insertion/deletions; MLPA, multiplex ligation-dependent probe amplification; MPS, massive parallel sequencing; SNV, single nucleotide variant; VUS, variant of unknown significance.

Adapted from Knoers et al³.

Another caveat of massive parallel sequencing techniques (especially for WES) is the difficulties in identifying large copy number variant (CNV). Chromosome microarrays or multiplex ligation-dependent probe amplification (MLPA) can be used to identify large CNVs or multiexon or single-exon CNVs (e.g., HNF1B), respectively. In cases of suspected mosaicism or mitochondrial diseases, genetic testing can be made on leucocytes but also in kidney cells collected from the urine.^15,16 In addition, clinicians need to make sure that targeted panels are regularly updated to include novel gene-disease relationships. This also stresses the importance of working with a clinical genetics team and/or genetic counsellors to provide optimal clinical care and to follow guidelines for molecular diagnosis.¹⁷

Variants of Unknown Significance Interpretation

Finding a variant of unknown significance is always challenging. The clinical nephrologist can help the genetic team and can contribute to provide additional arguments for the pathogenicity of a detected genetic variant of unknown significance: for example, provide extensive and detailed clinical information that helps in variant interpretation, perform segregation analysis in the family, help with functional testing by carefully preserving kidney tissue/biopsies, or extracting cDNA from urinary cells.

Polygenic Risk Score (PRS) and Pharmacogenomics

Large genome-wide association studies identifying hundreds of single nucleotide polymorphisms influencing the risk of CKD and other kidney related traits^18,19 are instrumental to develop PRS that can be used to test the combined association of these single nucleotide polymorphisms with a given outcome and to stratify populations at risk for the development of common diseases. More specifically, in the transplant setting, the impact of donor and recipient (N = 10,844) estimated glomerular filtration rate-derived PRS on posttransplant estimated glomerular filtration rate at different time-points has been assessed in a European renal transplant population.²⁰ PRS using recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with estimated glomerular filtration rate at 1-year posttransplant. Thirty-two percent of the variability in estimated glomerular filtration rate at 1-year posttransplant was explained by a model containing clinical covariates and combined donor-recipient PRS. Compared to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop KF and it is believed that much of this difference is due to APOL1 risk genotypes in AA individuals. To get better insights into this clinically relevant topic, the National Institutes of Health-sponsored APOLLO study is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes.²¹ Future studies will need to assess the combined or additive value of determining PRS in addition to monogenic risks such as APOL1 to allow precision medicine in the transplant setting. With respect to monogenic kidney disease, an exciting study was able to show that variable penetrance of kidney disease in autosomal dominant polycystic kidney disease (ADPKD) and in carriers of deleterious variants in COL4A3, COL4A4, or COL4A5 genes is partially explained by differences in polygenic risk profiles. These findings could be taken into consideration in the future to plan pretransplantation workup in carriers of such variants or even to evaluate family members as potential kidney donors.²² With respect to transplant complications and posttransplant management, it has been shown that recipient type 2 diabetes mellitus PRS was significantly associated with the development of post-KT diabetes mellitus.²³ Another example for transplant complications comes from the European ancestry renal transplant cohorts (N = 889), where PRS derived from nontransplant nonmelanoma skin cancer is predictive of occurrence and timing of nonmelanoma skin cancer in posttransplant patients.²⁴

Drug pharmacokinetics is influenced by variations in genes involved in drug metabolism and transport, whereas drug pharmacodynamics is affected by variants in genes encoding for drug-target proteins. Therefore, pharmacogenomic approaches in kidney transplant recipients could allow personalized immunosuppression regiments or other tailored drug adaptations. Indeed, it has been suggested that, among a cohort of 853 kidney allograft recipients, each recipient had at least 1 actionable pharmacogenomic diplotype (i.e., a specific combination of 2 haplotypes) and the majority carried 3 or 4 actionable diplotypes among the 12 genes that would require dose modifications or medication changes if they were prescribed these medications (including tacrolimus, azathioprine, clopidogrel, warfarin, simvastatin, voriconazole, antidepressants, and proton-pump inhibitors).²⁵ For tacrolimus in particular, the interindividual differences in pharmacokinetics are in large part determined genetically and single nucleotide polymorphisms in the CYP3A4 and CYP3A5 genes have been linked to an individual’s drug metabolizing phenotype. Currently, several prospective intervention trials, investigating the efficacy of initial algorithm-based dosing using polygenic and clinical factors in adult renal allograft recipients are ongoing (https://www.trialregister.nl/trial/7360; NCT03465410; NCT03020589; NCT03527238 see clinicaltrials.gov) (doi.org/10.1080/23808993.2020.1776107).

GKDs with Risk of Recurrence

Complement Mediated Diseases

aHUS

aHUS (MIM #235400) manifests with thrombotic microangiopathy associated with very poor kidney outcome if untreated. Pathogenic variants in alternative complement pathway genes account for approximately 50% of the predisposition to develop aHUS and lead typically to a dominant pattern of inheritance with reduced penetrance. In contrast, aHUS associated with pathogenic variants in DGKE (complete penetrance) and deletions of CFHR3/CFHR1 and CFHR1/CFHR4 are typically inherited in an autosomal recessive manner. Acquired autoantibodies against complement regulatory proteins have also been described.²⁶

The risk of aHUS recurrence after transplantation is driven by genetic findings. This risk is particularly high in patients with abnormalities in genes encoding for complement circulating proteins (complement factor H, complement factor I, complement factor B, and C3), whereas isolated genetic abnormalities in the transmembrane and intracellular proteins membrane cofactor protein and diacyl-glycerol kinase confer low risk of recurrence because allografts express normal proteins.^27,28

Screening for variants in complement genes usually includes at least 5 complement genes (CFH, C3, CFI, CFB, and MCP) and MLPA to identify potential CFHR1-CFH hybrid genes, which are caused by nonallelic homologous recombination. To date, more than 500 variants in these genes have been identified in patients with aHUS.²⁶ For individuals presenting early (e.g., before 1 year) or if there is evidence for autosomal recessive inheritance, single gene testing for DGKE could be considered. Otherwise, multigene panels are widely available and need to be complemented by appropriate testing for hybrid genes or CNVs (e.g., MLPA). Before availability of eculizumab (anti-C5 monoclonal antibody), the outcome after KT was poor, with a 60% to 80% risk of recurrence that was strongly associated with transplant failure.²⁹ The use of eculizumab as prophylaxis for aHUS recurrence after KT has profoundly modified kidney graft outcome.^29,30 The Kidney Disease: Improving Global Outcomes guidelines³¹ recommend life-long prophylaxis with eculizumab in patients with aHUS at moderate-risk and high-risk of recurrence after KT (Table 2).

Challenges for GKDs and KT (Table 4) include the absence of identification of a pathogenic variant in complement genes in 40% to 60% of patients with aHUS.^27,32 Other biochemical markers of complement system dysregulation, for example, related to C5b-9, are currently being investigated.^27,33 Some patients with secondary HUS may also have genetic defects in complement pathway,^34,35 raising the issue of whether systemic screening of complement genetic abnormalities in secondary HUS is required. The optimal period of prophylaxis with eculizumab after KT is also debatable. The recommendation for a lifelong prophylaxis after KT, especially in cases of high-risk mutations, is not supported by randomized data. Some studies have suggested that eculizumab could be stopped in patients with aHUS with native kidneys, with cases of relapse responding to prompt resumption of anti-C5 therapy.^36,37 These issues are important, considering the cost of the drug and the increased risk of meningococcal infection.

Table 4.

Genetic kidney diseases and kidney transplantation: key questions and ongoing trials

Disease	Key questions	Ongoing clinical trials
Atypical hemolytic and uremic syndrome	•Duration of eculizumab after transplantation •Clinical relevance of sC5b-9 in plasma, C5b-9 depositions in kidney biopsies, and ex vivo test for C5b-9 endothelial deposition for diagnosis-monitoring of aHUS •Utility of aHUS genetic screening in patients with secondary TMA •Availability of eculizumab, especially in developing countries
C3 glomerulopathy	•Biomarkers to stratify the risk of recurrence after kidney transplantation •Curative and/or prophylactic treatment for recurrence	Phase 2 study assessing safety and efficacy of pegcetacoplan in post-transplant recurrence of C3 glomerulopathy (NCT04572854) Managed Access Program with Iptacopan for C3 glomerulopathy (NCT05222412)
Primary hyperoxaluria	•RNAi alone to treat the hepatic metabolic defect (and replace liver transplantation) •Accurate assessment of systemic oxalosis to help physician decide on the right timing for kidney transplantation. •Availability of RNAi, especially in developing countries	Phase 3 trial investigating lumasiran in PH1 patients with advanced CKD including patients who undergo isolated kidney transplantation (NCT04152200)
Tuberous sclerosis complex	•Safety and efficacy of preemptive nephrectomy •Safety and efficacy of mTORi after transplantation
Fabry disease	•Safety and efficacy of long-term use of ERT (especially migalastat) after transplantation
Mitochondrial diseases	•Safety and efficacy of mTORi after transplantation
apolipoprotein L1 (APOL1)	•Impact of APOL1 variant on donor and recipient outcome after transplantation	Prospective observational study assessing the effects of renal-risk variants in the APOL1 gene on outcomes for kidneys from donors with recent African ancestry and the recipients of their kidneys, after deceased- and living-donor renal transplantation (NCT03615235)
Severe tubulopathy	•Risk-benefit balance in considering kidney transplantation in patients with severe tubulopathy impacting quality of life without kidney failure
Kidney graft with genetic disease	•Risk/benefits balance of using a graft with known mild genetic kidney diseases. Potential indications? Long-term outcome in case of living donation?

aHUS, atypical hemolytic and uremic syndrome; CKD, chronic kidney disease; ERT, enzyme replacement therapy; KT, kidney transplantation; mTORi, inhibitors of mechanistic target of rapamycin; RNAi, RNA interference; TMA, Thrombotic microangiopathy.

C3G

C3G (MIM #614809) is caused by the dysregulation of the alternative complement pathway with glomerular deposition of complement factors. The diagnosis relies on kidney biopsy showing intense C3 staining with no or minimal immunoglobulin staining.³⁸ Pathogenic variants in the alternative complement pathway, the same genes implicated in aHUS, are detected in about one-third of patients and lead to a dominant pattern of inheritance.³⁸ Recurrence rates of C3G after KT range from 67% to 84% (Table 2) with a median time to recurrence of 14 to 28 months in the 2 largest reported case series.³⁹ However, unlike aHUS, there are currently no data supporting a direct relationship between genetic defects and recurrent disease after transplantation.³⁹ Moreover, the use of eculizumab is rather disappointing for the treatment of C3G, when compared to aHUS.⁴⁰ In patients with C3G, posttransplantation use of eculizumab seemed to reduce allograft loss compared to plasma exchanges or rituximab⁴¹; however, its use as prophylactic treatment is not currently recommended (Table 4). Other strategies, including the complement C3 inhibitor pegcetacoplan, are currently tested in C3G (NCT04572854).

Crystalline Nephropathies

PH

PHs are a group of rare autosomal recessive diseases, characterized by the excessive production of oxalate in the liver. PH is more prevalent in countries with consanguinity (with a prevalence of 10% or more in some North African and Middle Eastern nations).⁴² Considering that the kidney is the sole organ that excretes oxalate, the constant high oxalate calcium load in PH leads to nephrocalcinosis, recurrent kidney stones, oxalate nephropathy, CKD, and KF. As CKD progresses, systemic accumulation of oxalate occurs, predominantly in bones, eyes, heart, skin, and central nervous system.^43,44 PH1 (MIM #259900) is the most frequent (+/− 80%) and severe form of PH, caused by a deficient peroxisomal alanine glyoxylate aminotransferase encoded by the AGXT gene.⁴⁴ The molecular pathogenesis behind PH1 is relatively complex. A “minor allele” (20% frequency in individuals of European origin), characterized by a cryptic mitochondrial targeting sequence acts synergistically with some pathogenic variants in cis and drives mislocalization to mitochondria. Overall, >200 AGXT pathogenic variants have been documented; however, a handful among them are common pathogenic variants, sometimes enriched in specific ethnicities, and accounting for the majority of PH1-causing alleles. Missense variants lead to loss of enzyme catalytic activity, loss of immunoreactivity, or mistargeting to mitochondria instead of peroxisomes. In addition, large deletions or intragenic deletions are described that require dedicated techniques (e.g., MLPA).⁴⁴ Most patients with PH1 reach KF in the first 2 to 3 decades of life.⁴² Current treatments are mostly conservative, including hyperhydration, vitamin B6, and sodium/potassium citrate. Patients harboring pathogenic variants resulting in mistargeting of alanine glyoxylate aminotransferase are most likely to respond to vitamin B6 treatment. Innovative therapeutic strategies are currently investigated, including RNA interference drugs that may correct the liver metabolic defect (and potentially replace liver transplantation).

Solid organ transplantation strategies for PH include liver transplantation (combined with KT or performed before KT-sequential approach) to cure the metabolic defect.^42,43 However, solid organ transplantation is challenging for patients with PH with KF, because of the high-risk of recurrence of oxalate nephropathy in the transplanted kidney, with risk of graft loss.42, 43, 44, 45, 46 Isolated KT may be considered in very selected patients who are vitamin B6-sensitive.⁴⁷ A more accurate assessment of systemic oxalosis using 18-Fluoro-D glucose positron emission tomography imaging may help to decide the right timing of KT.^48,49

Adenine Phosphoribosyltransferase (APRT) Deficiency

APRT deficiency (MIM #614723) is an autosomal recessive disorder of purine metabolism, causing the oxidization of adenine by xanthine oxidase (XO) into 2,8-dihydroxyadenine. Dihydroxyadenine is poorly soluble in urine, leading to the formation of kidney stones and crystalline nephropathy.^50,51 APRT deficiency is diagnosed by the absence of APRT activity in red blood cells or the identification of pathogenic mutations in the APRT gene. Treatment relies on XO inhibitors (allopurinol and febuxostat) reducing dihydroxyadenine production, along with high fluid intake and low-purine diet.⁵¹ The largest series have been mainly described in Iceland, Japan, and France.52, 53, 54 Unfortunately, APRT deficiency is often diagnosed in the setting of recurrence following KT, ranging from 10 days to more than 20 years after KT.^50,52 Improvement in allograft outcomes among patients who received treatment with XO inhibitor before or at the time of KT was recently suggested.⁵⁰ Large doses of allopurinol (400 mg/day or greater) may be needed to adequately prevent recurrence of APRT deficiency nephropathy. Consequently, XO inhibitors should not be stopped in dialyzed patients on waiting list for KT. After transplantation, azathioprine is contraindicated with XO inhibitors, given the well-known risk of agranulocytosis.⁵⁵

GKDs with Oncological Risk

Routine cancer screening should be performed for evaluation of candidates for KT.¹⁰ For patients with a history of cancer, the timing of KT after successful treatment depends on the type of cancer and stage at initial diagnosis. Some GKDs confer an increased oncological risk that may be increased by immunosuppressive regimen; thus influencing post-KT monitoring. Conversely, KF can be the consequence of cancer treatment, for example, chemotherapy. For patients (and their affected relatives) meeting any of the cancer genetics referral criteria, the American College of Medical Genetics guidelines recommend referring patients to a cancer genetics specialist⁵⁶ for work up and testing for monogenic cancer predisposition syndromes.

Tuberous Sclerosis Complex (TSC)

TSC (MIM #191100) is an autosomal dominant disorder with variable penetrance caused by mutations in either TSC1 or TSC2 genes coding for hamartin and tuberin, respectively. De novo mutations may occur in one-third of patients.⁵⁷ Diagnostic work up needs to exclude single nucleotide variant, as well as intragenic or whole gene deletions. It is also important to exclude TSC1/2 somatic mosaicism in cases where a clinical diagnosis is established but germline or blood genetic testing is negative. The clinical manifestations are related to benign tumors that develop in multiple organs, mainly the skin, brain, and kidney, but also the lungs, eyes, heart, and liver. Kidney lesions include angiomyolipoma (AML), renal cysts, oncocytoma and a higher risk to develop renal cell carcinoma (RCC) than in the general population.^57,58 In patients with enlarged cystic kidneys, a TSC2/PKD1 contiguous gene deletion should be excluded. Kidney AMLs and cysts are common features in mosaic TSC.⁵⁹ TSC-associated AMLs can be treated with mammalian target of rapamycin (mTOR) inhibitors as recommended first line therapy. The incidence of RCC in TSC is reported in 2% to 4% of patients, often in children and young adults, with a female predominance.⁶⁰ Patients with TSC2 mutations seem to be at greater risk for kidney cysts, AML and kidney malignancy (and other adverse outcomes such as intellectual disability and infantile spasms) compared to patients with TSC1 mutations.^61,62 Preemptive bilateral nephrectomy in patients reaching KF may avoid neoplasm development and AML bleeding although it requires confirmation.⁶³ If removal of native kidneys is not performed before KT, it seems reasonable to propose annual magnetic resonance imaging (MRI) surveillance.

Von Hippel-Lindau Disease

Von Hippel-Lindau disease (MIM #193300) is a dominantly inherited syndrome, caused by mutations in the VHL gene, and which predisposes to the development of various tumors, including RCC and pancreatic neuroendocrine tumors. RCC develops in 70% of patients at a younger age (45 years at diagnosis)⁶⁴ and more frequently multifocal and bilateral than in sporadic cases.⁶⁵ Diagnostic work-up needs to exclude both single nucleotide variants and intragenic or larger CNVs. It has been suggested that risk of RCC is lower in individuals with VHL deletions, especially deletions that extend 5′ and include BRK1.⁶⁶ Nephron-sparing surgery techniques such as partial nephrectomy are indicated in tumors larger than 3 cm and may reduce the risk of metastasis while preserving kidney function.⁶⁴ Although a prior cancer is not an absolute contraindication for KT, the recent Kidney Disease: Improving Global Outcomes guidelines¹⁰ suggest waiting 2 to 5 years before KT depending on the localization, size, and invasive nature of the malignancy. There are no specific recommendations for other organic malignancy, for example, pancreatic neuroendocrine tumors. Patients with Von Hippel-Lindau disease on dialysis and awaiting KT must be evaluated for RCC at least every 2 years, preferably using MRI.⁶⁷ Pancreas imaging should be monitored every 2 years, preferably with gadolinium-enhanced MRI.⁶⁸ We suggest continuing oncological screening after KT.

WT1 Pathogenic Variants

Wilms tumor (WT or nephroblastoma) is one of the most frequent kidney cancers in children. It can occur with rare syndromes that are associated with heterozygous variants in the WT1 gene with a dominant pattern of inheritance.⁶⁹

The WT, aniridia, genitourinary anomalies and range of developmental delays syndrome (MIM #194072) is caused by a deletion in chromosome 11p13, including WT1 and PAX6 genes.⁷⁰ Patients may experience WT, but also isolated proteinuria and focal segmental glomerulosclerosis, and have higher risk of CKD.⁷⁰ Current recommendations for WT screening in WT, aniridia, genitourinary anomalies and range of developmental delays syndrome include kidney ultrasound (US) every 3 months from birth or diagnosis until 8 years of age, followed by 6-month screens until the age of 18 years.⁷¹ It seems reasonable to continue the annual oncological screening after KT, based on US or MRI in adults for more accuracy.

Denys-Drash syndrome (MIM #194080) is caused by mutations in exons 8 and 9 of WT1 and is characterized by the association of early onset steroid-resistant nephrotic syndrome with mesangial sclerosis, WT and, in some patients, pseudohermaphrodism and increasing risk of gonadoblastoma.⁷² It is recommended to wait at least 1 to 2 years after completion of chemotherapy for WT before KT.⁷³ Furthermore, total nephrectomy is recommended for Denys-Drash syndrome at the time of KT because of the high risk of recurrence of WT.⁷³

Frasier syndrome (MIM #136680) is due to intron splicing variants in intron 9 of WT1 gene⁷⁴ and is associated with steroid-resistant nephrotic syndrome, gonadal tumors, and male pseudohermaphrodism. Prophylactic gonadectomy at time of diagnosis has been suggested, because the risk of gonadal tumor is up to 60%.⁷⁵

Birt-Hogg-Dube Syndrome

Birt-Hogg-Dube syndrome (MIM #135150) is an autosomal dominant condition characterized by benign skin hamartomas, pulmonary cysts leading to spontaneous pneumothorax, and an increased risk of RCC. This syndrome is caused by pathogenic variants in the FLCN gene encoding for the protein folliculin, a putative tumor suppressor gene.⁷⁶ Renal cancers occur in 12% to 34% of patients aged about 50 years, with variable histology (chromophobe and mixed chomophobe-oncocytic pattern mostly). Tumors <3 cm require active surveillance whereas larger tumors require nephron-sparing surgery. Some patients may develop colorectal cancer, which may justify performing colonoscopy screening at least 10 years earlier than in the general population.⁷⁷

Other ultrarare, syndromes associated with a higher risk of RCC include hereditary papillary renal carcinoma (MIM #605074); hereditary leiomyomatosis and renal cell cancer (MIM #150800); hereditary BAP-1-associated RCC (MIM #614327); and succinate dehydrogenase deficiency (MIM #614145).⁶⁴

Beckwith-Wiedemann Spectrum

Beckwith-Wiedemann syndrome (BWS, MIM #130650) is a congenital condition with a variable clinical manifestation of overgrowth, hyperinsulinism and which confers a high risk, up to 30%, of embryonal cancers (WT, neuroblastoma, and hepatoblastoma).^78,79 BWS is linked to molecular alterations in imprinted genes located on chromosome 11 (11p15) such as CDKN1C or IGF2. Genomic imprinting is an epigenetic condition by which only 1 copy of a gene is expressed depending on whether they are inherited from the father or the mother. Gene sequence is not modified but gene expression is silenced by epigenetic modifications (usually methylation) of DNA in a germ cell. These changes are frequently mosaic, thereby complicating genetic testing. Most commonly, BWS is caused by loss or gain of methylation at imprinting center 2 or 1, respectively. Paternal uniparental disomy at the BWS critical locus is seen in 20% to 30% of the cases, sometimes in mosaic forms. Maternally-inherited pathogenic variants in CDKN1C are frequently encountered in familial forms of BWS. Rarely, CNV involving the 11p15.5 locus are encountered. Molecular diagnosis algorithms usually start by performing DNA methylation tests at the 11p15 differentially methylated regions.⁷⁹ Patients with BWS also have an increased risk of hypercalciuria and nephrocalcinosis.⁷⁹ The recent guidelines suggest performing regular screening for embryonal tumors with US every 3 months until 7 years. Patients with IC1 gain of methylation are at highest risk for WTs, and patients with IC2 loss of methylation at lowest risk; and it has been suggested that the latter do not require regular US screening.⁷⁹ There is no consensus for the oncological screening after 7 years old.

GKDs with Special Considerations Regarding KT

Autosomal Dominant Polycystic Kidney Disease

ADPKD (MIM #173900; #613095) accounts for up to 10% of patients requiring kidney replacement therapy.⁸⁰ The vast majority of patients with ADPKD will end up with KF, with KT being the preferred modality of kidney replacement therapy.⁸¹ ADPKD, which involves all populations, is thus the most common monogenic disease encountered in KT patients. ADPKD is essentially caused by mutations in either PKD1 or PKD2, accounting for about 80% and 15% of the cases, respectively. These genes encode membrane proteins (polycystin-1 and polycystin-2) which play multiple roles in kidney tubular cells and other cell types. The remaining cases are associated with mutations in genes that modulate the expression or maturation of the polycystins, including IFT140, GANAB, PRKCSH, ALG8, SEC61B, and SEC63, that cause a mild form of ADPKD with variable cystic liver disease severity.⁸² Atypical cystic kidney diseases associated with tubulointerstitial damage have also been linked to mutations in DNAJB11, coding for a cofactor involved in the proper folding and assembly of membrane or secretory proteins; and HNF1B, coding for a transcription factor. Mutations in HNF1B can result in various kidney and extrarenal disorders.⁸³ In 50% of patients with HNF1B-related disease, a whole HNF1B gene deletion is detected, occurring in the context of the 1.4-megabase recurrent deletion flanked on each side by segmental duplications at position 17q12 and encompassing HNF1B along with 14 other genes. The 17q12 recurrent deletion syndrome combines structural or functional abnormalities of the kidney and urinary tract (∼90%), MODY5 (∼40%), and neurodevelopmental or neuropsychiatric disorders (∼50%). As indicated in Table 3, chromosomal microarray or another technique capable to detect CNVs is required to make this diagnosis.

ADPKD-like phenotypes have also been associated with mutations in COL4A1 in the HANAC syndrome (MIM #611773) and with mutations in the X-linked OFD1 gene, causing the ciliopathy named oral-facial-digital syndrome type 1 (MIM #311200).⁸²

The diagnosis of ADPKD is typically based on a positive family history and the evidence of multiple kidney cysts by kidney imaging. Genetic testing for ADPKD is useful in patients with early and severe manifestations, marked intrafamilial disease variability, lack of apparent family history, atypical kidney imaging, syndromic presentation, and in at-risk subjects for potential kidney donation.¹² The genetic testing for PKD1 requires specific approaches, reviewed recently.⁸² Patients harboring a mutation in PKD1 have larger kidneys and, on average, reach KF 20 years faster than those harboring a PKD2 mutation. Among PKD1 mutations, protein-truncating mutations (nonsense and frameshift) or large deletions are associated with a more severe kidney phenotype than nontruncating mutations.⁸²

The pretransplant work-up of patients with ADPKD should address the main complications of the disease.⁸¹ Prophylactic native nephrectomy is recommended only in patients with intractable kidney pain, recurrent and/or severe bleeding, infections or nephrolithiasis, suspicion of RCC, or when space is required for graft implantation.^81,82 The timing of prophylactic nephrectomy, pre-KT or during-KT, remains debated.^84,85 Pretransplant nephrectomy is usually restricted for patients who are highly symptomatic and/or oligoanuric with extremely large kidneys.⁸¹ Alternatively, transcatheter arterial embolization may reduce kidney volume by about 50% at 12 months.^86,87 The above decisions should also consider that the volume of native PKD kidneys decreases significantly after transplantation.⁸⁸ Importantly, RCC does not appear to occur more frequently in ADPKD than in other renal diseases.^89,90

Hepatomegaly caused by liver cysts can severely affect patient’s quality of life, with potential for fatigue, malnutrition, and secondary sarcopenia that may drive prioritization for liver transplantation.⁹¹ Indeed, experts suggest using skeletal muscle index <38.5 cm²/m² in females and 52.4 cm²/m² in males as an additional criteria to consider liver transplantation in patients with polycystic liver diseases. These parameters are considered more objective than the symptoms of discomfort or midarm circumference.

The prevalence of intracranial aneurysms (ICAs) is 4 times higher in patients with ADPKD than in the general population (9%–12% vs. 2%–3%), further enhanced (>20%) in case of positive family history of ICA.^81,82 The rupture rate of ICA in patients with ADPKD is much larger than in the general population, as also reflected by a much younger mean age of rupture.⁸² Pretransplant screening for ICAs using cerebral MRI is reasonable in ADPKD transplant candidates who have a family history of ICA and/or intracranial hemorrhage, or a personal history of ICA.⁸⁰ Universal screening has also been advocated by some, depending on the local situation and cost-utility analyses.⁹²

Alport Syndrome

Alport syndrome (AS) is caused by pathogenic variants in 3 genes, COL4A3, COL4A4, and COL4A5 and is the second most frequent cause of monogenic kidney disease after ADPKD.⁹³ Indeed, in the study of Groopman et al.,⁵ 92 of 3315 (0.27%) patients had a pathogenic variant in a COL4A genes. Although patients with AS who undergo KT have an excellent patient and graft survival, they may rarely (0.4% to 2%) develop antiglomerular basement membrane (anti-GBM) nephritis after transplantation.^94,95 Males with X-linked AS (MIM #301050) and truncating COL4A5 mutations are mostly at risk to develop de novo anti-GBM nephritis^96,97 with antibodies against the α5 (IV) chain not detected by routine enzyme-linked immunosorbent assay for anti-GBM directed to α3 (IV) chain.⁹⁸ Therefore, the diagnosis relies on kidney graft biopsy showing linear IgG staining along the glomerular basal membrane together with glomerular necrosis or crescentic lesions.⁹⁹ Plasmapheresis combined with cyclophosphamide administration and steroids, like in anti-GBM nephritis and Goodpasture syndrome, often fail to rescue graft function.⁹⁹ Patients with autosomal recessive Alport (MIM #203780) may also develop anti-GBM antibodies against α3 or α4 (IV) chains.¹⁰⁰

Cystinosis

Cystinosis (MIM #219800 and #219900) is a lysosomal storage disease caused by recessive mutations in the CTNS gene coding for the proton-driven transporter cystinosin that exports cystine out of lysosomes. The accumulation of cystine leads to multisystemic complications, including proximal tubular dysfunction (renal Fanconi syndrome) and most often, KF.¹⁰¹ Half of affected individuals of Northern European descent are homozygous for a 57kb deletion at 17p13 and arising apparently through a founder effect.¹⁰² Cystinosis diagnosis can be established by detecting cystine crystals in the cornea, elevated cystine levels in leukocytes, or the identification of biallelic pathogenic variants in CTNS on molecular genetic testing, including modalities able to detect the 57kb deletion (or other deletions, e.g., MLPA). Therapy with cysteamine, which allows cystine to exit lysosomes, has improved the prognosis of cystinosis, with a 9.1-year increase in the median age at dialysis from the 1970s to the 1990s.¹⁰³ Cysteamine must be continued after KT to prevent multiorgan complications resulting from the systemic lysosomal storage disease.^103,104 There is no risk of recurrence of the lysosomal storage disease in the kidney graft because wild-type cystinosin is operating in the kidney. Of note, protocol biopsies have shown cystine crystals within the interstitial tissue and glomeruli of the transplanted kidney, without any apparent manifestations.¹⁰²

Fabry Disease (FD)

FD (MIM #301500) is an X-linked, lysosomal storage disease due to inactivating mutations in the GLA gene coding for the lysosomal enzyme alpha-galactosidase A. The enzymatic defect leads to the multisystemic accumulation of glycosphingolipids, especially globotriaosylceramide, causing CKD, hypohydrosis, skin lesions (angiokeratomas), cardiomyopathy with arrythmias, strokes, and small-fiber peripheral neuropathy, which shortens the life expectancy.¹⁰⁵ Patients with FD can be treated with i.v. infusion of recombinant alpha-galactosidase or with oral chaperone therapy, which corrects the misfolding of the enzyme and rescues the trafficking to lysosomes.¹⁰⁶ These therapies enable cellular globotriaosylceramide clearance and may stabilize or slow decline in kidney function.¹⁰⁷ However, enzyme replacement therapy can lead to the formation of neutralizing antidrug antibodies, reducing the efficacy of therapy.¹⁰⁸ FD accounts for 0.2% of patients on hemodialysis.¹⁰⁹ KT is safe in FD, as recently confirmed by a meta-analysis pooling 424 patients.¹⁰⁸ Decreased plasma globotriaosylceramide levels, stable kidney function, decreased left ventricular mass and improved cardiac contractility were reported among transplanted patients on enzyme replacement therapy.¹¹⁰ To protect against the systemic accumulation of glycosphingolipids, enzyme replacement therapy should be continued on dialysis and after KT.¹⁰⁸ The development of enzyme replacement therapy antibodies seems to be rarer in patients with FD on immunosuppressive medications for KT.¹¹¹ Finding globotriaosylceramide deposits in the graft does not seem to impact on the outcome of the transplant.¹¹⁰ The effect of the oral chaperone migalastat in patients with KT has not been investigated so far (Table 4).

Influence of Immunosuppression: Posttransplant Diabetes, HNF1B, Mitochondrial Diseases, and TSC

The commonly used immunosuppressive regimen after KT is the association of tacrolimus, mycophenolate mofetil, and steroids, which is associated with a lower acute rejection risk compared to cyclosporine-based or mTOR inhibitor-based combinations.¹¹² The choice of the immunosuppressive regimen influences the risk for developing metabolic, oncologic, and infectious side effects after KT. For example, tacrolimus may be more associated with new-onset posttransplant diabetes (NODAT) that cyclosporine.¹¹³

NODAT is a common and severe complication after KT. Genetic variants have been identified as risk factors for development of posttransplant diabetes. The Swiss Transplant Cohort Study¹¹⁴ showed that patients carrying the SP110 rs2114592C>T single nucleotide polymorphism have 10-fold higher risk to develop posttransplant diabetes. Shaked et al.²³ recently reported a significant association between type 2 diabetes PRS in kidney transplant recipients and the development of NODAT.

Patients harboring a pathogenic variant in HNF1B are at high risk to develop diabetes and NODAT^115,116; as well as patients with mitochondrial diseases or cystinosis.^103,117 In case of NODAT, the use of metformin should be avoided in mitochondrial diseases because of the increased risk of lactic acidosis.¹¹⁸ The impact of a tacrolimus-free regimen in these patients needs to be explored. In line, the indications for inhibitors of mTOR after transplantation may be discussed in particular diseases such as mitochondrial disorders or TSC. Mitochondrial diseases are clinically heterogeneous and can manifest with a wide range of clinical symptoms affecting the nervous system and muscles, as well as the kidneys and the heart. mtDNA mutations are typically inherited from the mother but can occur de novo.¹⁶ Pathogenic mtDNA mutations are characterized by heteroplasmy, that is, a condition in which wild-type and mutated mtDNA molecules can coexist in the same cell. The expression of different clinical phenotypes is likely related to variable heteroplasmy levels within the affected tissues and the detection of heteroplasmy in urinary cells can be used to diagnose mitochondrial disease.¹¹⁸ In addition, it has been shown that for the single most common cause of mitochondrial disease, the m.3243A>G point mutation in the mitochondrial-encoded MTTL1 gene, the mutation load in urinary epithelium cells provided the best predictor of clinical outcome¹¹⁹ Currently, few treatment options for mitochondrial diseases are available and management is mainly supportive.¹²⁰ Experimental studies have shown that reduced mTOR signaling attenuates the disease in a mouse model of Leigh syndrome, a mitochondrial disease.¹²¹ Rapamycin has been used in 4 KT patients in replacement of calcineurin inhibitors and has shown to improve their quality of life.¹²² Further studies are needed to assess mTOR inhibitors in mitochondrial diseases with or without KT (Table 4).

In TSC, AMLs increase with age and can complicate with acute bleeding, which can necessitate arterial embolization or nephrectomy, further reducing kidney function.^61,123 Because the hamartin-tuberin complex normally inhibits the mTOR pathway involved in cell growth and proliferation, mTOR inhibitors have been proposed to reduce AML at risk of bleeding.^124,125 This treatment should lower the prevalence of KF among patients with TSC, even if mTOR inhibitors may induce proteinuria.⁵⁷ Series of KT patients with TSC are rare^63,123,126 and little is known about the course of AMLs in native kidneys after transplantation. The potential benefit of using mTOR inhibitors for AMLs after KT needs to be evaluated. Conversely, it is well described that mTOR inhibitors have beneficial effects on extrarenal features such as lymphangioleiomymatosis and subependymal giant cell astrocytoma, and also in refractory epilepsia.¹²⁷ This treatment should most likely be continued after KT to control further organ damage.

Living Donation and GKD

General Considerations

Kidney donors related to a recipient with a known genetic condition should be tested early during the donor-evaluation process.¹²⁸ There is consensus that donor candidates with a GKD that can cause KF should not donate, particularly in dominantly inherited diseases such as ADPKD (Figure 2).

Figure 2.

Genetic kidney diseases: Types of inheritance and related living donation. Representative pedigrees and typical diseases are provided for each modality of inheritance. Depending on the mode of transmission, the related living donation may be allowed (V), contraindicated (X) or discouraged (±).

For ADPKD, candidate related living donors should be evaluated for kidney cysts, using age-dependent criteria for US imaging¹²⁹ or MRI for higher sensitivity to detect subcentimeter kidney cysts.¹³⁰ Finding more than 10 kidney cysts in patients with familial history of ADPKD aged 16 to 40 years can make the diagnosis of ADPKD. The increased availability of genetic testing in ADPKD (stated earlier in this review) will facilitate the screen for potential kidney donors. In patients aged <30 years with normal MRI findings and in those with equivocal MRI findings, genetic testing is indicated.⁸²

Whether familial living donation is allowed in aHUS is controversial, considering that genetic mutations are not found after regular screening in 40% to 60% of cases.²⁶ It is currently recommended to consider living related donation in aHUS if the genetic factors are identified in the recipient and the related donor does not share the pathogenic variant(s).¹²⁸

In diseases with an autosomal recessive mode of inheritance, first-degree relatives may harbor a heterozygous mutation and related living donation is considered suitable.¹³¹ AS is an exception to this statement. In 2022, the revised guidelines⁹³ considered the risk of kidney donation in COL4A3 or COL4A4 carriers unacceptable in most cases even when donors are older than 40 years with a normal renal function and without proteinuria. For the X-linked AS, women previously called “carrier” are now preferentially called heterozygous female subjects of COL4A5 pathogenic variants.¹³² Indeed, some studies recognized a substantial risk of proteinuria and progressive kidney disease and also sensorineural hearing loss in these female patients.^133,134 The most recent consensus is that women with X-linked AS should be excluded from living donation.^93,132 This statement can be extended in other X-linked diseases such as FD or Dent disease.²

In mitochondrial diseases, due to maternal transmission and mitochondrial heteroplasmy, the mother of the affected proband should not be candidate for living donation and siblings should be discouraged.

Apolipoprotein 1

Risk variants in the APOL1 gene (namely G1 and G2) coding for the apolipoprotein L1 are prevalent in populations with ancestors from sub-Saharan Africa because they confer protection against Trypanosoma infection.¹³⁵ Patients carrying 2 risk variants (G1/G1, G1/G2, or G2/G2) are at increased susceptibility to develop various kidney diseases (hypertension-associated KF, focal segmental glomerulosclerosis, and HIV nephropathy) and CKD.¹³⁶ The high prevalence of APOL1 variants in Black individuals of recent African ancestry¹³⁷ and the strong association with CKD development have raised important questions in the KT setting.¹³⁸ In the context of living donation, whether APOL1 genotyping should be routinely performed in candidates with African ancestry and whether donor candidates carrying high-risk mutations should be excluded from donation are controversial issues. In favor of a systematic screening approach are the slightly increased rates of KF after nephrectomy in high-risk APOL1 donors compared to others.139, 140, 141 Moreover, Santoriello et al.¹⁴² found that African American donors, especially those harboring APOL1 high-risk genotypes, may predispose recipients to collapsing focal segmental glomerulosclerosis when exposed to second hits, such as acute rejection or viral infection that could activate podocyte innate immune pathways. In addition, Zhang et al.¹⁴³ reported the association of recipient APOL1 risk alleles with allograft survival and cellular rejection events. Conversely, Lee et al. found no difference in allograft survival at 5 years posttransplant for recipients with high-risk APOL1 genotypes.¹⁴⁴ Systematic screening of all deceased and living donors for APOL1 might allow better risk assessment information for the donor and better allocation of organs.^138,145 However, this approach may exclude patients from the survival benefit of KT (even if transplanted with a high-risk grafts) compared to the poor survival associated with prolonged dialysis. In addition, there is a lack of evidence for identifying high-risk APOL1 donors who are truly at risk of developing rapidly progressing CKD versus those who will not. Further studies are ongoing to address this issue (Table 4).

Kidney Graft Harboring a Genetic Disease: Contraindication?

The potential use of kidney grafts from a donor with a known GKD has been poorly studied. Individual reports and case-series suggest that kidneys from deceased donors with ADPKD may be suitable for KT.146, 147, 148, 149, 150, 151 For example, Shamali et al.¹⁵¹ identified 16 cases of donors with ADPKD (median age of 24 years) with normal kidney function at donation. Recipients had a mean age of 46 years old. After KT, 1 recipient had a primary nonfunction, and 2 had a transplantectomy because of infection and pain due to the size of the transplanted kidney. After a median follow-up of 36 months, 13 had a functioning graft with a median serum creatinine of 124 μmol/l. Therefore, although all grafts from ADPKD donors should not be considered for KT, some might be a good option, especially in old recipients with limited life expectancy or in case of marked intrafamilial heterogeneity.

The use of living donors with GKD has also been reported. Some patients with pauci-symptomatic genetic tubulopathy, such as Gitelman syndrome152, 153, 154, 155, 156 might be suitable for organ donation with good midterm outcomes for both the donor and the recipient.

In extremely rare situations, the possible indication of preemptive bilateral native nephrectomy followed by KT prior to KF has been raised. Such situations may include patients presenting invalidating manifestations of a genetic tubular disorder, for example, in children with Bartter syndrome presenting with life-threatening electrolyte disorders that cannot be compensated by supplementation.¹⁵⁷

Conclusion

Through access to genetic testing, a growing number of patients with CKD or KF have a molecular diagnosis of GKD. Implementing genetic testing in the context of KT and ensuring an optimal use of the genetic information requires specific measures (Table 5), which will need the involvement of multidisciplinary teams often operating in highly specialized tertiary care centers.⁶

Table 5.

Key steps for implementation of genetic testing in kidney transplantation

Obtain detailed family history in all patients with CKD

Document the age of onset of kidney disease manifestations

Encourage standardized phenotyping and multisystem evaluation

Increase genetic literacy among healthcare professionals, and in patients and their families

Define algorithms for genetic testing in case of CKD of unknown etiology

Plan periodic reanalysis of genetically unsolved cases

Ensure adequate return of genetic results to the patient, with appropriate genetic counseling

Ensure pretest genetic counseling and information on the medical and potential economic and psychosocial consequences of genetic testing

Promote multidisciplinary KT teams, including genetic counsellors

Develop and implement decision tools to guide genetic testing before KT

Take advantage of expert centers and international reference networks (e.g., ERNs)

Encourage participation in expert panels or case reviews

Encourage exchange of data and inclusion in large cohorts of genotyped patients

Interact with patient organizations

Use appropriate reference sets for patients from underrepresented populations with CKD

Encourage participation in research genomics protocols

CKD, chronic kidney disease; ERNs, European Reference Networks; KT, kidney translation.

An understanding of the different modalities of genetic testing, of the different types of variants, and their classification, needs to be integrated with detailed clinical and pathological insights to ensure the best interpretation of results, both for recipients and candidate-donors. Cost of the testing, turnaround time, and continuous pace of discovery regarding the genetic architecture of disease represent additional challenges (Table 4). Once validated, the genetic diagnosis offers immediate benefits in terms of clinical management of the patient and at-risk family members; and this is highly relevant for KT (Figure 1).

Clinicians dealing with kidney diseases should devise practical ways to implement multidisciplinary teams to use molecular testing in KT clinics.¹⁵⁸ The evolving perception of genetic testing in many countries; together with patient empowerment and more active roles for patient organizations, best practice guidelines, education, and delivery of the genetic information on physicians, patients, and society; and support from networks and national organizations such as National Organizations of Rare Disorders in the USA and Orphanet in Europe will facilitate such implementation.²

Mounting evidence suggests that variants in important genes are involved in a spectrum of kidney diseases, ranging from large-effect to small-effect sizes responsible for monogenic diseases or complex disorders including CKD, respectively.^159,160 Based on their prevalence, these variants can be identified by massive parallel sequencing and other modalities of genetic testing or by genome-wide association studies. As described above, genetic testing has a tremendous potential for impacting both the pre-KT and post-KT phases. At the other extreme of the spectrum, PRS, based on common variants identified by genome-wide association studies, may be helpful to identify individuals at high risk of CKD or other types of complications potentially relevant for KT. The use of such genetic information, which can be obtained before the onset of symptoms, would then be particularly useful to implement screening and prevention measures relevant for KT recipients and potential donors.^161,162

Disclosure

AD and NG declare fees from Alnylam. ND declares fees from Otsuka. All the other authors declared no competing interests.