[The Early Years of Nephrology at Molinette Hospital in Turin Told by Those Who Lived and Built Them].

This article, written by several authors, describes the birth and early development of the nephrology at Molinette Hospital in Torino, Italy. In particular, it supplies important information on Antonio Vercellone, very motivated and innovative clinician and one of the fathers of Italian nephrology, and on Giuseppe Piccoli, his right-hand man and then his successor. This article also shows the strong professional and human engagement that was requested to the young doctors who, in the early Sixties and Seventies of the past century, had chosen to devote their professional lives to the patients with kidney diseases: from endless workdays without schedules to the anguish caused by the shortage of artificial kidneys to the cure of very fragile and unfortunate patients, and much more.

Donor-derived acute myeloid leukemia in solid organ transplantation.

We report the transmission of acute myeloid leukemia (AML) undetected at donation from a deceased organ donor to two kidneys and one liver recipients. We reviewed the medical records, and performed molecular analyses and whole exome sequencing (WES) to ascertain AML donor origin and its molecular evolution. The liver recipient was diagnosed 11 months after transplantation and died from complications 2 months later. The two kidney recipients (R1 and R2) were diagnosed 19 and 20 months after transplantation and both received treatment for leukemia. R1 died of complications 11 months after diagnosis, while R2 went into complete remission for 44 months, before relapsing. R2 died 10 months later of complications from allogenic bone marrow transplantation. Microsatellite analysis demonstrated donor chimerism in circulating cells from both kidney recipients. Targeted molecular analyses and medical records revealed NPM1 mutation present in the donor and recipients, while FLT3 was mutated only in R1. These findings were confirmed by WES, which revealed additional founder and clonal mutations, and HLA genomic loss in R2. In conclusion, we report the first in-depth genomic analysis of AML transmission following solid organ transplantation, revealing distinct clonal evolution, and providing a potential molecular explanation for tumor escape.

"War to the knife" against thromboinflammation to protect endothelial function of COVID-19 patients.

In this viewpoint, we summarize the relevance of thromboinflammation in COVID-19 and discuss potential mechanisms of endothelial injury as a key point for the development of lung and distant organ dysfunction, with a focus on direct viral infection and cytokine-mediated injury. Entanglement between inflammation and coagulation and resistance to heparin provide a rationale to consider other therapeutic approaches in order to preserve endothelial function and limit microthrombosis, especially in severe forms. These strategies include nebulized heparin, N-acetylcysteine, plasma exchange and/or fresh frozen plasma, plasma derivatives to increase the level of endogenous anticoagulants (tissue factor pathway inhibitor, activated protein C, thrombomodulin, antithrombin), dipyridamole, complement blockers, different types of stem cells, and extracellular vesicles. An integrated therapy including these drugs has the potential to improve outcomes in COVID-19.

Potential role of effector memory T cells in chronic T cell-mediated kidney graft rejection.

BACKGROUND: Chronic T cell-mediated rejection (TCMR) in kidney graft is characterized by reduction of the vessel lumen with marked intimal thickening, fibrous hyperplasia of the small renal arteries and leukocyte infiltrates. The aim of this study was to find specific gene expression profiles in chronic TCMR kidney biopsies. METHODS: RNA extracted from archival formalin-fixed, paraffin-embedded renal biopsies was used for gene expression profiling. Our study included 14 patients with chronic TCMR and 10 with acute TCMR. Fifty-two cadaveric donors were used as controls. The results were validated in an independent set of kidney biopsies. RESULTS: We identified 616 and 243 differentially expressed genes with a fold change ≥1.5 and a false discovery rate <0.05 in chronic and acute TCMR, respectively. Pathway analysis revealed upregulation of OX40 signalling. This pathway is involved in the generation of CD8+ effector memory T cells and the upregulation of killer cell lectin-like receptor G1 (KLRG-1), B lymphocyte-induced maturation protein 1 (BLIMP-1) and CD25, which characterize CD8+ effector memory T cells. However, the enhanced OX40 signalling pathway was specific to chronic TCMR; a significant increase of KLRG-1+/CD8+ and BLIMP-1+/CD8+ was only detected in these specimens. CONCLUSIONS: These results suggest the involvement of memory-committed CD8+ effector T cells in chronic TCMR. The generation of effector memory T cells is mediated by the OX40 gene pathway, and could be considered a future target for the specific treatment of chronic TCMR.

De novo noncutaneous malignancies after kidney transplantation are associated with an increased risk of graft failure: results from a time-dependent analysis on 672 patients.

The aim of this study was to evaluate the association between cancer occurrence and risk of graft failure in kidney transplant recipients. From November 1998 to November 2013, 672 adult patients received their first kidney transplant from a deceased donor and had a minimum follow-up of 6 months. During a median follow-up of 4.7 years (3523 patient-years), 47 patients developed a nonmelanoma skin cancer (NMSC) and 40 a noncutaneous malignancy (NCM). A total of 59 graft failures were observed. The failure rate was 6 per 100 patient-year (pt-yr) after NCM versus 1.5 per 100 pt-yr in patients without NCM. In a time-dependent multivariable model, the occurrence of NCM appeared to be associated with failure (HR = 3.27; 95% CI = 1.44-7.44). The effect of NCM on the cause-specific graft failure was different (P = 0.002) when considering events due to chronic rejection (HR = 0.55) versus other causes (HR = 15.59). The reduction of the immunosuppression after NCM was not associated with a greater risk of graft failure. In conclusion, our data suggest that post-transplant NCM may be a strong risk factor for graft failure, particularly for causes other than chronic rejection.

Testing for the cytosine insertion in the VNTR of the MUC1 gene in a cohort of Italian patients with autosomal dominant tubulointerstitial kidney disease.

INTRODUCTION: Medullary cystic kidney disease type 1 (MCKD1; OMIM #174000) is a familial progressive tubule-interstitial nephropathy belonging to the recently defined group of autosomal dominant tubulointerstitial kidney diseases (ADTKD). CASE REPORT: A specific type of cytosine insertion in the extracellular variable number tandem repeat (VNTR) domain of the MUC1 gene causing the disease was tested in a group of 21 families with ADTKD. We identified this type of MUC1 mutation in two families, whose affected members are described in detail in this case report. Affected (ADTKD-MUC1) members developed end-stage renal disease (ESRD) with a higher incidence (p = 0.033) and at a younger age (p = 0.013) than probands with ADTKD but without this type of mutation. All patients with MUC1-associated kidney disease shared a rather unspecific tubule-interstitial laboratory pattern without medullary cysts, leading to ESRD between the age of 33 and 47 years. We were not able to identify any single common extra-renal feature among affected patients, even if they had various comorbidities, which are described in detail. CONCLUSIONS: We identified this type of MUC1 mutation in 9.5 % of families from an ADTKD Italian cohort; larger studies are needed to better define the criteria for genetic testing for this type of mutation.

The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients.

BACKGROUND: Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. METHODS: Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. RESULTS: One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. CONCLUSIONS: In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival.

The Role of TCF7L2 rs7903146 in Diabetes After Kidney Transplant: Results From a Single-Center Cohort and Meta-Analysis of the Literature.

BACKGROUND: Several genetic polymorphisms modulate the risk of posttransplant diabetes mellitus (PTDM), a complication associated with an increased morbidity and mortality after kidney transplantation; however, their clinical utility is still undefined. METHODS: Genetic analysis was performed in 464 kidney transplantation recipients to evaluate whether transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism is associated with the risk of PTDM and a meta-analysis of similar studies including our results was performed (total kidney transplantation recipients, n = 3105). A predictive model of PTDM was built on the basis of this polymorphism and clinical parameters. RESULTS: In our cohort, 163 patients possessed the CC genotype of rs7903146 (35.1%), 237 were CT (51.1%), and 64 were TT (13.8%): their 2 years PTDM incidence was, respectively, 7.8%, 11.9%, and 22.7%. At multivariate analysis, age (per year; hazard ratio [HR], 1.029; 95% confidence interval [95% CI], 1.005-1.054; P = 0.017), body mass index (25.0-29.9 vs <25.0; HR, 2.43; 95% CI, 1.40-4.23; P = 0.0018; ≥30 vs <25.0; HR, 5.70; 95% CI, 2.77-11.74; P < 0.0001), TCF7L2 rs7903146 (per each T allele; HR, 1.81; 95% CI, 1.26-2.59; P = 0.001) and previous transplants (HR, 2.80; 95% CI, 1.39-5.64; P = 0.004) emerged as independent predictive factors for PTDM.Meta-analysis of present and 5 previous studies showed higher risk of PTDM in carriers of rs7903146 TT genotype (odds ratio, 1.95; 95% CI, 1.39-2.74; P < 0.0001) and absence of heterogeneity among studies (I = 0%).Inclusion of this polymorphism in a predictive model appeared to improve its ability to stratify patients according to the risk of PTDM. CONCLUSIONS: In renal transplant patients, TCF7L2 rs7903146 is strongly and independently associated with PTDM and might hold the potential to identify patients at risk for this complication.

Impact of recipient ACE I/D genotype on kidney function in renal transplant patients: a meta-analysis of cross-sectional and longitudinal studies.

AIM: To perform a systematic review and meta-analysis of studies evaluating the influence of recipient angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism on kidney function in renal transplant recipients. MATERIALS & METHODS: A comprehensive search was performed through PubMed, Web of Knowledge and Cochrane databases up to December 2014. The methodological quality of identified studies was assessed using the MINORS criteria. RESULTS: A total of 15 studies evaluating the role of recipient ACE I/D were included in the meta-analysis. In overall analyzes and subsequent subgroup and sensitivity analyzes, no evidence emerged of an effect of ACE I/D on serum creatinine levels, creatinine clearance or glomerular filtration rate. CONCLUSION: Although further investigation is still needed to determine the role of donor ACE genotype, recipient ACE I/D does not play a significant role on kidney function in renal transplant patients.

[Bone protection in corticosteroid treated patients]. / Indagine sulla terapia di prevenzione del danno osseo nei pazienti trattati con corticosteroidi in Piemonte e valle d'Aosta.

The Piedmont Group of Clinical Nephrology compared the activity of 15 nephrology centers in Piedmont and Aosta Valley as regards bone protection in patients on corticosteroids therapy. Fracture prevalence shows great variability: in 4/15 centers (27%) no fractures were found, in 6/15 centers (40%) fractures were present in 1-4% of cases, in 1 center in 18% of patients. Clinical risk of fracture was based on sex, age and postmenopausal status in 11/14 of the centers (79%), history of fractures and bone disease in 4/14 centers (27%), smoking and alcohol consumption in 3 and 2 centers respectively, glucocorticoid dose and duration in 4, in children bone age and calcium phosphorus status. Dual energy X-ray absorptiometry was performed in 12 centers based on risk factors, in 8 (57%) DXA was performed during the follow-up, in 4 it was performed after 12 months and in 2 after 2-3 years. DXA is not prescribed in children. Only in one center, risk assessment is based on FRAX. Most of the patients are treated with vitamin D supplementation at a dose of steroids of 5 mg/d (80%). Calcium carbonate is used in 9 centers (60%), in two it is used only in the presence of low ionized calcium or bone mineral density. Bisphosphonates are used following AIFA prescription, in particular alendronate in all centers, risedronate in seven and denosumab in one. The analysis shows the great variability of the clinical and therapeutic approach regarding bone protection in patients on corticosteroids therapy, in Piedmont and Aosta Valley.

[What if it is not an acute pyelonephritis? A monocentric experience of renal infarcts]. / Quando non è una pielonefrite acuta: esperienza monocentrica di infarti renali.

BACKGROUND: Often the reduced contrast enhancement on CT renal imaging is radiologically interpreted as acute pyelonephritis (PNA), but it is the task of the clinician to assess a possible differential diagnosis such as a renal infarct and look for a cause. METHODS: In our experience (2010-2013), we hospitalized 51 patients with radiological imaging consistent with acute pyelonephritis in native kidneys. However, three of these cases result, after a second look, to be ischemic lesions, only sometimes complicated by over-infections (Tabella 1). FIRST CASE: a woman hospitalized for fever and flank pain with blood culture positive for Klebsiella Pneumoniae. Antibiotic therapy allowed a clinical-laboratory improvement, but after 45 days persisted a focal wedge to the CT scan. The labs showed a anemia due to a sickle cell disease (SLC). The overview was finally interpreted as a renal infarct secondary to a sickle cell anemia, initially complicated by over-infection. SECOND CASE: a men hospitalized for a acute flank pain. The CT scan showed a left renal infarct and a partial renal artery thrombosis, resulting in abuse of cannabinoids and LAC positivity.Third case: a woman hospitalized for flank pain and slight movement of inflammatory markers. CT showed a cuneiform area in the right kidney not vascularized, that did not resolved after prolonged antibiotic therapy. The labs evidence a heterozygous mutation of prothrombin and MTHFR causing the renal infarction. CONCLUSIONS: 6% of radiographic imaging consistent with acute pyelonephritis concealed an underlying infarct, due to a unknown state of thrombophilia. The presence of hypovascular imaging to the TC scan, therefore, requires a differential diagnosis between PNA and infarct, especially in the case of atypical development.

Impact of pre-transplant antiaggregant and anticoagulant therapies on early hemorrhagic and cardiovascular events after kidney transplantation.

BACKGROUND: Oral anticoagulation with vitamin K antagonists (VKA) and antiaggregant therapy (AAT) are common among dialysis patients, but it is not known if they increase the risk of hemorrhagic (HE) or cardiovascular events (CVE) in the early post-transplant weeks. METHODS: We conducted a retrospective analysis on 911 consecutive kidney transplants (KTxs) in order to analyze the impact of AAT and VKA on early HE and CVE-which might be related to their withdrawal-and to identify the main risk factors for these complications. RESULTS: We observed 21/911 HE (2.3%; 1 death, 4 allograft loss); risk factors for HE at multivariate analysis were: KTx before 2004 (when anti-factor Xa activity measurement was not available; odds ratio, OR 5.835, [95% confidence interval, 1.241-27.436], p = 0.026), and VKA (OR 7.090 [2.030-24.772], p = 0.002), while AAT was not a risk factor. CVE were 32/911 (3.5%; 3 deaths, 11 allograft loss): risk factors for CVE at multivariate analysis were: previous cardiovascular events (OR 4.180 [1.615-10.948], p = 0.0032) and cinacalcet use (OR 7.930 [3.002-20.945], p < 0.0001), while neither VKA nor AAT had any impact. CONCLUSIONS: In conclusion, HE and CVE are relatively rare but can be severe, but there are no pre-KTx modifiable risk factors. If an anticoagulant therapy with low molecular weight heparins has to be started soon after surgery, monitoring of anti-Xa activity is highly recommended.

Circulating suPAR levels are affected by glomerular filtration rate and proteinuria in primary and secondary glomerulonephritis.

BACKGROUND: Circulating levels of soluble urokinase-like plasminogen activator receptor (suPAR) have been associated with proteinuria and renal function in focal segmental glomerulosclerosis (FSGS). This study aimed to evaluate if circulating suPAR levels are independently associated with proteinuria in patients with non-FSGS glomerulonephritis. METHODS: This is a cross-sectional analysis of suPAR levels on 42 patients with primary non-FSGS glomerulonephritis (group GN) and 140 patients with secondary glomerulonephritis within an autoimmune disease (group AID). RESULTS: suPAR serum levels were significantly higher in AID patients (4,733 ± 3,073 pg/ml) than in healthy controls (1,908 ± 1,685 pg/ml; p < 0.001), whereas GN patients displayed intermediate levels (3,670 ± 2,435 pg/ml; p = 0.021). Multivariate analysis for elevated serum suPAR (>3,000 pg/ml) showed an independent association with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) [odds ratio (OR) = 4.19, 95% confidence interval (CI): 1.67-10.54, p = 0.002], proteinuria >0.5 g/day (OR = 2.97; 95% CI: 1.32-6.70; p = 0.009) and presence of secondary vs. primary GN (OR = 2.87, 95% CI: 1.25-6.23; p = 0.013). A general linear model confirmed that suPAR levels were significantly affected by proteinuria >0.50 g/day (coefficient +1,477 pg/ml), eGFR (-38 pg/ml per 1 ml/min/1.73 m(2) increase) and presence of secondary vs. primary GN (+1,368 pg/ml). CONCLUSIONS: This study shows that elevated serum suPAR levels are associated with reduced eGFR and presence of proteinuria in both primary and secondary GN, suggesting that circulating suPAR may represent a common biomarker of renal involvement in a wide spectrum of GN.

Can tonsillectomy modify the innate and adaptive immunity pathways involved in IgA nephropathy?

The benefits of tonsillectomy in IgA nephropathy (IgAN) are still debated. Tonsillectomy may remove pathogen sources and reduce the mucosal associated lymphoid tissue (MALT), limiting degalactosylated IgA1 (deGal-IgA1) production, which is considered to be the initiating pathogenetic event leading to IgA glomerular deposition. In the European network VALIGA, 62/1147 IgAN patients underwent tonsillectomy (TxIgAN). In a cross-sectional study 15 of these patients were tested and compared to 45 non-tonsillectomized IgAN (no-TxIgAN) and healthy controls (HC) regarding levels of deGal-IgA1, and markers of innate immunity and oxidative stress, including toll-like receptors (TLR)2, 3, 4 and 9 mRNAs, proteasome (PS) and immunoproteasome (iPS) mRNAs in peripheral blood mononuclear cells (PBMC), and advanced oxidation protein products (AOPP). Levels of deGal-IgA1 were lower in TxIgAN than in no-TxIgAN (p = 0.015), but higher than in HC (p = 0.003). TLR mRNAs were more expressed in TxIgAN than in HC (TLR4, p = 0.021; TLR9, p = 0.027), and higher in TxIgAN than in no-TxIgAN (p ≤ 0.001 for TLR2, 4, 9). A switch from PS to iPS was detected in PBMC of TxIgAN in comparison to HC and it was higher than in no-TxIgAN [large multifunctional peptidase (LMP)2/ß1, p = 0.039; LPM7/ß5, p < 0.0001]. The levels of AOPP were significantly higher in TxIgAN than HC (p < 0.001) and no-TxIgAN (p = 0.033). In conclusion, the activation of innate immunity via TLRs and ubiquitin-proteasome pathways and the pro-oxidative milieu were not affected by tonsillectomy, even though the levels of aberrantly galactosylated IgA1 were lower in patients with IgAN who had tonsillectomy. The residual hyperactivation of innate immunity in tonsillectomized patients may result from extra-tonsillar MALT.

[Acute pielonephritis and renal abscesses in Piedmont and Aosta Valley]. / Indagine sulla pielonefrite acuta e sugli ascessi renali in Piemonte e Valle d'Aosta.

The Piedmont Group of Clinical Nephrology compared the activity of 18 nephrology centers in Piedmont and Aosta Valley as regards acute pielonephritis (APN). Data from more than 500 cases per year of APN were examined. The microbial spectrum of APN consists mainly of Escherichia coli and Klebsiella pneumoniae. Diagnosis was based on both clinical and radiological criteria in most of the centers (computed tomography-CT o Magnetic Resonance Imaging-MRI). In four centers diagnosis was made with the radiological criteria and in one center only with the clinical features. CT and MRI were performed in about 47% and 44% of cases respectively. Urine culture was positive in 22 up to 100% of cases. The most commonly used antibiotics were fluoroquinolones (ciprofloxacin or levofloxacin) and ceftriaxone (50% of centers) or amoxicillin/clavulanic acid (25% of centers). In 75% of the centers, patients received a combination of two antibiotics (aminoglycoside in 22% of them ). In 72% of the centers, almost 50% of the patients were re-examined, while 38.8% of centers re-examined all the patients. Renal ultrasound was inappropriate to identify abscesses. The mean of patients in whom renal abscesses were detected by CT or MRI was 18.2%. The analysis shows a high variability in the way of diagnosing and treating APN in Piedmont and Aosta Valley regions. This suggests that even if APN is a frequent pathological condition, practical recommendations are required.

Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population.

BACKGROUND: Inactivating mutations of the calcium-sensing receptor (CaSR), of the G-protein subunit α11 (GNA11) and of the adaptor-related protein complex 2, sigma 1 subunit (AP2S1) genes are responsible for familial hypocalciuric hypercalcaemia (FHH). The aim of this study was to analyse prevalence and pathogenicity of CaSR, GNA11 and AP2S1 mutations in patients with an FHH phenotype and to compare them with a sample of patients with primary hyperparathyroidism (PHPT) in order to identify the most useful laboratory parameter for a differential diagnosis. METHODS: Patients with an FHH phenotype were studied with polymerase chain reaction amplification and direct sequencing of the entire CaSR, GNA11 and AP2S1 coding sequences. Novel mutations were introduced in a Myc-tagged human wild-type (WT) CaSR cDNA-expressing vector, and functional assay was performed on human embryonic kidney cells evaluating expression and function of mutated proteins. RESULTS: Among 16 FHH patients, none had an inactivating GNA11 or AP2S1 mutation while 3 (18.8%) carried a CaSR mutation and 10 (62.5%) at least one CaSR polymorphism. Within the latter group, 7 of 10 patients had more than one polymorphism (4.1 ± 2.1 per patient). Two novel CaSR mutations [c.2120A>T (E707V) and c.2320G>A (G774S)] were identified: the E707V mutation prevented CaSR expression (western blot), whereas the G774S mutation determined a reduced receptor sensitivity to calcium (IP3 assay). PHPT patients showed significantly (P < 0.001) higher serum calcium, parathyroid hormone, urinary calcium and calcium-creatinine clearance ratio (CCCR) and significantly lower serum phosphate than FHH ones. CONCLUSIONS: FHH should be clearly differentiated by PHPT to avoid unnecessary surgery: CCCR could be a useful screening tool while genetic analysis should include the two novel CaSR mutations herein described. The role of multiple polymorphisms deserves further investigation in patients with an FHH phenotype.

Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy.

BACKGROUND: Patients with a rare genetic disease may receive renal transplantation (KTx) without a correct diagnosis of causal nephropathy and therefore develop unexpected and even severe complications. The aim of the study was to describe the cases of rare genetic disorders diagnosed after KTx, in order to draw clinical lessons for the transplant physician. METHODS: We retrospectively assessed all patients who had received a diagnosis of a rare genetic disorder after KTx. RESULTS: In our center, more than 30% (278/911) of kidney transplant (KTx) recipients were diagnosed with a causal nephropathy: Prevalence of rare genetic disorders in this group was 4.32% (12/278), including 2,8-dihydroxyadeninuria (2,8-DHA) disease (n = 2), HNF-1B-associated nephropathy (n = 2), UMOD-related nephropathy (n = 5), Fabry disease (n = 1), INF2 focal segmental glomerulosclerosis (n = 1), and Senior-Løken syndrome (n = 1). 2,8-DHA nephropathy relapsed in both patients causing an acute renal failure and jeopardizing the graft. CONCLUSIONS: Kidney transplant recipients without a diagnosis of causal nephropathy appear to be a selected population in which rare genetic diseases might be more common than expected. As even a belated diagnosis after KTx can have a significant impact on graft and patient survival and on other family members, this possibility should be evaluated in KTx recipients without a known causal nephropathy.