Andrea Airoldi

Renal outcome and monoclonal immunoglobulin deposition disease in 289 old patients with blood cell dyscrasias: A single center experience

Monoclonal components (MC) formed by chains/fragments of intact/truncated globulin components produced in different lymphoproliferative diseases are responsible for monoclonal immunoglobulin deposition disease (MIDD) and consequent tissue damage by organized (amyloid fibrils) or non-organized (amorphous) deposits. The kidneys are the most commonly affected organs in MIDD, and renal failure represents an important adverse factor for prognosis. The renal outcome and the role of renal pathology in diagnosing MIDD was evaluated in 289 elderly patients with multiple myeloma (MM, n=115) and monoclonal gammopathy (MGUS, n=174). Renal impairment was the only significant risk factor for patient death, while significant risk factors for renal impairment were diabetes (HR 3.65, 95% CI: 2.08-6.41), light chain (LC) proteinuria (HR 2.18; 95% CI: 1.10-4.32) and type of MC (p=0.0019). Renal pathology documented MIDD in 12/30 cases (40%): six cases of AL-amyloidosis, two of LC disease, one of heavy chain disease and three of cast nephropathy, as well as four cases of glomerulonephritis, eight of arteriolosclerosis and six of normal picture. Main conclusions are that diabetes, sharing common glomerular damage with LC disease, is the strongest risk factor for progression of renal disease, and glomerular proteinuria or heavy LC proteinuria should raise a strong suspicion index of MIDD and prompt pathology assessment to reach the correct diagnosis.

Decreased Kidney Function and Crystal Deposition in the Tubules After Kidney Transplant

Adenine phosphoribosyltransferase (APRT) deficiency is an autosomal recessive purine enzyme defect that results in the inability to utilize adenine, which consequently is oxidized by xanthine dehydrogenase to 2,8-dihydroxyadenine (2,8-DHA), an extremely insoluble substance eventually leading to crystalluria, nephrolithiasis, and kidney injury. We describe a case of APRT deficiency not diagnosed until the evaluation of a poorly functioning kidney transplant in a 67-year-old white woman. After the transplant, there was delayed transplant function, urine specimens showed crystals with unusual appearance, and the transplant biopsy specimen showed intratubular obstruction by crystals identified as 2,8-DHA using infrared spectroscopy. APRT enzymatic activity was undetectable in red blood cell lysates, and analysis of the APRT gene showed 1 heterozygous sequence variant, a duplication of T at position 1832. The patient was treated with allopurinol, 300 mg/d, and transplant function progressively normalized. Because patients with undiagnosed APRT deficiency who undergo kidney transplant may risk losing the transplant because of an otherwise treatable disease, increased physician awareness may hasten the diagnosis and limit the morbidity associated with this disease.

Transurethral resection of the prostate in kidney transplant recipients: urological and renal functional outcomes at long-term follow-up.

To assess prospectively the safety and efficacy of transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms attributable to benign prostatic hyperplasia (BPH) in patients who have undergone renal transplantation (RT). To assess the impact of TURP on renal graft function.

Prevalence and Clinical Relevance of Occult Hepatitis B Virus Infection in Patients on the Waiting List for Kidney Transplantation

BACKGROUND Occult hepatitis B virus (HBV) infection can be defined as the long-lasting persistence of viral genomes in the liver tissue, and sometimes also in the serum at low levels of viremia in individuals with undetectable HBV surface antigen (HBsAg). Viral replication can be reactivated by immunosuppressive therapies or immunologic diseases, leading to the development of typical hepatitis B. METHODS All patients on the waiting list for renal transplantation at the only 2 transplant centers in our region (Piemonte, Italy) were checked for the presence of occult HBV infection by an highly sensitive quantitative HBV-DNA polymerase chain reaction (PCR) assay (nested PCR); the only exclusion criterion was HBsAg-positivity. The enrollment lasted from October 1, 2006, to May 31, 2007. The prospective follow-up will continue for 5 years. RESULTS HBV-DNA sequences were detected in blood samples from 10 of 300 cases examined (3.3%), being more frequent among Asian (1/3; 33.3%) and African (1/16; 6.25%) subjects as compared with the Caucasians (8/281; 2.8%; P = .011), among anti-hepatitis C virus (HCV) positive versus HCV negative patients (3/32 [9.3%] vs 7/268 [2.6%]; P = .004) and mainly among patients with a previous history of overt liver diseases (3/22 [14%] vs 7/278 [2.5%]; P = .019). HBV-DNA sequences became undetectable at 1 month after renal transplantation in 3 patients; the follow-up is in progress for these and the other patients. CONCLUSION Occult HBV infection occurs in patients undergoing renal transplantation. Longer observation and prospective studies will clarify the clinical impact of this occult infection on transplant outcomes and the possibility of viral reactivation related to immunosuppressive therapy.

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

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.

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.

The missing medullary sponge kidney

To the Editor: In a recent interesting review regarding etiologic mechanisms of stone formation,1 no mention was made of the role of medullary sponge kidney (MSK), characterized by ectasia and cystic formation in the medullary collecting precalyceal ducts.

Recognizing purple bag syndrome at first look

Purple urine bag syndrome is a clinical entity first described in 1978. Its typical discoloration is worrying for clinicians. In the past, these patients sometimes reached the emergency unit only because of this exceptional worrying urinary sign and underwent invasive diagnostic examinations including cystoscopy, without any abnormal finding. It is now clear that this astonishing phenomenon of double discoloration of the urine, appearing purple in the bag and dark blue in the test tube, results from the formation of 2 different pigments (indirubin and indigo) in very alkaline urines due to enzymes produced by gram-negative bacteria, such as indoxyl phosphatase/sulfatase, which can convert urinary metabolites of dietary tryptophan. Practicing physicians should identify purple urine bag syndrome as a usually benign medical condition diagnosed in asymptomatic patients, which only requires treatment of bacteriuria with antibiotics, prevention of constipation, substitution of catheter and acidification of the urine. After these measures, urine typically returns to its normal color.

Is Renal Living-Donor Transplantation Indicated in Adult Patients with Orthotopic Ileal Neobladder? Lessons Learned from a Clinical Case

Renal transplantation is the treatment of choice for patients with end-stage renal disease and it has already been described in the literature in patients with orthotopic neobladders, mostly in the paediatric population. We report the first case of a living-donor renal graft in an adult patient with a orthotopic neobladder that was performed after radical cystectomy for urinary tuberculosis and reflux nephropathy. This patient experienced urologic and metabolic complications since the early posttransplant period.

Endothelial Progenitor Cell-Derived Extracellular Vesicles Inhibit Kidney Ischemia-Reperfusion Injury through the transfer of Specific Micrornoa and Mrna Coding for the Transcription Factor NRF2: Relevance for Delayed Kidney Graft Function

Background and Aim Activation of the complement cascade and oxidative stress in tubular epithelial and peritubular endothelial cells are hallmarks of delayed kidney graft function (DGF) due to ischemia-reperfusion injury (IRI). Endothelial progenitor cells (EPCs) are bone marrow-derived precursors known to reverse IRI by paracrine mechanisms including the release of extracellular vesicles (EV), small particles playing a role in intercellular communication through the transfer of specific mRNA and microRNA. The aim of this study was to evaluate the regenerative role of EPC-derived EV in kidney IRI through the horizontal transfer of RNA involved in the inhibition of complement activation and of oxidative stress. Methods EPC were isolated from peripheral blood of healthy volouteers and EV obtained by supernatant ultracentrifugation were characterized for size, protein and RNA content. We evaluated the effects of EV in a rat model of kidney IRI and in vitro in human tubular epithelial and endothelial cells cultured in hypoxia in vitro. Results EPC-derived EV sized 60-130 nm and carried different subsets of mRNAs and microRNAs able to modulate cell proliferation, angiogenesis and apoptosis (eNOS, Akt, Bcl-XL, miR-126, miR-296). By RT-PCR, we also found within EV mRNAs coding for the complement inhibitors factor H, DAF (CD55), CD59 and for the anti-oxidant transription factgor nrf2. In experimental kidney IRI, EPC EV localized within peritubular capillaries and tubular cells exerting morphologic and functional protection from by reducing tubular cell apoptosis/senescence, endothelial-to-mesenchymal transition (EndoMT) and leukocyte infiltration. Moreover, EV administration reduced C5b9 deposition and enhanced the expression of factor H, DAF, CD59 and nrf2 in the ischemic kidney. In vitro, EV reduced hypoxia-induced apoptosis/senescence of tubular epithelial (caspase activation, Klotho expression) and endothelial cells (EndoMT) by up-regulating the expression of factor H, DAF, CD59 and nrf2, thus confirming the in vivo data. The role of specific mRNA transfer to hypoxic renal cells was confirmed by experiments using RNase-treated EV, EV released from EPC engineered to knock-down the complement inhibitors or nrf2 by specific siRNA, or EV produced by EPC transfected with siRNA Dicer, the intracellular enzyme essential for microRNA maturation. Conclusions EPC-derived EV protect the kidney from IRI by delivering pro-angiogenic, anti-apoptotic, complement inhibitors and anti-oxidant microRNAs and mRNAs coding for factor H, DAF, CD59 and nrf2 to injured tubular epithelial and endothelial cells. These results suggest the potential use of EPC-derived EVs as therapeutic tool to avoid or at least to limit IRI-associated DGF in kidney transplantation without the potential adverse effects of whole stem cell therapy including maldifferentiation and tumorigenesis.