Publications by authors named "Giacomo Colussi"

36 Publications

A simple method for the calculation of dialysis Kt factor as a quantitative measure of removal efficiency of uremic retention solutes: Applicability to high-dialysate vs low-dialysate volume technologies.

PLoS One 2020 29;15(5):e0233331. Epub 2020 May 29.

Division of Nephrology, Dialysis and Renal Transplantation, ASST GOM Niguarda, Milan, Italy.

Dialysis urea removal metrics may not translate into proportional removal efficiency of non-urea solutes. We show that the Kt factor (plasma volume totally cleared of any solutes) differentiates removal efficiency of non-urea solutes in different technologies, and can easily be calculated by instant blood-dialysate collections. We performed mass balances of urea, creatinine, phosphorus and beta2-microglobulin by whole dialysate collection in 4 low-flux and 3 high-flux hemodialysis, 2 high-volume post-hemodiafiltration and 7 short-daily dialysis with the NxStage-One system. Instant dialysate/blood determinations were also performed at different times, and Kt was calculated as the product of the D/P ratio by volume of delivered dialysate plus UF. There were significant differences in single session and weekly Kt (whole dialysate and instant calculations) between methodologies, most notably for creatinine, phosphorus and beta2-microglobulin. Urea Kt messured in balance studies was almost equal to that derived from the usual plasma kinetic model-based Daugirdas' equation (eKt/V) and independent V calculation, indicating full correspondence. Non-urea solute Kt as a fraction of urea Kt (i.e. fractional removal relative to urea) showed significant differences between technologies, indicating non-proportional removal of non-urea solutes and urea. Instant Kt was higher than that in full balances, accounting for concentration disequilibrium between arterial and systemic blood, but measured and calculated quantitative solute removal were equal, as were qualitative Kt comparisons between technologies. Thus, we show that urea metrics may not reliably express removal efficiency of non-urea solutes, as indicated by Kt. Kt can easily be measured without whole dialysate collection, allowing to expand the metrics of dialytic efficiency to almost any non-urea solute removed by dialysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233331PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259768PMC
August 2020

Single Session and Weekly Beta 2-Microglobulin Removal with Different Dialytic Procedures: Comparison between High-Flux Standard Bicarbonate Hemodialysis, Post-Dilution Hemodiafiltration, Short Frequent Hemodialysis with NxStage Technology and Automated Peritoneal Dialysis.

Blood Purif 2019 3;48(1):86-96. Epub 2019 May 3.

Division of Nephrology, Dialysis and Renal Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy,

Background: NxStage System One cycler (NSO) is a widespread system for home daily dialysis. Few data are available on the impact of this "low dialysate volumes system" on the removal rate of poorly diffusible, time-dependent solutes like β2-microglobulin (β2M).

Methods: Single-session and weekly balances of β2M were performed and compared in 12 patients on daily NSO, 13 patients on standard high-flux bicarbonate dialysis (BHD), 5 patients on standard post-dilution on line hemodiafiltration (HDF), and 13 patients on automated peritoneal dialysis (APD).

Results: Intradialytic fall of plasma water β2M levels (corrected for rebound) was 65.2 ± 2.6% in HDF, 49.8 ± 9.1% in BHD, and 32.3 ± 6.4% in NSO (p < 0.001 between all groups). Single treatment dialysate removal was much less in APD (19.4 ± 20.4 mg, p < 0.001) than in any extracorporeal technologies, and was less in NSO (126.2 ± 35.6 mg, p < 0.001) than in BHD (204.9 ± 53.4 mg) and HDF (181.9 ± 37.6 mg), with no differences between the latter 2; however weekly removal was higher in NSO (757.3 ± 213.7 mg, p < 0.04) than in BHD (614.8 ± 160.3 mg) and HDF (545.8 ± 112.8 mg). Extrapolated β2M adsorption to the membrane was negligible in BHD, 14.7 ± 9.5% of total removal in HDF and 18.3 ± 18.5% in NSO. Integration of single session data into a weekly efficiency indicator (K × t) showed total volume of plasma cleared in NSO (33.4 ± 7.7 L/week) to be higher than in BHD (26.9 ± 7.2 L/week, p < 0.01) and not different than in HDF (36.2 ± 4.7 L/week); it was negligible (3.2 ± 1.0) in APD.

Conclusions: Weekly β2M removal efficiency proved equal and highest in HDF and NSO (at a 6/week prescription), slightly lesser in BHD and lowest in APD.
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http://dx.doi.org/10.1159/000499830DOI Listing
December 2019

Treatment and long-term outcome in primary distal renal tubular acidosis.

Nephrol Dial Transplant 2019 06;34(6):981-991

Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.

Background: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome.

Methods: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form.

Results: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate.

Conclusion: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.
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http://dx.doi.org/10.1093/ndt/gfy409DOI Listing
June 2019

Home hemodialysis treatment and outcomes: retrospective analysis of the Knowledge to Improve Home Dialysis Network in Europe (KIHDNEy) cohort.

BMC Nephrol 2018 10 11;19(1):262. Epub 2018 Oct 11.

Queen Alexandra Hospital, Wessex Kidney Centre, Portsmouth, England.

Background: Utilization of home hemodialysis (HHD) is low in Europe. The Knowledge to Improve Home Dialysis Network in Europe (KIHDNEy) is a multi-center study of HHD patients who have used a transportable hemodialysis machine that employs a low volume of lactate-buffered, ultrapure dialysate per session. In this retrospective cohort analysis, we describe patient factors, HHD prescription factors, and biochemistry and medication use during the first 6 months of HHD and rates of clinical outcomes thereafter.

Methods: Using a standardized digital form, we recorded data from 7 centers in 4 Western European countries. We retained patients who completed ≥6 months of HHD. We summarized patient and HHD prescription factors with descriptive statistics and used mixed modeling to assess trends in biochemistry and medication use. We also estimated long-term rates of kidney transplant and death.

Results: We identified 129 HHD patients; 104 (81%) were followed for ≥6 months. Mean age was 49 years and 66% were male. Over 70% of patients were prescribed 6 sessions per week, and the mean treatment duration was 15.0 h per week. Median HHD training duration was 2.5 weeks. Mean standard Kt/V was nearly 2.7 at months 3 and 6. Pre-dialysis biochemistry was generally stable. Between baseline and month 6, mean serum bicarbonate increased from 23.1 to 24.1 mmol/L (P = 0.01), mean serum albumin increased from 36.8 to 37.8 g/L (P = 0.03), mean serum C-reactive protein increased from 7.3 to 12.4 mg/L (P = 0.05), and mean serum potassium decreased from 4.80 to 4.59 mmol/L (P = 0.01). Regarding medication use, the mean number of antihypertensive medications fell from 1.46 agents per day at HHD initiation to 1.01 agents per day at 6 months (P < 0.001), but phosphate binder use and erythropoiesis-stimulating agent dose were stable. Long-term rates of kidney transplant and death were 15.3 and 5.4 events per 100 patient-years, respectively.

Conclusions: Intensive HHD with low-flow dialysate delivers adequate urea clearance and good biochemical outcomes in Western European patients. Intensive HHD coincided with a large decrease in antihypertensive medication use. With relatively rapid training, HHD should be considered in more patients.
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http://dx.doi.org/10.1186/s12882-018-1059-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186139PMC
October 2018

Renal transplants from older deceased donors: Is pre-implantation biopsy useful? A monocentric observational clinical study.

World J Transplant 2018 Aug;8(4):110-121

School of Nephrology, Milano-Bicocca University, Milan 20126, Italy.

Aim: To compare survival of kidney transplants from deceased extended criteria donors (ECD) according to: (1) donor graft histological score; and (2) allocation of high score grafts either to single (SKT) or dual (DKT) transplant.

Methods: Renal biopsy was performed as part of either a newly adopted DKT protocol, or of surveillance protocol in the past. A total 185 ECD graft recipients were categorized according to pre-implantation graft biopsy into 3 groups: SKT with graft score 1 to 4 [SKT, = 102]; SKT with donor graft score 5 to 8 [SKT, = 30]; DKT with donor graft score 5 to 7 (DKT, = 53). Graft and patient survival were analyzed by Kaplan-Meier curves and compared by log-rank test. Mean number of functioning graft years by transplant reference, and mean number of dialysis-free life years by donor reference in recipients were also calculated at 1, 3 and 6 years from transplantation.

Results: There were no statistically significant differences in graft and patient survival between SKT and SKT, and between SKT and DKT. Recipient renal function (plasma creatinine and creatinine clearance) at 1 years did not differ in SKT and SKT (plasma creatinine 1.71 ± 0.69 and 1.69 ± 0.63 mg/dL; creatinine clearance 49.6 + 18.5 and 52.6 + 18.8 mL/min, respectively); DKT showed statistically lower plasma creatinine (1.46 ± 0.57, < 0.04) but not different creatinine clearance (55.4 + 20.4). Due to older donor age in the DKT group, comparisons were repeated in transplants from donors older than 70 years, and equal graft and patient survival in SKT and DKT were confirmed. Total mean number of functioning graft years by transplant reference at 1, 3 and 6 post-transplant years were equal between the groups, but mean number of dialysis-free life years by donor reference were significantly higher in SKT (mean difference compared to DKT at 6 years: 292 [IQR 260-318] years/100 donors in SKT and 292.5 [(IQR 247.8-331.6) in SKT].

Conclusion: In transplants from clinically suitable ECD donors, graft survival was similar irrespective of pre-implantation biopsy score and of allocation to SKT or DKT. These results suggest use of caution in the use of histology as the only decision criteria for ECD organ allocation.
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http://dx.doi.org/10.5500/wjt.v8.i4.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107519PMC
August 2018

Long-term Effect of Islet Transplantation on Glycemic Variability.

Cell Transplant 2018 05 5;27(5):840-846. Epub 2018 Jun 5.

6 Division of Nephrology, Dialysis and Renal Transplantation Niguarda Hospital, Milan, Italy.

Islet transplantation has been reported to restore normoglycemia and the overall metabolic control in type 1 diabetes mellitus (DM). In the most experienced centers, islet transplantation clinical outcome is similar to that of the whole pancreas transplantation. Long-term islet transplantation function remains a very interesting matter worth discussing. A progressive islet function decrease was reported, probably due to islet exhaustion. In 5 islet-transplanted patients with at least 3-yr follow-up and still insulin independent, their glycemic control was characterized by a blinded retrospective continuous glucose monitoring system (CGMS). Islet transplantation restored glycemic control and glucose variability. Data were compared with patients in the waiting list. All the parameters of glycemic variability tested had improved significantly in patients who had islet transplantation compared with those patients who were on the waiting list. In conclusion, islet transplantation is able to maintain a proper glucose control and normalize glycemic variability in selected patients. A blinded retrospective CGMS is a useful method to characterize glucose homeostasis deeply in vivo in islet-transplanted patients.
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http://dx.doi.org/10.1177/0963689718763751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047271PMC
May 2018

Renal Transplants from Older Deceased Donors: Use of Preimplantation Biopsy and Differential Allocation to Dual or Single Kidney Transplant according to Histological Score Has No Advantages over Allocation to Single Kidney Transplant by Simple Clinical Indication.

J Transplant 2018 16;2018:4141756. Epub 2018 May 16.

Division of Nephrology, Dialysis and Kidney Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Background: Grafts from elderly donors (ECD) are increasingly allocated to single (SKT) or dual (DKT) kidney transplantation according to biopsy score. Indications and benefits of either procedure lack universal agreement.

Methods: A total of 302 ECD-transplants in period from Jan 1, 2000, to Dec 31, 2015, were allocated to SKT (SKT) on clinical grounds alone (before Dec 2010, pre-DKT era, = 170) or according to a clinical-histological protocol (after Dec 2010, DKT era, = 132) to DKT ( = 48), SKT biopsy-based protocol ("high-risk", SKT, = 51), or SKT clinically based protocol ("low-risk", SKT, = 33). Graft and patient survival were compared between the two periods and between different transplant categories.

Results: Graft and overall survival in recipients from ECD in pre-DKT and DKT era did not differ (5-year graft survival 87.7% and 84.2%, resp.); equal survival in the 2 ECD periods was shown in both donor age ranges of 60-69 and >70-years, and in low-risk or high-risk ECD categories. Within the DKT protocol SKT showed worst graft and overall survival in the 60-69 donor age range; DKT did not result in significantly better outcome than SKT from ECD in either era. One-year posttransplant creatinine clearance in recipients did not differ between any ECD transplant category. At 3 and 5 years after transplantation there were significantly higher total dialysis-free recipient life years from an equal donor number in the pre-DKT era than in the DKT protocol.

Conclusions: Use of a biopsy-based protocol to allocate grafts from aged donors to SKT or DKT did not result in better short term graft survival than a clinically based protocol with allocation only to SKT and reduced overall recipient dialysis-free life years in time.
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http://dx.doi.org/10.1155/2018/4141756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976897PMC
May 2018

Phosphate and Calcium Control in Short Frequent Hemodialysis with the NxStage System One Cycler: Mass Balance Studies and Comparison with Standard Thrice-Weekly Bicarbonate Dialysis.

Blood Purif 2018 16;45(4):334-342. Epub 2018 Feb 16.

Division of Nephrology, Dialysis and Renal Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Background: Short frequent dialysis with NxStage System One cycler (NSO) has become increasingly popular as home hemodialysis prescription. Short dialysis sessions with NSO might not allow adequate phosphate (P) removal.

Methods: Single-session and weekly balances of P and calcium (Ca) were compared in 14 patients treated with NSO (6 sessions/week) and in 14 patients on standard bicarbonate dialysis (BHD).

Results: NSO and BHD showed similar plasma P fall, with end-dialysis plasma P slightly lower in BHD (2.2 ± 0.5 vs. 2.7 ± 0.8 mg/dL, p < 0.02). Single-session P removal was lower in NSO, but weekly removal was higher (3,488 ± 1,181 mg vs. 2,634 ± 878, p < 0.003). Plasma Ca increase was lower in NSO, with similar PTH fall. Ca balance varied according to start plasma Ca, dialysate to blood Ca gradient and net ultrafiltration.

Conclusions: short, frequent home hemodialysis with NSO, on a 6/week-based prescription, allows higher weekly P removal than BHD. With the dialysate Ca concentration in use (6 mg/dL), total plasma Ca and iCa concentration increase is lower in NSO.
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http://dx.doi.org/10.1159/000487123DOI Listing
February 2019

[Home Daily Hemodialysis with NxStage System One: monocentric italian casistic results].

G Ital Nefrol 2017 Sep 28;34(5):119-133. Epub 2017 Sep 28.

S.C. Nefrologia, Dialisi e Trapianto Renale, ASST, Grande Ospedale Metropolitano Niguarda, Milano, Italy.

NxStage System One is a new dialytic technology based on easy setup, simplicity of use and reduced dimensions, which is increasingly in use worldwide for home hemodialysis treatments. The system utilizes a low amount of dialysate, usually 15-30 liters according to anthropometric patients' values. The dialysate is supplied at very low flux, generally about 1/3 of blood flow, in order to obtain an elevated saturation of dialysate for solutes. In these conditions the clearance of urea will be almost equal to dialysate flow rate. In order to achieve an obptimal weekly clearance evaluated by Std Kt/V the dialysis sessions are repeated six times a week. In this way a good control of blood voleme can be reached. In this paper we report our experience of treatment with NxStage System One in 12 patients from May 2011 to Dicember 2016.
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September 2017

Response.

Biol Blood Marrow Transplant 2017 11 15;23(11):2014-2015. Epub 2017 Aug 15.

Medicina Interna, Dipartimento di Fisiopatologia Medico Chirurgica, Università degli Studi di Milano, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.

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http://dx.doi.org/10.1016/j.bbmt.2017.07.017DOI Listing
November 2017

[Dialysis and cookers: a project for the empowerment of patients in managing their own chronic renal failure].

G Ital Nefrol 2017 Jun;34(3):70-84

ASST Grande Ospedale Metropolitano Niguarda, Milano.

The phosphate and potassium control is indispensable to dominate the secondary hyperparathyroidism and reduce cardiovascular mortality in dialysis patients. Most of them receive only theoretical nutritional information. We therefore organized a cooking workshop for dialysis patients, with a multidisciplinary team consisting of nurses, nephrologists, a dietitian and a professional chef, to directly teach the patients and their families how to realize a low phosphorus and potassium menu, assessing the proper use of phosphate binders, and blood tests at baseline and at three and six months. Twenty-four patients, out of 133, attended the workshop with a family member, filling out a questionnaire on eating habits, knowledge about phosphorus and potassium, and about binders. Theoretical and practical information about phosphorus and potassium metabolism, about binders, and cooking techniques were given during the evening, we then prepared a meal, eaten all together. The questionnaire was repeated at the end of the evening, and all the participants reported an improvement of the considered variables. Phosphorus and potassium plasma levels and the number of binders did not change after three and six months. Coping with the dietary changes related to the start of the dialytic therapy in an informal atmosphere, with a family member, is highly appreciated, clinically useful, logistically and economically sustainable. A customized and long-lasting counselling is probably required to modify plasma levels of phosphorus and potassium and binder's consumption. The poor dietary knowledge detected in our patients and the satisfaction about the course both confirm the training needs in this area.
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June 2017

[Immunosuppression in kidney transplantation: a way between efficacy and toxicity].

G Ital Nefrol 2017 Apr;34(2):29-39

S.C. Nefrologia, ASST-Grande Ospedale Metropolitano Niguarda, Milano.

Renal transplantation is the best treatment for patients with end-stage renal disease. Over the last decades, the introduction of new immunosuppressive agents resulted into the reduction of the incidence of acute rejection and early graft loss. Despite this progress, there has been little improvement in the average life of the transplant. The main reasons of late failure are patient's death due to several complications (e.g. cancer, infectious or metabolic), and progressive deterioration of renal function caused by immunological and non-immunological factors. The immunosuppressive therapy can be distinguished into two components: the induction therapy and the maintenance therapy. The former has the aim to implement intense and immediate immunosuppression. This therapy is mostly useful in transplant with high immunological risk, although it is correlated with an increased risk of cytopenias and viral infections. The latter offers the rationale to prevent organ rejection and minimize drug toxicity. This is generally constituted by the association of two or three drugs with different mechanism of action. The most common application of this scheme includes a calcineurin inhibitor in combination with an antimetabolite and a minimum dose of steroids. Immunosuppressive therapy is also associated to an increased risk of infections and cancer development. For instance, each class of drugs is related to a different profile of toxicity. The choice of treatment protocol should take into account the clinical characteristics of the donor and recipient. Furthermore, this treatment may change anytime when clinical conditions result into complications.
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April 2017

Acquired Complement Regulatory Gene Mutations and Hematopoietic Stem Cell Transplant-Related Thrombotic Microangiopathy.

Biol Blood Marrow Transplant 2017 Sep 15;23(9):1580-1582. Epub 2017 May 15.

Laboratory of Medical Genetics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.

Hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA) is a severe complication whose pathophysiology is unknown. We describe 6 patients in which the disease was associated with complement regulatory gene abnormalities received from their respective donors. It is suggested that mutated and transplanted monocyte-derived cells are responsible for production of abnormal proteins, complement dysregulation, and, ultimately, for the disease. This observation might have important drawbacks as far as HSCT-TMA pathophysiology and treatment are concerned.
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http://dx.doi.org/10.1016/j.bbmt.2017.05.013DOI Listing
September 2017

The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis.

Kidney Int 2017 05 21;91(5):1243-1255. Epub 2017 Feb 21.

Department of Biomedical Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy; Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy. Electronic address:

Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient.
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http://dx.doi.org/10.1016/j.kint.2016.12.017DOI Listing
May 2017

Sustained Islet Allograft Function After Peritransplant Treatment Using Exenatide With and Without Everolimus.

Transplantation 2016 11;100(11):e117-e118

1 Diabetology Unit, Niguarda Hospital, Milan, Italy. 2 Tissue Therapy Unit, Niguarda Hospital, Milan, Italy. 3 Surgical Department, Niguarda Hospital, Milan, Italy. 4 Interventional Radiology Unit, Niguarda Hospital, Milan, Italy. 5 Anesthesiology Unit, Niguarda Hospital, Milan, Italy. 6 Division of Nephrology, Dialysis and Renal Transplantation, Niguarda Hospital, Milan, Italy.

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http://dx.doi.org/10.1097/TP.0000000000001441DOI Listing
November 2016

Islet Transplantation in Pediatric Patients: Current Indications and Future Perspectives.

Endocr Dev 2016 10;30:14-22. Epub 2015 Dec 10.

The first islet transplantation in diabetes mellitus was performed more than 20 years ago. Since then, clinical results have progressively improved. Nowadays, islet transplantation can be considered a real therapeutic option after pancreatectomy for painful chronic pancreatitis (autotransplantation) and in selected adult patients affected by type 1 diabetes mellitus (allotransplantation). Better results are mainly due to the advances in the standardization of islet isolation and purification procedures as well as in the pharmacological treatment of recipients. Anti-inflammatory treatments facilitate islet engraftment and prevent metabolic exhaustion and functional β-cell apoptosis; new strategies better control islet graft rejection. As a consequence, islet transplantation activities are no longer confined to few centers only, rather thousands of transplants are now performed all over the world. Many attempts are actually undertaken to find solutions to current problems of islets transplantation, from toxicity of immunosuppressive therapy to the limited engraftment, function and duration. There is general hope that these procedures will offer a safe and feasible therapeutic option for an increasing number of patients suffering from diabetes mellitus, including pediatric patients.
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http://dx.doi.org/10.1159/000439322DOI Listing
July 2016

Risk factors associated with efficacy outcomes in kidney transplantation: analysis of a contemporary cohort of patients from the A2309 trial.

Clin Nephrol 2015 Jun;83(6):338-44

A multivariate analysis of risk factors for a composite endpoint of treated biopsy proven acute rejection (BPAR), graft loss, death, or loss to follow-up was undertaken in a cohort of 833 de novo kidney transplants from an international trial (A2309). Patients were randomized to everolimus (trough concentration 3-8 ng/mL or 6-12 ng/mL) with reduced cyclosporine or to mycophenolic acid (MPA) with standard cyclosporine. Cox proportional hazard modeling, incorporating a range of recipient, donor, and transplant variables, showed that treatment group (i.e., randomization to either everolimus 3-8 ng/mL or 6-12 ng/mL vs. MPA) showed no significant association with risk of the composite efficacy endpoint at either month 12 or month 24 (significance level 0.05). At month 12, Cox proportional hazard modeling showed that black race (hazard ratio (HR) 1.68; 95% confidence interval (CI) 1.08, 2.60; p=0.021), increasing donor age in years (HR 1.01; 95% CI 1.00, 1.03; p=0.022), and delayed graft function (DGF; yes vs. no, HR 2.75; 95% CI 1.82, 4.16; p< 0.001) predicted higher risk of the composite endpoint; female gender (female vs. male HR 0.67; 95% CI 0.48, 0.93; p=0.017), and < 3 HLA mismatches (HR 0.70; 95% CI 0.50, 0.99; p=0.049) were associated with reduced risk. At month 24, increasing recipient age in years (HR 0.99; 95% CI 0.98, 0.99; p=0.028), black recipient race (HR 1.62; 95% CI 1.09, 2.42; p=0.018), increasing donor age in years (HR 1.01; 95% CI 1.00, 1.02; p=0.008) and delayed graft function (DGF) (HR 2.60; 95% CI 1.78, 3.82; p<0.001) were predictive of risk. These findings show that, independently from type of immunosuppression, organ quality (expressed by DGF), donor age and recipient age, race and gender appear to be the main determinants of efficacy within 2 years after kidney transplantation.
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http://dx.doi.org/10.5414/CN108568DOI Listing
June 2015

Chronic hypercalcaemia from inactivating mutations of vitamin D 24-hydroxylase (CYP24A1): implications for mineral metabolism changes in chronic renal failure.

Nephrol Dial Transplant 2014 Mar 13;29(3):636-43. Epub 2013 Nov 13.

Division of Nephrology, Dialysis and Renal Transplantation, A.O. Ospedale Niguarda-Ca' Granda, Milan, Italy.

Background: Loss-of-function mutations of vitamin D-24 hydroxylase have recently been recognized as a cause of hypercalcaemia and nephrocalcinosis/nephrolithiasis in infants and adults. True prevalence and natural history of this condition are still to be defined.

Methods: We describe two adult patients with homozygous mutations and six related heterozygous carriers. Mineral and hormonal data in these patients were compared with that in 27 patients with stage 2-3 chronic kidney disease and 39 healthy adult kidney donors.

Results: Probands had recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four). Corticosteroids did not reduce plasma and urine calcium levels, but ketoconazole did, indicating that 1,25(OH)(2)D production is not maximally depressed despite coexisting hypercalcaemia, high 1,25(OH)(2)D and depressed PTH, and that 1,25(OH)(2)D degradation through vitamin D-24 hydroxylase is a regulator of plasma 1,25(OH)(2)D levels. Both probands had vascular calcifications and high bone mineral content. One developed stage 3b renal failure: in this patient 1,25(OH)(2)D decreased within normal limits as glomerular filtration rate (GFR) fell and PTH rose to high-normal values, yet hypercalcaemia persisted and the ratio of 1,25(OH)(2)D to GFR remained higher than normal for any degree of GFR.

Conclusions: This natural model indicates that vitamin D-24 hydroxylase is a key physiologic regulator of calcitriol and plasma calcium levels, and that balanced reduction of 1,25(OH)(2)D and GFR is instrumental for the maintenance of physiologic calcium levels and balance in chronic kidney diseases.
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http://dx.doi.org/10.1093/ndt/gft460DOI Listing
March 2014

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Nature 2012 Jan 22;482(7383):98-102. Epub 2012 Jan 22.

Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.
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http://dx.doi.org/10.1038/nature10814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278668PMC
January 2012

[Renal outcome after pancreas transplant in patients with unstable diabetes mellitus].

G Ital Nefrol 2010 Nov-Dec;27 Suppl 52:S78-81

S.C. Nefrologia, A.O. Ospedale Niguarda Ca' Granda, Milano, Italy.

Combined kidney-pancreas transplant is currently the best treatment option for patients with type 1 diabetes associated with chronic renal failure. The favorable results of simultaneous pancreas-kidney transplants (SPK), introduced in the early 1990s, led to the introduction of the pancreas after kidney transplant (PAK) and the pancreas transplant alone (PTA), a good option for patients with uncontrolled diabetes. The superior results of SPK over PAK are partly related to better donor selection and partly to immunological factors. In conclusion, PAK transplant is a good preemptive choice for patients for whom a living kidney donor is available, so that long-term uremia while the patient is waiting for a cadaver pancreas graft can be avoided. Despite a high surgical complication rate in all types of pancreas transplant (SPK, PAK, PTA), patient survival is good and graft survival is improving year by year.
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March 2011

The mutation c.1196_1202dup7bp (p.Ser402X) in the SLC12A3 gene clusters in Italian Gitelman syndrome patients and reflects the presence of a common ancestor.

Nephrol Dial Transplant 2011 Feb 30;26(2):557-61. Epub 2010 Jul 30.

Dipartimento di Scienze Materno-Infantili, Universita degli Studi di Milano, Laboratorio di Genetica Medica, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Milan, Italy.

Background: Inactivating mutations in the SLC12A3 gene are the main cause of Gitelman's syndrome (GS), a renal tubular disorder inherited as an autosomal recessive trait. In our cohort of patients, we identified 11 probands from 11 apparently unrelated Italian families that carry the c.1196_1202dup7bp mutation, which appears to be more frequent than other mutations in Italian GS patients. Therefore, we characterized in greater detail the SLC12A3 locus and its vicinity in those patients that carry this mutation in order to detect a possible shared haplotype. Three further probands characterized in France, carrying the same mutation, were also included in this study.

Methods: Sequence or fragment analyses were carried out to investigate seven intragenic polymorphisms (rs3217425, rs3816119, rs2304483, rs2278490, rs2278489, rs2289116 and rs2289115) that flank the mutation, as well as two extragenic markers, D16S3071 and D16S3057, flanking the SLC12A3 locus in the 5' and 3' termini, respectively.

Results: A shared haplotype co-segregates with the mutation both in Italian and French probands. Moreover, all the Italian families originate from a restricted area of Italy. Likewise, the French probands come from an area of France close to the north of Italy.

Conclusion: It is likely that the c.1196_1202dup7bp mutation in the SLC12A3 gene reflects the presence of a common ancestor in an area covering the northern-central part of Italy and eastern France. A modified genotyping strategy for GS patients originating from this area has to be considered.
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http://dx.doi.org/10.1093/ndt/gfq458DOI Listing
February 2011

A thiazide test for the diagnosis of renal tubular hypokalemic disorders.

Clin J Am Soc Nephrol 2007 May 14;2(3):454-60. Epub 2007 Mar 14.

Unité Operative Nefrologia, Ospedale di Circolo e Fondazione Macchi, Varese, Italy.

Although the diagnosis of Gitelman syndrome (GS) and Bartter syndrome (BS) is now feasible by genetic analysis, implementation of genetic testing for these disorders is still hampered by several difficulties, including large gene dimensions, lack of hot-spot mutations, heavy workup time, and costs. This study evaluated in a cohort of patients with genetically proven GS or BS diagnostic sensibility and specificity of a diuretic test with oral hydrochlorothiazide (HCT test). Forty-one patients with GS (22 adults, aged 25 to 57; 19 children-adolescents, aged 7 to 17) and seven patients with BS (five type I, two type III) were studied; three patients with "pseudo-BS" from surreptitious diuretic intake (two patients) or vomiting (one patient) were also included. HCT test consisted of the administration of 50 mg of HCT orally (1 mg/kg in children-adolescents) and measurement of the maximal diuretic-induced increase over basal in the subsequent 3 h of chloride fractional clearance. All but three patients with GS but no patients with BS and pseudo-BS showed blunted (<2.3%) response to HCT; patients with BS and the two patients with pseudo-BS from diuretic intake had increased response to HCT. No overlap existed between patients with GS and both patients with BS and pseudo-BS. The response to HCT test is blunted in patients with GS but not in patients with BS or nongenetic hypokalemia. In patients with the highly selected phenotype of normotensive hypokalemic alkalosis, abnormal HCT test allows prediction with a very high sensitivity and specificity of the Gitelman genotype and may avoid genotyping.
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http://dx.doi.org/10.2215/CJN.02950906DOI Listing
May 2007

A novel type of familial transthyretin amyloidosis, ATTR Asn124Ser, with co-localization of kappa light chains.

Amyloid 2007 Jun;14(2):141-5

Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-0811, Japan.

A 68-year-old Italian woman who had a clinical history of thyroidectomy in 2002 presented with slowly progressing renal insufficiency and non-nephrotic proteinurea in 2004. A renal biopsy showed the occurrence of amyloid; the thyroid biopsy previously taken also revealed amyloid infiltration. Other amyloid-containing tissues included bone marrow and heart. The plasma cell level in the bone marrow was found to be less than 5% and both serum and urine samples were positive for a monoclonal kappa light chain band. DNA analysis unexpectedly revealed the presence of a novel transthyretin (TTR) mutation, ATTR Asn124Ser. Histologically, amyloid deposits in the thyroid had a homogeneous appearance with moderate Congophilia. In immunohistochemistry, a kappa light chain antiserum showed positive immunoreactivity with amyloid deposits in the thyroid. Furthermore, a TTR antiserum, anti-TTR50-127, also recognized a number of amyloid deposits stained positive with the kappa light chain antiserum. Overall, the kappa light chain antiserum reacted with most of the amyloid deposits in the thyroid, whereas TTR immunoreactivity was scarcer, with a scattered appearance. In contrast, only the anti-TTR50-127 antiserum labeled amyloid in the kidney, albeit not all deposits. In this study, we report a patient having a novel TTR variant, ATTR Asn124Ser, with co-localization of kappa light chains in the amyloid deposits in the thyroid tissue.
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http://dx.doi.org/10.1080/13506120701259895DOI Listing
June 2007

Quantitative analysis of convective dose in hemofiltration and hemodiafiltration: "predilution" vs. "postdilution" reinfusion.

Hemodial Int 2007 Jan;11(1):76-85

U.O. Nefrologia, A.O. Ospedale di Circolo e Fondazione Macchi, Varese, Italy.

In hemofiltration (HF) and hemodiafiltration (HDF), removal of medium and high-molecular-weight solutes is greatly enhanced by convective mechanisms as compared with simple diffusion; increasing convective flows may allow greater removal rates of these solutes. Use of "predilution" (pre-H[D]F) may allow higher ultrafiltration rates than the "postdilution" mode (post-H[D]F); yet, the dilution of plasma water may have unpredictable effects on "endogenous" water convection. We have applied a mathematical analysis to evaluate and compare endogenous water convective flow rates in pre-H(D)F vs. post-H(D)F. Endogenous plasma water recovered in ultrafiltrate was calculated according to patient (hematocrit, total protein level) and session parameters (blood flow, ultrafiltration rate, programmed weight loss), in absolute terms and as a fraction of endogenous plasma water delivery to the filter. Maximally efficient post-H(D)F was modelled according to a preset postfilter hematocrit or filtration fraction. Nomograms were constructed expressing endogenous water convective fluxes in relation to parameters of interest (ultrafiltration rate, blood flow, hematocrit) with both post-H(D)F and pre-H(D)F, and "efficiency" of pre-H(D)F vs. post-H(D)F (as the ratio of endogenous water convective flow rate with the 2 techniques) as a function of the ultrafiltration/reinfusion rate. In post-H(D)F, the model predicts maximal ultrafiltration rates within the limits of a preset hemoconcentration at the filter outlet; additionally, the model allows to calculate ultrafiltration/reinfusion quantities to be set in pre-H(D)F to equal and overcome maximal convective efficiency of post-H(D)F. This "equivalence" ultrafiltration rate may greatly vary according to patient's hematocrit and blood flow, so that the ultrafiltrate-reinfusate volume available in the system dictates, in any patient, which mode of reinfusion may attain higher "endogenous" convective flow rates. Pre-H(D)F may allow higher fractional and absolute "endogenous" convective flow rates as compared with post-H(D)F, provided that adequate amounts of reinfusate are available. For lower reinfusate volumes than "equivalence" values, post-H(D)F remains a better option.
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http://dx.doi.org/10.1111/j.1542-4758.2007.00157.xDOI Listing
January 2007

Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia.

J Clin Endocrinol Metab 2006 Jun 21;91(6):2055-61. Epub 2006 Mar 21.

Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 459, Indianapolis, Indianapolis 46202, USA.

Context: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome of hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum 1,25-dihydryxyvitamin-D concentration, myopathy, and osteomalacia. Fibroblast growth factor 23 (FGF23) is a phosphaturic protein overexpressed in tumors that cause TIO and is, at least partly, responsible for the manifestations of TIO.

Objective: The objective of this study was to determine the sensitivity of FGF23 measurements in TIO.

Design: FGF23 concentrations were measured on stored samples with three ELISAs.

Setting: This study was conducted at subspecialty referral centers.

Patients: Twenty-two patients with suspected TIO, 13 with confirmed tumors, were studied.

Interventions: There were no interventions in this study.

Main Outcome Measure: FGF23 concentration was the main outcome measure of this study.

Results: Elevated FGF23 concentrations were detected using the Immunotopics C-terminal assay in 16 of 22 TIO patients (for a sensitivity of 73%), the Immunotopics Intact assay in five of 22 patients (sensitivity, 23%), and the Kainos Intact assay in 19 of 22 patients (sensitivity, 86%). In the 13 patients with confirmed tumors, the sensitivity was higher with all assays: 92% for the Immunotopics C-terminal assay, 38% for the Immunotopics Intact assay, and 100% for the Kainos assay.

Conclusion: The Kainos Intact assay was the most sensitive, followed by the Immunotopics C-terminal assay. The findings of normal FGF23 concentrations in some patients with TIO may indicate that FGF 23 is not responsible for the hypophosphatemia in these patients or that FGF23 secretion by some tumors is partially responsive to serum phosphate. Normal FGF23 concentrations should be interpreted in relation to the serum phosphate and 1,25-dihydryxyvitamin-D concentrations.
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http://dx.doi.org/10.1210/jc.2005-2105DOI Listing
June 2006

Pseudohyperkalemia in leukemias.

Authors:
Giacomo Colussi

Am J Kidney Dis 2006 Feb;47(2):373

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http://dx.doi.org/10.1053/j.ajkd.2005.10.032DOI Listing
February 2006

Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors.

J Clin Endocrinol Metab 2004 Nov;89(11):5583-91

Dipartimento di Endocrinologia e Metabolismo, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy.

We investigated the involvement of the HRPT2 gene by loss of heterozygosity analysis and direct sequencing in a kindred with hyperparathyroidism-jaw tumor syndrome (HPT-JT) and three kindreds with familial isolated primary hyperparathyroidism (FIHP). Seven patients with sporadic parathyroid cancers and 35 with parathyroid adenomas with no family history of primary hyperparathyroidism or HPT-JT were also studied. A germline heterozygous substitution G to A was found in the donor splice site of intron 1 in one of the three FIHP families. No mutations were identified in the HPT-JT kindred. A somatic HRPT2 mutation was found in four of seven patients with parathyroid cancers, two of which were unreported frameshift mutations (195insT and 195insA) in exon 2. Consistent with recent findings, two of seven patients with sporadic parathyroid cancer had germline mutations. Four adenomas showed loss of heterozygosity at HRPT2, whereas a somatic HRPT2 mutation was found in one. In conclusion, we provide additional evidence for a strong association between HRPT2 gene mutations and sporadic parathyroid cancer. The finding that two of the seven patients with sporadic parathyroid cancer carried an HRPT2 germline mutation suggests that they might have occult HPT-JT. Our results also confirm the need for testing HRPT2 gene in FIHP families.
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http://dx.doi.org/10.1210/jc.2004-0294DOI Listing
November 2004

Aldosterone and potassium balance in dialysis patients.

Nephrol Dial Transplant 2004 Jul;19(7):1938-9

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http://dx.doi.org/10.1093/ndt/gfh264DOI Listing
July 2004

Paricalcitol, calcitriol, and survival of patients undergoing hemodialysis.

Authors:
Giacomo Colussi

N Engl J Med 2003 Nov;349(20):1971-2; author reply 1971-2

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http://dx.doi.org/10.1056/NEJM200311133492018DOI Listing
November 2003

Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics.

Hum Mol Genet 2003 Dec 21;12(24):3369-84. Epub 2003 Oct 21.

DIBIT-San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.

The disease complex medullary cystic disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) is characterized by alteration of urinary concentrating ability, frequent hyperuricemia, tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure. MCKD/FJHN is caused by mutations of the gene encoding uromodulin, the most abundant protein in urine. Here, we describe new missense mutations in three families with MCKD/FJHN and demonstrate allelism with a glomerulocystic kidney disease (GCKD) variant, showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD/FJHN as hyperuricemia and impairment of urine concentrating ability. Furthermore, we provide the first functional characterization of uromodulin mutations. The four newly identified mutants were characterized by immunofluorescence and FACS analysis on transfected cells. These experiments showed that all uromodulin mutations cause a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry on GCKD and MCKD/FJHN kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle's loop. Electron microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic reticulum. Consistently, patient urines show a severe reduction of excreted uromodulin. The maturation impairment is consistent with the clinical findings and suggests a pathogenetic mechanism leading to these kidney diseases.
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http://dx.doi.org/10.1093/hmg/ddg353DOI Listing
December 2003