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Significance Statement: To optimize the diagnosis of genetic kidney disorders in a cost-effective manner, we developed a workflow based on referral criteria for in-person evaluation at a tertiary center, whole-exome sequencing, reverse phenotyping, and multidisciplinary board analysis. This workflow reached a diagnostic rate of 67%, with 48% confirming and 19% modifying the suspected clinical diagnosis. We obtained a genetic diagnosis in 64% of children and 70% of adults. A modeled cost analysis demonstrated that early genetic testing saves 20% of costs per patient. Real cost analysis on a representative sample of 66 patients demonstrated an actual cost reduction of 41%. This workflow demonstrates feasibility, performance, and economic effect for the diagnosis of genetic kidney diseases in a real-world setting., Background: Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice., Methods: Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion., Results: We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%., Conclusions: A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting., (Copyright © 2023 by the American Society of Nephrology.)

During the novel coronavirus pandemic, organ transplant recipients represent a frail susceptible category due to long-term immunosuppressive therapy. For this reason, clinical manifestations may differ from general population and different treatment approaches may be needed. We present the case of a 36-year-old kidney-transplanted woman affected by Senior-Loken syndrome diagnosed with COVID-19 pneumonia after a contact with her positive mother. Initial symptoms were fatigue, dry cough, and coryza; she never had fever nor oxygen supplementation. Hydroxychloroquine and lopinavir/ritonavir were started, and the antiviral drug was replaced with darunavir/cobicistat after 2 days for diarrhea. Immunosuppressant levels were closely monitored, and we observed very high tacrolimus trough levels despite initial dose reduction. The patient was left with steroid therapy alone. The peculiarity of clinical presentation and the management difficulties represent the flagship of our case report. We stress the need for guidelines in transplant recipients with COVID-19 infection with particular regard to the management of therapy., (© 2020 Wiley Periodicals LLC.)

Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and renal impairment. Mutations in genes encoding inhibitors of the alternative pathway of the complement system are involved in ∼50% of the cases. Thrombomodulin (THBD) gene mutations occur in ∼3-5% of the cases. The risk of aHUS recurrence after kidney transplantation depends on the complement abnormality involved. In all three cases of THBD mutation reported to date, aHUS recurred after kidney transplantation (KT) with early graft loss. No data exist about therapeutic approaches before kidney transplantation to reduce the risk of recurrence in patients carrying this mutation. Favourable data on the use of eculizumab have been reported, in terms of plasmatherapy withdrawal and renal function recovery in aHUS recurrence after KT. To our knowledge, this case report presents the first case of successful kidney transplantation in a patient with aHUS due to THBD mutation who was treated with a single plasma-exchange immediately before surgery without recurrence of the disease 12 months after transplantation.

PGL3 syndrome is caused by mutations in the SDHC gene. At present, only a few families affected by SDHC mutations have been reported in the literature and in each of them the clinical presentation was characterised by paragangliomas located only in the head and neck regions. No evidence of thoracic or abdominal catecholamine-secreting chromaffin tumours has been reported to date. We report the case of a 15-year-old girl with hypertension and a norepinephrine-secreting abdominal paraganglioma who was found to harbour a novel nonsense SDHC mutation, demonstrating that the clinical presentation of PGL3 syndrome can be more diverse than expected.

Background: Sudden onset of nephrotic syndrome after allogeneic stem cell transplantation is rare and has been associated mostly with membranous glomerulonephritis related to chronic graft-versus-host disease (cGVHD). We report a case of nephrotic syndrome and rapidly progressive renal failure occurring in a young woman 3 years after allogeneic stem cell transplantation from her HLA-identical brother. In the renal biopsy, a diffuse mononuclear cell infiltrate was observed. Furthermore, histological analysis, immunofluorescence, and electron microscopy of the kidney specimen defined the diagnosis as minimal change disease, a T-cell-mediated glomerulopathy associated with lymphoproliferative disorders, but that has never been described as an isolated manifestation of cGVHD., Methods: The differential diagnosis was performed by using immunohistochemistry and laser capture microdissection combined with Taq-Man quantitative polymerase chain reaction., Results: Infiltrating mononuclear cells in renal tissue consisted of T cells expressing DNA levels of a Y chromosome-specific gene quantitatively similar to those observed in a male subject, showing that these cells derived from the transplant donor and definitely excluding leukemia relapse. However, the large number of infiltrating T cells allowed the possibility that in this patient, minimal change disease could be related to an atypical form of GVHD., Conclusion: This is the first study to use molecular techniques to show the differential diagnosis of nephrotic syndrome after allogeneic stem cell transplantation. This novel method approach might represent a key tool to characterize kidney infiltrate after allogeneic stem cell transplantation.

In experimental models, the chemokine CXCL10/IP-10 is required for graft failure owing to both acute and chronic rejection. In the present study, pretransplantation sera from 316 cadaver kidney graft recipients were tested for serum CXCL10 and CCL22/MDC levels by an ELISA assay. Kidney graft recipients with normally functioning grafts showed significantly lower serum CXCL10 levels than patients who experienced graft failure, whereas no differences for serum CCL22 levels were observed. After the assignment of all patients to four groups according to serum CXCL10 levels, the death-censored survival rates of grafts were 97.5%, 93.6%, 89.7%, 78.7% (p = 0.0006) at 5 years, while no influence was observed on patient survival. Accordingly, patients with the highest CXCL10 levels showed an increased frequency and severity of rejection episodes. Serum C-reactive protein (CRP) level was also assayed in the same samples. Increase of serum CRP levels represented a predictive parameter for death, but not for graft failure. Multivariate analysis demonstrated that among the analyzed variables, CXCL10 had the highest predictive power of graft loss (RR 2.787). Thus, measurement of pretransplant serum CXCL10 levels might represent a clinically useful parameter to identify subjects who are at high risk of severe rejection and graft failure., (Copyright 2004 Blackwell Munksgaard)

We describe a case in which nodular macroglossia, a very rare type of tongue involvement, was associated with the co-deposition of lambda light chain and beta-2 microglobulin fibrils in the tongue. The combined presence of two different amyloid fibrils did not lead to a more unfavourable clinical outcome. We believe that both these features often remain underdiagnosed and are in fact more frequent than reported. A careful clinical examination of the tongue together with serum immunofixation should be routine in all patients with dialysis-related amyloidosis in order to investigate the prevalence and type of tongue involvement and to rule out other types of amyloidosis. In all cases of suspected mixed amyloidosis, immunohistochemical characterization of fibrils should be carried out by electron microscopy.

Lipid peroxidation (LP) has recently been suggested to trigger the atherosclerotic process as well as to worsen the progression of renal disease. Autoantibodies against oxidized low-density lipoproteins (Ox-LDLAb) were considered to provide a sensitive marker to detect LDL oxidation in vivo. To date few studies have been reported on Ox-LDLAb levels in patients with different degrees of renal failure. The aim of this study was to evaluate the influences of renal function, dietary manipulation, and lipids on Ox-LDLAb concentrations in uremic patients either on conservative or replacement therapy. Seventy-one patients (42 males, 29 females) aged 60 +/- 19 years with chronic renal failure (CRF) of different etiology and degree were divided into four groups according to serum creatinine levels [sCr(mg/dl)] and diet: CRF I > or = 1.5-3.0, CRF II > 3.0-5.5, and CRF III > 5.5 were all patients on a conventional low-protein diet, while a fourth group included patients on a vegetarian diet supplemented with keto analogues and amino acids (CRF SD >3.0). A further group was represented by patients on dialysis therapy. All patients were examined for Ox-LDLAb, triglycerides (TG), total cholesterol, HDL and LDL cholesterol, and apolipoproteins Apo A1, Apo B, and Lp(a). The results were compared with those of 20 controls (9 males and 11 females) aged 52 +/- 11 years with sCr <1.5 mg/dl. Ox-LDLAb increased, although not significantly, with TG and Lp(a) from the early stages of CRF along with the deterioration of renal function. However, TG and Lp(a) levels were significantly higher in all groups of patients except those on vegetarian diet (CRF SD). This group also showed the lowest Ox-LDLAb levels. No relationship was observed between lipids or apolipoproteins and Ox-LDLAb. Hyperlipidemic patients did not show higher Ox-LDLAb levels than normolipidemics. Our results show a progressive increase of LP as the renal function declines, which may account for the increased risk of cardiovascular disease reported in uremia. Dialysis does not correct significantly the oxidative state observed in patients with end-stage renal disease. Vegan diet, by reducing LP, TG, and Lp(a), is supposed to decrease the risk of cardiovascular disease and worth being reconsidered as an alternative effective therapeutic tool in patients with advanced CRF., (Copyright 2001 S. Karger AG, Basel.)

Unlabelled: BACKGROUND. Anti-neutrophil cytoplasmic autoantibodies (ANCA) have been described in patients suffering from systemic vasculitis such as Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and other pathological conditions. In this paper we report a greater incidence of ANCA in hemodialysis patients as compared to peritoneal dialysis patients, pre-dialytic uremic patients and non-renal patients; a possible role for dialysis bioincompatibility in ANCA generation was also investigated., Methods: A total of 335 uremics in substitutive treatment (176 in hemodialytic treatment and 159 in peritoneal dialysis) were examined for ANCA positivity. A total of 189 patients with advanced renal failure in conservative treatment and 100 healthy subjects were used as control. The dialysis techniques were standard hemodialysis (n = 119), low volume hemodiafiltration (n = 26) and hemofiltration (n = 31). ANCA positivity was examined by immunofluorescence (IF): diffuse finely granular staining was considered as classical positive reaction (C-ANCA) and P-ANCA was diagnosed if a perinuclear staining was observed. EIA for proteinase-3 (anti PR-3) and myeloperoxidase-antibodies (anti-MPO) were also performed., Results: In non-renal patients and in patients with pre-dialytic renal insufficiency none were found ANCA positive. In peritoneal dialysis patients all but one were ANCA negative with IF, with all EIA test resulting negative. In hemodialytic patients, a positive IF test was found in 26 (14.7%) for P-ANCA and in 5 (2.8%) for C-ANCA; using the EIA test 23 (13%) patients were positive for MPO and 12 (6.8%) for PR-3., Conclusions: No correlation with age, primary renal diseases, dialytic age, dialysis membrane materials was found; regarding the different extracorporeal dialytic techniques a higher incidence (p < 0.02) was detected in patients undergoing HDF Backfiltration of contaminated dialysate may induce ANCA via an increased cytokine generation.

Lipoprotein abnormalities are common in uraemia and are considered important factors for development of atherosclerosis and progression of renal disease. Reduction of total antioxidant capacity (TAC) and lipid peroxidation (LP) probably play a major role in both processes. The aim of this study was to assess the effect of renal function, dietary manipulation and lipids on TAC of uraemic patients with different chronic renal failure (CRF). Sixty patients (36M, 24F), aged 60 +/- 12 years were divided into five groups according to serum creatinine levels (sCr,mg/dl)--CRFI, 1.5-3; CRFII, > 3-5.5; CRFIII, > 5.5; CRFIV, > 3 on vegetarian supplemented diet (SD); CRFV haemodialysis patients (HD)- and investigated for TAC by enhanced chemiluminescent assay, autoantibodies against oxidized LDL (oxLDLAb), lipids, apolipoprotein AI, B, Lp(a) and uric acid (UA). The results were compared to a control group of 19 people (8M, 11F), aged 52 +/- 11 years with sCr < 1.5. TAC increased significantly with the progression of CRF and was strongly related to both sCr and UA. Lipids and SD did not show any influence on TAC. Unexpectedly, lipid peroxidation did not correlate to TAC, neither to sCr or UA. HD accounted for a mild reduction of both TAC and LP. Patients on SD showed a marked reduction of LP as compared to patients with a similar degree of renal failure (CRF-III) but on conventional diet. Our results suggest that elevated TAC in uraemia is likely to be dependent on increased UA levels and does not seem to induce an effective protection in vivo from oxidative stress. In conclusion, TAC does not appear to be a reliable method for assessing the oxidative susceptibility of CRF patients.

The different mechanisms of acidosis buffering were investigated in 15 RDT patients dialyzed in cross-over with four depurative techniques: acetate dialysis (AD), bicarbonate dialysis (BD), lactate hemofiltration (LHF) and hemodiafiltration (HDF) with acetate bath and lactate reinfusion fluid. Blood pH, bicarbonate, blood gases, intraerythrocytic pH - on red cell hemolisates - anion gap, L-lactate, pyruvate, adenosinmonophosphate (ADP) and 2-3 Diphosphoglycerate (2-3 DPG) levels were evaluated. During AD the intradialytic buffering is initially achieved by the CO2 fall and later by the acetate metabolism and an important bicarbonate shift from the intra to the extracellular space. A physiological compensation is obtained during BD with bicarbonate administration and a mild ventilatory response to the pCO2 increase. In LHF the massive lactate administration, with plasma levels of 7 mmol/l, strongly alters the Central Nervous System elettroneutrality inducing a hyperventilatory response with a purely pulmonary acidosis buffering. Furthermore the lactate/pyruvate ratio rose as high as 40:1 with ADP increase and cellular energy depletion. In HDF several different mechanisms are associated: the CO2 fixation, the acetate muscular metabolism, the intra-extracellular bicarbonate shift with the pulmonary response driven by lactate Central Nervous System penetration.

Outside the central nervous system, calcitonin-gene-related peptide (CGRP) plays an important role in the control of regional blood flow. The present authors studied the renal haemodynamic effects of CGRP in the model of isolated perfused rat kidney (IPRK). This experimental model avoids the complex feed-back mechanisms activated by any modification of renal perfusion pressure. It was found that the infusion of CGRP in the IPRK induced a marked decrease of perfusion pressure; this vasoactive effect is well measured by the glomerular morphometric analysis that shows a striking increase in the glomerular diameter and volume.

Preliminary results of the efficacy of high-dose intravenous human IgG in patients with biopsy-confirmed idiopathic membranous nephropathy (IMGN) were reported. Five patients with normal renal function (creatinine clearance 125.2 +/- 16 ml/min/1.73 m2 BSA) (Group A) and 4 patients with moderate renal insufficiency (creatinine clearance 65.5 +/- 8.3 ml/min/1.73 m2 BSA) (Group B) received pulse doses of IgG (0.4 g/kg BW) for 3 consecutive days; these 3-day boli were repeated 3 times at 21-day intervals; since then for a 10-month period one bolus once every 3 weeks has been administered. Five responder patients at the end of the trial received a new renal biopsy. In 4 Group A patients complete remission of proteinuria (daily proteinuria less than 0.2 g) was observed, whereas 1 patient showed partial remission (proteinuria 2 g/day). In Group B patients, 1 showed complete remission and 2 partial remission; in 1 patient no variation of proteinuria was noted. In responder patients clinical and biological findings of the nephrotic syndrome disappeared and a statistically significant increase of creatinine clearance was observed. In control biopsies at the end of the trial the immunofluorescence staining failed to find immunodeposits and recovery of glomerular lesions at light microscopy. In conclusion, IgG therapy seems to be of benefit to patients with IMGN but a randomized clinical trial to confirm this preliminary report is needed.

The effects (in five therapeutic cycles) of Cisplatin on urinary enzyme excretion (specific markers of tubular damage), fractional excretion of sodium, fractional reabsorption of phosphate, serum Creatinine and creatinine Clearance were assessed in 17 female patients with ovarian carcinoma. An immediate reduction of sodium fractional excretion was observed: this appears a more sensible Cisplatin-nephrotoxicity marker than serum Creatinine and creatinine Clearance. No significant variations were noted in fractional reabsorption of phosphate or urinary Lysozyme and Beta-2-microglobulin but there was a significant increase of other urinary enzymes, confirming the potential nephrotoxicity of DDP treatment.

Forty-one patients with urinary tract infections were randomly assigned to receive for six days gentamicin, amikacin, sisomicin or netilmicin. The dose for each patient was calculated according to creatinine clearance and lean body mass in order to avoid overdosages. Urinary enzymes (alpha-glucosidase, gamma-glutamyltranspeptidase and muramidase), serum creatinine and creatinine clearance, proteinuria and urinary sediment were evaluated for nephrotoxicity. None of the patients developed nephrotoxicity, but urinary enzymes rose significantly in all. The statistical analysis of enzymuria during the treatment permitted the definition of a rank order of the nephrotoxic potential of the aminoglycosides studied.

Renal effects of enalapril maleate in ten hypertensive patients with glomerulonephritis were evaluated after 1 and 16 weeks of therapy. Systemic blood pressure decreased, glomerular filtration rate was not significantly changed, and sodium fractional excretion and renal plasma flow increased, whereas renal vascular resistances and filtration fraction decreased acutely at the end of the study. Proteinuria diminished, but no variations in qualitative pattern were observed. ACE inhibitors, promoting efferent rather than afferent arteriolar vasodilatation and reduction of glomerular permeability coefficient, may reduce glomerular capillary hypertension and the development of proteinuria.