Síndrome nefrótico secundario en neurofibromatosis tipo 1. A propósito de dos casos / Secondary glomerulonephritis in neurofibromatosis type 1. Two case reports

La Neurofibromatosis tipo I (NF-1) es un desorden neurocutáneo, con clínica multisistémica de tipo autosómica dominante de diagnóstico clínico. Hay escasas publicaciones sobre la afectación rwnal de esta enfermedad, siendo la patología vascular renal y los tumores suprarrenales, la forma de afectación renal más frecuente, y excepcional los casos descritos de afectación glomerular. Presentamos dos casos de síndrome nefrótico en pacientes con diagnóstico de NF-1. El primer caso, la paciente es una mujer de 41 años, diagnosticada de NF-1 durante el estudio de un síndrome nefrótico córtico-resistente, con diagnóstico de cambios mínimos. El segundo caso es una mujer de 71 años con antecedente de NF-1, con un síndrome nefrótico y una amiloidosis renal secundaria. A pesar de la escasez de información publicada actualmente sobre ello, se ha sugerido una posible asociación entre la NF-1 y el síndrome nefrótico, debida a mecanismos moleculares comunes en ambas patologías. Destacamos la importancia de estudiar un origen primario tratable del síndrome nefrótico

Neurofibromatosis type 1 (NF-1) is an autosomal dominant neurocutaneous disorder with systemic clinical manifestations. There are few publications about the renal effects of this disease, with renal vascular disease and adrenal tumors being the most frequent forms of renal involvement, while cases describing glomerular effects are exceptional. Despite the lack of published information, common molecular mechanisms in both NF-1 and nephrotic syndrome, involving the mTOR pathway, were suggested to explain a possible association between both pathologies. We present two cases of renal involvement in the form of nephrotic syndrome in patients diagnosed with NF1. A 41-year-old female was diagnosed of NF-1 in the context of a nephrotic syndrome with resistance to steroid treatment; the renal biopsy revealed a diagnosis of minimal changes disease. The second case is other 71-year-old woman with a history of NF-1, who presented a nephrotic syndrome and secondary renal amyloidosis

Proteinuria typing: how, why and for whom?

The typing of proteinuria is one of the complementary examinations carried out during the exploration of proteinuria. It aims to separate and identify the different proteins, or fractions of proteins, that make up proteinuria. The nature and relative importance of the proteins present reflect the location of the renal involvement and help to determine the etiology. The typing of a proteinuria also allows the detection of a monoclonal component in urine and its quantification. Finally, it allows highlighting the existence of a proteinuria of overload that can occur in the absence of kidney damage. Many methods allow the typing of proteinuria, and these have benefited in recent years from technological advances. The purpose of this review is to summarize typing methods currently used, their benefits and limitations, and the help that these diagnostic tools can provide to the management of patients.

Generation of a Core Set of Items to Develop Classification Criteria for Scleroderma Renal Crisis Using Consensus Methodology.

OBJECTIVE: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS: An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. RESULTS: Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSION: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.

[Preeclampsia: New Classifications]. / Präeklampsie: neue Definitionen.

Preeclampsia: New Classifications Abstract. Preeclampsia is a multisystem disease leading to systemic impairment of the maternal endothelial function. A dysbalance of pro- and antiangiogenic factors appears to be significantly involved. The vascular disease leads to the manifestation of symptoms such as arterial hypertension and involvement of end organs such as kidney, liver and brain. The classical diagnostic criterion for arterial hypertension, 'proteinuria' has been downgraded and is no longer obligatory for diagnosis, if other criteria, as maternal organ dysfunction or intrauterine growth retardation, are present. In addition, white-coat hypertension has been included in the classification of hypertension in pregnancy. To classify preeclampsia as 'mild' is being discouraged in the clinical setting to account for the possibility of rapid worsening with significant danger for mother and foetus.

The diagnosis of pre-eclampsia using two revised classifications in the Finnish Pre-eclampsia Consortium (FINNPEC) cohort.

BACKGROUND: The Finnish Pre-eclampsia Consortium (FINNPEC) case-control cohort consisting of 1447 pre-eclamptic and 1068 non-pre-eclamptic women was recruited during 2008-2011 to study genetic background of pre-eclampsia and foetal growth. Pre-eclampsia was defined by hypertension and proteinuria according to the American College of Obstetricians and Gynecologists (ACOG) 2002 classification. The ACOG Task Force Report on Hypertension in Pregnancy (2013) and The International Society for the Study of Hypertension in Pregnancy (ISSHP) (2014) have published new classifications, in which proteinuria is not necessary for diagnosis when specific symptoms are present. For diagnoses based on proteinuria, the ISSHP 2014 criteria raised its threshold to 2+ on dipstick. We studied how the new classifications would affect pre-eclampsia diagnoses in the FINNPEC cohort. METHODS: We re-evaluated pre-eclampsia diagnosis using the ACOG 2013 and the ISSHP 2014 classifications in pre-eclamptic women whose proteinuria did not exceed 1+ on dipstick (n = 68), in women with gestational hypertension (n = 138) and in women with chronic hypertension (n = 66). RESULTS: The number of women with pre-eclampsia increased 0.8 % (1459/1447) according to the ACOG 2013 criteria and 0.6 % (1455/1447) according to the ISSHP 2014 criteria. All 68 women with the amount of proteinuria not exceeding 1+ on dipstick diagnosed originally pre-eclamptic met the ACOG 2013 criteria but only 20 women (29.4 %) met the ISSHP 2014 criteria. Seven (5.1 %) and 35 (25.4 %) women with gestational hypertension were diagnosed with pre-eclampsia according to the ACOG 2013 and the ISSHP 2014 criteria, respectively. Correspondingly five (7.6 %) and 21 (31.8 %) women with chronic hypertension were diagnosed with pre-eclampsia according to the ACOG 2 013 and the ISSHP 2014 criteria. CONCLUSIONS: Only minor changes were observed in the total number of pre-eclamptic women in the FINNPEC cohort when comparing the ACOC 2002 classification with the ACOG 2013 and ISSHP 2014 classifications.

Validation of chronic kidney disease risk categorization system in Chinese patients with kidney disease: A cohort study.

AIM: To validate the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines risk stratification system based on the combination of estimated glomerular filtration rate (eGFR) and proteinuria. METHODS: This was a cohort study. A total of 1219 study population were recruited. Estimated GFR and proteinuria measured by using 24 h urine protein excretion rate (PER) were predictors. Adverse outcomes included all-cause mortality (ACM) and end-stage renal disease (ESRD). Follow-up was done by regular visit, telephone interview and electronic medical records. RESULTS: Over a median follow-up of 4.6 years, 153 (12.6%) and 43 (3.5%) patients experienced ESRD and ACM, respectively. On multivariable analysis, the adjusted hazard ratio for ESRD and ACM (compared with patients with eGFR > 60 mL/min per 1.7 m²) was of 29.8 and 3.6 for those with eGFR of 15-29 mL/min per 1.73 m², respectively. The adjusted hazard ratio for ESRD and ACM (compared with patients with PER < 150 mg/24h) was of 15.9 and 3.9 for those with PER > 500 mg/24h. Higher KDIGO guidelines risk categories (indicating lower eGFR or higher proteinuria) were associated with a graded increase in the risk for the ESRD (P < 0.001) and ACM (P < 0.001). Reclassification of KDIGO guidelines risk categories yielded net reclassification improvements for those with ESRD or ACM event (NRIevents ) of 33.3% or 30.2%. CONCLUSION: Lower eGFR and higher proteinuria are risk factors for ESRD and ACM in Chinese patients. The KDIGO guidelines risk categorization system assigned patients who went on to have the event to more appropriate CKD risk categories.

Urinary serum- and glucocorticoid-inducible kinase SGK1 reflects renal injury in patients with immunoglobulin A nephropathy.

AIM: Serum- and glucocorticoid-inducible kinase SGK1 functions as an important regulator of transepithelial sodium transport by activating epithelial sodium channel in renal tubules. Considerable evidence demonstrated that SGK1 was associated with hypertension and fibrosing diseases, such as diabetic nephropathy and glomerulonephritis. The present study was performed to evaluate the role of SGK1 played in immunoglobulin A (IgA) nephropathy. METHODS: Seventy-six patients of biopsy-proven IgA nephropathy and 33 healthy volunteers were enrolled in this study. All patients and healthy volunteers' urinary and serum samples were tested for SGK1 expression by indirect enzyme-linked immunosorbent assay. Meanwhile all patients' renal tissues were semi-quantified for SGK1 expression by immunohistochemistry assay. The relationships between SGK1 expressions and clinical or pathological parameters were also assessed. RESULTS: SGK1 expression was upregulated in urine and renal tubules in patients of Oxford classification T1 and T2, whereas its expression in serum did not increase significantly. Relationship analysis indicated that urinary and tissue SGK1 expressions were associated with heavy proteinuria and renal insufficiency in patients with IgA nephropathy. On the other hand, RAS blockades would reduce the SGK1 levels both in urine and renal tissues. CONCLUSION: These results suggested that urinary SGK1 should be a good indicator of tubulointerstitial damage in patients of IgA nephropathy. SGK1 expressions in urine and renal tissues were associated with the activity of renin-angiotensin-aldosterone system.

Podocyte involvement in lupus nephritis based on the 2003 ISN/RPS system: a large cohort study from a single centre.

OBJECTIVE: The podocyte lesion in LN is still an intriguing controversy. We assess the associations between podocyte lesions and clinico-pathological features in a large cohort of LN patients. METHODS: The clinico-pathological data of 202 patients with renal biopsy-proven LN were retrospectively studied. The degree of podocyte lesions was assessed morphologically and its correlations with clinico-pathological parameters were further analysed. RESULTS: The podocyte foot processes of most LN patients significantly effaced, reflected by the median foot process width (FPW) of 1397.39 nm, and 13 patients met the histological criteria of lupus podocytopathy. The FPW was correlated with proteinuria (r = 0.509, P < 0.001) and the cut-off value of FPW, >1240 nm, could differentiate nephrotic proteinuria from non-nephrotic proteinuria with sensitivity 81.5% and specificity 62.7%. The FPW varied significantly with different types of LN, and the patients with combined LN presented with the most severe lesions. The complete remission rate was significantly higher and the long-term renal outcome was better in the group with calcineurin inhibitors than that with other regimens in patients with FPW >1240 nm. CONCLUSION: Podocyte damage was common in LN. Pure lupus podocytopathy might act as an extreme form of lupus podocyte lesion, and more patients might present with severe podocyte effacement concealed in different types of LN, which needs further investigation.

Classification of human immunodeficiency virus-infected patients with chronic kidney disease using a combination of proteinuria and estimated glomerular filtration rate.

BACKGROUND: In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) updated the 2002 Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guideline for chronic kidney disease (CKD). The 2012 KDIGO guideline elaborated the identification and prognosis of CKD by combining albuminuria with estimated glomerular filtration rate (eGFR). Identification of CKD with a high risk for a poor prognosis was investigated in human immunodeficiency virus (HIV)-infected individuals by applying the new guideline. METHODS: A total of 1,447 HIV-infected patients (1,351 male, 96 female; mean age 44.4 ± 11.5 years) were classified using a combination of eGFR and dipstick proteinuria, as a convenient alternative to albuminuria. Proteinuria was classified into 3 grades-(A1) - and +/- , (A2) 1+ and 2+ , and (A3) 3+ and 4+. eGFR was classified into 6 grades-(G1) ≤90, (G2) 60-89, (G3a) 45-59, (G3b) 30-44, (G4) 15-29, and (G5) <15 mL/min/1.73 m(2). RESULTS: Mean CD4 cell count was 487 ± 214 /µL, with 80.7 % of patients having an undetectable HIV-RNA level. The prevalence of CKD stage ≤2 and stage ≥3 classified according to KDOQI staging was 93.4 and 6.6 %, respectively. Using the new KDIGO classification, the prevalence of CKD with either a low (green) or moderately increased (yellow) risk was 96.9 %, while the prevalence for a high (orange) and very high (red) risk was 3.1 %. CONCLUSION: The use of the new KDIGO classification may reduce the prevalence of HIV-infected CKD individuals who are at high risk for a poor prognosis by nearly a half.

[Feasibility of SLEDAI-2000 and BILAG-2004 scoring systems for assessing renal disease activity in children with lupus nephritis].

OBJECTIVE: To study feasibility of Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2000) and British Isles Lupus Assessment Group 2004 (BILAG-2004) scoring systems for assessing renal disease activity in children with lupus nephritis (LN). METHODS: The clinical data of 159 children with systemic lupus erythematosus (SLE) and LN were collected, and disease activity was assessed by SLEDAI-2000 and BILAG-2004 scoring systems. The correlations between SLEDAI-2000 and BILAG-2004 scores and 24-hour urinary protein excretion and renal pathology index were analyzed. The SLEDAI-2000 and BILAG-2004 scoring systems were evaluated using ROC curve. RESULTS: Approximately one third (31.5%) of the 159 children had a moderate level of 24-hour urinary protein excretion. Among the 37 patients undergoing renal biopsy, 46.0% had diffuse LN (type Ⅳ). 24-hour urinary protein excretion was positively correlated with both SLEDAI-2000 (r=0.36, P<0.05) and BILAG-2004 scores (r= 0.39, P<0.05). Children with types Ⅰ, Ⅱ, Ⅲ, and Ⅳ LN had pathology activity index (AI) which positively correlated with SLEDAI-2000 scores (r=0.86, 0.88, 0.84, 0.77 respectively; P<0.05) and BILAG-2004 scores (r= 0.88, 0.98, 0.86, 0.89 respectively; P<0.05). SLEDAI-2000 score showed the best correlation with AI in patients with type Ⅱ LN, followed by those with type Ⅰ LN. BIILAG-2004 score showed the best correlation with AI in patients with type Ⅱ LN, followed by those with type Ⅳ LN. The BILAG-2004 scoring system had an area under the ROC curve (AUC) of 0.93, and the SLEDAI-2000 scoring system had an AUC of 0.88. CONCLUSIONS: BILAG-2004 and SLEDAI-2000 scoring systems can be used to assess renal disease activity of patients with LN. The BILAG-2004 scoring system can provide more reliable and comprehensive assessment.

Exploratory study of proteins in urine of patients with histoplasma antigenuria.

Disseminated histoplasmosis is an invasive fungal infection that can be fatal in patients with weak immune system. The goal of our exploratory study was to evaluate differences in urinary protein profiles among samples of healthy individuals, patients with proteinuria (PRU), and histoplasma antigenuria (HIS), and to identify physiological pathways associated with the excreted proteins. Urine samples were depleted of abundant proteins, deglycosylated, digested with trypsin, fractionated and analyzed by nano-LC-QTOF. The total number of human proteins identified in the samples was 117, of which 20 and 23 were unique to the samples from patients with PRU and HIS, respectively. Pathway analysis of proteins identified in samples of PRU and HIS patients suggested increased levels of proteins associated with acute response signaling, coagulation system, prothrombin activation, glucocorticoid regulation and the lipid antigen presentation signaling pathway networks. The obtained data provide information on protein expression associated with HIS, and suggest that further more rigorous studies aimed at the identification of proteins associated with proteinuria of different causes are feasible.

The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults.

To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.

[Detection and estimation of chronic kidney disease]. / Détection et estimation du niveau de la maladie rénale chronique.

The prevalence of chronic kidney disease is increasing. An early and precise diagnosis of renal insufficiency requires a measurement of the glomerular filtration rate. Formulas based on serum creatinine to determine the glomerular filtration rate have brought, compared to serum creatinine alone, an improvement in this precision. However, in many clinical conditions, they may give incorrect information. Using 24 h urine collection, calculation of creatinine clearance can be more adequate and accurate in conditions where patient's anthropometric characteristics are far from the normal range. However, this 24 h urine collection is often variable and its validity could be criticized. When a very precise determination of glomerular filtration rate is needed, a method of reference is required such as that using chrome EDTA or iohexol. Each nephrological exploration also needs a urine analysis for detection of proteinuria. When a positive urine dipstick test is noted, a quantification of proteinuria must be done either after 24 h urine collection or more easily by determining the proteinuria/creatininuria ratio on an urine sample.

Reliability of different expert systems for profiling proteinuria in children with kidney diseases.

This study was designed to compare three urinary protein expert systems for profiling proteinuria in children with kidney diseases. Freshly voided urine specimens were collected from 61 children with glomerular diseases, 19 children with tubular diseases and 25 healthy children aged 3-16 years. The urinary protein expert systems were: (1) albumin/total protein ratio (APR), (2) alpha-1-microglobulin/alpha-1-microglobulin + albumin algorithm (AAA), and (3) the complex urine protein expert system (UPES, PROTIS) algorithm. APR correctly identified glomerular proteinuria in 47/61 children, tubular proteinuria in 16/19 children and normal proteinuria in 23/25 healthy children. AAA correctly identified glomerular proteinuria in 61/61 children and tubular proteinuria in 18/19 children, and 25/25 healthy children were characterized as having no abnormal proteinuria. AAA was not influenced by the stage of chronic kidney disease. UPES differentiated the type of proteinuria in children with glomerular diseases into glomerular (50/61 patients) and mixed glomerulo-tubular (6/61 patients). Tubular proteinuria was identified in 16/19 patients and described as mixed glomerulo-tubular proteinuria in 3/19 patients. Mixed glomerulo-tubular proteinuria was found only in children with chronic kidney disease stages 2-5 of glomerular and tubular diseases. In conclusion, the AAA and UPES had the highest accuracy levels.

Urinary proteomics.

Protein measurement in urine has been used for many years for the diagnosis and monitoring of renal disease. The pattern of urinary protein excretion can be used to identify the cause of the disease and to classify proteinuria. In recent years, proteomics has proven to be a powerful tool in investigation and clinical medicine. Proteomics employs a protein separation method and the identification of proteins using mass spectrometry. One of the objectives of clinical proteomics is the identification of biological markers of disease. To accomplish this, it is necessary to have a normal proteome of the medium in question, which in our case is urine. Comparison of the normal urinary proteome with the urinary proteome from patients with a defined disease can detect proteins expressed differentially from one another. The aim of this review is to present the situation of urinary proteomics, putting special emphasis on its application in the diagnosis of glomerular diseases, renal allograft rejection, urological cancers and urolithiasis.

Idiopathic membranous nephropathy in children.

Idiopathic membranous nephropathy (MN) is a rare cause of asymptomatic proteinuria (AP) or nephrotic syndrome (NS) in childhood. To improve our understanding of its clinical course, we retrospectively reviewed 19 cases of idiopathic MN seen in our hospital over a period of 28.5 years, i.e., from January 1977 to July 2005. Eight patients (39%) had AP and 11 (61%) presented with NS. All eight AP patients achieved remission, regardless of treatment modality. Oral corticosteroid was given to all 11 NS patients, but only three of them responded to corticosteroid. Of the eight steroid non-responders, three achieved remissions with the addition of cyclosporine, and the five who were not administered additional immunosuppressive drugs had persistent NS. At the latest evaluation, all six NS patients that achieved remission remained free of proteinuria and had a normal renal function. Moreover, two of the 5 steroid non-responders showed persistent nephrotic-range proteinuria but a stable renal function. The remaining three steroid non-responders progressed into chronic renal insufficiency, and this progression was preceded by renal vein thrombosis (RVT) in two of the three patients. Presentation with NS (P=0.045) and the development of RVT (P=0.010) were identified as poor prognostic factors.

[Proteinuria]. / Protéinurie.

Several health organizations recommend that people be regularly checked for proteinuria to detect and treat kidney disease before it progresses. Proteinuria detected by a simple dipstick test should be confirmed by a quantitative measurement to assess persistent proteinuria. Most proteins are too big to pass through the kidneys' filters into the urine unless the kidneys are damaged. Markers of kidney damage in addition to proteinuria include abnormalities in the urine sediment, ultrasound of the kidneys and estimation of kidney function (creatinemia to calculate glomerular filtration rate). These assessments provide clues to the type (diagnosis) of chronic kidney disease and will the risk for developing progressive kidney failure. Thus, early detection of kidney disease will result in a more timely introduction of therapy that may slow the course of kidney disease. Microalbuminuria (albumin excretion above the normal range) that a marker of microvascular lesions in diabetes and hypertension is associated with a worth cardiovascular prognosis. Level of proteinuria in excess of 3,0 g/d in glomerular disease strongly determines the extent of kidney damage and renal prognosis.