Kidney biopsy for the diagnosis and treatment of kidney diseases. Recommendations from the French speaking Society of Nephrology (SFNDT) and French National Authority for Health (HAS) 2022

Kidney Biopsy (KB) is a crucial diagnostic tool in the field of renal diseases and is routinely performed in nephrology departments. A previous survey conducted by the Société Francophone de Néphrologie Dialyse Transplantation (SFNDT) revealed significant disparities in clinical practices, sometimes conflicting with the existing literature and recently published recommendations. In response, the SFNDT wished to promote the development of best practice guidelines, under the auspices of the French National Authority for Health (HAS), to establish a standardized framework for performing kidney biopsies in France.

La biopsie rénale (BR) est un outil diagnostique crucial dans le domaine des maladies rénales et est pratiquée en routine dans les services de néphrologie. Une précédente enquête menée par la Société francophone de néphrologie, dialyse et transplantation (SFNDT) a révélé d'importantes disparités dans les pratiques cliniques, parfois en contradiction avec la littérature existante et les recommandations récemment publiées. En réponse, la SFNDT a souhaité promouvoir l'élaboration de recommandations de bonnes pratiques, sous l'égide de la Haute Autorité de santé (HAS), afin d'établir un cadre standardisé pour la réalisation des biopsies rénales en France.

The uptake of [18F]-fluorodeoxyglucose by the renal allograft correlates with the acute Banff scores of cortex inflammation but not with the 1-year graft outcomes.

Introduction: [18F]FDG PET/CT noninvasively disproves acute kidney allograft rejection (AR) in kidney transplant recipients (KTRs) with suspected AR. However, the correlation of biopsy-based Banff vs. PET/CT-based scores of acute inflammation remains unknown, as does the prognostic performance of [18F]FDG PET/CT at one year post suspected AR. Methods: From 2012 to 2019, 114 [18F]FDG-PET/CTs were prospectively performed in 105 adult KTRs who underwent per cause transplant biopsies. Ordinal logistic regression assessed the correlation between the extent of histological inflammation and the mean standardized [18F]FDG uptake values (mSUVmean). Functional outcomes of kidney allografts were evaluated at one year post per cause biopsy and correlated to mSUVmean. Results: A significant correlation between mSUVmean and acute Banff score was found, with an adjusted R 2 of 0.25. The mSUVmean was significantly different between subgroups of "total i", with 2.30 ± 0.71 in score 3 vs. 1.68 ± 0.24 in score 0. Neither the function nor the survival of the graft at one year was statistically related to mSUVmean. Discussion: [18F]FDG-PET/CT may help noninvasively assess the severity of kidney allograft inflammation in KTRs with suspected AR, but it does not predict graft outcomes at one year.

Proteinuria in COVID-19: prevalence, characterization and prognostic role.

BACKGROUND: Proteinuria has been commonly reported in patients with COVID-19. However, only dipstick tests have been frequently used thus far. Here, the quantification and characterization of proteinuria were investigated and their association with mortality was assessed. METHODS: This retrospective, observational, single center study included 153 patients, hospitalized with COVID-19 between March 28th and April 30th, 2020, in whom total proteinuria and urinary α1-microglobulin (a marker of tubular injury) were measured. Association with mortality was evaluated, with a follow-up until May 7th, 2020. RESULTS: According to the Kidney Disease Improving Global Outcomes staging, 14% (n = 21) of the patients had category 1 proteinuria (< 150 mg/g of urine creatinine), 42% (n = 64) had category 2 (between 150 and 500 mg/g) and 44% (n = 68) had category 3 proteinuria (over 500 mg/g). Urine α1-microglobulin concentration was higher than 15 mg/g in 89% of patients. After a median follow-up of 27 [14;30] days, the mortality rate reached 18%. Total proteinuria and urinary α1-microglobulin were associated with mortality in unadjusted and adjusted models. This association was stronger in subgroups of patients with normal renal function and without a urinary catheter. CONCLUSIONS: Proteinuria is frequent in patients with COVID-19. Its characterization suggests a tubular origin, with increased urinary α1-microglobulin. Tubular proteinuria was associated with mortality in COVID-19 in our restropective, observational study.

COVID-19-associated Nephropathy Includes Tubular Necrosis and Capillary Congestion, with Evidence of SARS-CoV-2 in the Nephron.

Background: Kidney damage has been reported in patients with COVID-19. Despite numerous reports about COVID-19-associated nephropathy, the factual presence of the SARS-CoV-2 in the renal parenchyma remains controversial. Methods: We consecutively performed 16 immediate (≤3 hours) postmortem renal biopsies in patients diagnosed with COVID-19. Kidney samples from five patients who died from sepsis not related to COVID-19 were used as controls. Samples were methodically evaluated by three pathologists. Virus detection in the renal parenchyma was performed in all samples by bulk RNA RT-PCR (E and N1/N2 genes), immunostaining (2019-nCOV N-Protein), fluorescence in situ hybridization (nCoV2019-S), and electron microscopy. Results: The mean age of our COVID-19 cohort was 68.2±12.8 years, most of whom were male (69%). Proteinuria was observed in 53% of patients, whereas AKI occurred in 60% of patients. Acute tubular necrosis of variable severity was found in all patients, with no tubular or interstitial inflammation. There was no difference in acute tubular necrosis severity between the patients with COVID-19 versus controls. Congestion in glomerular and peritubular capillaries was respectively observed in 56% and 88% of patients with COVID-19, compared with 20% of controls, with no evidence of thrombi. The 2019-nCOV N-Protein was detected in proximal tubules and at the basolateral pole of scattered cells of the distal tubules in nine out of 16 patients. In situ hybridization confirmed these findings in six out of 16 patients. RT-PCR of kidney total RNA detected SARS-CoV-2 E and N1/N2 genes in one patient. Electron microscopy did not show typical viral inclusions. Conclusions: Our immediate postmortem kidney samples from patients with COVID-19 highlight a congestive pattern of AKI, with no significant glomerular or interstitial inflammation. Immunostaining and in situ hybridization suggest SARS-CoV-2 is present in various segments of the nephron.

[Lupus nephropathy: Insight in new treatments]. / La néphropathie lupique : les nouvelles perspectives de traitement.

Systemic lupus erythematosus is a chronic autoimmune disease. Both acquired and innate immune systems are involved in the development of this systemic disease. Lupus nephritis usually is the most serious manifestation of systemic lupus erythematosus, with significant morbidity and mortality. The physiopathological development of the renal involvement of lupus has been increasingly elucidated over the years and various target therapies have recently been developed. After some physiopathological reminders, we discuss the conventional treatment of lupus nephritis as well as the various therapeutic advances, in particular the contribution and the place of the new target therapies in the treatment of the lupus nephritis.

IgG4-related membranous glomerulonephritis and generalized lymphadenopathy without pancreatitis: a case report.

BACKGROUND: IgG4-related disease is a recently described pathologic entity. This is the case of a patient with nephrotic syndrome and lymphadenopathy due to IgG4-related disease. Such a kidney involvement is quite peculiar and has only been described a few times recently. Renal biopsy showed a glomerular involvement with membranous glomerulonephritis in association with a tubulo-interstitial nephropathy. Moreover, the patient was not suffering from pancreatitis. CASE PRESENTATION: The patient is a middle-aged man of Moroccan origin. He has developed recurrent episodes of diffuse lymphadenopathies, renal failure and nephrotic syndrome. Renal biopsies showed membranous glomerulonephritis. DISCUSSION AND CONCLUSION: The diagnostic approach of this atypical presentation is discussed in this case report as well as diagnostic criteria, therapeutic strategies, biomarkers and pathophysiology of IgG4-related disease. IgG4-related membranous glomerulonephritis is a well-established cause of membranous glomerulonephritis. It must be sought after in every patient with a previous diagnosis of IgG4-related disease and in every patient with this histological finding on renal biopsy. Corticoids are still the first-line treatment of IgG4-related disease. New therapeutic strategies are needed to avoid glucocorticoids long term side-effects. Interestingly, the patient was prescribed cyclophosphamide in addition to glucocorticoids for an immune thrombocytopenia. This treatment had a very good impact on his IgG4-related disease.

In-depth phenotyping of a Donnai-Barrow patient helps clarify proximal tubule dysfunction.

BACKGROUND: The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin cause autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/FOAR), which is characterized by LMW proteinuria. The pathophysiology of DB/FOAR-associated PT dysfunction remains unclear. CLINICAL CASE: A 3-year-old girl presented with growth retardation and proteinuria. Clinical examination was unremarkable, except for a still-opened anterior fontanel and myopia. Psychomotor development was delayed. At 6, she developed sensorineural hearing loss. Hypertelorism was noted when she turned 12. Blood analyses, including renal function parameters, were normal. Urine sediment was bland. Proteinuria was significant and included albumin and LMW proteins. Immunoblotting analyses detected cubilin and type 3 carbonic anhydrase (CA3) in the urine. Renal ultrasound was unremarkable. Optical examination of a renal biopsy did not disclose any tubular or glomerular abnormality. Electron microscopy revealed that PT apical endocytic apparatus was significantly less developed. Immunostaining for megalin showed a faint signal in PT cytosol contrasting with the distribution of cubilin at the apical membrane. The diagnostic procedure led to identifying two mutations of the LRP2 gene. CONCLUSIONS: The functional loss of megalin in DB/FOAR causes PT dysfunction characterized by increased urinary shedding of CA3 and cubilin.

Activation of the calcium-sensing receptor before renal ischemia/reperfusion exacerbates kidney injury.

Activation of the calcium-sensing receptor (CaSR) by ischemia/reperfusion (I/R) favours apoptosis in cardiomyocytes, hepatocytes and neurons. Its role in renal I/R is unknown. We investigated the impact of pharmacological preactivation of the CaSR on kidney structure and function in a murine model of bilateral renal 30-min ischemia and 48-hour reperfusion, and in a 6-year cohort of kidney transplant recipients (KTR). C57BL/6J mice were administered daily with CaSR agonist, R-568, or with vehicle for 48 hours. Evaluation of serum urea and creatinine levels, renal histology and urine metabolome by nuclear magnetic resonance showed that R-568 was not nephrotoxic per se. Following I/R, serum urea and creatinine levels increased higher in R-568-treated animals than in controls. Jablonski's score was significantly greater in R-568-treated kidneys, which showed a higher rate of cell proliferation and apoptosis in comparison to controls. Next, we retrospectively identified 36 patients (10.7% of our cohort) who were treated by CaSR agonist, cinacalcet, at the time of kidney transplantation (KTx). After matching these to 61 KTR upon type of donor, cold ischemic time, residual diuresis, and donor age, we observed that delayed graft function, i.e. need for dialysis in the first week after KTx, occurred in 42 and 23% of cinacalcet-treated and control groups, respectively (p≤0.05). These data suggest that pharmacological preactivation of the CaSR before renal I/R exacerbates kidney injury.

Overlap syndrome consisting of PSC-AIH with concomitant presence of a membranous glomerulonephritis and ulcerative colitis.

The association of primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) is known as an overlap syndrome (OS). OS can also be described in the setting of concomitant presence of AIH and PSC. These diseases can in some cases be associated with ulcerative colitis. In this case report we describe, to our knowledge, the first case in the literature of a young Caucasian male suffering from ulcerative colitis and an overlap syndrome consisting of an association between PSC-AIH, with the concomitant presence of a membranous glomerulonephritis.

Two novel mutations of the CLDN16 gene cause familial hypomagnesaemia with hypercalciuria and nephrocalcinosis.

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis is an autosomal-recessive disease caused by mutations in the CLDN16 or CLDN19 genes, which encode tight junction-associated proteins, claudin-16 and -19. The resultant tubulopathy leads to urinary loss of Mg(2+) and Ca(2+), with subsequent nephrocalcinosis and end-stage renal disease (ESRD). An 18-year-old boy presented with chronic kidney disease and proteinuria, as well as hypomagnesaemia, hypercalciuria and nephrocalcinosis. A kidney biopsy revealed tubular atrophy, interstitial fibrosis and segmental sclerosis of some glomeruli. Two novel mutations in the CLDN16 gene were identified: c.340C>T (nonsense) and c.427+5G>A (splice site). The patient reached ESRD at 23 and benefited from kidney transplantation.

Peritoneal equilibration test with conventional 'low pH/high glucose degradation product' or with biocompatible 'normal pH/low glucose degradation product' dialysates: does it matter?

BACKGROUND: The evaluation of the peritoneal transport characteristics is mandatory in peritoneal dialysis (PD) patients. This is usually performed in routine clinical practice with a peritoneal equilibration test (PET) using conventional dialysates, with low pH and high glucose degradation product (GDP) concentrations. An increasing proportion of patients are now treated with biocompatible dialysates, i.e. with physiological pH and lower GDP concentrations. This questions the appropriateness to perform a PET with conventional solutions in those patients. The aim of our study is to compare the results of the PET using biocompatible and conventional dialysates, respectively. METHODS: Nineteen stable PD patients (13 males, 6 females; mean age: 67.95±2.36 years, mean body surface area: 1.83±0.04 m2, dialysis vintage: 2.95±0.19 years) were included, among which 10 were usually treated with biocompatible and 9 with conventional solutions. Two PETs were performed, within a 2-week interval, in each patient. PET sequence (conventional solution first or biocompatible solution first) was randomized in order to avoid 'time bias'. Small (urea, creatinine and glucose), middle (beta-2-microglobulin) and large molecules' (albumin and alpha-2-macroglobulin) dialysate/plasma (D/P) concentration ratios and clearances were measured during each PET. Ultrafiltration (UF) and sodium filtration were also recorded. Results of both tests were compared by the Wilcoxon paired test. RESULTS: No statistical difference was found between both dialysates for small molecule transport rates or for sodium filtration and UF. However, a few patients were not similarly classified for small-solute transport characteristics within the PET categories. Beta-2-microglobulin and albumin D/P ratios at different time points of the PET were significantly higher with the biocompatible, when compared with the conventional, solutions: 0.10±0.03 versus 0.08±0.02 (P<0.01) and 0.008±0.003 versus 0.007±0.003 (P=0.01), respectively. A similar difference was also observed for beta-2-microglobulin that was higher with biocompatible dialysates (1.04±0.32 versus 0.93±0.32 mL/min, respectively). CONCLUSION: Peritoneal transport of water and small solutes is independent of the type of dialysate which is used. This is not the case for the transport of beta-2-microglobulin and albumin that is higher under biocompatible dialysates. Vascular tonus modification could potentially explain such differences. The PET should therefore always be carried out with the same dialysate to make longitudinal comparisons possible.

[Fibrillary nonamyloid glomerulonephritis: a rare etiology of nephrotic syndrome]. / La glomérulonéphrite fibrillaire non amyloïde: une cause rare de syndrome néphrotique.

The fibrillary nonamyloïd glomerulonephritis is a glomerulopathy with fibrillar, nonamyloid deposits of predominantly polyclonal immunoglobulin G. It is an idiopathic glomerulopathy responsible for heavy proteinuria, generally in the nephrotic range, and renal failure up to end stage in 40 % of the cases after five years. The histologic pattern is variable, correlating with renal prognosis. The Congo red-negativity of the deposits and the size of the fibrils on electron microscopy make the differential diagnosis with amyloid deposits. There is no specific efficient therapy. Recurrence in the transplant is frequent, but with better renal prognosis.

Mature erythrocyte parameters as new markers of functional iron deficiency in haemodialysis: sensitivity and specificity.

BACKGROUND: The percentage of hypochromic red blood cells (RBCs) (%HYPO) has been demonstrated as the best predictor of response to iron loading in haemodialysis patients treated with recombinant human erythropoietin (rHuEPO). However, we have previously shown that this parameter is positively influenced by erythropoietic activity since reticulocytes are considered hypochromic by cell counters. New cell counters are able to determine cell volume and haemoglobin (Hb) concentration separately on reticulocytes and mature erythrocytes. The aim of this study was to assess the sensitivity and specificity of mature erythrocyte parameters in detecting functional iron deficiency (FID). METHODS: A total of 32 stable chronic haemodialysis patients in the maintenance phase of rHuEPO therapy were included. Classical parameters of iron monitoring and mature erythrocyte parameters were measured after a 4-week iron-free period. Patients were classified as responders (R) or non-responders (NR) to an iron load of 100 mg iron sucrose at each dialysis session for 4 weeks, according to whether their Hb increased by >1 g/dl at the end of iron loading. RESULTS: Twelve patients were identified as responders. Receiver operating characteristic (ROC) curve analysis demonstrated %HYPO and its corresponding parameter on mature erythrocyte, %HYPOm, as the best predictors of FID. The other parameters were ordered as follows: tranferrin saturation (TSAT), ferritin (FRT), mature RBC Hb content (CHm), mean corpuscular Hb concentration (MCHC), percentage of mature erythrocytes with a low CHm (%lowCHm), mean content in Hb (MCH) and reticulocyte Hb content CHr. Comparing the parameters at different cut-offs, the best sensitivity, specificity and efficiency were demonstrated for %HYPOm> 6%. CONCLUSION: The best efficiency to predict FID was found for %HYPOm> 6%. The predictive value of %HYPO was quite similar. The clinical impact of %HYPOm in iron monitoring should also be tested in the induction phase of rHuEPO treatment because of its independence from erythropoietic activity.

Increased iron absorption during autologous blood donation supported by recombinant human erythropoietin therapy.

BACKGROUND: Recombinant human erythropoietin (rHuEPO) therapy improves the success of autologous blood (AB) donation programs before elective surgery. The aim of this study was to evaluate iron absorption during an AB donation program with or without rHuEPO. STUDY DESIGN AND METHODS: Thirty-two patients were randomly assigned among placebo (Group 1) or 300 (Group 2) or 600 UI per kg rHuEPO (Group 3) on the first, second, and third donation visits. All patients also received daily oral iron (200 mg Fe(+)). RESULTS: The number of units collected in Group 3 was higher than in Group 1 (4.6 +/- 0.5 vs. 3.6 +/- 0.8 units; p < 0.01). Red blood cell (RBC) production increased in a rHuEPO dose-dependent manner. With rHuEPO, the RBC volume collected per unit presented a lower decrease with number of donated units than with placebo and was similar to that of homologous blood units. Storage iron did not influence the number of units collected, whereas circulating mobilizable iron was the limiting factor. Oral iron absorption increased in a rHuEPO dose-dependent manner (12-fold with 600 UI/kg rHuEPO) and was proportional to erythropoietic activity. CONCLUSION: rHuEPO does not only improve the number of AB units collected but also their quality. Storage iron cannot meet marrow iron requirements, but rHuEPO strongly increased oral iron absorption in a dose-dependent fashion through stimulation of erythropoietic activity.

Mature erythrocyte indices: new markers of iron availability.

This study was aimed at evaluating mature erythrocyte indices as new markers of iron status. Contrarily to those in the whole red blood cell (RBC) population, mature erythrocyte parameters are valid markers of iron status that remain independent of erythropoietic activity. When reticulocytosis is low, these parameters are similar to whole RBC parameters.

Impact of erythropoietic activity on red cell parameters in chronic renal failure patients.

We measured red cell parameters during recombinant human erythropoietin (rHuEPO) therapy associated with appropriate iron supplementation in chronic hemodialysis patients. Increased erythropoietic activity led to a bias in red cell parameter determination. The percentage of hypochromic red blood cells, usually used as the most effective predictor of response to iron supplementation, increased following the appearance of a younger red cell population since the same Hb content in these younger, larger cells gives a lower Hb concentration.

Comparison of plasma cardiac troponins T and I in chronically hemodialyzed patients in relation to cardiac status and age.

Cardiac troponins (cTnT and cTnI) are useful tools for risk stratification in patients with unstable angina. However, their value in patients with renal failure has been questioned. In this study, we determined cTnT and cTnI at 3-month intervals during 9 months in 97 chronic renal failure (CRF) patients treated with hemodialysis. cTnT was measured using a third generation immunoassay and cTnI by fluorimetric immunoassay with a detection limit similar to that of cTnT (0.01 microg/l). In the renal patients without coronary heart disease (CHD(-) group), cTnT was more frequently elevated above cut-off for acute myocardial infarction (AMI) (up to 21.6%) than cTnI (no patient). In the absence of CHD, cTnT levels were positively correlated to age, and more than half of the CHD(-) patients aged over 60 years had cTnT levels above the upper reference limit (URL) of 0.04 microg/l (0.059+/-0.042 microg/l). cTnI increased with age in parallel to cTnT but mean levels did not exceed the URL of 0.08 microg/l in the CHD(-) patients aged over 60 years (0.036+/-0.031 microg/l). In the patients with documented cardiac events (CHD(+)) we found higher troponin levels than in the CHD(-) patients of the corresponding age, but for cTnl the differences between CHD(+) and CHD(-) patients were significant in the patients aged < or =60 years only (0.049+/-0.054 vs. 0.019+/-0.018 microg/l, p<0.05). For cTnT, the differences between patients with and without coronary events also tended to be less important in the eldest patients. There was a significant correlation between cTnI and cTnT levels in the CHD(-) and in the CHD(+) groups. Changes in the plasma levels of cardiac troponins are common in hemodialysis patients in the absence of CHD, and advanced age appears to amplify these changes. The reason could be that most hemodialysis patients with advanced age have subclinical lesions and demonstrate release characteristics of troponins that compare to those in patients with symptomatic coronary events. Therefore, it will be important to analyze troponin elevations above the URL or above the cut-off concentration for AMI in asymptomatic renal patients in relation to prognosis.