The relationship between histopathological features, immunosuppression and outcome in patients undergoing native kidney biopsies.

AIMS: To assess retrospectively the association between histopathological lesions on renal biopsy and subsequent impairment of renal function across the spectrum of kidney diseases and to explore the influence of immunosuppressive therapy within the first 6 months after biopsy on this association. METHODS AND RESULTS: Clinical data from 488 adult patients having a renal biopsy reported at a single centre from 2017 to 2019 were obtained during a median follow-up period of 786 days. Seventeen semi-quantitative histology parameters were recorded at the time of biopsy, 14 of which were suitable for assessment of association with loss of eGFR by multivariable Cox regression analysis, measurement of eGFR slope and measurement of eGFR 12 months after biopsy. A widely used histopathological chronicity score was also assessed. Clinical baseline variables including prescription of immunosuppression were recorded. Seven of 14 histology parameters: mesangial matrix expansion, global glomerulosclerosis, tubular atrophy, interstitial fibrosis, arteriolosclerosis, mesangial hypercellularity and acute tubular injury; and the chronicity score, predicted loss of kidney function by all three measures. Prescription of immunosuppression was more likely in patients with active inflammatory pathology and less likely in patients with chronic fibrotic pathology, and was associated with reduced risk of loss of eGFR. CONCLUSIONS: This retrospective study demonstrates the prognostic significance and complex relationship with immunosuppression of routinely reported histopathological variables in patients having native kidney biopsies, across the spectrum of kidney diseases. It provides useful information for renal biopsy prognostication and design of retrospective studies, including machine learning models.

Salt loading decreases urinary excretion and increases intracellular accumulation of uromodulin in stroke-prone spontaneously hypertensive rats.

Uromodulin (UMOD) is the most abundant renal protein secreted into urine by the thick ascending limb (TAL) epithelial cells of the loop of Henle. Genetic studies have demonstrated an association between UMOD risk variants and hypertension. We aimed to dissect the role of dietary salt in renal UMOD excretion in normotension and chronic hypertension. Normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) (n=8/sex/strain) were maintained on 1% NaCl for 3 weeks. A subset of salt-loaded SHRSP was treated with nifedipine. Salt-loading in SHRSP increased blood pressure (ΔSBP 35 ± 5 mmHg, P<0.0001) and kidney injury markers such as kidney injury marker-1 (KIM-1; fold change, FC 3.4; P=0.003), neutrophil gelatinase-associated lipocalin (NGAL; FC, 2.0; P=0.012) and proteinuria. After salt-loading there was a reduction in urinary UMOD excretion in WKY and SHRSP by 26 and 55% respectively, compared with baseline. Nifedipine treatment reduced blood pressure (BP) in SHRSP, however, did not prevent salt-induced reduction in urinary UMOD excretion. In all experiments, changes in urinary UMOD excretion were dissociated from kidney UMOD protein and mRNA levels. Colocalization and ex-vivo studies showed that salt-loading increased intracellular UMOD retention in both WKY and SHRSP. Our study provides novel insights into the interplay among salt, UMOD, and BP. The role of UMOD as a cardiovascular risk marker deserves mechanistic reappraisal and further investigations based on our findings.

Diagnostic and prognostic significance of extent of subepithelial electron dense deposits in membranous glomerulonephritis.

There are limited data concerning the range and diagnostic significance of the extent of subepithelial electron dense deposits (SEEDD) in membranous glomerulonephritis (MGN). We described the range, and assessed the diagnostic and prognostic significance of extent of SEEDD, particularly in patients with sparse SEEDD, where diagnostic difficulty can arise. Adult renal biopsies with a confident or suspected histological diagnosis of MGN between 2013 and 2020 were included. Patients were classified based on extent of SEEDD as having either global MGN (GMGN, >75% SEEDD), segmental MGN (SMGN, 25%-75% SEEDD), or sparse-SEEDD (<25% SEEDD). Clinical and other features were compared. One hundred and eleven (74%) patients had GMGN; 23 (15%) had SMGN; and 16 (11%) had sparse-SEEDD. Patients with sparse-SEEDD had a significantly shorter duration of nephrotic syndrome prior to biopsy. 53% of patients with GMGN and 14% with SMGN had serum anti-phospholipase A2 receptor (PLA2r) antibodies. Patients with sparse-SEEDD did not have anti-PLA2r antibodies. Urine protein:creatinine ratio was significantly lower in sparse-SEEDD patients after 3, 6, 9, and 12 months. The proportion of sparse-SEEDD patients in complete remission from nephrotic range proteinuria at 6 and 12 months was significantly higher than that of GMGN patients. Analysis of a subgroup suggested sparse-SEEDD patients responded more rapidly to steroid containing immunosuppression than GMGN patients. There is a wide range of extent of SEEDD in patients with MGN. Sparse-SEEDD appears distinct from SMGN and GMGN and may be either an early form of MGN, or an epiphenomenon associated with another primary disease process, particularly minimal change disease.

Predicting outcome in acute interstitial nephritis: a case-series examining the importance of histological parameters.

AIMS: The clinical significance of common histological parameters in acute interstitial nephritis (AIN) is uncertain. We aimed to evaluate the utility of histology in predicting clinical outcomes in patients with AIN. METHODS AND RESULTS: Adult renal biopsies yielding a diagnosis of AIN between 2000 and 2015 were re-examined. Patients were divided into groups based on: (i) the percentage of non-fibrotic cortex containing inflammation (NFI score) (NFI-1 = 0-24%; NFI-2 = 25-74%; NFI-3 = 75-100%) and (ii) the percentage of cortex containing tubular atrophy (TA score) (TA1 = 0-9%; TA2 = 10-24%; TA3 = 25-100%). The primary outcome was a composite of ≥50% reduction in serum creatinine (sCr) or an estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m2 1 year post-biopsy. From a total of 2817 native renal biopsies, there were 120 patients with AIN and adequate data for analysis. Of these, 66 (56%) achieved the primary outcome. On univariable logistic regression, NFI-3 was associated with a 16 times increased likelihood of achieving the primary outcome compared to NFI-1 [odds ratio (OR) = 16, 95% confidence interval (CI) = 5.2-50)]. In contrast, TA3 was associated with a 90% reduced likelihood of achieving the primary outcome compared to TA1 (OR = 0.10, 95% CI = 0.0-0.3). Maximal clinical utility was achieved by combining TA and NFI into a single prognostic 'TANFI' score, which had an independent predictive effect on the primary outcome in a multivariable regression model consisting of age, sex, baseline sCr and identified drug cause. CONCLUSIONS: In patients with biopsy-proven AIN, a lower percentage of cortical tubular atrophy and, paradoxically, a higher percentage of inflammation in non-fibrosed cortex were associated with an increased likelihood of a positive clinical outcome.

Reproducibility of the Oxford classification of immunoglobulin A nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the VALidation of IGA study cohort.

BACKGROUND: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. RESULTS: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). CONCLUSION: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.

Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort.

BACKGROUND: There is a need for early identification of children with immunoglobulin A nephropathy (IgAN) at risk of progression of kidney disease. METHODS: Data on 261 young patients [age <23 years; mean follow-up of 4.9 (range 2.5-8.1) years] enrolled in VALIGA, a study designed to validate the Oxford Classification of IgAN, were assessed. Renal biopsies were scored for the presence of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1-2) (MEST score) and crescents (C1). Progression was assessed as end stage renal disease and/or a 50 % loss of estimated glomerular filtration rate (eGFR) (combined endpoint) as well as the rate of renal function decline (slope of eGFR). Cox regression and tree classification binary models were used and compared. RESULTS: In this cohort of 261 subjects aged <23 years, Cox analysis validated the MEST M, S and T scores for predicting survival to the combined endpoint but failed to prove that these scores had predictive value in the sub-group of 174 children aged <18 years. The regression tree classification indicated that patients with M1 were at risk of developing higher time-averaged proteinuria (p < 0.0001) and the combined endpoint (p < 0.001). An initial proteinuria of ≥0.4 g/day/1.73 m2 and an eGFR of <90 ml/min/1.73 m2 were determined to be risk factors in subjects with M0. Children aged <16 years with M0 and well-preserved eGFR (>90 ml/min/1.73 m2) at presentation had a significantly high probability of proteinuria remission during follow-up and a higher remission rate following treatment with corticosteroid and/or immunosuppressive therapy. CONCLUSION: This new statistical approach has identified clinical and histological risk factors associated with outcome in children and young adults with IgAN.

Kidney biopsy findings in primary Sjögren syndrome.

BACKGROUND: Renal involvement is rare in primary Sjögren syndrome (PSS). In this study, we examined renal biopsy findings in patients with PSS and correlated them with their clinical and renal findings. METHODS: Twenty-five patients with PSS who underwent renal biopsies from two renal units in Scotland between 1978 and 2013 were identified from renal biopsy database. We examined the renal morphologic, clinical and renal findings at the time of renal biopsy, renal and patient outcomes. RESULTS: The diagnosis of PSS preceded renal biopsy in 18/25 patients. In this group, the median duration of the disease was 5.5 years. Significant proteinuria, combined microscopic haematuria and proteinuria and reduced renal excretory function were found in 76, 56 and 84% of patients, respectively. The 3-year actuarial patient survival was significantly lower in patients with glomerulonephritis as compared with tubulointerstitial nephritis (66 versus 100%, P = 0.02). There was no difference in 3-year actuarial renal survival between these two groups (92 versus 92%, P = 1.0). CONCLUSIONS: Renal biopsy is rare in PSS and often reveals diverse pathological findings. Glomerulonephritis, as compared with tubulointerstitial nephritis, is associated with higher early mortality. Further studies are needed to evaluate the utility of renal biopsy and its impact on disease management.

MicroRNA-214 antagonism protects against renal fibrosis.

Renal tubulointerstitial fibrosis is the common end point of progressive renal disease. MicroRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the function of miR-214 in this setting and the effect of its manipulation remain unknown. We assessed the effect of inhibiting miR-214 in an animal model of renal fibrosis. In mice, genetic deletion of miR-214 significantly attenuated interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects, and in vivo biodistribution studies demonstrated that anti-miR-214 accumulated at the highest levels in the kidney. Notably, in vivo inhibition of canonical TGF-ß signaling did not alter the regulation of endogenous miR-214 or miR-21. Whereas miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, suggesting that miR-214 induces antifibrotic effects independent of Smad 2/3. Furthermore, TGF-ß blockade combined with miR-214 deletion afforded additional renal protection. These phenotypic effects of miR-214 depletion were mediated through broad regulation of the transcriptional response to injury, as evidenced by microarray analysis. In human kidney tissue, miR-214 was detected in cells of the glomerulus and tubules as well as in infiltrating immune cells in diseased tissue. These studies demonstrate that miR-214 functions to promote fibrosis in renal injury independent of TGF-ß signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney.

Acute interstitial nephritis secondary to vedolizumab.

We present a patient with an acute kidney injury thought secondary to acute interstitial nephritis as a result of vedolizumab maintenance therapy for Crohn's disease. This appears to be a rare but serious side effect in patients receiving this treatment which clinicians should consider in the event of renal dysfunction.

Renal Disease in Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder characterised by lymphocytic infiltration of the exocrine glands, predominantly the salivary and lacrimal glands, leading to sicca symptoms. Patients may have extraglandular disease involving multiple organs, including the kidneys. 5% of patients with pSS can have renal involvement. Kidney disease in pSS presents a diagnostic challenge, as clinical symptoms are often insidious and can precede sicca symptoms. pSS affects the kidney through lymphocytic infiltration of renal tubules or immune complex deposition, leading to an array of clinical features. Tubulointerstitial nephritis is the most common histological pattern of kidney disease. Other tubular injuries include renal tubular acidosis with hypokalaemia, Fanconi's syndrome and diabetes insipidus. Glomerular disease is less common and typically involves an immune complex-mediated process. Optimal treatment for kidney diseases in pSS is not established, and treatment is guided by the pattern of disease. For tubulointerstitial nephritis, management involves electrolyte imbalance correction and the use of immunosuppression, including steroids. Treatment of glomerular disease is targeted to the histological pattern, and often requires a combination of immunosuppressive agents. The risk of end-stage kidney disease is low. Nevertheless, patients with pSS and kidney disease have significantly reduced quality of life.

Assessment of active tubulointerstitial nephritis in non-scarred renal cortex improves prediction of renal outcomes in patients with IgA nephropathy.

BACKGROUND: The addition of tubulointerstitial inflammation to the existing pathological classification of IgA nephropathy (IgAN) is appealing but was previously precluded due to reportedly wide inter-observer variability. We report a novel method to score percentage of non-atrophic renal cortex containing active tubulointerstitial inflammation (ATIN) in patients with IgAN and assess its utility to predict clinical outcomes. METHODS: All adult patients with a native renal biopsy diagnosis of IgAN between 2010 and 2015 in a unit serving 1.5 million people were identified. Baseline characteristics, biopsy reports and outcome data were collected. ATIN was calculated by subtracting the percentage of atrophic cortex from the percentage of total cortex with tubulointerstitial inflammation, with ≥10% representing significant ATIN. The primary outcome was a composite of requiring renal replacement therapy or doubling of serum creatinine. RESULTS: In total 153 new cases of IgAN were identified, of which 111 were eligible for inclusion. Of these, 76 (68%) were male and 54 (49%) had ATIN on biopsy. During a median follow-up of 2.3 years, 34 (31%) reached the primary outcome. On univariable Cox regression analysis, ATIN was associated with a five-fold increase in the primary outcome [hazard ratio (HR) (95% confidence interval) 4.9 (95% confidence interval (CI) 2.1-11.3)]. On multivariable analysis, mesangial hypercellularity, tubular atrophy and interstitial fibrosis and ATIN independently associated with renal outcome (P = 0.02 for ATIN). Inter-observer reproducibility revealed fair agreement in the diagnosis of ATIN (κ=0.43, P = 0.05). CONCLUSIONS: Within our centre, ATIN was significantly associated with renal outcome in patients with IgAN, independently of established histological features and baseline clinical characteristics.

ANCA-associated renal vasculitis following anti-tumor necrosis factor alpha therapy.

We report the case of a 62-year-old woman with rheumatoid arthritis treated with adalimumab, an anti-tumor necrosis factor alpha drug, who presented with 4 weeks of lethargy, upper respiratory tract symptoms, a vasculitic skin rash, and rapidly deteriorating renal function. She had cytoplasmic antineutrophil cytoplasmic antibodies and skin and renal biopsy specimens diagnostic of small vessel vasculitis and necrotizing crescentic glomerulonephritis, respectively. After immunosuppressive therapy and discontinuation of adalimumab therapy, vasculitis resolved and renal function recovered. This is the first report of antineutrophil cytoplasmic antibody associated necrotizing glomerulonephritis with adalimumab.

A Case of Lenvatinib-Induced Focal Segmental Glomerulosclerosis (FSGS) in Metastatic Medullary Thyroid Cancer.

We describe a case of lenvatinib (E7080) associated focal segmental glomerulosclerosis (FSGS) encountered during the treatment of metastatic medullary thyroid cancer. Proteinuria is a relatively common side effect of VEGF-targeted treatments and can occasionally result in treatment discontinuation. Here, we describe a patient who developed secondary FSGS necessitating discontinuation of treatment at first but who was subsequently rechallenged with anti-VEGF-targeted treatment without recurrence of proteinuria. Lenvatinib was a novel experimental agent at the time the treatment took place; however, its recent licensing for the treatment of thyroid malignancies in the UK makes reporting of these adverse effects all the more important now.

Early focal segmental glomerulosclerosis as a cause of renal allograft primary nonfunction.

Background. Primary focal segmental glomerulosclerosis (FSGS) is one of the commonest causes of glomerular disease and if left untreated will often progress to established renal failure. In many cases the best treatment option is renal transplantation; however primary FSGS may rapidly recur in renal allografts and may contribute to delayed graft function. We present a case of primary nonfunction in a renal allograft due to biopsy-proven FSGS. Case Report. A 32-year-old man presented with serum albumin of 22 g/L, proteinuria quantified at 12 g/L, and marked peripheral oedema. Renal biopsy demonstrated tip-variant FSGS. Despite treatment, the patient developed progressive renal dysfunction and was commenced on haemodialysis. Cadaveric renal transplantation was undertaken; however this was complicated by primary nonfunction. Renal biopsies failed to demonstrate evidence of acute rejection but did demonstrate clear evidence of FSGS. The patient was treated to no avail. Discussion. Primary renal allograft nonfunction following transplantation is often due to acute kidney injury or acute rejection. Recurrent FSGS is recognised as a phenomenon that drives allograft dysfunction but is not traditionally associated with primary nonfunction. This case highlights FSGS as a potentially aggressive process that, once active in the allograft, may prove refractory to targeted treatment. Preemptive therapies in patients deemed to be at high risk of recurrent disease may be appropriate and should be considered.

AA amyloidosis in a patient with Langerhans cell histiocytosis.

We report the case of a 37-year-old woman who presented with progressive renal dysfunction and proteinuria, in whom renal biopsy confirmed a diagnosis of AA amyloidosis. No evidence of chronic suppurative infection, connective tissue disease or malignancy was found. A past history of Langerhans cell histiocytosis (LCH) diagnosed in childhood was noted for which the patient had been successfully treated with surgical excision, corticosteroids, radiotherapy and chemotherapy. Renal disease in LCH is not widely recognized and thus we describe a patient with LCH in whom AA amyloidosis developed in the absence of any other established cause.

A rare cause of nephrotic syndrome in autosomal-dominant polycystic kidney disease.

We report the case of a 49-year-old lady who presented with hypertension, breathlessness and malaise. She was thrombocytopenic, with polycystic kidneys on imaging, and was found to have nephrotic syndrome. Serological results were consistent with systemic lupus erythematosus (SLE) and a renal biopsy confirmed WHO class V lupus nephritis. This is the first reported case of nephrotic syndrome due to lupus nephritis in a patient with autosomal dominant polycystic kidney disease (ADPKD) and underlines the importance of renal biopsy in patients with ADPKD and nephrotic range proteinuria.