Chronic Tubulointerstitial Damage Research Articles

#2187 Rare disease, novel approach: C3GN and Iptacopan case report

Abstract Background and Aims C3 glomerulonephritis (C3GN) is a rare disease characterised on biopsy by proliferative lesions of predominant C3 deposition on immunofluorescence, particularly deposits within the mesangium and capillary walls. Dysregulation of the alternative complement pathway is thought to be the underlying mechanism [1]. There are no approved treatments for C3G and prognosis is poor, with 50% progression to kidney failure over 10 years and similar rates of transplant loss due to disease recurrence. Iptacopan (a selective Factor B complement inhibitor) is proposed to suppress key enzymes involved in the alternative pathway cascade [2]. It is being studied in clinical trials of C3G [3]. We sought to describe our experience in diagnosing and managing a 25-year-old with C3GN who presents with nephrotic syndrome, hypertension, and a reduction in his estimated glomerular filtration rate (eGFR) with a novel small molecule therapeutic. Method This report charts the clinical course of one male patient over 11 months from presentation with C3GN, to the introduction of immunosuppression and of Iptacopan, and the assessment of his response to the foregoing. The patient consented to the publication of his case. Results A 25-year-old male with a background of autism spectrum disorder was referred to his regional nephrology service due to reduction in his eGFR and proteinuria. His creatinine was 158 µmol/L with an eGFR was 51.8 ml/ml/1.73 m2 (CKD-EPI equation); urinary protein creatinine ratio (uPCR) 500 mg/mmol; urinary albumin creatinine ratio (uACR) 400.2 mg/mmol. Serum album 32g/L. His C3 0.22 (normal range 0.82–1.85 g/L); C4 0.27 (normal 0.15–0.53 g/L). A renal biopsy was performed which demonstrated diffuse MPGN dominant C3 staining; cholesterol crystals; and moderate to severe chronic tubulointerstitial damage. 1 mg/kg oral prednisolone with mycophenolate mofetil (MMF) titrated up to a dose of 1g twice a day was initiated. As he was established on the therapy his eGFR rose back to 57.9 ml/min over approximately 8 weeks from a nadir of 33.8 ml/min. Following initial weaning of his prednisolone dose, his eGFR dropped back down to 29.7 ml/min with a creatinine of 250 µmol/L. With involvement and clinical support from the National Renal Complement Therapeutics Centre an application was made to Novartis for the compassionate use of Iptacopan which was commenced early August 2023 (he would not have been eligible for recruitment into any current clinical trials). His latest eGFR is 47.5 ml/ml/1.73 m2 with a uACR of 9.1 mg/mmol and normal C3 and C5b-9 levels after 5 months of Iptacopan. His prednisolone dose is 10 mg. MMF continues at 2g total dose. Conclusion Iptacopan has so far resulted in the normalisation of serum C3 levels, reduction of uACR and stabilisation of serum creatinine as we have reduced the prednisolone dose.

Renal Immune-related Adverse Event of Pembrolizumab Masked by Pemetrexed.

A Japanese woman in her 60s developed a kidney injury 9 weeks after treatment with pemetrexed, carboplatin, and pembrolizumab for stage IV lung adenocarcinoma. A renal biopsy showed chronic tubulointerstitial damage with minimal focal interstitial inflammation, consistent with pemetrexed-induced nephropathy; thus, pemetrexed was withdrawn. However, the kidney injury continued to worsen. A repeated biopsy showed severe acute tubulointerstitial nephritis, suggestive of a pembrolizumab-induced immune-related adverse event (irAE). The worsening after pemetrexed discontinuation suggested that the irAE had already begun, as the first biopsy showed focal inflammation. This case suggests thatcombining immune checkpoints and chemotherapy requires considering concurrent drug-induced nephrotoxicity.

Clinical findings and kidney morphology in chronic kidney disease of unknown cause in India.

Chronic kidney disease of unknown cause (CKDu) is an emerging health problem in India and other countries worldwide. However, clinical descriptions, including kidney pathology, are scarce. This is a descriptive case series of patients with CKDu from an endemic region in India, with a focus on clinical and biochemical characteristics, kidney biopsy findings, and environmental exposure. Patients with suspected CKDu, aged 20-65, and eGFR 30-80mL/min/1.73m2 from rural areas with endemic prevalence of CKDu were included. The exclusion criteria were diabetes mellitus, uncontrolled hypertension, proteinuria >1g/24h, or other known kidney diseases. The participants underwent kidney biopsies, and blood and urine samples were collected. Fourteen participants (3 females, 11 males) with a mean eGFR of 53 (range 29-78) mL/min/1.73m2 were included. Kidney biopsies showed a combination of chronic tubulointerstitial damage, glomerulosclerosis, and glomerular hypertrophy, with varying degrees of interstitial inflammation. Eight participants had polyuria (diuresis≥3L/day). The urinary sediments were bland, with no haematuria. Serum potassium and sodium levels were, in most cases, normal but within the lower reference interval. The kidney morphology and clinical characteristics in patients with CKDu in India were similar to those described for CKDu in Central America and Sri Lanka.

Single-Nephron GFR in Different Glomerular Basement Membrane Stages of Membranous Nephropathy.

Alterations in single-nephron dynamics have been demonstrated in animal models of membranous nephropathy (MN). This study applied a recently developed technique to estimate single-nephron parameters in human MN. Single-nephron GFR (SNGFR) and single-nephron urinary protein excretion (SNUPE) were calculated by dividing total GFR and UPE by the total estimated number of non-sclerotic glomeruli (NSG). The NSG number per kidney was estimated using cortical volume assessment and biopsy-based stereology. MN staging by electron microscopy was performed using Ehrenreich-Churg (EC) criteria. Single-nephron parameters were analyzed in relation to clinicopathological factors known to associate with disease outcomes. The study included 109 MN patients (mean age 65 years; 73% male; eGFR 62 mL/min, 36% on renin-angiotensin aldosterone system [RAAS] inhibitors pre-biopsy). EC stages were I, 19%;II, 49%; III, 26%; and IV, 6%. There was no difference in glomerular volume among EC stage groups. With advancing EC stage, SNGFR and SNUPE decreased from mean 56 to 42 nL/min and 5.1 to 3.8 μg/day, respectively. In multivariable models, EC stage was associated with SNGFR even after adjustment for key clinicopathological factors, such as reduced GFR, serum albumin, UPE, segmental glomerulosclerosis, chronic tubulointerstitial damage and pre-biopsy use of RAAS inhibitors. In contrast, EC stage was not associated with glomerular volume and SNUPE after multivariable adjustment. These results provide the first clinical evidence of alterations in single-nephron dynamics with advancing EC stage of human MN and support a role for disease-specific GBM structural lesions as determinants of SNGFR.

Predictors of long-term outcomes in pediatric focal segmental glomerulosclerosis.

Available data on primary focal segmental glomerulosclerosis (FSGS) in children usually report on short follow-up and small samples. Furthermore, the application of the Columbia classification for FSGS in children has not yet been fully agreed. We aimed to confirm the prognosis and risk factors of FSGS in a large cohort of Chinese children. Two hundred seventy-four children with primary FSGS from a single center were enrolled from 2003 to 2018. Long-term renal survival and related risk factors were evaluated by the Kaplan-Meier method and Cox multivariate regression analysis. Receiver operating characteristic (ROC) curve analysis further tested the effect of various risk factors in predicting renal outcomes. The composite end-point included ≥ 50% reduction in estimated glomerular filtration rate and/or end-stage renal disease or death. One hundred twenty-five children were diagnosed with not otherwise specified (NOS) (45.6%) variant; 79 with tip lesions (28.8%), 32 with collapsing (11.7%), 31 with cellular (11.3%), and 7 with perihilar lesions (2.6%). The renal survival rate was 80.73% at 5years, 62.58% at 10years and 34.66% at 15years. Multivariate analysis showed that chronic tubulointerstitial damage ≥ 25% (HR 4.14, 95% CI 1.49-11.50, P < 0.01), collapsing variant [(reference: NOS) HR 2.16, 95% CI 1.10-4.27, P = 0.03], segmental sclerosis (HR 1.03, 95% CI 1.01-1.04, P < 0.01) and age at biopsy (HR 0.91, 95% CI 0.85-0.98, P = 0.01) were significantly associated with renal outcomes. ROC curve analysis showed an excellent diagnostic yield of the Columbia classification. The combination of Columbia classification, CTI ≥ 25% and segmental sclerosis had the best predictive value for renal outcomes (AUC = 0.867, sensitivity = 77.78%, specificity = 82.27%, P < 0.01). This study reports a renal survival rate of Chinese children with FSGS of 62.58% at 10years and 34.66% at 15years. Prognosis is poorer in patients with collapsing variant or CTI ≥ 25% and good in patients with tip variant. The Columbia classification is confirmed as a valuable tool for predicting prognosis of Chinese children with FSGS.

The Pathological and Clinical Diversity of Acute Vascular Rejection in Kidney Transplantation.

Vascular rejection (VR) is characterized by arteritis, steroid resistance, and increased graft loss but is poorly described using modern diagnostics. We screened 3715 consecutive biopsies and retrospectively evaluated clinical and histological phenotypes of VR (n = 100) against rejection without arteritis (v0REJ, n = 540) and normal controls (n = 1108). Biopsy sample size affected the likelihood of arterial sampling, VR diagnosis, and final Banff v scores ( P < 0.001). Local v and cv scores were greatest in larger arteries (n = 258). VR comprised 15.6% of all rejection episodes, presented earlier (median 1.0 mo, interquartile range, 0.4-8 mo) with higher serum creatinine levels and inferior graft survival, versus v0REJ ( P < 0.001). Early VR (≤1 mo) was common (54%) and predicted by sensitization, delayed function, and prior corticosteroid use, with associated acute dysfunction and optimal therapeutic response, independent of Banff v score. Late VR followed under-immunosuppression in 71.4% (noncompliance 38.8%, iatrogenic 32.6%), and was associated with chronic interstitial fibrosis, incomplete renal functional recovery and persistent inflammation using sequential histopathology. The etiology was "pure" antibody-mediated VR (n = 21), mixed VR (n = 36), and "pure" T cell-mediated VR (n = 43). Isolated VR (n = 34, Banff i < 1 without tubulitis) comprised 24 T cell-mediated VR and 10 antibody-mediated VR, presenting with mild renal dysfunction, minimal Banff acute scores, and better graft survival compared with inflamed VR. Interstitial inflammation influenced acute renal dysfunction and early treatment response, whereas chronic tubulointerstitial damage determined long-term graft loss. VR is a heterogenous entity influenced by time-of-onset, pathophysiology, accompanying interstitial inflammation and fibrosis. Adequate histological sampling is essential for its accurate diagnostic classification and treatment.

Pathomorphological sequence of nephron loss in diabetic nephropathy.

Following our previous reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN) (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. Am J Physiol Renal Physiol 312: F1101-F1111, 2017; Löwen J, Gröne E, Gröne HJ, Kriz W. Am J Physiol Renal Physiol 317: F399-F410, 2019), we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulointerstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerged from two defects: 1) increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium and 2) a defect of glomerular vessels consisting of increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of accumulated worn-out GBM material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule (BC) to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally intact podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulotubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myofibroblasts resulting in interstitial fibrosis.NEW & NOTEWORTHY Based on analysis of 918 human biopsies, essential derangement in diabetic nephropathy consists of accumulation of worn-out glomerular basement membrane in the mesangium that may advance to global sclerosis. The most frequent pathway to nephron dropout starts with the penetration of glomerular capillaries into Bowman's capsule (BC), delivering an exudate into BC that spreads around the entire glomerular circumference and via the glomerulotubular junction onto the tubule, resulting in glomerular sclerosis and chronic tubulointerstitial damage.

MO004PRIMARY BILIARY CHOLANGITIS PRESENTING WITH RENAL FANCONI SYNDROME: A FORGOTTEN PHENOTYPE

Abstract Background and Aims Primary biliary cholangitits (PBC) is an autoimmune liver disease, leading to liver fibrosis and cirrhosis. It is a rare disease affecting 1 in 3-4000 people and is more common in females. Symptoms may go unnoticed and include itch and fatigue. Most patients have anti-mitochondrial antibodies (AMA) as well as raised gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels. First line treatment for PBC is ursodeoxycholic acid and is usually continued lifelong. It improves liver biochemistry, histological progression of liver disease and liver transplant-free survival. Renal complications of PBC include distal renal tubular acidosis (RTA), tubule-interstitial nephritis (TIN) and renal Fanconi syndrome. Method We reviewed a case of PBC presenting with renal Fanconi syndrome. Results A 48-year-old female was referred to the renal clinic due to progressive decline in renal function since she was diagnosed with type 2 diabetes in 2007. She was also known to have AMA (&amp;gt;1:640) and previously had transient transaminitis. She was clinically well with no major symptoms but reported that she had had a few episodes of urinary tract infection in the previous year. Her diabetes was managed with lifestyle modifications in the past until a few months ago when Metformin was introduced. However, her HbA1c level had never been greater than 55 mmol/mol. Urine dipstick in the clinic showed pH of 6, blood+, glucose+++, protein+++ and ketone trace. The severity of glycosuria was inconsistent with her glycaemic control. There was a disparity between her urine albumin/creatinine ration (ACR) of 18.8g/mol and protein/creatinine ratio (PCR) of 124mg/mmol. Myeloma screen was negative and further urine analysis showed generalised aminoaciduria. She also had hypouricaemia, intermittent hypophosphataemia and non-anion gap metabolic acidosis. These results are in keeping with renal Fanconi syndrome. Her eGFR was 48 ml/min/1.72m2 in 2007 and was 21 ml/min/1.72m at the time of review. A renal biopsy was undertaken, and the appearances were suggestive of mild tubulo-interstitial nephritis; the glomeruli were unremarkable; there was mild chronic tubulo-interstitial damage. She was started on oral steroid, sodium bicarbonate and ursodeoxycholic acid. The course of steroid had a slight transitory beneficial effect on the renal function. Conclusion Distal RTA is the usual renal feature of PBC, occurring in 1/3 of cases with advanced disease. In contrast, proximal RTA associating with renal Fanconi syndrome occurs rarely. Like our case, the cases that have been previously reported show that Fanconi syndrome occurred during the early phase of PBC in the absence of marked hepatic abnormalities, and were associated with CKD. Fanconi syndrome and TIN are renal features of mitochondrial cytopathies and are perhaps a forgotten association of PBC. Antimitochondrial antibodies may play a role in the onset of tubulo-interstitial nephritis and Fanconi syndrome.

Angiotensin II type 1a receptor loss ameliorates chronic tubulointerstitial damage after renal ischemia reperfusion

We investigate whether suppressing the activation of the angiotensin II type 1a receptor (AT1a) can ameliorate severe chronic tubulointerstitial damage (TID) after renal ischemia reperfusion (IR) using AT1a knockout homozygous (AT1a−/−) male mice. To induce severe chronic TID after renal IR, unilateral renal ischemia was performed via clamping of the right renal pedicle in both AT1a−/− and wild-type (AT1a+/+) mice for 45 min. While marked renal atrophy and severe TID at 70 days postischemia was induced in the AT1a+/+ mice, such a development was not provoked in the AT1a−/− mice. Although the AT1a+/+ mice were administered hydralazine to maintain the same systolic blood pressure (SBP) levels as the AT1a−/− mice with lower SBP levels, hydralazine did not reproduce the renoprotective effects observed in the AT1a−/− mice. Acute tubular injury at 3 days postischemia was similar between the AT1a−/− mice and the AT1a+/+ mice. From our investigations using IR kidneys at 3, 14, and 28 days postischemia, the multiple molecular mechanisms may be related to prevention of severe chronic TID postischemia in the AT1a−/− mice. In conclusion, inactivation of the AT1 receptor may be useful in preventing the transition of acute kidney injury to chronic kidney disease.

SUN-109 THE ROLE OF SHEAR WAVE ELASTOGRAPHY IN EVALUATING CHRONIC ALLOGRAFT INJURY AND SUBCLINICAL REJECTION

Subclinical rejection (SCR) has been identified contributing to chronic allograft injury and subsequent graft loss after kidney transplantation. Studies have shown SCR to be associated with chronic tubulointerstitial damage. To date, histologic examination of renal allograft biopsy remained as gold standard to diagnosed SCR. However, it is invasive and has a substantial risk of bleeding. Shear wave elastography (SWE) is an emerging non-invasive ultrasound technique that measures tissue stiffness.

Utility of urinary tubular markers for monitoring chronic tubulointerstitial injury after ischemia-reperfusion.

The aim of this study was to elucidate whether urinary tubular markers during the chronic phase of acute kidney injury (AKI) are associated with chronic tubulointerstitial damage. Male human L-type fatty acid binding protein (L-FABP) chromosomal transgenic (Tg) mice underwent ischaemic reperfusion (I/R) injury via renal pedicle clamping for either 10min or 20min. Contralateral nephrectomy was performed at the time of tissue reperfusion. The kidneys were analyzed 20days after the last I/R. Serum creatinine levels 20days post-I/R were significantly higher in the 20min I/R than in the 10min I/R and control groups and were similar between the 10min I/R and control groups. The degree of tubulointerstitial damage 20days post-I/R was significantly more severe in the 20min I/R than in the 10min I/R and control groups, as well as in the 10min I/R than in the control group. Urinary levels of human L-FABP, albumin, and kidney injury molecule-1 (KIM-1) 20days post-I/R were significantly higher in the 20min I/R than in the control group, whereas urinary L-FABP was significantly higher in the 10min I/R than in the control group. Conversely, urinary neutrophil gelatinase-associated lipocalin levels did not significantly differ between the three groups. Finally, the urinary levels of human L-FABP, albumin, and KIM-1 levels 20days post-I/R were significantly correlated with the degree of renal damage. Urinary levels of human L-FABP, albumin and, KIM-1 may be useful for monitoring AKI-to-CKD transition in clinical practice.

Morphological and clinical findings in Sri Lankan patients with chronic kidney disease of unknown cause (CKDu): Similarities and differences with Mesoamerican Nephropathy.

In Sri Lanka, an endemic of chronic kidney disease of unknown origin (CKDu) is affecting rural communities. The endemic has similarities with Mesoamerican Nephropathy (MeN) in Central America, however it has not yet been clarified if the endemics are related diagnostic entities. We designed this study of kidney biopsies from patients with CKDu in Sri Lanka to compare with MeN morphology. Eleven patients with CKDu were recruited at the General Hospital, Polonnaruwa, using similar inclusion and exclusion criteria as our previous MeN studies. Inclusion criteria were 20–65 years of age and plasma creatinine 100–220 μmol/L. Exclusion criteria were diabetes mellitus, uncontrolled hypertension and albuminuria >1g/24h. Kidney biopsies, blood and urine samples were collected, and participants answered a questionnaire. Included participants were between 27–61 years of age and had a mean eGFR of 38±14 ml/min/1.73m2. Main findings in the biopsies were chronic glomerular and tubulointerstitial damage with glomerulosclerosis (8–75%), glomerular hypertrophy and mild to moderate tubulointerstitial changes. The morphology was more heterogeneous and interstitial inflammation and vascular changes were more common compared to our previous studies of MeN. In two patients the biopsies showed morphological signs of acute pyelonephritis but urine cultures were negative. Electrolyte disturbances with low levels of serum sodium, potassium, and/or magnesium were common. In the urine, only four patients displayed albuminuria, but many patients exhibited elevated α-1-microglobulin and magnesium levels. This is the first study reporting detailed biochemical and clinical data together with renal morphology, including electron microscopy, from Sri Lankan patients with CKDu. Our data show that there are many similarities in the biochemical and morphological profile of the CKDu endemics in Central America and Sri Lanka, supporting a common etiology. However, there are differences, such as a more mixed morphology, more interstitial inflammation and vascular changes in Sri Lankan patients.

124 HISTOPATHOLOGY FINDINGS OF RENAL BIOPSIES PERFORMED IN PATIENTS WITH ACUTE KIDNEY INJURY

Category: Epidemiology and Outcomes from AKI Presenter: Dr Shahnon Anuar Keywords: Acute kidney injury, renal biopsy findings Renal biopsy in acute kidney injury (AKI) provides important information for diagnosis, treatment, and prognosis. 1.To ascertain the renal pathologic correlations of native renal biopsies done for AKI in Selayang Hospital.2.To ascertain the renal and patient outcome of the AKI at 3 months’ post renal biopsy. This retrospective study was performed on all patients who underwent renal biopsies for AKI in Selayang Hospital from 1.1.2015 to 31.12.2016. Patients’ demography, clinical and histopathology data, laboratory results, renal and patient outcome were retrieved from hospital’s electronic medical record. Results were analyzed using SPSS version 23. Between the years 2015-2016, 230 native renal biopsies were done. Of these, 22% (51 patients) had AKI. Mean age were 34.6 ± 15.5 years. Twenty-eight (54.9%) were male and 21 (41.2%) had no prior medical illness. Forty-nine biopsies (96.1%) were done at the inferior pole of the left kidney. The renal histopathology results of the biopsies were: Lupus nephritis, 39.2% (20), Focal segmental glomerulosclerosis (FSGS), 13.7% (7), IgA nephropathy, 7.8% (4), Membranoproliferative glomerulonephritis, 3.9% (2), Membranous nephropathy, 3.9% (2), Minimal change disease, 9.8% (5), Postinfectious glomerulonephritis, 2% (1), Acute Interstitial Nephritis, 5.9% (3), Anti-neutrophil Cytoplasm Antibodies-associated glomerulonephritis, 2% (1). Four patients (7.8%) had inconclusive renal biopsies. Two (3.9%) had chronic tubulointerstitial damage on the renal biopsy. Twenty-six patients (51%) had full recovery of renal function while 13 (25.5%) developed chronic kidney disease. Two (3.9%) require longterm renal replacement therapy; one had crescentic IgA nephropathy, the other had nonHodgkin’s lymphoma with membranoproliferative glomerulonephritis with severe chronic tubulointerstitial changes. Two patients died less than 3 months post renal biopsy due to complications related to underlying disease (both patients had lupus nephritis class IV on renal biopsy). The prevalence of lupus nephritis is high in the younger age group (12-30 years old). These data highlight the value of renal biopsy in guiding management strategies in patients with AKI.

047 COMBINATION OF TENOFOVIR/EMTRICITABINE WITH PROTEASE INHIBITOR - BASED REGIMEN INDUCED ACUTE KIDNEY INJURY REQUIRING HAEMODIALYSIS: A CASE REPORT

Category: Other Presenter: Dr CHUI MUNN ANG Keywords: Human Immunodeficiency Virus, Tenofovir, Protease Inhibitor, Acute Kidney Injury 51 years old with Human Immunodeficiency Virus and Hepatitis C; non compliant to medication, was switched to Tenofovir/Emtricitabine (TDF/FTC) and Lopinavir/ Ritonavir (LPV/r). Renal profile (RP) was normal and urine FEME showed protein 2+ with viral load of 311 748 copies/ml and CD 4 count of 55 cell/ul prior to initiation of therapy. He presented with uraemia after 4 months; normotensive, afebrile with no evidence of fluid overload or infection. Blood parameters showed acute kidney injury with severe metabolic acidosis (ph 7.052, HCO3 9.6mmol/L, urea 48.7mmol/L, creatinine 1771umol/L); Urine showed microscopic haematuria, proteinuria and glycosuria. Ultrasound showed no evidence of obstruction. TDF/FTC and LPV/r were withheld. Regular hemodialysis was only required for 1 month. RP after 3 months showed urea 5.8mmol/L, creatinine 209 umol/L. Renal biopsy showed 33% of focal global glomerulosclerosis with moderate chronic tubulointerstitial damage and acute tubular necrosis. TDF is eliminated by a combination of glomerular filtration and proximal tubular secretion with 20 - 30% of the drug actively transported into renal proximal tubule cells by anion transporters; hence drug interaction of LPV/r with these transporters favours intracellular accumulation and increases risk of renal toxicity (AUC of TDF increased by 32%). The proximal tubular cells injury leads to failure of reabsorption of low molecular weight proteins, glucose, amino acids, phosphate and uric acid; as well as failure of H+ secretion which reflects on the proteinuria, glycosuria, acute kidney injury with renal tubular acidosis requiring renal replacement; supported by evidence of acute tubular necrosis with interstitium occasionally infiltrated by eosinophils from renal biopsy which suggest a case of drug induced nephropathy likely TDF. The combination of TDF/FTC with LPV/r is associated with greater declines in renal function hence patient should be closely monitored to look for any early signs of renal impairment.

Renal Morphology, Clinical Findings, and Progression Rate in Mesoamerican Nephropathy

Mesoamerican nephropathy (MeN) is a chronic kidney disease affecting rural inhabitants in Central America. We have previously described the renal morphology in 8 patients from El Salvador. To confirm the renal pathology, we have studied kidney biopsies from patients with MeN in Nicaragua. Follow-up urine and blood samples from both biopsy studies were collected to investigate the natural history. Case series. In the kidney biopsy study, 19 male sugarcane workers in Nicaragua with suspected MeN were investigated with questionnaires, kidney biopsies, and blood and urine analysis. Inclusion criteria were age 20 to 65 years and plasma creatinine level of 1.13 to 2.49mg/dL or estimated glomerular filtration rate (eGFR) of 30 to 80mL/min/1.73m2. Exclusion criteria were proteinuria with protein excretion >3g/24 h, uncontrolled hypertension, diabetes mellitus, or other known kidney disease. In the follow up-study, blood and urine from the kidney biopsy study in Nicaragua (n=18) and our previous biopsy study of MeN cases in El Salvador (n=7) were collected 1 to 1.5 and 2 to 2.5 years after biopsy, respectively. Renal morphology, clinical, and biochemical characteristics, change in eGFR per year. eGFR was calculated using the CKD-EPI creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C (eGFRcr-cys) equations. In the kidney biopsy study, participants had a mean eGFRcr of 57 (range, 33-96) mL/min/1.73m2. 47% had low plasma sodium and 21% had low plasma potassium levels. 16 kidney biopsies were representative and showed glomerulosclerosis (mean, 38%), glomerular hypertrophy, and signs of chronic glomerular ischemia. Mild to moderate tubulointerstitial damage and mostly mild vascular changes were seen. In the follow up-study, median duration of follow-up was 13 (range, 13-27) months. Mean change in eGFRcr was-4.4±8.4 (range,-27.7 to 10.2) mL/min/1.73m2 per year. Most patients had stopped working with sugarcane cultivation. 3 biopsy specimens had 4 or fewer glomeruli. This study confirms the renal morphology of MeN: chronic glomerular and tubulointerstitial damage with glomerulosclerosis and chronic glomerular ischemia. Follow-up data show that eGFRs, on average, deteriorated.

Protective Effects of Dimedone Pyrone on Podocytes in Rats with Diabetic Nephropathy

Purpose: To investigate the effect of dimedone pyrone (DP) on podocytes in rats with diabetic nephropathy (DN).Methods: The rats were randomly assigned into 5 experimental groups (n = 10), viz, non-diabetic control with no treatment (ND/NT), diabetic with no treatment (DG/NT), diabetic treated with 5 mg/kg dimedone pyrone (DG/DP 5), diabetic treated with 10 mg/kg dimedone pyrone (DG/DP 10) and diabetic treated with 20 mg/kk dimedone pyrone (DG/DP 20) group. Clinical parameters, including 24 h urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), blood glucose (GLU), and kidney weight (KW)/body weight (BW) were determined after 12 weeks of treatment. Hematoxylin and eosin staining was used to examine renal pathological changes while transmission electron microscopy (TEM) was employed for evaluation of structural changes in the podocytes. The expression levels of nephrin and podocin were evaluated using immunofluorescence staining.Results: Dimedone pyrone caused a significant decrease in SCR, BUN, GLU, KW/BW and 24 h urine protein in DG/DP 20 group compared to DG/NT group. Furthermore, incidences of glomerular disorders, chronic tubulo-interstitial damage and glomerular podocyte lesions decreased significantly following dimedone pyrone treatment. Glomeruli, tubules and podocytes exhibited pathomorphological improvements while nephrin and podocin protein expression levels were significantly higher in the nephridial tissue. Decrease in relative kidney weight (KW/BW) and 24 h urinary protein level were improved significantly on treatment with dimedone pyrone. Moreover, glomerular disorder, chronic tubulo-interstitial damage and glomerular podocyte lesions were also suppressed. The improvement was more significant in DG/DP 20 compared to DG/DP 5 and DG/DP 10 groups.Conclusion: Dimedone pyrone exhibits a protective effect on the podocytes of rats and may be of therapeutic importance in the treatment of diabetic nephropathy.Keywords: Dimedone pyrone, Podocin, Diabetic neuropathy, Nephrin, Glomerular disorders

Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4.

Mild hyperuricemia has been linked to the development and progression of tubulointerstitial renal damage. However the mechanisms by which uric acid may cause these effects are poorly explored. We investigated the effect of uric acid on apoptosis and the underlying mechanisms in a human proximal tubule cell line (HK-2). Increased uric acid concentration decreased tubule cell viability and increased apoptotic cells in a dose dependent manner (up to a 7-fold increase, p<0.0001). Uric acid up-regulated Bax (+60% with respect to Ctrl; p<0.05) and down regulated X-linked inhibitor of apoptosis protein. Apoptosis was blunted by Caspase-9 but not Caspase-8 inhibition. Uric acid induced changes in the mitochondrial membrane, elevations in reactive oxygen species and a pronounced up-regulation of NOX 4 mRNA and protein (p<0.05). In addition, both reactive oxygen species production and apoptosis was prevented by the NADPH oxidase inhibitor DPI as well as by Nox 4 knockdown. URAT 1 transport inhibition by probenecid and losartan and its knock down by specific siRNA, blunted apoptosis, suggesting a URAT 1 dependent cell death. In summary, our data show that uric acid increases the permissiveness of proximal tubule kidney cells to apoptosis by triggering a pathway involving NADPH oxidase signalling and URAT 1 transport. These results might explain the chronic tubulointerstitial damage observed in hyperuricaemic states and suggest that uric acid transport in tubular cells is necessary for urate-induced effects.

Telomere Length, Cardiovascular Risk and the Discrepancy Between Baseline and Post-Transplant Renal Allograft Histology.

Background: The impact of senescence (biological aging) on post-transplant renal allograft histology is unknown. Methods: In blood samples from 300 deceased kidney donors, telomere length was measured. The recipients of these kidneys underwent protocol biopsies at 3, 12, 24, 36 and 60 months. Results: Both at baseline and at 3 months post-transplant, shorter donor telomere length associated significantly with cv (arteriosclerosis)(p=0.0002 and p=0.03 respectively), independent of classic cardiovascular risk factors. In contrast, and similar to what was seen in baseline biopsies, older donor calendar age associated significantly with IFTA and Gs in protocol biopsies performed at 3 months post-transplantation (p<0.0001). In addition, older donor age correlated with cv in 3-months protocol biopsies (p<0.0001). Shorter telomere length did not associate with any other histological lesion in this earliest phase post-transplant. In protocol biopsies performed later than 3 months post-transplant (at 12, 24, 36 and 60 months), older donor age associated with the same histological lesions as in the baseline biopsies (p<0.0001) but also with cv (p<0.0001) and ah (p=0.01). Interestingly, at these later time points after transplantation, shorter donor telomere length did no longer correlate with cv or other histological lesions. Telomeres were significantly shorter in biopsies with early presentation of cv in contrast to biopsies with late presentation of cv (p=0.05). Conclusion: Older donor calendar age associates with glomerulosclerosis and chronic tubulo-interstitial damage at all time points after transplantation. In contrast, donor telomere shortening, as hallmark of renal allograft biological age, correlates with intrarenal arteriosclerosis in the early months post-transplant, but not with other histological features. Later after transplantation, the impact of donor telomere shortening on graft histology decreased, likely due to other post-transplant factors that affect post-transplant histology, not related to donor kidney biological age. Whether this discrepancy can be explained by accelerated ageing associated with rejection or infectious episodes, warrants further study.

Effect of Cordyceps sinensis and Tripterygium wilfordii polyglycosidium on podocytes in rats with diabetic nephropathy.

The aim of the present study was to investigate the effects of Cordyceps sinensis (CS) and Tripterygium wilfordii polyglycosidium (TWP) on podocytes in rats with diabetic nephropathy (DN). DN rat models were established and divided randomly into normal control (group A), DN (group B), CS (group C), TWP (group D) and CS and TWP groups (group E). After 12 weeks, levels of 24-h urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), white blood cells, blood glucose (GLU), aspartate aminotransferase, alanine aminotransferase and kidney weight (KW)/body weight (BW) were determined. Renal pathological changes were evaluated using hematoxylin and eosin staining, whereas the structural changes in the podocytes were observed under a transmission electron microscope. The expression levels of nephrin and podocin were evaluated using immunofluorescence staining. Compared with group A, the SCR and BUN levels in group B were higher (P<0.05) and the GLU, KW/BW and the 24-h urine protein were markedly higher (P<0.01). Moreover, incidences of glomerular disorders, chronic tubulointerstitial damage and glomerular podocyte lesions in groups B, C, D and E were observed, compared with group A. The high cortical expression of nephrin and podocin protein decreased. Compared with group B, the KW/BW and 24-h urinary protein level in groups C, D and E were lower (P<0.01). The glomeruli, tubules and podocytes exhibited pathomorphological improvements and the nephrin and podocin protein expression levels were higher in the nephridial tissue. A decrease in KW/BW and the 24-h urinary protein level, as well as improvements in glomerular disorder, chronic tubulointerstitial damage and glomerular podocyte lesions, were observed in groups C, D and E. Therefore, the results demonstrated that CS and TWP exhibited a protective effect on the podocytes of rats with DN. Moreover, CS combined with TWP increased this protective effect.

Rare association of cutaneous vasculitis, IgA nephropathy and antiphospholipid antibody syndrome with tuberculous lymphadenitis

Dear Editor, We read with great interest the article by Bueno Filho et al. entitled “Rare association of cutaneous vasculitis, IgA nephropathy and antiphospholipid antibody syndrome with tuberculous lymphadenitis” that was published in the esteemed journal Clinics. The authors presented an interesting case of cutaneous vasculitis, IgA nephropathy and antiphospholipid antibody syndrome with tuberculous lymphadenitis in a 45-year-old woman (1). I would like to mention a few points regarding this paper. A definitive pathologic IgA nephropathy diagnosis based on immunostaining assays requires the presence of dominant mesangial IgA depositions in the absence of significant C1q depositions to rule out lupus nephritis (2–5), which the authors should note. Moreover, the detection of significant fibrin deposition along with IgA deposits can help differentiate between primary IgA nephropathy and Henoch-Schonlein purpura nephropathy (2–5). Therefore, the authors should also discuss this point. Bueno Filho et al. classified the morphologic lesions of IgA nephropathy in renal biopsies as “focal and segmental sclerosis with mild focal and chronic tubulointerstitial damage”. Indeed, as a result of the publication of the Oxford classification of IgA nephropathy in 2009 (2,5), it is necessary to describe the morphologic lesions of IgA nephropathy according to this classification system (6–8). Furthermore, figure 2C shows a normal glomerulus, which is in contrast to the described morphologic features. The authors reported the final diagnosis as a combination of tuberculous lymphadenitis, cutaneous leukocytoclastic vasculitis, primary IgA nephropathy and anti-phospholipid antibody syndrome. However, the presence of morphologic lesions upon renal biopsy suggests anti-phospholipid syndrome nephropathy and should have been reported (9–11). Anti-phospholipid antibody syndrome is a vaso-occlusive disease (12,13) that affects renal tissue and has various morphologic lesions, some of which are characteristic of the disease (14). Accurate documentation and reporting of such rare cases are necessary to determine the complete spectrum of this disorder and improve the understanding of its pathophysiology. Bueno Filho et al. merit compliments for bringing this interesting case to this journal for discussion. Such discussions may help increase awareness of anti-phospholipid antibody syndrome among pathologists and nephrologists, particularly in developing countries.