COVID-19 pneumonia in a kidney transplant recipient successfully treated with tocilizumab and hydroxychloroquine.

Coronavirus disease 2019 (COVID-19) pneumonia has been poorly reported in solid organ transplanted patients; prognosis is uncertain and best management unclear. We describe the case of a 61-year-old kidney transplant recipient with several comorbidities who was hospitalized and later received a diagnosis of COVID-19 pneumonia; the infection was successfully managed with the use of hydroxychloroquine and a single administration of tocilizumab, after immunosuppression reduction; the patient did not require mechanical ventilation. During the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, transplant clinicians should be readily informed about new cases of COVID-19 pneumonia in solid organ transplant recipients, with focus on therapeutic strategies employed and their outcome.

Bilateral decompression retinopathy after deep sclerectomy with mitomycin C in a child with tubulointerstitial nephritis and uveitis syndrome.

INTRODUCTION: To report the first case of bilateral ocular decompression retinopathy after uneventful non-perforating deep sclerectomy with mitomycin C in a child with tubulointerstitial nephritis and uveitis syndrome. CASE DESCRIPTION: An 8-year-old girl affected by tubulointerstitial nephritis and uveitis syndrome developed ocular hypertension (45 mmHg in the right eye and 42 mmHg in the left eye) associated with recurrent episodes of uveitis and chronic use of steroids despite maximum hypotensive medical treatment. Bilateral non-perforating deep sclerectomy with mitomycin C (0.2 mg/mL, 1 min) was performed under general anesthesia without complications. The first postoperative day, the visual acuity was reduced to 0.6 in the right eye and 0.05 in the left eye and the intraocular pressure was 3 mmHg in both eyes. Fundoscopy revealed bilateral optic nerve swelling and diffuse retinal hemorrhages, some of them with scattered-white centers. About 2 months after surgery, the visual acuity was normal and the fundus examination showed complete resolution. CONCLUSION: The ocular decompression retinopathy is an uncommon complication after non-perforating deep sclerectomy. This is the first case of bilateral ocular decompression retinopathy reported after non-perforating deep sclerectomy in a child with ocular hypertension secondary to recurrent uveitis and chronic use of steroids associated with tubulointerstitial nephritis and uveitis syndrome.

Kidney disease and organ transplantation in methylmalonic acidaemia.

OBJECTIVES: MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre-, peri-, and post-transplant course of all children with MMA who underwent liver or combined liver-kidney transplant in our centers. DESIGN AND METHODS: Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years. RESULTS: Five children with MMA underwent liver transplant (4/5) and combined liver-kidney transplant (1/5). Three were Mut0 and two had a cobalamin B disorder. Four of five were transplanted between ages 3 and 5 years. Renal dysfunction prior to transplant was seen in 2/5 patients. Post-transplant (one liver transplant and one combined transplant) renal function improved slightly when using creatinine-based GFR formula. We noticed in 2 patients a big discrepancy between creatinine- and cystatin C-based GFR calculations. One patient with no renal disease developed renal failure post-liver transplantation. Serum MMA levels have decreased in all to <300 µmol/L. Four patients remain on low protein diet, carnitine, coenzyme Q, and vitamin E post-transplant. CONCLUSIONS: MMA is a complex metabolic disorder. Renal disease can continue to progress post-liver transplant and close follow-up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post-transplant can halt the progression of renal disease remains unclear.

Recurrence of Tubulointerstitial Nephritis Without Uveitis, in a Patient with Previous Tubulointerstitial Nephritis and Uveitis Syndrome After Transplant.

We report a case of recurrent tubulointerstitial nephritis without uveitis in a patient with previous tubulointerstitial nephritis and uveitis syndrome after transplant. A 26-year-old male patient who had been diagnosed with tubulointerstitial nephritis and uveitis syndrome at 8 years of age developed end-stage renal failure and subsequently underwent living-donor related renal transplant at 17 years old. The 1st recurrence of tubulointerstitial nephritis and uveitis occurred 36 months after transplant, which was treated with increased immunosuppressive drugs. Graft function worsened again to estimated glomerular filtration rate of 25 mL/min/1.73 m² at 76 months after transplant. Transplant ultrasonography was unremarkable. Virology tests (including cytomegalovirus, BK virus, and Epstein-Barr virus tests) were all negative, with negative donor-specific antibodies. Urine protein creatinine ratio was unremarkable. A biopsy showed chronic allograft rejection and graft sclerosis, and immunosuppressive medications were subsequently decreased. The patient's renal function continued to decline over the next 3 months, with estimated glomerular filtration rate showing 18 mL/min/1.73 m², prompting a further renal biopsy that showed granulomatous interstitial nephritis and moderate interstitial fibrosis. This was consistent with a further relapse of tubulointerstitial nephritis but without uveitis. His renal function improved over the next few months after tacrolimus was reintroduced.

Discovery of a novel dominant mutation in the REN gene after forty years of renal disease: a case report.

BACKGROUND: Heterozygous mutations in the gene encoding renin (REN) cause autosomal dominant tubulointerstitial kidney disease (ADTKD), early-onset anaemia and hyperuricaemia; only four different mutations have been described in the published literature to date. We report a novel dominant REN mutation discovered in an individual after forty years of renal disease. CASE PRESENTATION: A 57 year old Caucasian woman with chronic kidney disease stage five was reviewed in a regional joint renal genetics clinic. She had initially been diagnosed with chronic pyelonephritis in adolescence, around the same time that she was investigated for anaemia out of keeping with her degree of renal impairment. Hyperuricaemia was identified in her twenties following an episode of gout. A diagnosis of ADTKD was not made until the age of 37 years, when her mother was also found to have kidney disease and commenced haemodialysis. The patient's renal function continued to slowly deteriorate and, twenty years later, her sister was worked up as a potential donor for kidney transplantation. Revisiting the maternal family history during the transplant work up prompted a referral to clinical genetics and urgent REN genetic testing was requested for the patient, leading to discovery of a heterozygous mutation in the REN gene: c.49 T > C, p.(Trp17Arg). This variant was not identified in her otherwise healthy sister, allowing pre-emptive live renal transplantation to take place shortly afterwards. CONCLUSIONS: In an era where genetic testing is becoming much more readily available, this case highlights the importance of considering a genetic aetiology in all patients with long-standing renal disease and a relevant family history. Establishing a genetic diagnosis of ADTKD-REN in this individual with chronic anaemia, hyperuricaemia and slowly progressive renal impairment helped to identify a suitable live kidney donor and allowed successful pre-emptive transplantation to take place.

Ruptured Hemangioma of a Native Kidney: An Unusual Cause of Postoperative Hemorrhage in Kidney Transplant Recipients.

BACKGROUND Retroperitoneal bleeding as a consequence of non-traumatic kidney or allograft rupture is well known, but there are no reports on hemorrhagia from a native kidney after allogeneic renal transplantation. Therefore, we present the first such case to be published and highlight the possibility of this complication after renal transplantation. CASE REPORT We report the case of a 28-year-old male patient who developed early post-transplant hemorrhagia from a ruptured native kidney. The patient underwent left-sided nephrectomy. Histopathological examination revealed ruptured hemangioma of the patient's native left kidney. The further postoperative period was not complicated. The patient was discharged on the 18th postoperative day, with good transplant function. CONCLUSIONS Transplantologists should be aware of the fact that in patients with uncontrolled blood pressure, native kidney hemangioma may rupture in the early post-transplant period, and it can be a life-threating and difficult to diagnose complication.

Loss of CD11b exacerbates murine complement-mediated tubulointerstitial nephritis.

Acute complement activation occurs in the tubulointerstitium (TI) of kidneys transplanted from Crry(-/-)C3(-/-) mice into complement-sufficient wildtype mice, followed by marked inflammatory cell infiltration, tubular damage and interstitial fibrosis. We postulated iC3b-CD11b interactions were critical in this TI nephritis model. We transplanted Crry(-/-)C3(-/-) mouse kidneys into CD11b(-/-) and wildtype C57BL/6 mice. Surprisingly, there was greater inflammation in Crry(-/-)C3(-/-) kidneys in CD11b(-/-) recipients compared to those in wildtype hosts. Kidneys in CD11b(-/-) recipients had large numbers of CD11b-Ly6ChiCCR2hiF4/80+ cells consistent with inflammatory (M1) macrophages recruited from circulating monocytes of the host CD11b(-/-) animal. There was also an expanded population of CD11b(+)CD11c(+)Ly6C(-)F4/80(hi) cells. Since these cells were CD11b(+), they must have originated from the transplanted kidney; their surface protein expression and appearance within the kidney were consistent with the intrinsic renal mononuclear cellular population. These cells were markedly expanded relative to all relevant controls, including the contralateral donor kidney and Crry(-/-)C3(-/-) mouse kidneys in CD11b(+/+) wildtype recipients. Direct evidence for their in situ proliferation was the presence of nuclear Ki67 and PCNA in CD11b(+)F4/80(+) cells. Thus, in this experimental model in which there is unrestricted C3 activation, CD11b(+) monocytes limit their own infiltration into the kidney and prevent proliferation of endogenous mononuclear cells. This suggests a role for outside-in iC3b-CD11b signals in limiting intrinsic organ inflammation.

TGF expression and macrophage accumulation in atherosclerotic renal artery stenosis.

BACKGROUND AND OBJECTIVES: Atherosclerotic renal artery stenosis (ARAS) reduces renal blood flow and is a potential cause of chronic kidney injury, yet little is known regarding inflammatory pathways in this disorder in human participants. This study aimed to examine the hypothesis that reduced renal blood flow (RBF) in ARAS would be associated with tissue TGF-ß activation and inflammatory cell accumulation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cross-sectional study of ARAS of varying severity compared transjugular biopsy specimens in patients with ARAS (n=12, recruited between 2008 and 2012) with tissue from healthy kidney donors (n=15) and nephrectomy specimens from individuals with total vascular occlusion (n=65). ARAS patients were studied under controlled conditions to measure RBF by multidetector computed tomography and tissue oxygenation by blood oxygen level-dependent magnetic resonance imaging. RESULTS: Compared with the nonstenotic contralateral kidneys, RBF was reduced in poststenotic kidneys (242±149 versus 365+174 ml/min; P<0.01) as was single-kidney GFR (28±17 versus 41±19 ml/min; P<0.01), whereas cortical and medullary oxygenation were relatively preserved. Tissue TGF-ß immunoreactivity was higher in ARAS patients compared with those with both normal kidneys and those with total occlusion (mean score 2.4±0.7 versus 1.5+1.1 in the nephrectomy group and versus 0±0 in donors; P<0.01). By contrast, the number of CD68+ macrophages was higher with greater disease severity (from 2.2±2.7 in normal to 22.4±18 cells/high-power field in nephrectomy samples; P<0.001). CONCLUSIONS: The results of this study indicate robust stimulation of TGF-ß associated with macrophage infiltration within the human kidney with vascular occlusive disease.

Detection of clinical and subclinical tubulo-interstitial inflammation by the urinary CXCL10 chemokine in a real-life setting.

Urinary CXCL10 is a promising noninvasive biomarker for tubulo-interstitial allograft inflammation, but its diagnostic characteristics have not been assessed in a real-life setting. We investigated urinary CXCL10 in 213 consecutive renal allograft recipients having 362 surveillance biopsies at 3/6 months and 80 indication biopsies within the first year posttransplant. Allograft histology results were classified as (i) acute Banff score zero, (ii) interstitial infiltrates only, (iii) tubulitis t1, (iv) tubulitis t2-3 and (v) isolated vascular compartment inflammation. For clinical and subclinical pathologies, urinary CXCL10 correlated well with the extent of tubulo-interstitial inflammation. To determine diagnostic characteristics of urinary CXCL10, histological groups were separated into two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (i.e. tubulitis t1-3 and isolated vascular compartment inflammation). For subclinical pathologies, AUC was 0.69 (sensitivity 61%, specificity 72%); for clinical pathologies, AUC was 0.74 (sensitivity 63%, specificity 80%). A urinary CXCL10-guided biopsy strategy would have reduced performance of surveillance and indication biopsies by 61% and 64%, respectively. Missed (sub)clinical pathologies were mostly tubulitis t1 and isolated vascular compartment lesions. In real life, urinary CXCL10 had clinically useful diagnostic properties making it a candidate biomarker to guide allograft biopsies.

Adenovirus interstitial nephritis and rejection in an allograft.

Viral infections are an important complication of solid organ transplantation. Although polyoma is the virus that most commonly infects the renal allograft, adenoviral infections are also reported. We describe the clinical and pathologic findings in a patient with adenoviral infection associated with acute rejection of the renal allograft. The pathologic findings of adenovirus infection usually include a granulomatous interstitial nephritis, which is helpful in distinguishing from acute rejection. We discuss the differential diagnosis and pathophysiology of allograft viral infections and concomitant rejection.

Pathogenesis of renal injury in the megabladder mouse: a genetic model of congenital obstructive nephropathy.

Congenital obstructive nephropathy (CON) is the most common cause of chronic renal failure in children often leading to end-stage renal disease. The megabladder (mgb) mouse exhibits signs of urinary tract obstruction in utero resulting in the development of hydroureteronephrosis and progressive renal failure after birth. This study examined the development of progressive renal injury in homozygous mgb mice (mgb-/-). Renal ultrasound was used to stratify the disease state of mgb-/- mice, whereas surgical rescue was performed using vesicostomy. The progression of renal injury was characterized using a series of pathogenic markers including alpha smooth muscle isoactin (α-SMA), TGF-ß1, connective tissue growth factor (CTGF), E-cadherin, F4/80, Wilm's tumor (WT)-1, and paired box gene (Pax) 2. This analysis indicated that mgb-/- mice are born with pathologic changes in kidney development that progressively worsen in direct correlation with the severity of hydronephrosis. The initiation and pattern of fibrotic development observed in mgb-/- kidneys appeared distinctive from previous animal models of obstruction. These observations suggest that the mgb mouse represents a unique small animal model for the study of CON.

A case of second renal transplantation with acute antibody-mediated rejection complicated with BK virus nephropathy.

We reported a 40-year-old female case of second renal transplantation with antibody-mediated rejection (AMR) complicated by BK virus nephropathy. She started hemodialysis (HD) at the age of 17 because of IgA nephropathy. At the age of 18, she underwent living-donor kidney transplantation from her father, but two and a half years after transplantation, she developed chronic rejection. This time, she received cadaveric renal transplantation under the negative cross-match (AHG-LCT), and HLA-AB 1 mismatch and -DR 1 mismatch. Immunosuppressive therapy was initiated using the following four immunosuppressants: methylprednisolone, mycophenolate mofetil, cyclosporine, and basiliximab. However, renal graft showed delayed function, the biopsy showed glomerulitis (g2), endarteritis (v1), and cellular infiltration (ptc3) consisting mainly of mononuclear cells in the peritubular capillary with diffusely positive C4d and anti-SV 40 large T-antigen-positive renal tubular epithelial cells on post-operative day 19. The donor-specific antibody for HLA-B46 was proven by the LAB screen method. We performed plasma exchange three times and administered immunoglobulin (15 g in total). Then, methylprednisolone pulse therapy was added, and the serum creatinine (SCr) levels gradually decreased. On post-operative day 44, the patient was removed from HD and was discharged with SCr level of 3.3 mg/dL.

Effect of the proteasome inhibitor bortezomib on humoral immunity in two presensitized renal transplant candidates.

BACKGROUND: Recipient presensitization represents a major hurdle to successful renal transplantation. Previous case series have suggested that the proteasome inhibitor bortezomib directly affects the alloantibody-secreting plasma cells in rejecting allograft recipients. However, the ability of this agent to desensitize nonimmunosuppressed transplant candidates before transplantation is currently unknown. METHODS: In this analysis, two sensitized hemodialysis patients were selected to receive two subsequent bortezomib cycles. Bortezomib was given at 1.3 mg/m(2) on days 1, 4, 8, and 11. Dexamethasone was added to the second cycle to enhance treatment efficiency. Serial immune monitoring included cytotoxic panel reactive antibody testing, Luminex single antigen testing for anti-human leukocyte antigen (HLA) IgG with or without C4d-fixing capability, and ABO antibody detection. RESULTS: During a half-year follow-up period, cytotoxic panel reactive antibody decreased from 87% to 80% (patient 1) and 37% to 13% (patient 2). Patient 1 showed a 40% reduction in binding intensities of identified Luminex HLA single antigen reactivities and, in parallel, slight reductions in ABO blood group antibody and total immunoglobulin levels. In patient 2, bortezomib did not affect circulating antibody levels in a meaningful way. Both patients showed a more than 50% reduction in the levels of anti-HLA antibody-triggered C4d deposition to Luminex beads. CONCLUSION: Our initial experience suggests that, without additional immunosuppressive measures, bortezomib has modest effects on circulating antibodies against HLA or blood group antigens. The reduced levels of antibody-triggered complement fixation, however, imply potential clinical relevance of proteasome inhibition for recipient desensitization.

Recurrence of granulomatous interstitial nephritis in transplanted kidney.

Sarcoidosis is a multisystemic disease of unknown etiology. Minor renal involvement is not rare but kidney failure is uncommon and only rare cases of recurrent disease in a kidney transplant have been published. We report a patient who at age 10 yr developed ESRD secondary to renal sarcoidosis with GIN. Her disease subsequently recurred in the transplanted kidney despite standard immunosuppression with prednisone, tacrolimus, and mycophenolate mofetil. The recurrent disease appeared to respond to increased immunosuppression, which included infliximab. However, the patient died of disseminated histoplasmosis three yr post-transplant.

Wnt/beta-catenin signaling promotes renal interstitial fibrosis.

Wnts compose a family of signaling proteins that play an essential role in kidney development, but their expression in adult kidney is thought to be silenced. Here, we analyzed the expression and regulation of Wnts and their receptors and antagonists in normal and fibrotic kidneys after obstructive injury. In the normal mouse kidney, the vast majority of 19 different Wnts and 10 frizzled receptor genes was expressed at various levels. After unilateral ureteral obstruction, all members of the Wnt family except Wnt5b, Wnt8b, and Wnt9b were upregulated in the fibrotic kidney with distinct dynamics. In addition, the expression of most Fzd receptors and Wnt antagonists was also induced. Obstructive injury led to a dramatic accumulation of beta-catenin in the cytoplasm and nuclei of renal tubular epithelial cells, indicating activation of the canonical pathway of Wnt signaling. Numerous Wnt/beta-catenin target genes (c-Myc, Twist, lymphoid enhancer-binding factor 1, and fibronectin) were induced, and their expression was closely correlated with renal beta-catenin abundance. Delivery of the Wnt antagonist Dickkopf-1 gene significantly reduced renal beta-catenin accumulation and inhibited the expression of Wnt/beta-catenin target genes. Furthermore, gene therapy with Dickkopf-1 inhibited myofibroblast activation; suppressed expression of fibroblast-specific protein 1, type I collagen, and fibronectin; and reduced total collagen content in the model of obstructive nephropathy. In summary, these results establish a role for Wnt/beta-catenin signaling in the pathogenesis of renal fibrosis and identify this pathway as a potential therapeutic target.

Medicolegal reflections about a case of cardiac death after renal transplantation.

Cardiovascular disease is the most common cause of death in patients with renal transplant. Acute coronary syndrome due to coronary artery disease, and left ventricular hypertrophy leading to chronic heart failure account for the majority of sudden arrhythmic deaths after transplantation. Furthermore death with functioning graft represents the main cause of graft loss, particularly after the first post-transplantation year. Although cardiovascular disease leads to morbidity and mortality in renal transplant recipients, its pathogenesis is poorly understood. The high incidence of cardiovascular disease in patients after renal transplant is chiefly due to high occurrence and accumulation of traditional risk factors before and after transplantation. Hypertension, post-transplant diabetes mellitus and hyperlipidemia increase the risk for cardiovascular events. Also 'non traditional' risk factors are associated with cardiovascular disease. Moreover several immunosuppressive drugs interfere with the cardiovascular system. The authors present a case of cardiac death following renal transplant in a patient with history of cardiovascular disease prior transplantation. Initially treated by hemodialysis, after 3 years he received a cadaveric renal transplant. The post-transplantation period was without surgery complications, immunological or infectious, except for a scarce control of blood pressure. A month after the operation, the patient developed thrombophlebitis, plus extra-peritoneal swelling. After ten days in hospital he suddenly died. The aim of the manuscript is to remark on the legal relevance of patient's consensus to transplant. It is necessary to well inform patients of an operation's risks and complications. Furthermore, the exceeding demand with respect to organ availability raises ethical issues about organ allocation.