Proliferative Glomerulonephritis With Fibrils, Monoclonal κ Light Chain, and C3 Deposits.

There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin is demonstrated. Recently, proliferative GN with monoclonal immunoglobulin deposits (PGNMID) has incorporated a light chain variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of C3 is found in addition to monotypic light chain, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year-old man who presented with nephrotic syndrome and was found to have κ light chain multiple myeloma. Immune staining of the glomerulus was positive only for κ light chain and C3, with the striking appearance of nonamyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for light chain and complement and consider local mechanisms whereby monoclonal κ light chain fibrils may have triggered AP activation within the glomerulus.

The utility of magnetic resonance imaging in prostate cancer diagnosis in the Australian setting.

Objectives: To investigate the utility of Magnetic Resonance Imaging (MRI) for prostate cancer diagnosis in the Australian setting. Patients and methods: All consecutive men who underwent a prostate biopsy (transperineal or transrectal) at Royal Melbourne Hospital between July 2017 to June 2019 were included, totalling 332 patients. Data were retrospectively collected from patient records. For each individual patient, the risk of prostate cancer diagnosis at biopsy based on clinical findings was determined using the European Randomized study of Screening for Prostate Cancer (ERSPC) risk calculator, with and without incorporation of MRI findings. Results: MRI has good diagnostic accuracy for clinically significant prostate cancer. A PI-RADS 2 or lower finding has a negative predictive value of 96% for clinically significant cancer, and a PI-RADS 3, 4 or 5 MRI scan has a sensitivity of 93%. However, MRI has a false negative rate of 6.5% overall for clinically significant prostate cancers. Pre- biopsy MRI may reduce the number of unnecessary biopsies, as up to 50.0% of negative or ISUP1 biopsies have MRI PI-RADS 2 or lower. Incorporation of MRI findings into the ERSPC calculator improved predictive performance for all prostate cancer diagnoses (AUC 0.77 vs 0.71, P = .04), but not for clinically significant cancer (AUC 0.89 vs 0.87, P = .37). Conclusion: MRI has good sensitivity and negative predictive value for clinically significant prostate cancers. It is useful as a pre-biopsy tool and can be used to significantly reduce the number of unnecessary prostate biopsies. However, MRI does not significantly improve risk predictions for clinically significant cancers when incorporated into the ERSPC risk calculator.

Noninfectious mixed cryoglobulinaemic glomerulonephritis and monoclonal gammopathy of undetermined significance: a coincidental association?

BACKGROUND: Cryoglobulins are cold-precipitable immunoglobulins that may cause systemic vasculitis including cryoglobulinaemic glomerulonephritis (CGN). Type 1 cryoglobulins consist of isolated monoclonal immunoglobulin (mIg), whereas mixed cryoglobulins are typically immune complexes comprising either monoclonal (type 2) or polyclonal (type 3) Ig with rheumatoid activity against polyclonal IgG. Only CGN related to type 1 cryoglobulins has been clearly associated with monoclonal gammopathy of undetermined significance (MGUS) using the conventional serum-, urine- or tissue-based methods of paraprotein detection. CASE PRESENTATION: We present four patients with noninfectious mixed (type 2 or 3) CGN and MGUS. Two patients had type 2 cryoglobulinaemia, one had type 3 cryoglobulinaemia, and one lacked definitive typing of the serum cryoprecipitate. The serum monoclonal band was IgM-κ in all four cases. Treatments included corticosteroids, cyclophosphamide, plasma exchange, and rituximab. At median 3.5 years' follow-up, no patient had developed a haematological malignancy or advanced chronic kidney disease. Other potential causes of mixed cryoglobulinaemia were also present in our cohort, notably primary Sjögren's syndrome in three cases. CONCLUSION: Our study raises questions regarding the current designation of type 2 CGN as a monoclonal gammopathy of renal significance, and the role of clonally directed therapies for noninfectious mixed CGN outside the setting of haematological malignancy.

Durable remission of C3 glomerulonephritis with mycophenolate mofetil.

In C3 glomerulopathy, uncontrolled complement C3 activation via the alternative pathway results in glomerular C3 deposition and, in many cases, progressive renal failure. Despite advances in understanding of C3G pathogenesis over the last few years, there are no proven treatments. We describe a patient in whom C3 glomerulopathy was associated with renal impairment and elevated serum free kappa light chains. An initial response to corticosteroids was followed by relapse once steroids were weaned, prompting use of mycophenolate mofetil to maintain remission. We discuss some of the diagnostic and therapeutic issues surrounding C3G, including in the setting of monoclonal gammopathy.

Histological and Extended Clinical Outcomes After ABO-Incompatible Renal Transplantation Without Splenectomy or Rituximab.

BACKGROUND: Excellent short-term results have been reported in ABO-incompatible (ABOi) renal transplant recipients managed solely with antibody removal and conventional immunosuppression. However, long-term clinical outcomes with this regimen and predictive information from protocol biopsies are lacking. METHODS: We compared outcome data in ABOi and ABO-compatible (ABOc) recipients receiving this regimen approximately 4 years posttransplant, and histology from biopsies approximately 12 months posttransplant. RESULTS: Patient and graft survivals among 54 ABOi recipients were 98.1% and 90.7%, respectively, at 4 years. Graft function was similar between ABOi (creatinine, 140.3 µmol/L) and ABOc recipients (creatinine, 140.2 µmol/L) (P = 0.99), with no significant change over the study period in either group (Δcreatinine, -0.83 vs 6.6 µmol/L) (P = 0.59). There was no transplant glomerulopathy in biopsies from either group. Interstitial fibrosis (IF) and tubular atrophy (TA) was present in 7 (28%) of 25 ABOi compared with 7 (20.6%) of 34 ABOc (P = 0.52). Progression of IF/TA from implantation was noted in 6 (24%) of 25 ABOi and 6 (17.6%) of 34 ABOc, respectively. C4d staining without antibody-mediated rejection was present in 13 (52%) 25 early posttransplant biopsies from ABOi recipients by immunohistochemistry, but in only 4 (16%) of 25 at 12 months. CONCLUSIONS: ABO-incompatible renal transplant performed with antibody removal and conventional immunosuppression continues to provide excellent patient and graft survival, and stable renal function over 4 years. Coupled with absent transplant glomerulopathy and low rates of progressive IF/TA on earlier biopsies, this suggests that ABOi with conventional immunosuppression and antibody removal, without rituximab or splenectomy, can achieve long-term outcomes comparable to ABO-compatible transplantation.

Alport Syndrome in Women and Girls.

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Inheritance is X-linked (85%) or autosomal recessive (15%). Many renal physicians think of Alport syndrome as primarily affecting men. However, twice as many women are affected by the X-linked diseases. Affected women are commonly undiagnosed, but 15%-30% develop renal failure by 60 years and often hearing loss by middle age. Half of their sons and daughters are also affected. Autosomal recessive Alport syndrome is less common, but is often mistaken for X-linked disease. Recessive inheritance is suspected where women develop early-onset renal failure or lenticonus. Their family may be consanguineous. The prognosis for other family members is very different from X-linked disease. Other generations, including parents and offspring, are not affected, and on average only one in four of their siblings inherit the disease. All women with Alport syndrome should have their diagnosis confirmed with genetic testing, even if their renal function is normal, because of their own risk of renal failure and the risk to their offspring. Their mutations indicate the mode of inheritance and the likelihood of disease transmission to their children, and the mutation type suggests the renal prognosis for both X-linked and recessive disease. Women with X-linked Alport syndrome should be tested at least annually for albuminuria and hypertension. The "Expert guidelines for the diagnosis and management of Alport syndrome" recommend treating those with albuminuria with renin-angiotensin-aldosterone system (RAAS) blockade (and adequate birth control because of the teratogenic risks of angiotensin converting enzyme inhibitors), believing that this will delay renal failure. Current recommendations are that women with autosomal recessive Alport syndrome should be treated with RAAS blockade from the time of diagnosis. In addition, women should be offered genetic counseling, informed of their reproductive options, and monitored closely during pregnancy for the development of hypertension.

Antiphospholipid syndrome in renal transplantation.

Antiphospholipid syndrome (APS) may occur in isolation or in association with systemic lupus erythematosus (SLE), with the potential to cause renal failure via several distinct pathologies. Renal transplantation in the presence of APS carries a risk of early graft loss from arterial or venous thrombosis, or thrombotic microangiopathy (TMA). Whilst perioperative anticoagulation reduces the risk of large vessel thrombosis, it may result in significant haemorrhage, and its efficacy in preventing post-transplant TMA is uncertain. Here, we report a patient with end-stage kidney disease (ESKD) due to lupus nephritis and APS, in whom allograft TMA developed soon after transplantation despite partial anticoagulation. TMA resolved with plasma exchange-based therapy albeit with some irreversible graft damage and renal impairment. We discuss the differential diagnosis of post-transplant TMA, and current treatment options.

Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis.

Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC.

Decreased viral load and symptoms of polyomavirus-associated chronic interstitial cystitis after intravesical cidofovir treatment.

Interstitial cystitis causes disabling bladder pain and is usually diagnosed in the absence of infection. We describe a patient with interstitial cystitis who had high urinary levels of polyomavirus that decreased dramatically after initiation of intravesical cidofovir treatment; the patient also showed substantial improvement in symptoms. Another patient had milder symptoms of cystitis and intermittent polyomavirus shedding. Polyomaviruses, particularly BK virus, may cause some cases of interstitial cystitis.

Diagnosis of peripheral pulmonary carcinoid tumor using endobronchial ultrasound.

A 51-year-old woman with severe asthma underwent bronchoscopy and endobronchial ultrasound (EBUS) for investigation of a 15-mm peripheral lung nodule. Histology demonstrated a typical carcinoid tumor. Pulmonary location is the second commonest site for carcinoid tumors. Diagnosis of peripheral carcinoid tumor of the lung is difficult due to its small size, poor accuracy of cytologic diagnosis, and low sensitivity of positron emission tomography in detecting it. EBUS has a high diagnostic yield and a low complication rate in the evaluation of small solitary pulmonary nodules. The ultrasound appearance of carcinoid tumors is identical to that of lung carcinomas. Prompt diagnosis of carcinoid tumor is desirable as regional lymph node metastasis is seen in 10% of patients and is associated with a reduced 5-year survival. We feel that, where possible, all patients presenting with solitary pulmonary nodules should be investigated initially using EBUS due to its high diagnostic rate and the very low incidence of adverse events.

Pelvic lipomatosis associated with proliferative cystitis occurring in two brothers.

Pelvic lipomatosis is a rare disorder of benign mature adipose tissue proliferation around the bladder and rectum. Most cases are associated with proliferative cystitis, in particular, cystitis glandularis. The etiology of pelvic lipomatosis and its association with proliferative cystitis are not well understood. This is the first reported case of familial pelvic lipomatosis. The pathogenesis and the possibility that this disorder could be secondary to genetic abnormalities of the HMG-IC (high mobility group) gene on chromosome 12 are discussed.