Urinary Diagnostic Cytology Beyond the Research of Neoplastic Cells: Usefulness of Erythrocyte Morphology Evaluation to Recognize Microhematuria Source.

Background: Urine cytology is useful to diagnose urinary neoplasms, whereas its role in the study of microhematuria is debatable. Usually, standard urinalysis (dipstick test and sediment examination with bright field microscope) detects the presence of microhematuria, but only urinalysis with phase-contrast microscopy (PCM) (dipstick test and sediment examination with PCM) allows the observation of red blood cell (RBC) morphology and identify their source. Usually glomerular diseases show RBCs with morphological alterations in high percentages, whereas on urologic bleeding, RBCs are rather homogeneous without morphological alterations. Aims: We compare, for the first time, RBC morphology observed in urine cytology and in urinalysis with PCM, to verify whether urinary cytology allows the recognition of the source of bleeding. Methods and Material: A total of 60 patients who had performed both urine cytology and urinalysis with PCM for microhematuria, detected with standard urinalysis, were investigated. Urine cytology showed RBCs and were negative for neoplastic cells or for inflammatory events. Urine samples were processed with the automated method ThinPrep®. RBCs with abnormal and variable shapes were defined as deformed. RBCs of the same spherical shape were defined as non-deformed. Results: Fifty-six urine cytology with RBCs deformed were confirmed in 55 urinalysis with PCM. One case showed RBCs non deformed in urine cytology and in urine sediment. Overall, agreement, between RBC morphology in urine cytology and urinalysis with PCM, was found in 56/60 cases (93%). Conclusions: Therefore, since sediment examination with PCM is available in only few laboratories, we propose that cytopathologist always reports, in urine cytology, any morphological abnormalities of RBCs in order to provide information of the hematuria origin and correctly refer the patient to a nephrologist rather than a urologist.

Case Report: Optic Atrophy and Nephropathy With m.13513G>A/MT-ND5 mtDNA Pathogenic Variant.

Isolated complex I deficiency represents the most common mitochondrial respiratory chain defect involved in mitochondrial disorders. Among these, the mitochondrial DNA (mtDNA) m.13513G>A pathogenic variant in the NADH dehydrogenase 5 subunit gene (MT-ND5) has been associated with heterogenous manifestations, including phenotypic overlaps of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, Leigh syndrome, and Leber's hereditary optic neuropathy (LHON). Interestingly, this specific mutation has been recently described in patients with adult-onset nephropathy. We, here, report the unique combination of LHON, nephropathy, sensorineural deafness, and subcortical and cerebellar atrophy in association with the m.13513G>A variant.

[Relevance of an accurate microscopic examination of urinary sediment in a patient after mitral valve surgery].

Hemoglobinuria, clinically revealing as gross hematuria associated with anemia, increased hemolysis indices, acute kidney injury (AKI), can all be caused by mechanical intravascular hemolysis following mitral valve surgery. It can result from factors related to the surgical procedure or acquired later, such as paravalvular leak (PL), whose definite diagnosis is based on transesophageal echocardiography. We report the case of a patient who experienced macrohematuria and AKI, initially attributed to acute glomerulonephritis, two months after mitral valve surgery. Careful microscopic examination of the urinary sediment was a diriment diagnostic tool to differentiate acute renal failure caused by hemoglobinuria from hematuria in the course of acute glomerulonephritis, directing clinicians to investigate post-operative valvular dysfunction. From the literature review we can deduce that, notwithstanding new technologies in cardiac surgery, this rare form of AKI from intravascular hemolysis requires immediate nephrological attention and that the use of microscopic urinary sediment is decisive.

PLA2R Immunohistochemistry Staining in Membranous Glomerulopathy: A Challenging Stain to Interpret But a Potentially Useful Diagnostic Tool.

Circulating autoantibodies to phospholipase A2 receptor (PLA2R-Ab) are detected in >70% of patients with primary membranous glomerulonephritis (MGN). Detection of PLA2R antigen in renal tissue, with immunohistochemistry (PLA2R IHC), strongly correlates with serum PLA2R-Ab, although it is more sensitive. As PLA2R IHC in literature has no univocal interpretation, we suggest reliable criteria for a standard approach for the assessment of immunostaining for differential diagnosis between primary and secondary MGN. We analyzed PLA2R IHC expression in 40 biopsies of patients with MGN and serum PLA2R-Ab titer at the time of biopsy. We carefully evaluated, at high magnification, the immunostaining pattern and distribution, regardless of intensity, in capillary loops, mesangium, and podocytes of all glomeruli.We defined, adopting this approach, positive stain when a granular pattern, coarse and/or fine, diffuse or focal, and global or segmental were observed. Negative stain was defined by mesangial staining, when there was a dirty pattern, or a peripheral staining of capillary loops with a smoky linear pattern. Podocytes showed homogenous cytoplasmatic stain both in positive and negative cases and in external negative controls. We found PLA2R IHC and serum PLA2R-Ab positivity in early-middle stage MGN compared with advanced stage more frequently. Correct stratification of patients with MGN needs PLA2R-Ab detection in serum and renal tissue. PLA2R IHC test, although a challenging stain, can be an easy diagnostic tool but requires reliable interpretation keys for a standard approach to the assessment of immunostaining.

WITHDRAWN: Nephrotic syndrome in primary myelofibrosis with renal extramedullary hematopoiesis and glomerulopathy in the JAK inhibitor era.

Ahead of Print article withdrawn by publisher. The publisher apologizes for any inconvenience this has caused. The article was scheduled for the journal "Clinical Nephrology. Case Studies" (issn 2196-5293). The article is available in PubmedCentral: https://www.ncbi.nlm.nih.gov/pubmed/29350220 
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Nephrotic syndrome in primary myelofibrosis with renal extramedullary hematopoiesis and glomerulopathy in the JAK inhibitor era.

Primary myelofibrosis (PMF) is an uncommon form of myeloproliferative neoplasm (MPN) characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow that, in fully-developed disease, is associated with reactive deposition of fibrous connective tissue, extramedullary hematopoiesis (EMH), and splenomegaly. Kidney involvement is rare and clinically presents with proteinuria, nephrotic syndrome, and renal insufficiency. Renal damage can be due to EMH and glomerulopathy. Renal EMH presents three patterns: infiltration of the interstitium with possible renal failure caused by functional damage of parenchyma and vessels, infiltration of capsule and pericapsular adipose tissue, and sclerosing mass-like lesions that can cause hydronephrosis and hydroureter with obstructive uropathy and renal failure. Glomerulopathy associated with PMF is rarely described, ranging from 1 month to 18 years from diagnosis of the neoplasm to renal biopsy. It is characterized by expansion and hypercellularity mesangial, segmental sclerosis, features of chronic thrombotic microangiopathy (TMA), and intracapillary hematopoietic cells infiltrating in absence of immune-mediated glomerulonephritis. We present a nephrotic syndrome in PMF-related glomerulopathy, associated with EMH, without renal failure, in a patient under treatment for 2 years with JAK2 inhibitor ruxolitinib. Despite treatment, the patient died 7 months after renal biopsy. Nephrologists still know very little about this topic and there is no homogeneous data about incidence, pathogenesis, and optimal treatment of this poor prognostic PMF-associated nephrotic syndrome. We focus on data in the literature in the hope of stimulating hematologists, nephrologists, pathologists to future studies about the natural history of renal involvement, useful for optimal management of this rare pathology.

Thrombotic microangiopathic nephropathy, pulmonary hypertension and nephromegaly: case report of a patient treated with endothelin receptor antagonist.

The coexistence of thrombotic microangiopathic nephropathy and pulmonary hypertension has only been described in association with malignancy and its treatment. Here we describe a 14-year-old boy with no prior medical history who presented with hypertension, proteinuria and nephromegaly, and then developed progressive pulmonary hypertension. Renal histology showed lesions consistent with glomerulopathy due to thrombotic microangiopathy (TMA). Pulmonary hypertension was controlled by the use of an oral endothelin receptor antagonist (bosentan). Although renal function deteriorated at the onset of pulmonary hypertension, an improvement was observed after the bosentan treatment. Nephromegaly persisted, but current creatinine clearance values are within the normal range. While this case exemplifies how thrombotic microangiopathic nephropathy may be associated with pulmonary hypertension, a therapeutic role of endothelin antagonists is suggested, not only for pulmonary hypertension but also for microangiopathic nephropathy.

Increased acid excretion in kidney stone formers with essential hypertension.

BACKGROUND: Although several studies have reported that kidney stone disease and hypertension are associated, the link between the two conditions has not been identified. This study investigated urinary excretion of different solutes, particularly citrate and acids, in kidney stone formers and examined their association with high blood pressure. METHODS: The retrospective study included 234 consecutive subjects, aged 47.0 +/- 15.6, attending our metabolic clinic after episodes of kidney stones. Essential hypertension was present in 82 patients (35.0%). A difference in the urinary excretion of some of the investigated components was found between subjects with normal blood pressure and those with hypertension. RESULTS: The results showed that hypertensive subjects were older and had a higher body mass index (BMI) and serum uric acid. They had a significantly lower urinary pH (5.6 +/- 0.4 versus 6.0 +/- 0.5) and citrate (2.55 +/- 1.36 versus 2.83 +/- 1.65 mmol/24 h), higher titratable acid (38.8 +/- 19.0 versus 26.8 +/- 15.0 mEq/24 h) and ammonium (41.6 +/- 17.6 versus 34.2 +/-12.4 mmol/24 h). Logistic regression analysis with the presence of hypertension as the dependent variable produced a model with the following predictors: age (P < 0.0001), BMI (P = 0.026), titratable acid (P = 0.025) and low urinary citrate level (P = 0.033). Urinary acid excretion increased with the stage of hypertension. No difference was found in the urinary excretion of other solutes. CONCLUSIONS: These findings suggest that essential hypertension and acid excretion are linked in stone formers.