[Renal Side Effects of Novel Molecular Targeted Oncologic Agents].

The introduction of innovative therapies has changed the scenario of complications. The delay in the recognition of kidney adverse effects is partly due to the timing of the development of the kidney damage which occurs later than the observation period of registration studies, and partly to the exclusion of patients with known kidney impairment from registration trials. Renal disease has a significant impact on the management of cancer patients and often leads to discontinuation of therapy. Histological evaluations of kidney disorders induced by targeted/immunotherapy are very limited. Renal biopsy is critical for the management of renal toxicities and should be especially encouraged for patients showing adverse renal effects to novel cancer agents. We recently examined the histological features of patients treated with new cancer agents who underwent renal biopsy for new onset renal failure and/or urinary abnormalities. The cohort included 42 patients. The most frequently administered therapies were immunotherapy (54.8%) and anti-angiogenic treatments (45.2%). The most common adverse effect was tubular interstitial nephritis in the first group and thrombotic microangiopathy in the second one. Based on histological findings, definitive discontinuation of treatment could be restricted to a very limited number of patients. All of them had anti-VEGF-related TMA. Treatment discontinuation was unneeded in patients treated with ICIs. In patients treated with multidrug therapy, the histological findings made it possible to identify the weight of drug-related specific injury. Based on this data, renal biopsy should be considered in every cancer patient who develops urinary abnormalities or shows a worsening of renal function during treatment with immunotherapy or targeted therapy.

Outcomes of allograft from donor kidney microthrombi and secondary recipient thrombotic microangiopathy: should we consider loosening the belt? / ä¾›ä½“è‚¾å¾®è¡€æ “å’Œç»§å‘æ€§å—ä½“è¡€æ “æ€§å¾®è¡€ç®¡ç— å¯¹åŒç§å¼‚ä½“ç§»æ¤è‚¾çš„å½±å“ï¼šæˆ‘ä»¬åº”è¯¥æ”¾æ¾è­¦æƒ•å—ï¼Ÿ.

There is currently a huge worldwide demand for donor kidneys for organ transplantation. Consequently, numerous marginal donor kidneys, such as kidneys with microthrombi, are used to save patients' lives. While some studies have shown an association between the presence of microthrombi in donor kidneys and an increased risk for delayed graft function (DGF) (McCall et al., 2003; Gao et al., 2019), other studies have demonstrated that microthrombi negatively impact the rate of DGF (Batra et al., 2016; Hansen et al., 2018), but not graft survival rate (McCall et al., 2003; Batra et al., 2016; Gao et al., 2019). In contrast, Hansen et al. (2018) concluded that fibrin thrombi were not only associated with reduced graft function six months post-transplantation but also with increased graft loss within the first year of transplantation. On the other hand, Batra et al. (2016) found no significant differences in the DGF rate or one-year graft function between recipients in diffuse and focal microthrombi groups. To date, however, the overall influence of donor kidney microthrombi and the degree of influence on prognosis remain controversial, necessitating further research.

Risk of skin cancer in kidney, liver and heart recipients: A nationwide population-based study in Taiwan.

Background Previous population-based studies in western countries had revealed increased skin cancer risk among transplant recipients compared to the general population. However, population-based studies in Asia on skin cancer among recipients of different transplanted organs were lacking in the literature. Aims This study aims to estimate skin cancer risk among recipients in Taiwan, examine the association between each specific type of skin cancer and each type of transplanted organ, and compare skin cancer risk between different immunosuppressive regimens. Methods This population-based retrospective cohort study identified 7550 patients with heart, lung, kidney or liver transplantation and 30,200 controls matched for gender, age and comorbidity index from the National Health Insurance Research Database in Taiwan between 2000 and 2015. Using multivariable Cox proportional hazard models, we estimated the hazard ratios and 95% confidence intervals for the correlation of skin cancer with organ transplantation as well as immunosuppressive regimen. Results Organ transplant recipients in Taiwan had an increased risk of skin cancer with adjusted hazard ratios of 4.327 (95% confidence intervals 2.740-6.837, P < 0.001), with the greatest risk, observed among heart recipients (adjusted hazard ratios 6.348, 95% confidence intervals 3.080-13.088, P < 0.001). The risk of non-melanoma skin cancer and melanoma was 4.473 (95% confidence intervals 2.568-7.783, P < 0.001) and 3.324 (95% confidence intervals 1.300-8.172, P < 0.001), respectively. When comparing immunosuppressants, those with calcineurin inhibitors carried the highest risk of skin cancer (adjusted hazard ratios 4.789, 95% confidence intervals 3.033-7.569, P < 0.001), followed by those with antimetabolites (adjusted hazard ratios 4.771, 95% confidence intervals 3.025-7.541, P < 0.001). Limitations We could not evaluate confounding behavioural risk factors of skin cancers that were not documented in the database, nor could we recognize patients' compliance with immunosuppressants. Conclusion Organ recipients have a greater risk of skin cancer. Clinicians should inform recipients of the importance of photoprotection and regular dermatologic follow-up.

Kidney biomarkers in tropical infections: an update.

Neglected tropical diseases affect over 1 billion people, and cause 170,000 deaths each year. They result in disability, stigma and disfigurement, and also push families into poverty. Tropical infections can involve the kidney, presenting as a wide variety of ways, varying from transient urinary abnormalities to severe acute kidney injury (AKI). It is important to assess renal function in patients with tropical infections for earlier detection of AKI, appropriate treatment and prevention of Chronic Kidney Disease (CKD) outcome in some of them. There was an exponential increase in research on new kidney biomarkers that were earlier and specific for renal damage but few in the scope of tropical infections. In this review, we focus on kidney biomarkers that are being studied in some of the most prevalent tropical infections such as visceral leishmaniasis, leptospirosis, malaria, schistosomiasis and leprosy. Further studies are needed to evaluate the usefulness of renal biomarkers in the early diagnosis of renal diseases associated with tropical infections.

Hansen's disease with lepra reaction presenting with IgA dominant infection related glomerulonephritis.

Various renal abnormalities in leprosy have been described largely in literature but the occurrence of IgA dominant infection related glomerulonephritis in leprosy with type 2 lepra reaction has not been reported so far. We present here a 60-year-old man with a history of leprosy in the past admitted with type 2 lepra reaction, rapidly progressive glomerulonephritis with severe renal failure requiring dialysis and diagnosed to have IgA dominant infection related glomerulonephritis.

Assessment of liver and renal functions in human immunodeficiency virus-infected persons on highly active antiretroviral therapy: A mixed cohort study.

BACKGROUND: Indian data on potential hepatorenal toxic effects of highly active antiretroviral therapy (HAART) in HIV/AIDS-affected persons is lacking. OBJECTIVES: To assess hepatorenal abnormalities in HIV-infected persons on HAART in a hospital-based mixed cohort study using concurrent and nonconcurrent data analysis. METHODS: Hepatorenal function tests, urinalysis and ultrasonogaphy for liver/kidneys (when applicable) were assessed in 400 (men 185; women 215) persons aged 2-84 (mean 47.8) years on HAART. Acute liver toxicity, acute kidney injury and chronic kidney disease were defined depending upon abnormal serum alanine aminotransferase, urea and creatinine levels/clearance as per standard guidelines. RESULTS: The duration of HAART was 1 month to 9 years (mean 3.7 years) with 284 (71%) individuals being on treatment for ≤5years. The major HAART regimens included zidovudine + lamivudine + nevirapine in 175 (43.8%), tenofovir + lamivudine + efavirenz in 174 (43.5%) and zidovudine + lamivudine + efavirenz in 20 (5%) individuals and were associated with grade-1 hepatic dysfunction in 57 (14.3%) individuals, with men aged between 31 and 45 years on antiretroviral therapy for >5 years being mainly affected. Forty two (17.1%) of 246 individuals with anemia and 15 (9.7%) of 154 individuals without anemia showed hepatic dysfunction. None had acute kidney injury, chronic kidney disease or abnormal urinalysis or ultrasonography. In contrast, the pretreatment elevated serum alanine amiotranerase in 99 (22.3%) and blood urea and/or creatinine levels in 16 (4%) individuals decreased significantly post highly active antiretroviral therapy. CONCLUSIONS: The study reflects the low frequency of regimen based highly active antiretroviral therapy-associated hepatic or nephrotoxicity despite prolonged use, especially in the absence of other risk factors. Preexisting anemia appears an important risk factor for highly active antiretroviral therapy-induced hepatotoxicity (OR 1.90, Cl 95% CI 1.02-3.57, P = 0.04). Highly active antiretroviral therapy-associated nephrotoxicity was not a significant problem. Study of viral load or other risk factors and potential of each drug for hepatorenal toxicity/dysfunction in HIV affected were not part of the study. A small number of subjects and retrospective analysis of biochemical parameters were other important limitations.

Acute renal failure by rapidly progressive glomerulonephritis with IgA deposition in a patient concomitantly diagnosed with multibacillary Hansen's disease: a case report.

Rapidly progressive glomerulonephritis (RPGN) is a renal disease with an extensive differential diagnosis. This paper reports the case of a 55-year-old female patient diagnosed with Hansen's disease with acute progressive renal impairment after developing lower limb pyoderma. The association between Hansen's and kidney disease has been well documented, with glomerulonephritis (GN) ranked as the most common form of renal involvement. Post-infectious glomerulonephritis (PIGN) in adults has been associated with a number of pathogens occurring in diverse sites. The patient described in this case report had RPGN and biopsy findings suggestive of PIGN with C3 and IgA detected on immunofluorescence and kidney injury secondary to recent infection by Staphylococcus, a well-documented manifestation of renal impairment in patients with Hansen's disease.

It is time to review concepts on renal involvement in leprosy: pre- and post-treatment evaluation of 189 patients.

BACKGROUND: Functional and morphological renal lesions have been widely described in leprosy for decades. Nevertheless few studies have assessed renal function pre- and during treatment after the advent of multidrug therapy (MDT). METHODS: This is a prospective study involving 189 consecutive patients, with all forms of leprosy (Ridley-Jopling scale). Laboratory (serum urea and creatinine, estimated GFR, urinalysis, microalbuminuria, urinary RBP) and clinical features of renal disease were evaluated previously and after onset (3 and 8 months later) of MDT. RESULTS: One hundred and eighty-nine patients (M 1.8: F 1; mean age 44 ± 16 years) were included just after diagnosis of leprosy and before the introduction of MDT. Mean time until manifestation of symptoms and/or signs of leprosy was 29 ± 56 months (25 days-480 months). Microhematuria and microalbuminuria were detected in 7.5% and 9.6% of the cases, respectively. Elevated serum creatinine was detected in 34% pre-MDT; this was statistically more frequent in males, hypertensive and frequent users of non-steroidal anti-inflammatory drugs (NSAID), as well as in patients with erythema nodosum lepromatosum, 45.5% by the time of diagnosis, 18% after 3 months and 9% after 8 months of MDT (p = 0.039). CONCLUSIONS: Our results suggest that functional renal lesions in leprosy are currently mild and predominantly of glomerular origin, in opposition to the severe involvement described in the past. This improved outcome of renal disease secondary to leprosy is possibly due to the advent of MDT and effective treatment of episodes of reaction, leading to shorter periods of active infectious disease.

Urinary monocyte chemotactic protein-1 (MCP-1) in leprosy patients: increased risk for kidney damage.

BACKGROUND: We aimed to evaluate urinary MCP-1 and oxidative stress through urinary malondialdehyde (MDA) in leprosy and correlate them with traditional, but less sensitive markers of renal disease. METHODS: This is a cross-sectional study of 44 patients with diagnosis of leprosy and no previous treatment. Skin smear was assessed through a bacteriological index - from 0 to 6+. Glomerular filtration rate (GFR), protein excretion rate, microalbuminuria, urinary oxidative stress, malondialdehyde (MDA) and urinary MCP-1 were measured. Also, high- sensitivity C-reactive protein (hs-CRP) was measured in the blood. Fifteen healthy subjects composed a control group. RESULTS: Age and gender were similar between leprosy patients and control groups. No patient had a GFR < 60 mL/min/1.73 m2 or albumin excretion rate greater than 30 mg/g-Cr. Leprosy patients had higher urinary protein excretion (97.6 ± 69.2 vs. 6.5 ± 4.3 mg/g-Cr, p < 0.001), urinary MCP-1 (101.0 ± 79.8 vs. 34.5 ± 14.9 mg/g-Cr, p = 0.006) and urinary MDA levels (1.77 ± 1.31 vs. 1.27 ± 0.66 mmol/g-Cr, p = 0.0372) than healthy controls. There was a positive correlation between urinary MCP-1 and bacteriological index in skin smears (r = 0.322, p = 0.035), urinary protein excretion (r = 0.547, p < 0.001), albumin excretion rate (r = 0.414, p = 0.006) and urinary MDA (r = 0.453, p = 0.002). After adjusting for hs-CRP, urinary MCP-1 remained correlated with albumin excretion rate (rpartial = 0.483, p = 0.007) and MDA levels (rpartial = 0.555, p = 0.001). CONCLUSION: Leprosy patients with no clinical kidney disease have increased urinary MCP-1 mainly in lepromatous polar form. Inflammatory (MCP-1) and oxidative stress markers suggest leprosy patients are at high risk of developing kidney disease.

Sphingolipids as new biomarkers for assessment of delayed-type hypersensitivity and response to triptolide.

BACKGROUND: Hypersensitivity diseases are associated with many severe human illnesses, including leprosy and tuberculosis. Emerging evidence suggests that the pathogenesis and pathological mechanisms of treating these diseases may be attributable to sphingolipid metabolism. METHODS: High performance liquid chromatography-tandem mass spectrometry was employed to target and measure 43 core sphingolipids in the plasma, kidneys, livers and spleens of BALB/c mice from four experimental groups: control, delayed-type hypersensitivity (DTH) model, DTH+triptolide, and control+triptolide. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to identify potential biomarkers associated with variance between groups. Relationships between the identified biomarkers and disease markers were evaluated by Spearman correlation. RESULTS: As a treatment to hypersensitivity disease, triptolide significantly inhibit the ear swelling and recover the reduction of splenic index caused by DTH. The sphingolipidomic result revealed marked alterations in sphingolipid levels between groups that were associated with the effects of the disease and triptolide treatment. Based on this data, 23 potential biomarkers were identified by OPLS-DA, and seven of these biomarkers correlated markedly with the disease markers (p<0.05) by Spearman correlation. CONCLUSIONS: These data indicate that differences in sphingolipid levels in plasma and tissues are related to DTH and treatment with triptolide. Restoration of proper sphingolipid levels may attribute to the therapeutic effect of triptolide treatment. Furthermore, these findings demonstrate that targeted sphingolipidomic analysis followed by multivariate analysis presents a novel strategy for the identification of biomarkers in biological samples.

Crescentic glomerulonephritis: a clinical and histomorphological analysis of 46 cases.

BACKGROUND: Crescentic glomerulonephritis (CrGN), defined as crescents involving more than 50% of the glomeruli, includes pauci-immune, immune complex-mediated and anti-glomerular basement membrane disease. OBJECTIVES: The present study was aimed at evaluating the various clinical, biochemical and histological parameters in CrGN with respect to these categories and clinical outcome. MATERIALS AND METHODS: Renal biopsies diagnosed as CrGN between Jan 2008 and Feb 2010 were included. Clinical and laboratory parameters were retrieved along with the therapeutic approach and clinical outcome, wherever available. Renal biopsy slides were evaluated for various glomerular, tubulo-interstitial and arteriolar features. Appropriate statistical tests were applied for significance. RESULTS: A total of 46 cases of CrGN were included; majority (71.7%) of cases were pauci-immune (PI) while 28.3% were immune complex-mediated (IC). Among clinical features, gender ratio was significantly different between PI and IC groups (P = 0.006). The various histological parameters, including proportion of cellular crescents, tuft necrosis and Bowman's capsule rupture, were similar in both the groups. Four unusual associations, including idiopathic membranoproliferative glomerulonephritis (MPGN), multibacillary leprosy, acute lymphoblastic leukemia and C1q nephropathy were detected. Adequate follow-up information was available in 21 (46%) of the patients. Of these, 11 (52.4%) were dialysis-dependent at the last follow-up. Adult patients required renal replacement therapy more frequently than pediatric cases (P = 0.05). Presence of arteriolar fibrinoid necrosis also showed association with poor clinical outcome (P = 0.05). CONCLUSIONS: Crescentic glomerulonephritis remains one of the main causes of acute renal failure with histological diagnosis. Immunohistologic examination is essential for accurate classification into one of the three categories. This condition should be considered in rare causal associations like leprosy or MPGN with renal failure, to allow for timely performed renal biopsy and appropriate aggressive therapy.

Toxicological assessment of Ricinus communis Linn root extracts.

Ricinus communis Linn (Euphorbiaceae) plant parts are claimed to be used as carminative, asthma, bronchitis, leprosy, anti-inflammatory, cathartic, and aphrodisiac. The toxicological study was carried out in the root part of the plant. The collected root was extracted with methanol and water. The extracts were vacuum-dried to yield the respective aqueous (AE) and methanol (ME) extracts. Toxicological assessment sought to determine the safety of Ricinus communis root extracts. The extracts were evaluated in the acute toxicity study (OECD-423 guidelines) and 90 days repeated dose toxicological assessment in Wistar albino rats. The acute oral toxicity of the aqueous (AE) and methanol (ME) extracts did not produce any toxic symptoms or mortality at the dose level of 2000 mg/kg in rats. In the 90 days (sub-chronic toxicity) repeated dose toxicity study the extracts (AE and ME) were administered 1000 mg/kg daily through oral route. The sub-chronic toxicity study demonstrated no significant changes in body weight, food, and water intake. Hematology parameters RBC, WBC, DLC, Hb, blood clotting time, and the biochemical parameters glucose, blood urea nitrogen, creatinine, total cholesterol, total protein, total bilirubin AST, ALT, and ALP were estimated. Histopathology observation of the major vital organs (liver, kidney, heart, spleen, lungs, ovary, testis, and brain) were tested. The hematology, biochemical and histopathology evaluations did not show any adverse effects in any of the organs tested. These results demonstrate the non-toxic nature of the root extracts AE and ME can be used for long-term usage in clinical practice.

Renal involvement in leprosy: report of progression from diffuse proliferative to crescentic glomerulonephritis.

Renal involvement in leprosy has been reported rarely in the literature. Acute kidney injury in patients with leprosy is uncommon and may occur due to acute tubular necrosis, drug-induced interstitial nephritis and rarely crescentic glomerulonephritis. The latter with histologic confirmation of the diagnosis has been reported in very few cases of leprosy. A 25-year-old male, on therapy for multibacillary leprosy, was found to have deranged renal functions on evaluation for a history of nausea, vomiting, swelling and episode of haematuria. Kidney biopsy was performed twice over a period of 2 weeks, showing progression from diffuse proliferative glomerulonephritis to crescentic glomerulonephritis, pauci-immune in nature. The patient was treated aggressively with intravenous steroids, following which his renal functions stabilized. Crescentic glomerulonephritis, an extremely rare phenomenon in leprosy, should be considered in these patients presenting with features of acute kidney injury. Timely performed renal biopsy assists in accurate diagnosis and appropriate management of the patient, hence preserving renal parenchyma. Rapid progression from diffuse proliferative glomerulonephritis to crescentic glomerulonephritis in a patient with leprosy is described herein for the first time in the literature.

[Correlation between dose/plasma concentration and assessment of hepatic and renal changes in Wistar rats treated with the ROM scheme]. / Correlação entre dose/concentração plasmática e avaliação de alterações hepáticas e renais em ratos Wistar tratados com o esquema ROM.

Leprosy, a chronic granulomatous infectocontagious disease transmitted by Mycobacterium leprae, continues to be prevalent today, especially in underdeveloped countries and its paucibacillary form with a single lesion is being treated with rifampicin (600mg), ofloxacin (400mg) and minocycline (100mg) administered as a single dose (ROM scheme). Thus, the objective of the present study was to investigate the dose/plasma concentration correlation versus biochemical changes occurring in male Wistar rats receiving a single dose of rifampicin, ofloxacin and minocycline in mono- and polytherapy. Rifampicin and ofloxacin showed an increased concentration in plasma when administered in polytherapy, whereas minocycline was reduced, probably due to interference with its biotransformation and excretion. Biochemical analyses showed that rifampicin is probably responsible for hepatic and renal changes and that the medicamentous interactions involving the drug require individualized studies, especially when the drug is associated with ofloxacin and minocycline therapy.

Correlação entre dose/concentração plasmática e avaliação de alterações hepáticas e renais em ratos Wistar tratados com o esquema ROM / Correlation between dose/plasma concentration and assessment of hepatic and renal changes in Wistar rats treated with the ROM scheme

A hanseníase, doença crônica, granulomatosa, infecto-contagiosa, transmitida pelo Mycobacterium leprae, ainda se mantém prevalente nos dias atuais, principalmente em países subdesenvolvidos e a sua forma paucibacilar com lesão única, vem sendo tratada através da administração de rifampicina (600mg), ofloxacina (400mg) e minociclina (100mg), em dose única (esquema ROM). Assim, o objetivo deste trabalho foi investigar a correlação dose/concentração plasmática versus alterações bioquímicas na administração da rifampicina, ofloxacina e minociclina a ratos machos Wistar, em regime de dose única em mono e politerapia. Concluímos que a rifampicina e a ofloxacina sofreram um aumento na concentração plasmática quando administrados em politerapia, enquanto que a minociclina sofreu uma redução, provavelmente por interferências na biotransformação e excreção. Constatamos através das análises bioquímicas que a rifampicina provavelmente é a responsável por alterações hepáticas e renais, e que as interações medicamentosas envolvendo o fármaco exigem estudos individualizados principalmente quando o fármaco é usado associado a ofloxacina e minociclina.