Demystifying normal-anion-gap metabolic acidosis: pathophysiology, aetiology, evaluation and diagnosis.

Normal-anion-gap metabolic acidosis (NAGMA) is a common but often under-recognised and poorly understood condition, especially by less-experienced clinicians. In adults, NAGMA might be an initial clue to a more significant underlying pathology, such as autoimmune diseases, hypergammaglobulinemia or drug toxicities. However, identifying the aetiology can be challenging due to the diverse processes involved in the development of acidosis. A better understanding of the pathophysiology of NAGMA can help treating physicians suspect and evaluate the condition early and reach the correct diagnosis. This article provides an overview of renal acid-base regulation, discusses the pathophysiological processes involved in developing NAGMA and provides a framework for evaluation to reach an accurate diagnosis.

Thromboembolic phenomena in patients with nephrotic syndrome: pathophysiology, risk factors, prophylaxis and treatment.

Thromboembolic events resulting from disturbances in the body's balance of thrombotic and antithrombotic abilities are among the most life-threatening complications of nephrotic syndrome. Certain causes of nephrotic syndrome leave the patient particularly susceptible to thromboembolism. The severity of proteinuria and degree of hypoalbuminaemia are other common predictors of risk. Timely initiation of prophylactic therapy can help prevent morbidity and mortality associated with this complication in patients with nephrotic syndrome. The duration of treatment and choice of therapeutic agent depends on several factors, including the degree of hypoalbuminaemia, risk factors for thrombosis and risk of bleeding. This article reviews current understanding of the pathophysiology and risk factors for thromboembolism associated with nephrotic syndrome, and summarises recommendations and strategies for preventing and treating thromboembolic events in patients with nephrotic syndrome.

Complements and Their Role in Systemic Disorders.

The complement system is critical to the body's innate defense against exogenous pathogens and clearance of endogenous waste, comprising the classical, alternative, and lectin pathways. Although tightly regulated, various congenital and acquired diseases can perturb the complement system, resulting in specific complement deficiencies. Systemic rheumatic, neurological, ophthalmological, renal, and hematological disorders are some prototypical complement-mediated diseases. An adequate understanding of the mechanisms of the normal complement system and the pathophysiology of complement dysregulation is critical for providing diagnostic clues and appropriately managing these conditions. This review guides clinicians in understanding the role of complement factors in systemic diseases and what diagnostic and therapeutic options are available for complement-mediated disorders.

Is It Time to Give Peritoneal Dialysis Its Due Place in Managing Acute Kidney Injury: Lessons Learnt from COVID-19 Pandemic.

Despite comparable outcomes with the extracorporeal dialysis modalities, peritoneal dialysis (PD) is seldom considered a viable option for managing acute kidney injury (AKI) in developed and resource-rich countries, where continuous renal replacement therapies (CRRTs) are the mainstay of treating AKI. PD has fewer infrastructure requirements and has been shown to save lives during conflicts, natural disasters, and pandemics. During the ongoing COVID-19 pandemic, the developed world was confronted with a sudden surge in critically ill AKI patients requiring renal replacement therapy. There were acute shortages of CRRT machines and the trained staff to deliver those treatments. Some centres developed acute PD programmes to circumvent these issues with good results. This experience re-emphasised the suitability of PD for managing AKI. It also highlighted the need to review the current management strategies for AKI in developed countries and consider incorporating PD as a viable tool for suitable patients. This article reviews the current evidence of using PD in AKI, attempts to clarify some misconceptions about PD in AKI, and argues in favour of developing acute PD programmes.

Real-World Experience of Using Etelcalcetide for Secondary Hyperparathyroidism in Community-Based Hemodialysis Centers in Singapore.

Introduction Chronic kidney disease-related mineral and bone disorder (CKD-MBD), characterized by abnormalities in calcium, phosphate, and parathyroid hormone metabolism, with impaired bone turnover and extravascular calcification is a known complication of advanced chronic kidney disease (CKD). Secondary hyperparathyroidism (SHPT) develops early in the disease and its prevalence gradually increases with the disease progression, becoming almost universal in patients with end-stage renal disease (ESRD). The treatment for SHPT includes synthetic vitamin D analogs, calcitriol or calcimimetics. Recently, intravenous etelcalcetide was introduced as a second-generation calcimimetic. This article provides the real-world experience of using etelcalcetide in multiethnic Asian patients receiving hemodialysis at community-based hemodialysis centers in Singapore. Methods This study was real-world evidence, generated by a retrospective clinical audit of routine clinical care of hemodialysis patients in community-based centers in Singapore who received etelcalcetide for treating SHPT. The information on the starting and maximum dose of etelcalcetide, duration of treatment on hemodialysis, parathyroid hormone (PTH) levels, dialysate calcium, concomitant medications, and reasons for discontinuation were collected from the medical records. PTH levels were collected at four-, eight-, and twelve-month intervals. Results A total of 148 patients received etelcalcetide during the study period. Ten patients died and twenty discontinued their treatment, with 118 patients remaining on treatment. Demographically, the patients included Chinese, Malay, Indians, and those belonging to other racial groups. The starting dose of etelcalcetide ranged from 2.5 mg once per week to 7.5 mg three times a week. There was a 16.8% reduction (p=<0.001) in intact-PTH after four months of therapy. Target intact-PTH level of less than 60 pmol/L, was reported as 1.4% at baseline, with 22.3% at four months (p<0.001) and 25.9% at eight months (p=0.028). Calcium and phosphate levels were also tracked as part of the safety and efficacy measures of using etelcalcetide. No symptomatic hypocalcemia was noted and phosphate levels were noted to decline significantly. Overall, the calcium-phosphate product reduced at four months (13.2%, p=<0.001) and eight months (12.7%, p<0.05). An analysis of concomitant medication usage, dialysate calcium utilized, and the side effects of etelcalcetide were also recorded. Finally, a brief descriptive analysis of the patient's subjective feedback regarding etelcalcetide was also reported, especially regarding the reduction in pill burden and overall compliance to medications. Conclusion Etelcalcetide is safe and effective for treating SHPT in multi-ethnic Asian hemodialysis patients and can be considered an alternative to oral cinacalcet. Our study showed no side effects, which was one of the key reasons for non-compliance to traditional calcimimetics. A favorable compliance profile with reduced pill burden was noted by using this intravenous calcimimetic.

Association of monoclonal gammopathy of undetermined significance and C3 glomerulopathy.

Monoclonal gammopathy of undetermined significance (MGUS) is usually an asymptomatic pre-malignant condition caused by the proliferation of clonal plasma cells. Often considered a benign condition, it has the potential to progress to malignant plasma cell or lymphoproliferative disorders. Moreover, MGUS can rarely cause glomerular disease by activating the alternative complement pathway resulting in immunoglobulin-negative C3-positive glomerulonephritis called C3 glomerulopathy. Because of its rarity, the diagnosis might not be considered by the treating physicians, leading to delayed diagnosis or misdiagnosis. Untreated C3 glomerulopathy can lead to irreversible glomerular damage and end-stage renal failure, and a high index of suspicion is essential for timely diagnosis and management. Here, we present the case of a patient with a prior diagnosis of MGUS who presented with proteinuria and microscopic haematuria and was diagnosed with C3 glomerulopathy. The patient had complete resolution of the disease after receiving treatment with a combination of dexamethasone, lenalidomide and bortezomib for the underlying MGUS.

Hyponatremia in COVID-19 Is Not Always Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH): A Case Series.

Hyponatremia is a common complication in COVID-19-positive patients and is associated with significant mortality and morbidity. Several cases of COVID-19-related hyponatremia secondary to the Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) have been reported in the literature, which might suggest that SIADH is almost always the underlying cause of hyponatremia in COVID-19 infections. However, COVID-19-related hyponatremia can have diverse underlying etiologies, similar to hyponatremia in non-COVID-19 patients, and requires a thorough assessment to reach a correct diagnosis and implement appropriate management.

How to work up an adult patient with metabolic acidosis.

Metabolic acidosis is a common complication among acutely unwell hospitalised patients. Untreated, it can result in undesirable cardiovascular, respiratory and neurological consequences. Metabolic acidosis can occur as an isolated entity or coexist with other acid-base disorders, making diagnosing the aetiology difficult. Accurate identification of the underlying cause is imperative for proper and timely management. A systematic approach can help simplify the assessment of patients and can aid in establishing the correct diagnosis, even in more complex cases. This article provides a practical, step-by-step guide for the assessment of adult patients with metabolic acidosis.

The modality of choice, manual or automated, for urgent start peritoneal dialysis.

Over the last decade, urgent start peritoneal dialysis (USPD), defined as initiation of peritoneal dialysis (PD) before the traditionally recommended break-in period of 2-4 weeks, has increasingly been seen as a viable option for late-presenting end-stage renal disease patients, obviating the need for haemodialysis via central venous catheter. Different prescriptions and protocols involving both manual and automated exchanges have been published, but there is no head-to-head comparison of the two modalities and no consensus on the most suitable modality exists. Evaluation of the available evidence suggests that PD can be initiated urgently using either or both options without much difference in the outcome. The two most critical aspects dictating the success of a USPD programme are using low dwell volumes and keeping patients in a strict supine position during the dialysis exchanges in the first couple of weeks of the therapy. These measures are crucial in keeping the intraperitoneal pressure to a minimum and reduce the risk of mechanical complications, including catheter leaks and malpositioning.

Is surgical PD catheter insertion safe for urgent-start peritoneal dialysis?

Urgent-start peritoneal dialysis (USPD) is increasingly seen as a viable alternative to hemodialysis through a central venous catheter for late-presenting end-stage renal disease patients. However, concerns remain about starting dialysis early following the surgical implantation of the peritoneal dialysis (PD) catheter; urgent PD is often thought to be a safe option only after minimally invasive percutaneous catheter insertions. Analysis of the cumulative data from published literature presented in this review appears to negate this general perception and shows that compared to the percutaneous catheter insertions, starting PD urgently following surgically placed catheter is not associated with more catheter leaks, dysfunctions, or other complications. The outcome of USPD is independent of the mode of catheter insertion. Instead, measures to minimize intra-peritoneal pressure including using the low initial dwell volume based on patient's weight and body habitus and keeping patients in strict supine posture during exchanges in the first 2 weeks of treatment are the two most important factors ensuring a minimization of the risk of catheter-related complications.

Should antiviral monotherapy with nucleotide analogs be the primary treatment option for focal segmental glomerulosclerosis-related nephrotic syndrome in chronic hepatitis B infection?

Renal involvement is the most common extrahepatic manifestation of chronic hepatitis B virus (HBV) infection. While membranous nephropathy is the most frequent, the association with focal segmental glomerulosclerosis (FSGS) is not as strong, and only a few cases have been described in the literature. In particular, the tip variant FSGS is extremely rare and to our knowledge has not previously been described in association with chronic HBV infection. The management of such cases can be challenging. Immunosuppression may lead to enhanced viral replication and flare-up of the hepatic disease. Antiviral treatment has been reported to induce remission in hepatitis B-associated glomerulonephritis in a few cases. However, their use is primarily restricted to the treatment of associated liver disease, and the current guidelines do not provide specific recommendations on HBV-mediated kidney disease in the absence of hepatic involvement. We describe a case of nephrotic syndrome due to secondary tip variant FSGS in a patient with chronic HBV infection who went into complete remission with antiviral therapy alone and present an argument for the use of oral antiviral agents as the primary treatment option for FSGS-related nephrotic syndrome in chronic HBV-infected patients without progressive liver disease.

Tritrophic interactions between parasitoids and cereal aphids are mediated by nitrogen fertilizer.

Host plant nutritional quality can directly and indirectly affect the third trophic levels. The aphid-parasitoid relationship provides an ideal system to investigate tritrophic interactions (as the parasitoids are completely dependent for their development upon their hosts) and assess the bottom up forces operating at different concentrations of nitrogen applications. The effects of varying nitrogen fertilizer on the performance of Aphidius colemani (V.) reared on Sitobion avenae (F.) and Aphidius rhopalosiphi (D.) reared on Rhopalosiphum padi (L.) were measured. Parasitism and percent emergence of parasitoids were positively affected by nitrogen fertilizer treatments while developmental duration (egg, larval, and pupal stages) was not affected by increasing nitrogen inputs. In males and females of both parasitoid species, adult longevity increased with the increasing nitrogen fertilizer. Hind tibia length and mummy weight of both parasitoid species increased with nitrogen fertilizer concentrations, as a result of larger aphids. This study showed that nitrogen application to the soil can have important consequences for aboveground multitrophic interactions.

Calciphylaxis and sodium thiosulphate: a glimmer of hope in desperate situation.

BACKGROUND: Calciphylaxis is an uncommon and often under diagnosed condition affecting patients undergoing chronic dialysis. Its pathogenesis is poorly understood. The abnormalities of calcium, phosphate and parathyroid hormone homeostasis leading to vascular calcification and ischaemic skin necrosis are thought to be the central problem. Meticulous wound care and aggressive metabolic control remain the cornerstone of the treatment; however, the overall benefit of these treatment options remains low and mortality and morbidity remain very high. Sodium thiosulphate is an inorganic salt, which is used for treating acute cyanide poisoning, recurrent calcium urolithiasis and nephrocalcinosis. Recently, it has also been reported to be useful in treating severe cases of calciphylaxis with promising results. METHODS: A resistant case of calciphylaxis in a patient on long-term haemodialysis was treated with sodium thiosulphate (50 ml solution with 50% sodium thiosulphate) three times a week during the end of each dialysis session. RESULTS: The skin lesions started to heal after two weeks and completely resolved after five months of treatment. CONCLUSIONS: Sodium thiosulphate can be a safe and effective treatment option for resistant and severe cases of calciphylaxis.

Advanced native kidney renal cell carcinoma in renal transplant recipients: role of sirolimus as dual anti-cancer and anti-rejection agent.

The incidence of native kidney renal cell carcinoma (RCC) in renal transplant recipients is 15 times higher than the general population. These tumors are often found incidentally when imaging is performed for another indication. At that stage tumors are usually small and asymptomatic but it is possible that they may escape detection until a more advanced stage. Early stage RCC can be treated with radical nephrectomy but the treatment of advanced RCC may be more complicated and is associated with a poorer prognosis. RCC in context of renal transplant presents a special therapeutic challenge; balancing treatment of a potentially lethal malignancy in a redundant organ whilst maintaining good allograft function.We describe 2 cases of advanced renal cell carcinoma of native kidneys in renal transplant recipients and present our experience with sirolimus as a dual immunosuppressive and anti-tumor agent.

Review of eprodisate for the treatment of renal disease in AA amyloidosis.

Secondary (AA) amyloidosis is a multisystem disorder complicating chronic infections or inflammatory diseases. It is characterized by extracellular deposit of fibrils composed of fragments of serum amyloid A (SAA), an acute phase reactant protein. The kidney is the most frequent organ involved, manifesting as progressive proteinuria and renal impairment. Attenuation of the level of circulating SAA protein by treating the underlying inflammatory condition remains the primary strategy in treating AA amyloidosis. However, at times, achieving adequate control of protein production can prove difficult. In addition, relapse of renal function often occurs rapidly following any subsequent inflammatory stimulus in patients with existing amyloidosis. Recently there has been an interest in finding other potential strategies targeting amyloid deposits themselves. Eprodisate is a sulfonated molecule with a structure similar to heparan sulfate. It competitively binds to the glycosaminoglycan-binding sites on SAA and inhibits fibril polymerization and amyloid deposition. Recent randomized clinical trial showed that it may slow down progressive renal failure in patients with AA amyloidosis. However confirmatory studies are needed and results of a second Phase III study are eagerly awaited to clarify whether or not eprodisate has a place in treating renal amyloid disease.