Kidney Dysfunction and Pathology in the Setting of Hemophagocytic Lymphohistiocytosis.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a clinicopathologic syndrome produced by dysregulated activation of the immune system. Acute kidney injury (AKI) and proteinuria have been infrequently described in the setting of HLH, and investigations of underlying histopathologic changes in the kidney are limited. Methods: To characterize kidney pathology in HLH, a retrospective review of 30 patients' clinical and laboratory data, and kidney tissue was performed (18 from autopsy, and 12 biopsied patients). Results: HLH was associated with infection (83%), autoimmune disease (37%), and malignancy (20%), including 30% with concurrent autoimmune disease and infection. Nephrological presentations included subnephrotic range proteinuria (63%), AKI (63%), hematuria (33%), chronic kidney disease (CKD, 20%), nephrotic range proteinuria (13%), and nephrotic syndrome (7%); and 40% of patients required hemodialysis (HD). Among the 12 patients who underwent kidney biopsy, 6 subsequently showed improved kidney function and the remainder had progressive CKD with most progressing to end-stage kidney disease. Autopsy patients had a median terminal admission of 1 month, and 33% of the biopsied patients died (ranging from 0.3-5 months post-biopsy). Variable pathologies were identified, including acute tubular injury (ATI, 43%), lupus nephritis (LN, 23%), collapsing glomerulopathy (17%), thrombotic microangiopathy (TMA, 17%), and cortical necrosis (10%). Most autopsied patients had significant kidney pathology other than ATI that likely contributed to kidney function decline. A majority of patients with HLH exhibited kidney dysfunction that likely contributed to the poor prognosis. Conclusion: Kidney dysfunction in HLH should not be assumed to be solely attributable to ATI, and in certain scenarios a kidney biopsy may be warranted.

Finerenone: A Novel Third-Generation Mineralocorticoid Receptor Antagonist.

Finerenone is a novel third-generation, selective nonsteroidal mineralocorticoid receptor antagonist (MRA) that was approved by the Food and Drug Administration in July of 2021 for its use in adults with chronic kidney disease and Type II diabetes mellitus. Randomized controlled trials The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease showed decreased adverse kidney and cardiovascular outcomes, respectively, in this population. The incidence of hyperkalemia, while higher in the study versus placebo group, was lower than older generations of MRAs (spironolactone and eplerenone) and proved to be an infrequent cause for drug discontinuation. The incidences of other adverse effects such as gynecomastia and acute kidney injury were similar in both the study and the placebo groups. This is the first third-generation MRA authorized to use to reduce the burden of cardiorenal disease.

Secondary haemophagocytic lymphohistiocytosis in a patient with new-onset systemic lupus erythematosus: the challenges of timely diagnosis and successful treatment.

Haemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disease driven by abnormal macrophage activation and regulatory cell dysfunction. HLH can be primary due to genetic mutations or secondary due to infection, malignancy or autoimmune conditions. We describe a woman in her early 30s who developed HLH while being treated for newly diagnosed systemic lupus erythematosus (SLE) complicated by lupus nephritis as well as concomitant cytomegalovirus (CMV) reactivation from a dormant infection. The trigger for this secondary form of HLH may have been either aggressive SLE and/or CMV reactivation. Despite prompt treatment with immunosuppressive therapies for SLE consisting of high-dose corticosteroids, mycophenolate mofetil, tacrolimus, etoposide for HLH and ganciclovir for CMV infection, the patient developed multiorgan failure and passed away. We demonstrate the difficulty in identifying a specific cause for secondary HLH when multiple conditions are present (SLE and CMV) and the fact that, despite aggressive treatment for both conditions, the mortality for HLH remains high.

The Fatty Kidney and Beyond: A Silent Epidemic.

As the prevalence of obesity rises in the United States, so does the incidence of obesity-related kidney disease. Obesity itself is an independent risk factor for chronic kidney disease where the pathophysiology is complex, involving altered hemodynamics, renin-angiotensin-aldosterone system overactivation, and adipokines leading to inflammation and fibrosis. Obesity-related kidney disease comprises both obesity-related glomerulopathy and fatty kidney disease. Obesity-related glomerulopathy is a consequence of glomerular hyperfiltration and often presents clinically with subnephrotic proteinuria and pathologically with glomerulomegaly with or without focal glomerulosclerosis. Fatty kidney disease is the effect of renal ectopic fat contributing to chronic kidney disease. Whether the renal ectopic fat is a distinct clinical entity or a pathologic mechanism contributing to obesity-related glomerulopathy, the treatment paradigm of weight and proteinuria reduction remains the same. We present the pathophysiology behind obesity-related kidney disease, clinical outcomes, and treatment strategies, which include lifestyle interventions, use of renin-angiotensin-aldosterone system inhibitors, glucagon-like peptide 1 receptor agonists, sodium-glucose co-transporter-2 inhibitors, and bariatric surgery. With old and novel therapeutics, we are attempting to stave off the silent epidemic that obesity-related kidney disease is becoming.

Hypertension in Pregnancy: What We Now Know.

PURPOSE OF REVIEW: Hypertensive disorders of pregnancy remain a highly morbid condition that affects both the mother and fetus, complicate approximately 10% of pregnancies worldwide, and contribute to immediate and long-term cardiovascular outcomes. There is still much to learn regarding pathogenesis and treatment goals. RECENT FINDINGS: There is updated information on the pathogenesis of preeclampsia and treatment thresholds for HTN in pregnancy. l-Kynurenine, a metabolite of the essential amino acid l-tryptophan, has been implicated in preeclampsia as decreased levels were found in a uninephrectomized pregnant mouse model of preeclampsia, where replacement of l-kynurenine rescued the preeclamptic state. Further, data from CHIPS (The Control of HTN in Pregnancy Study) and CHAP (Chronic HTN and Pregnancy) trials demonstrate not only the safety of lowering blood pressure to either a diastolic goal of 85 mmHg (CHIPS) or less than 160/105 mmHg (CHAP) without detriment to the fetus but the CHAPS trial has also shown a decrease in the rate of preeclampsia in the treatment group. SUMMARY: We will summarize the different types of hypertensive disorders in pregnancy, updates on the pathogenesis of preeclampsia, and appropriate HTN management based on the latest evidence in order to better care for mother and child.

Obesity-related glomerulopathy in the presence of APOL1 risk alleles.

Nephropathic apolipoprotein L1 (APOL1) risk alleles (G1/G2) have been associated with focal segmental glomerulosclerosis, HIV-associated nephropathy, Systemic lupus erythematosus (SLE)-associated collapsing glomerulopathy and other glomerulonephritides. These alleles confer protection from Trypanosoma brucei infections which are enriched in sub-Saharan African populations. We present a young woman with obesity, hypertension, subnephrotic range proteinuria who was found to have obesity-related glomerulopathy on kidney biopsy while harbouring two high-risk APOL1 alleles (G1/G2). Given the potential effects on lipid metabolism and their association with obesity, the presence of APOL1 risk alleles may impact cardiovascular health in addition to renal disease in these patients.

Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms-like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

Acute Kidney Injury in Obstetric Patients.

Obstetric-related acute kidney injury (obstetric AKI) is an important and complex public health problem; its early recognition and proper treatment are key in preventing maternal and fetal adverse outcomes. While the incidence of obstetric AKI has drastically declined in some developing countries due to reduction of sepsis-related causes, the opposite has been observed in other developed nations in the last decade due to advanced maternal age and the presence of comorbidities. The diagnosis of obstetric AKI has been made difficult by the physiologic decrease in serum creatinine of pregnancy as well as the absence of a uniform definition for AKI in this population. The most common causes of obstetric AKI include pre-renal etiologies such as hyperemesis gravidarum and post-abortal sepsis, intra-renal causes which comprise the thrombotic microangiopathies (preeclampsia/HELLP, thrombotic thrombocytopenic purpura, pregnancy associated-hemolytic uremic syndrome, lupus nephritis), and post-renal causes due to obstruction from kidney stones or iatrogenic injuries during delivery. A kidney biopsy is rarely required and should be reserved for cases where the diagnosis will change management, preferably before the third trimester. A multidisciplinary approach with the maternal-fetal-medicine specialist and nephrologist, along with the intensivist and hematologist may be needed. In this review, we will present the latest updates on the global epidemiology, focus on the most challenging thrombotic microangiopathy diagnoses, summarize treatment recommendations, and delineate the ongoing challenges as well as novel strategies to tackle this public health burden which does not seem to be disappearing.

Atypical presentation of allergic interstitial nephritis likely induced by ciprofloxacin.

Though the prevalence of drug induced allergic interstitial nephritis (AIN) appears to be increasing, the diagnostic and treatment strategies still remain vague. We present a 56-year-old man with a history of hypertension, chronic kidney disease stage IIIa, recent exposure to ciprofloxacin who presented with acute kidney injury. Though the suspicion of AIN was high, his urinary sediment was bland, that is, no leucocytes or leucocyte casts. A renal biopsy subsequently showed features of AIN correlating with a resolving phase of inflammation. Given the resolving nature of the pathology, we chose not to complete a course of corticosteroids despite his need for temporary haemodialysis. He was able to fully recover his renal function. In this report, we emphasise the unreliable nature of the urinary sediment in the diagnosis of AIN, the utility of a renal biopsy in helping to guide treatment, and the controversial data in corticosteroid treatment.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits associated with parvovirus B19.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is included in the group of dysproteinaemias causing renal disease. Only a minority of cases are associated with a haematological malignancy. Two cases have been linked to acute parvovirus B19 infections. We report a 36-year-old African-American woman who presented with renal dysfunction, proteinuria, haematuria and a kidney biopsy reported as PGNMID with IgG3-kappa deposits. Her evaluation for a haematological malignancy was unrevealing. Her parvovirus IgM and IgG levels were positive. The patient was initially treated with an ACE inhibitor and spontaneously remitted with minimal proteinuria after 1 month. Repeat parvovirus B19 serologies 6 months later showed persistent IgG and DNA by PCR positivity but IgM negativity. Given the clinical scenario, we believe that her PGNMID was induced by acute parvovirus B19 infection, which appeared to resolve once her acute infection abated. In this report, we describe our latest understanding of PGNMID.

Light chain proximal tubulopathy with cast nephropathy in monoclonal gammopathy of renal significance.

Kidney tubular disorders due to monoclonal immunoglobulin light chains are common manifestations of B-cell neoplasm. Cast nephropathy (CN) is the most frequent type of these disorders and may present with acute kidney injury (AKI) due to the presence of excess light chains in the distal tubules. Light chain proximal tubulopathy (LCPT) is an uncommon form of renal disease and may present as Fanconi syndrome due to proximal tubular cell damage by intracellular deposition of light chains. The concomitant disorder of both CN and LCPT is rare given the inherent differences in the biochemical properties of the immunoglobulin light chains of each disorder. We report a 64-year-old man who presented with AKI and Fanconi syndrome who was discovered to have both CN and LCPT due to the underlying disorder of monoclonal gammopathy of renal significance and who has responded favourably with conventional chemotherapy. We also review the existing literature on this interesting subject.

Complement-Mediated Disorders in Pregnancy.

Complement-mediated disorders in pregnancy span a large spectrum and have been implicated in all three complement pathways: classical, lectin, and alternative. Our understanding of these disorders in recent years has advanced due to a better understanding of complement regulatory proteins, such as complement factor H, complement factor I, membrane cofactor protein, and thrombomodulin that particularly affect the alternative complement pathway. Enthusiasm in genotyping for mutations that encode these proteins has allowed us to study the presence of genetic variants which may predispose women to develop conditions such as pregnancy-associated hemolytic uremic syndrome (P-aHUS), thrombotic thrombocytopenic purpura, preeclampsia/hemolysis, elevated liver enzymes, low platelets (HELLP), systemic lupus erythematosus/antiphospholipid syndrome, and peripartum cardiomyopathy. The advent of the anti-C5-antibody eculizumab to quench the complement cascade has already proven in small case series to improve maternal kidney outcomes in complement-mediated obstetric catastrophes such as P-aHUS and HELLP. In this review, we will detail the pathogenesis behind these complement-mediated pregnancy disorders, the role of complement variants in disease phenotype, and the most up-to-date experience with eculizumab in this population.

Acute kidney injury in pregnancy.

PURPOSE OF REVIEW: Pregnancy-related acute kidney injury (Pr-AKI) is associated with increased maternal and fetal morbidity and mortality and remains a large public health problem. RECENT FINDINGS: Pr-AKI incidence has globally decreased over time for the most part. However, the cause presents a disparity between developing and developed countries, reflecting differences in socioeconomic factors and healthcare infrastructure - with the noteworthy outlier of increased incidence in the United States and Canada. Although Pr-AKI can be secondary to conditions affecting the general population, in most cases it is pregnancy specific. Septic abortion, hyperemesis gravidarum, and hemorrhage have become less prevalent with access to healthcare but are being displaced by thrombotic microangiopathies, such as preeclampsia, hemolysis, elevated liver enzymes, low platelets syndrome, thrombotic thrombocytopenic purpura, and pregnancy-associated hemolytic-uremic syndromes, as well as acute fatty liver of pregnancy. Understanding these conditions plays a pivotal role in the timely diagnosis and enhancement of therapeutic approaches. SUMMARY: In this review, we focus on the renal physiology of the pregnancy, epidemiology, and specific conditions known to cause Pr-AKI, summarizing diagnostic definition, insights in pathophysiology, clinical considerations, and novel treatment approaches, thus providing the reader a framework of clinically relevant information for interdisciplinary management.

Hypertension and Pregnancy: Management and Future Risks.

Pregnancy-induced hypertension is a major cause of maternal and fetal morbidity and mortality. The overall strategies of defining and managing these conditions are aimed at preventing cardiovascular and cerebrovascular complications in the mother without jeopardizing fetal well-being. Our understanding of the origin of these disorders is evolving. Women with chronic hypertension should undergo a prepregnancy evaluation and close monitoring during and after pregnancy to ensure medication safety and to prevent end-organ damage. Based on available data, the current recommendation is that antihypertensive therapy should be initiated only in women with severe hypertension (defined as systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥105 mm Hg). It is now becoming more and more clear that hypertensive complications during pregnancy are potentially linked to cardiovascular, kidney, and metabolic diseases later in life. This review discusses the spectrum of hypertensive disorders of pregnancy, general management principles, and the need to monitor for long-term cardiovascular sequelae for decades afterward.

Recurrent case of pregnancy-induced atypical haemolytic uremic syndrome (P-aHUS).

Pregnancy-induced atypical haemolytic uremic syndrome (P-aHUS) is a rare condition characterised by microangiopathic haemolytic anaemia, thrombocytopenia and renal failure. It accounts for approximately 7% of total HUS cases. Here, we present a case of recurrent P-aHUS in a 25-year-old Hispanic woman. Pregnancy was the clear trigger in both instances, and the disease manifested in first week of the postpartum period. Because of her significant obstetric history, a multidisciplinary approach was adopted to monitor her second pregnancy antepartum and post partum. As the patient developed recurrence of P-aHUS 4 days after her delivery, she was immediately administered eculizumab within few hours of disease manifestation. The patient normalised her haematological parameters within 1 week but sustained dialysis-requiring renal failure for a total of 6 weeks. This case highlights the advances as well as the ongoing uncertainties, especially with respect to the use of eculizumab, in this rare but morbid disease.

Haemophagocytic lymphohistiocytosis with collapsing lupus podocytopathy as an unusual manifestation of systemic lupus erythematosus with APOL1 double-risk alleles.

Haemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome caused by excessive immune activation. Secondary HLH has been described in autoimmune diseases. We detail the case of a 28-year-old African American woman who developed HLH in the setting of systemic lupus erythematosus with collapsing lupus podocytopathy superimposed on mesangial proliferative lupus nephritis class II. Genotyping for APOL1 risk alleles revealed the presence of double (G1/G2) risk alleles. Our patient achieved a complete renal recovery and resolution of HLH within 1 month of treatment with steroids and mycophenolate mofetil, highlighting the importance of prompt, aggressive therapy.

Mentorship in Medicine and Nephrology: More Important Than Ever.

Mentorship has always been important in medicine. In fact, one can argue that that is how doctors are trained. Moreover, mentorship has been proven to preserve and elevate those who wish to pursue academic medicine. In nephrology, mentorship has become paramount, as interest in the field has declined during this decade. In this article, we will delineate how mentorship impacts physician careers, describe different types of mentors and their characteristics, and summarize responsibilities of mentors and mentees. We will discuss specific challenges in nephrology and the steps that have been taken to address them via mentorship. We conclude that mentorship is a powerful tool that can help provide an optimistic future for our field.

Unusual case of levamisole-induced dual-positive ANCA vasculitis and crescentic glomerulonephritis.

Cocaine adulterated levamisole is an increasingly reported cause of skin necrosis, arthralgia and systemic vasculitis, but renal involvement is uncommon. We present a case of a 40-year-old Hispanic man with a history of cocaine abuse who presented with acute kidney injury to the rheumatology clinic where he was being treated for chronic inflammatory arthritis. He was found to have a serum creatinine of 2.5 mg/dL, microscopic haematuria and subnephrotic proteinuria, along with positive proteinase 3, myeloperoxidase, anticardiolipin antibodies and an elevated antinuclear antibody titre. The renal pathology revealed focal necrotising glomerulonephritis with crescentic features and mild immune type deposition. The patient was treated with cocaine abstinence, pulse dose steroids followed by maintenance prednisone, rituximab and cyclophosphamide. His renal function subsequently improved but did not normalise. We believe that his incomplete improvement was due to the degree of kidney injury on presentation as well as recidivism with cocaine use.

Proteinuric Kidney Diseases: A Podocyte's Slit Diaphragm and Cytoskeleton Approach.

Proteinuric kidney diseases are a group of disorders with diverse pathological mechanisms associated with significant losses of protein in the urine. The glomerular filtration barrier (GFB), comprised of the three important layers, the fenestrated glomerular endothelium, the glomerular basement membrane (GBM), and the podocyte, dictates that disruption of any one of these structures should lead to proteinuric disease. Podocytes, in particular, have long been considered as the final gatekeeper of the GFB. This specialized visceral epithelial cell contains a complex framework of cytoskeletons forming foot processes and mediate important cell signaling to maintain podocyte health. In this review, we will focus on slit diaphragm proteins such as nephrin, podocin, TRPC6/5, as well as cytoskeletal proteins Rho/small GTPases and synaptopodin and their respective roles in participating in the pathogenesis of proteinuric kidney diseases. Furthermore, we will summarize the potential therapeutic options targeting the podocyte to treat this group of kidney diseases.

Acute Kidney Injury in Pregnancy: The Changing Landscape for the 21st Century.

Pregnancy-related acute kidney injury (Pr-AKI) remains a large public health problem, with decreasing incidences in developing countries but seemingly increasing incidences in the United States and Canada. These epidemiologic changes are reflective of the advances in medical and obstetric care, as well as changes in underlying maternal risk factors. The risk factors associated with advanced maternal age, such as hypertension, diabetes, chronic kidney disease, and those associated with reproductive technologies such as multiple gestations, are increasing. Traditional causes of Pr-AKI, such as septic abortions and puerperal sepsis, have been replaced by hypertensive diseases, such as preeclampsia and thrombotic microangiopathies comprising thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS). In this review, we discuss the global impact of Pr-AKI on maternal and fetal outcomes, the predominant etiologies, and key clinical features to distinguish diagnoses, such as preeclampsia/hemolysis elevated liver function test and low platelet (HELLP) syndrome, acute fatty liver disease of pregnancy (AFLP), and other thrombotic microangiopathies. New insights into the pathogenesis of preeclampsia, TTP/aHUS, and AFLP that have unearthed possible therapeutic targets are summarized. We also delve into special consideration needed to give to pyelonephritis and postobstructive causes of Pr-AKI. With each diagnosis, we offer the latest treatment recommendations, such as the positive reports from the use of eculizumab to treat aHUS. In the end, we hope to arm the clinician with the best tools to understand and address this morbid problem that does not seem to be disappearing.