Cystic Diseases of the Kidneys: From Bench to Bedside.

Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia. Cilia are essential to the signaling cascades, and their dysfunction has been tied to a range of renal cystic diseases initiating with studies on the oak ridge polycystic kidney (ORPK) mouse model. Here, we delve into renal cystic pathologies that have been tied with ciliary proteosome and highlight the genetics associated with each. The pathologies are grouped based on the mode of inheritance, where inherited causes that result in cystic kidney disease phenotypes include autosomal dominant and autosomal recessive polycystic kidney disease, nephronophthisis (Bardet-Biedl syndrome and Joubert Syndrome), and autosomal dominant tubulointerstitial kidney disease. Alternatively, phakomatoses-, also known as neurocutaneous syndromes, associated cystic kidney diseases include tuberous sclerosis (TS) and Von Hippel-Lindau (VHL) disease. Additionally, we group the pathologies by the mode of inheritance to discuss variations in recommendations for genetic testing for biological relatives of a diagnosed individual.

Clinical Dilemma of Corneal Opacity, Very Low High-density Lipoprotein, and Nephrotic Syndrome: Mystery Revealed.

Lecithin-cholesterol acyltransferase (LCAT) is a liver enzyme necessary for the formation of cholesteryl esters in plasma from free cholesterol. The rare autosomal recessive disease resulting from familial deficiency of this enzyme can lead to nephropathy with kidney involvement generally being the most common cause of death. In addition, the disease process can engender corneal opacity, very low high-density lipoprotein, normochromic anemia, and nephropathy. We present this case of a 35-year-old male who initially visited for a second opinion for renal failure and nephrotic range proteinuria. He underwent renal biopsy which displayed focal segmental glomerulosclerosis-type injury pattern and was started on futile high-dose steroid therapy. A second renal biopsy coincided with the development of corneal opacity leading to a confirmatory testing of LCAT deficiency through biochemistry panel.

Risk factors and outcomes of COVID associated mucormycosis in kidney transplant recipients.

BACKGROUND: Invasive mucormycosis (IM) is a life-threatening fungal infection occurring mostly in solid organ transplant (SOT) recipients, patients with hematological malignancies, and diabetes. A sudden spurt of mucormycosis has been reported in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic in India; however, there is little data about coronavirus disease 2019 (COVID-19) associated mucormycosis (CAM) in kidney transplant recipients (KTRs). METHODS: We describe the clinical presentations, risk factors, treatment and outcomes of 11 mucormycosis cases in KTRs post-COVID-19 infection from February 2020 to June 2021 at a single center in India. RESULTS: Mucormycosis was seen in 11/102 (10.7%) KTRs during the pandemic. Six patients had mild disease and rest five had moderate disease. Seven patients had pre-existing diabetes mellitus and four developed new onset hyperglycemia after receiving steroids for COVID-19 infection. All had poorly controlled sugars at the time of presentation. Most common presentation was rhino-orbital-cerebral mucormycosis (ROCM) in 10/11 (89%) patients and one has pulmonary mucormycosis. All patients received combination of amphotericin B and surgical debridement/excision of affected tissue followed by posaconazole prophylaxis. Nine patients recovered, however two patients succumbed to their illness after median of 14 (7-21) days from diagnosis. One patient developed acute T-cell-mediated rejection during the course of recovery. At last follow up, the mean serum creatinine was 2.05 mg/dl as compared to 1.4 mg/dl at presentation. CONCLUSIONS: IM is a common fungal infection in transplant recipients in India after COVID-19. Early diagnosis and prompt treatment with combination of surgical debridement and liposomal amphotericin B are key to better outcomes in CAM. Judicious use of steroids and control of hyperglycemia is key to avoid flaring up of the fungal infection.

Diagnosis and Management of Renal Cystic Disease of the Newborn: Core Curriculum 2021.

Renal cystic disease encompasses a large variety of illnesses with various phenotypic expressions that can manifest in utero, in infancy, and in childhood. These diseases may be unilateral or bilateral and present with single or multiple cysts. Various cystic diseases may also progress to chronic kidney disease (CKD), including kidney failure, and hepatic disease, thus potentially being life threatening. The prevalence and serious complications of CKD in the pediatric population make it vital that health care providers detect these conditions early and provide effective management. This installment of AJKD's Core Curriculum in Nephrology discusses various genetic and sporadic kidney cystic diseases, including multicystic dysplastic kidney, nephronophthisis, cystic dysplasia, hepatocyte nuclear factor 1-ß (HNF1-ß) nephropathy, Bardet-Biedl syndrome, Meckel-Gruber syndrome, Zellweger syndrome, calyceal diverticulum, autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic kidney disease (ADPKD). This article discusses the epidemiology, genetics and pathophysiology, diagnosis, presentation, and management for each of these renal cystic diseases, with particular attention to prenatal care and pregnancy counseling.

Hypertensive Crisis in Pediatric Patients: An Overview.

Hypertensive crisis can be a source of morbidity and mortality in the pediatric population. While the epidemiology has been difficult to pinpoint, it is well-known that secondary causes of pediatric hypertension contribute to a greater incidence of hypertensive crisis in pediatrics. Hypertensive crisis may manifest with non-specific symptoms as well as distinct and acute symptoms in the presence of end-organ damage. Hypertensive emergency, the form of hypertensive crisis with end-organ damage, may present with more severe symptoms and lead to permanent organ damage. Thus, it is crucial to evaluate any pediatric patient suspected of hypertensive emergency with a thorough workup while acutely treating the elevated blood pressure in a gradual manner. Management of hypertensive crisis is chosen based on the presence of end-organ damage and can range from fast-acting intravenous medication to oral medication for less severe cases. Treatment of such demands a careful balance between decreasing blood pressure in a gradual manner while preventing damage end-organ damage. In special situations, protocols have been established for treatment of hypertensive crisis, such as in the presence of endocrinologic neoplasms, monogenic causes of hypertension, renal diseases, and cardiac disease. With the advent of telehealth, clinicians are further able to extend their reach of care to emergency settings and aid emergency medical service (EMS) providers in real time. In addition, further updates on the evolving topic of hypertension in the pediatric population and novel drug development continues to improve outcomes and efficiency in diagnosis and management of hypertension and consequent hypertensive crisis.

Renal Manifestations of Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors, and seizures. TSC can manifest in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts, and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.

Development of acute kidney injury following pediatric cardiac surgery.

Acute kidney injury (AKI) in the pediatric population is a relatively common phenomenon. Specifically, AKI has been found in increasing numbers within the pediatric population following cardiac surgery, with up to 43% of pediatric patients developing AKI post-cardiac surgery. However, recent advances have allowed for the identification of risk factors. These can be divided into preoperative, intraoperative, and postoperative factors. Although the majority of pediatric patients developing AKI after cardiac surgery completely recover, this condition is associated with worse outcomes. These include fluid overload and increased mortality and result in longer hospital and intensive care unit stays. Detecting the presence of AKI has advanced; use of relatively novel biomarkers, including neutrophil gelatinase associated lipocalin, has shown promise in detecting more subtle changes in kidney function when compared to conventional methods. While a single, superior treatment has not been elucidated yet, novel functions of medications, including fenoldopam, theophylline and aminophylline, have been shown to have better outcomes for these patients. With the recent advances in identification of risk factors, outcomes, diagnosis, and management, the medical community can further explain the complexities of AKI in the pediatric population post-cardiac surgery.

Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy.

Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. We identified two ADAMTS9 mutations (c.4575_4576del [p.Gln1525Hisfs∗60] and c.194C>G [p.Thr65Arg]) that appear to cause NPHP-RC. Although ADAMTS9 is known to be a secreted extracellular metalloproteinase, we found that ADAMTS9 localized near the basal bodies of primary cilia in the cytoplasm. Heterologously expressed wild-type ADAMTS9, in contrast to mutant proteins detected in individuals with NPHP-RC, localized to the vicinity of the basal body. Loss of ADAMTS9 resulted in shortened cilia and defective sonic hedgehog signaling. Knockout of Adamts9 in IMCD3 cells, followed by spheroid induction, resulted in defective lumen formation, which was rescued by an overexpression of wild-type, but not of mutant, ADAMTS9. Knockdown of adamts9 in zebrafish recapitulated NPHP-RC phenotypes, including renal cysts and hydrocephalus. These findings suggest that the identified mutations in ADAMTS9 cause NPHP-RC and that ADAMTS9 is required for the formation and function of primary cilia.

Cascade plasmapheresis as preconditioning regimen for ABO-incompatible renal transplantation: a single-center experience.

BACKGROUND: Removal of anti-ABO is an important component of the preconditioning regimen for ABO-incompatible (ABOi) renal transplant. Cascade plasmapheresis (CP) is one of the extracorporeal methods of antibody removal, others being conventional plasma exchange (PE) and immunoadsorption. There is no previous published experience with CP in this context. The purpose of this study was to present an early experience with this approach. STUDY DESIGN AND METHODS: Consecutive ABOi renal transplant recipients in whom CP was used for pre- and posttransplant anti-ABO removal were included. All the patients received intravenous rituximab 2 weeks before transplant. After 1 week, CP was started along with oral tacrolimus and mycophenolate sodium. Alternate-day CP was done to attain immediate pretransplant antibody titer of not more than 8. RESULTS: Fifteen ABOi renal transplant recipients had baseline (pretreatment) antibody titers ranging from 16 to 512. Desensitization rate was 100%. The mean number of procedures before transplant to achieve titer of not more than 8 was 3.27 ± 1.39. Patient survival was 93% and death-censored graft survival was 87%. Biopsy-proven acute rejection was seen in three patients (20%), one (6.67%) being acute antibody mediated rejection. The complication rate during CP was 4% and two patients had bleeding complication after surgery. Posttransplant infection rate was 13%. CONCLUSION: Based on limited number of patients, we conclude that CP is a safe and effective extracorporeal method for pretransplant ABO antibody removal in patients undergoing ABOi transplant. Patients undergoing CP met target preoperative antibody titers and the clinical outcomes were acceptable.

Novel techniques and newer markers for the evaluation of "proximal tubular dysfunction".

Renal Fanconi syndromes are both clinically challenging and physiologically fascinating. The diagnosis requires a certain index of suspicion to correctly identify the clinical symptomatology and pursue the appropriate laboratory evaluations. The renal Fanconi syndrome (FS) is a defect of proximal tubular function attributable to different rare inherited diseases or acquired disorders caused by a multitude of exogenous agents. It can manifest as complete or incomplete FS, characterized by low molecular weight proteinuria, glucosuria, aminoaciduria, and loss of electrolytes, bicarbonate and lactate. Implementation of new methods and recent findings from urinary proteome pattern in patients with renal FS has led to the identification of new markers for proximal tubular dysfunction. Future combined proteomic and metabonomic studies will provide additional potential biomarkers and may help to gain novel insights in the diagnosis and differentiation of the various forms of FS. Moreover, the observation of poor renal uptake of 99 mTc-DMSA in patients with tubular proteinuria, which is not fully understood yet, may also help to elucidate the individual basis of FS in early stages. This review focuses on the new advances in the evaluation of proximal tubular dysfunction in various forms of Fanconi syndrome.