Kenar D. Jhaveri

Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review

Background: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patients own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers. Summary: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system database were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hyponatremia were toxicities caused by ipilimumab. The main adverse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3-10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2-3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9-29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of immune checkpoint inhibitors is extremely important.

Preserved Renal-Allograft Function and the PD-1 Pathway Inhibitor Nivolumab

To the Editor: Inhibition of immune checkpoints with the use of antibodies targeting programmed cell death 1 (PD-1) or monoclonal antibodies against cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) has been used clinically in patients with various types of cancer. In the limited number of reported cases in which these antibodies have been used in patients who have undergone kidney transplantation,1 these agents have been associated with cell-mediated and antibody-mediated rejection (see Table S2 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). We report on a patient who received a renal transplant from a living related donor. .xa0.xa0.

Treatment of refractory thrombotic thrombocytopenic purpura using multimodality therapy including splenectomy and cyclosporine

ADAMTS13 mediated thrombotic thrombocytopenic purpura (TTP) is an immunological disease that is very difficult to treat. Plasma exchange, with plasma replacement and steroids have been the first line of treatment for this condition. Ten to 20% of the patients either have no response or a partial response to the treatment. Refractory TTP has been treated in few case reports with anti-CD20 agents, intravenous gamma globulin, vincristine and splenectomy. We report two cases of refractory TTP that responded to multimodality immunosuppressive therapy that included splenectomy, intravenous gamma globulin, and cyclosporine after numerous plasma exchange treatments, steroids, rituximab and vincristine had failed to induce remission. Combining drugs that target T and B lymphocytes is a standard in organ transplantation and deserves more consideration in the treatment of severe and refractory autoimmune diseases such as TTP.

Coeliac sprue-associated membranoproliferative glomerulonephritis (MPGN)

Coeliac sprue (CS) may occur in association with immune complex-mediated diseases, including IgA nephropathy, dermatitis herpetiformis and thyroiditis. An association of CS with membranoproliferative glomerulonephritis (MPGN) type 1 is rare, with only two prior cases reported. Here we describe a 45-year-old man with no prior medical history who presented initially with microhaematuria, subnephrotic proteinuria and hypocomplementaemia. A renal biopsy revealed MPGN type 1 with negative serologic workup for secondary causes. The patient was treated conservatively with angiotensin-converting enzyme inhibitors. Several months later, he developed daily non-bloody diarrhoea and was found to have worsening hypoalbuminaemia, hypophosphataemia and severe iron deficiency anaemia. A diagnosis of CS was established based on elevated tTGA (IgA anti-tissue transglutaminase) antibody and positive IgA antiendomysial antibody titres. Proteinuria resolved completely following the initiation of a gluten-free diet, without the use of immunosuppressive therapy and despite tapering of angiotensin-converting enzyme inhibitor. This case illustrates that CS-associated MPGN may precede overt clinical evidence of coeliac disease and may respond to gluten-free diet, without resort to immunosuppressive therapy.

Left Ventricular Assist Devices and the Kidney

Left ventricular assist devices (LVADs) are common and implantation carries risk of AKI. LVADs are used as a bridge to heart transplantation or as destination therapy. Patients with refractory heart failure that develop chronic cardiorenal syndrome and CKD often improve after LVAD placement. Nevertheless, reversibility of CKD is hard to predict. After LVAD placement, significant GFR increases may be followed by a late return to near baseline GFR levels, and in some patients, a decline in GFR. In this review, we discuss changes in GFR after LVAD placement, the incidence of AKI and associated mortality after LVAD placement, the management of AKI requiring RRT, and lastly, we review salient features about cardiorenal syndrome learned from the LVAD experience. In light of the growing number of patients using LVADs as a destination therapy, it is important to understand the effect of these devices on the kidney. Additional research and long-term data are required to better understand the relationship between the LVAD and the kidney.

A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR <30 mL/min) and end stage renal disease on hemodialysis:

Capecitabine (Xeloda) is an orally administered precursor of 5′deoxy-5-fluorouridine, which is a preferentially activated to 5-fluorouracil in tumors. It is used in the treatment of colorectal, gastric, and breast cancers. Based on a single Phase II trial, which included a total of 4 patients with severe renal impairment (GFR <30u2009mL/min), the manufacturer issued a ‘Dear Doctor’ letter contraindicating the use of capecitabine in these patients since a high rate of grade 3 and 4 adverse events were observed and because these patients tolerated shorter treatment durations.1 We retrospectively studied 12 patients with a GFR <30u2009mL/min, including 2 patients with end stage renal disease on hemodialysis, who received capecitabine for mean duration of 7.1 months (1–26 months). The mean serum creatinine at the time of initiation of the drug was 2.63u2009mg/dL (1.8–6.4u2009mg/dL) and mean GFR was 20.9u2009mL/min (8–29u2009mL/min). Two patients remained on capecitabine after they progressed to end stage renal disease (ESRD) requiring hemodialysis (HD) for an additional 17 and 6 months, respectively. Most patients reported grade 1 and 2 adverse effects (AE), 2 patients reported grade 3 diarrhea and one patient died while on treatment with capecitabine. The starting dose ranged from 250 to 1000u2009mg/m2, given twice daily at variable intervals. Dose modifications, with reductions of up to 50% of the starting dose, were made following reports of AEs. Serum tumor marker levels and/or follow up imaging studies were available on 9 patients. Response to capecitabine was documented in 4 patients, stable disease in 2, and disease progression in 3. We conclude that, with close monitoring of their clinical and chemical data, and with dose modification based on reported AEs, capecitabine can be safely administered to patients with severe renal impairment, including patients on hemodialysis.

The Case ∣ Triple acid–base disorder after drug abuse

A 56-year-old male was presented to our medical center after a suicide attempt. His past medical history was significant for type 2 diabetes requiring insulin, depression treated with paroxetine, and previous intravenous drug abuse on methadone maintenance. On the night before admission he had ingested an unknown quantity of 400xa0mg tablets of quetiapine and 90xa0mg of methadone. On the way to the hospital, he was given naloxone 0.4xa0mg and intravenous fluids. At presentation to the hospital, he was afebrile, with blood pressure 96/56xa0mmxa0Hg, heart rate of 110 per min, and respiratory rate of 40 per min. On physical examination, he was drowsy with dilated pupils, clear lungs, regular heart sounds without murmurs, and decreased bowel sounds. His labs revealed serum sodium 119xa0mequiv./l, chloride 70xa0mequiv./l, potassium 3.8xa0mequiv./l, bicarbonate 28xa0mequiv./l, calcium 8.2xa0mg/100xa0ml, phosphorus 3.7xa0mequiv./l (subsequently 1.7xa0mequiv./l), blood urea nitrogen 64xa0mg/100xa0ml, and creatinine of 1.8xa0mg/100xa0ml (up from 0.8xa0mg/100xa0ml the week prior). His anion gap was calculated at 23.5. His arterial blood gas revealed a pH of 7.86, a PCO2 of 14xa0mmxa0Hg and PO2 178xa0mmxa0Hg.

Strongyloides Stercolaris-Associated Tip Variant Focal Segmental Glomerulosclerosis

Massini Merzkani, Nupur N. Uppal, Daniel W. Ross, Pranisha Gautam-Goyal, Prashant Malhotra, Hitesh H. Shah, Kenar D. Jhaveri and Vivette D. D’Agati Division of Kidney Diseases and Hypertension, North Shore University Hospital and Long Island Jewish Medical Center, Hofstra Northwell School of Medicine, Great Neck, New York, USA; Division of Infectious Diseases, North Shore University Hospital and Long Island Jewish Medical Center, Hofstra Northwell School of Medicine, Manhasset, New York, USA; and Department of Pathology, Columbia University Medical Center, New York, New York, USA

Nephropathology Education During Nephrology Fellowship Training in the United States

Vinodh Mechery, Tahyna Hernandez, Anna T. Mathew, Rimda Wanchoo, Surya V. Seshan, Kenar D. Jhaveri and Hitesh H. Shah Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA; Division of Kidney Diseases and Hypertension, Department of Medicine, North Shore University Hospital and Long Island Jewish Medical Center, Zucker School of Medicine at Hofstra/ Northwell, Great Neck, New York, USA; and Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, USA