Arterial hypertension (AH) is a global challenge that greatly impacts cardiovascular morbidity and mortality worldwide. AH is a major risk factor for the development and progression of kidney disease. Several antihypertensive treatment options are already available to counteract the progression of kidney disease. Despite the implementation of the clinical use of renin–angiotensin aldosterone system (RAAS) inhibitors, gliflozins, endothelin receptor antagonists, and their combination, the kidney damage associated with AH is far from being resolved. Fortunately, recent studies on the molecular mechanisms of AH-induced kidney damage have identified novel potential therapeutic targets. Several pathophysiologic pathways have been shown to play a key role in AH-induced kidney damage, including inappropriate tissue activation of the RAAS and immunity system, leading to oxidative stress and inflammation. Moreover, the intracellular effects of increased uric acid and cell phenotype transition showed their link with changes in kidney structure in the early phase of AH. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for hypertensive nephropathy management in the future. In this review, we would like to focus on the interactions of pathways linking the molecular consequences of AH to kidney damage, suggesting how old and new therapies could aim to protect the kidney.

Background and Aims Acute kidney injury (AKI) is a major complication in cancer patients receiving immune checkpoint inhibitors (ICIs). Previous studies have not accurately distinguished the various potential underlying causes of AKI due to the limited use of renal biopsy. Here, we reviewed cases of biopsy-proven acute tubulointerstitial nephritis (ATIN) in patients treated with ICIs to describe the clinical and laboratory characteristics and outcomes of this condition. Method We conducted a pooled analysis of clinical cases published up to 1 May 2022. The search terms on PubMed were [(Pembrolizumab OR Nivolumab OR Ipilimumab OR Atezolizumab OR Avelumab OR Durvalumab) AND (Nephritis)]. Only cases with biopsy-proven ATIN were included. Among a total of 111 patients identified, 83 were eligible for this analysis. We added two patients from our Institution. We collected data on clinical characteristics, renal biopsy findings, and laboratory examinations. AKI was graded according to the KDIGO criteria. As outcomes, we considered: complete renal recovery if serum creatinine returned to baseline +0.3 mg/dL, no recovery if patients needed dialysis and partial recovery in other cases. Results Overall, 85 patients (56 male) with an age of 61.4±19 years were evaluated. 43 patients (51%) had melanoma, 25 (30%) non-small cell lung cancer, 8 renal carcinoma, and 9 other cancers. ICI treatment consisted of PD-1, PDL-1 (nivolumab, pembrolizumab, atezolizumab) and CTLA4 inhibitors (i) (ipilimumab) or combination PD-1i-CTLA4i (Table 1). Renal toxicity developed after a median of four cycles of therapy, but in most cases (n = 59) after at least three treatment cycles. Eleven patients (14%) presented with AKI stage 1, 16 patients (20.5%) with stage 2, and 51 patients (65.5%) with AKI stage 3, including five patients requiring dialysis. Among AKI3 patients there was a significantly higher prevalence of patients at the first therapy line (p = 0.04), while all the 19 patients treated with the dual ICI blockade developed AKI3, compared with 29 patients out of the 52 taking a single agent (Figure 1A). Seventy-seven patients received steroids, while 7 patients did not receive any therapy. ICI treatment was withdrawn in 65 out of 69 patients with available data. Following AKI resolution, in 15 patients ICI was restarted, but in six (40%) AKI recurred. Overall, 32 patients (40%) presented a complete renal recovery, 45 patients (56.2%) had a partial recovery, and 3 patients (3.8%) did not recover. Among patients who did not fully recover, there was a higher prevalence of those treated with dual ICI blockade and presenting with AKI stage 3 (Figure 1B). At logistic regression, complete renal recovery was inversely associated with dual ICI blockade (OR 0.1, 95CI 0.02-0.5, p = 0.006) and AKI 3 (OR 0.31, 95CI 0.1-0.9, p = 0.04), but only the association with dual ICI therapy remained significant at multivariate analysis. Conclusion ICI-related ATIN may develop late after the initiation of therapy. It may present as a severe form of AKI, particularly in patients with dual ICI blockade. Although this complication may be partially reversible, concerns remain about the renal function sequelae and the possibility of restarting treatment after AKI resolution due to the risk of recurrence.

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BACKGROUND AND AIMS Tiredness and fatigue are common symptoms in patients with chronic kidney disease (CKD), but their underlying mechanisms are unknown and treatments unavailable. Patients with CKD display abnormalities along the entire oxygen cascade, with impaired diffusive and convective oxygen transport, thus contributing to a reduced tissue oxygen supply. Hypoxic adaptation is largely regulated by hypoxia-inducible factor 1 (HIF-1α), encoded by the HIF-1Α gene [1],  and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α). In response to hypoxia or anemia, the muscle HIF-1α target genes increase oxygen transport through angiogenesis, responsiveness to insulin, cell proliferation and apoptosis/survival [2]. PGC-1α controls the expression of genes involved in mitochondrial biogenesis, energy homeostasis and glucose metabolism. PGC-1α is correlated with a total-body aerobic capacity [3], and its decrease has been detected in muscles of elderly persons and type 2 diabetes patients [3,4]. We hypothesized that desensitization of the HIF-1α driven oxygen-sensing mechanisms occurs in CKD patients. METHOD HIF-1α, PGC1α gene and protein expression, studied by Rt–PCR and immunohistochemistry, were assessed in the rectus abdominis muscle biopsies from 31 CKD patients with non-dialysis CKD 5 (18 M/13 F, eGFR 8 ± 1 mL/min) and were compared with those obtained in 10 subjects with normal renal function (7M/3F).  HIF-1α,  PGC1α expression was studied also in C2C12 myotubes exposed to 10% normal serum or uremic serum (US) for 48 h. In addition, mitofusin-2 (MFN2), nuclear factor erythroid 2-related factor 2 (NRF2), and oxidative phosphorylation (OXPHOS) related to mitochondria integrity were monitored by Rt–PCR and/or western blot. Changes in the membrane potential were quantified by JC1 staining and fluorimeter analysis. RESULTS Despite anemia (Hb 9.5 ± 1 g/dL),  HIF-1α mRNA was severely blunted in the muscle of CKD patients, as well as PGC1α that resulted down-regulated in 62.5% of them (P < 0.05) (Fig. 1). Log HIF-1α mRNA was directly related to log eGFR (r = 0.632, P < 0.02), suggesting that the hypoxic response in muscle progressively down-regulates as the renal function declines. In cultured myotubes, US decreases PGC1α, HIF1α, MFN2, NRF2 and OXPHOS and membrane potential (P < 0.05–0.01). CONCLUSION In patients with non-dialysis CKD, PGC1α and HIF1α are down-regulated, as well as in an in vitro model that resembles the uremic milieu. On the one hand, these findings are in keeping with impaired oxidative metabolism in the advanced stage of CKD, while on the other hand, they may account for the fatigue often referred by these patients. Moreover, our study suggests that the HIF prolyl hydroxylase inhibitor (HIF-PHIs), currently in clinical development, might be targeted on muscle metabolism and function and tested in the treatment of myopathy and fatigue in CKD.

Background and Aims 38 years old man with C3GN linked to Monoclonal Gammopathy recovers from dialysis after treatment with Daratumamb. Case report C3 glomerulonephritis related to monoclonal gammopathy is a challenging entity and the efficacy of treatment with Daratumumab is not clearly defined yet. We would like to describe the case of a stunning renal response to Daratumumab in a young man with MGUS and C3 glomerulonephritis. In July 2021 a 38 years old man presented to our nephrology division with full nephrotic syndrome, creatinine 1.2 mg/dl, low C3 and little IgG lambda spike of 2 g/dL on serum electrophoresis. Kidney biopsy revealed a membranoproliferative GN with bright C3 staining by immunofluorescence, no other positive immune-reactant and no masked deposits on pronase digested tissue. Electron microscopy confirmed the presence of subendothelial electron dense deposits. The diagnosis was consistent with C3 glomerulonephritis. Complement genetic test and C3 nephritic factor were negative. Assuming a form of C3GN associated to monoclonal gammopathy (MGRS), a bone marrow biopsy was performed and revealed a small clonal plasma cells population. In November 2021 he was started on velcade/dexamethasone but unfortunately stopped early due to severe side effects. Subsequently he begun cyclophosphamide and steroids without clinical or serological response. In few months renal function rapidly worsened requiring dialysis since April 2022. A repeat kidney biopsy confirmed C3GN with still moderate activity and low chronicity. In May 2022 he was started on Daratumamab/Lenalidome/Dexamethasone. After eight months of dialysis the diuresis progressively increased and the renal function improved so remarkably that dialysis was discontinued since December 2022. At present the patient renal function is stable with creatinine 3.5 mg/dl, proteinuria 3g/L, and monoclonal component decreased to 1.1 g/L from 3.5 g/L. He continues Daratumumab single agent monthly and we have scheduled a further renal biopsy in the next week. To our knowledge this is the first time a patient recovers from dialysis after treatment with Daratumamb for a C3GN linked to a monoclonal gammopathy. It definitely makes this case unique and inspiring for further studies and considerations regardinf this intriguing field of MGRS.