Nerve cross-sectional area in advanced uremic neuropathy: A nerve ultrasound pilot study.

BACKGROUND AND PURPOSE: Uremic neuropathy (UN) is a disabling neuropathy in end-stage kidney disease (ESKD) affecting the majority of patients receiving long-term hemodialysis (HD). One previous nerve ultrasound study reported an increased cross-sectional area (CSA) of the median nerve in moderate UN, while another study found enlarged sural nerves in small-fiber polyneuropathy associated with ESKD. The present cohort study aims to analyze bilateral CSA of multiple nerves in UN. METHODS: Ten nondiabetic ESKD patients with UN on HD for at least 2 years and 10 healthy age-matched controls underwent bilateral ultrasound examinations with CSA measurements in 13 arm and leg nerve sites. Nerve conduction studies (NCS) and the total neuropathy score (TNS) were recorded. Pearson's coefficient and the Mann-Whitney U-test were used to analyze correlations and compare groups. RESULTS: ESKD patients presented advanced neuropathic symptoms (mean TNS 15.9). NCS showed significantly reduced motor and sensory amplitudes in the UN group compared to the control group, and a slightly reduced nerve CSA was observed in 5 of 13 nerve sites (p < .05); the other nerve sites were not enlarged. Sural nerve CSA (p < .05) and sensory amplitude (p < .01) were negatively correlated with the TNS. CONCLUSIONS: Nerve enlargement was not observed in the present study in advanced UN. A reduced nerve CSA observed in the sural nerve suggests an axonal loss associated with long-term HD in ESKD. During clinical workup of an acute disease of the peripheral nervous system in ESKD patients, nerve enlargement might be attributable to other causes than chronic UN.

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients.

ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP.

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities <10% at the time of stopping caplacizumab treatment developed a nonfavorable outcome (disease exacerbation or relapse). In some cases, prolongation of the treatment interval to every other day was feasible and resulted in a sustained reduction of von Willebrand factor activity. ADAMTS13 activity measurements are central for a rapid diagnosis in the acute setting but also to tailor disease management. An ADAMTS13 activity-guided approach seems safe for identifying the individual time point when to stop caplacizumab to prevent overtreatment and undertreatment; this approach will result in significant cost savings without jeopardizing the well-being of patients. In addition, von Willebrand factor activity may serve as a biomarker for drug monitoring.

External Validation of the Kidney Failure Risk Equation and Re-Calibration with Addition of Ultrasound Parameters.

BACKGROUND AND OBJECTIVES: Progression of CKD toward ESRD is heterogeneous. The Kidney Failure Risk Equation (KFRE) was developed to identify CKD patients at high risk of ESRD. We aimed to externally validate KFRE and to test whether the addition of predefined Duplex ultrasound markers - renal resistive index (RRI) or difference of resistive indices in spleen and kidney (DI-RISK) - improved ESRD prediction. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The prospective Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg evaluation (CARE FOR HOMe) study recruits CKD stage G2-G4 patients referred to a tertiary referral center for nephrologic care. Four hundred three CARE FOR HOMe participants enrolled between 2008 and 2012 had available RRI measurements at study inclusion; they were subsequently followed for a mean of 4.4±1.6 years. This subcohort was used to validate KFRE and to assess the added value of the ultrasound markers (new models KFRE+RRI and KFRE+DI-RISK). Model performance was assessed by log-likelihood ratio test, c-statistic, integrated discrimination improvement metrics (for study participants without subsequent ESRD [IDI No ESRD] and for patients with ESRD [IDI ESRD]), and calibration plots. If either new model improved on KFRE, we determined to validate it in an independent cohort of 162 CKD patients. RESULTS: KFRE predicted ESRD in CARE FOR HOMe participants with a c-statistic of 0.91 (95% confidence interval, 0.83 to 0.99). Adding RRI improved the KFRE model (P<0.001), and the KFRE+RRI model was well calibrated; however, the c-statistic (0.91 [0.83-1.00]) was similar, and overall sensitivity (IDI No ESRD=0.05 [0.00-0.10]) or overall specificity (IDI ESRD=0.00 [0.00-0.01]) did not improve. Adding DI-RISK did not improve the KRFE model. In the external validation cohort, we confirmed that the KFRE+RRI model did not outperform KFRE. CONCLUSIONS: Routine Duplex examinations among CKD patients did not improve risk prediction for progression to ESRD beyond a validated equation.

Dialysate concentration and pharmacokinetics of 2F-Ara-A in a patient with acute renal failure.

Fludarabine is frequently used for treatment of B-cell chronic lymphocytic leukemia and in conditioning regimes for hematopoietic cell transplantations. The total body clearance of the principal metabolite 2-fluoro-ara-A (2F-Ara-A) correlates with the creatinine clearance. We report data on total dialysate concentration as well as pharmacokinetics of 2F-Ara-A in a patient with anuric acute renal failure. On three consecutive days the patient received a daily dose of 80 mg (40 mg/m(2)) fludarabine and underwent three consecutive extended (daily) dialysis (ED) sessions. ED removed a considerable amount of the drug. The average dialysis clearance was 33.85 ml/min which is about 25% of the clearance in patients without renal failure. No toxic side effects of the treatment were observed. This case suggests that fludarabine treatment can be considered in patients requiring dialysis if dose reduction and adequate removal of the drug by hemodialysis is provided.

Chimerism of metanephric adenoma but not of carcinoma in kidney transplants.

Recipient-derived cells integrate into renal allografts inducing organ-specific microchimerism. Circulating pluripotent progenitor cells with high plasticity for differentiation were suggested as a potential source of allograft chimerism. Whether or not these cells also contribute to tumor formation in renal transplants is unknown. We analyzed six histologically different tumors in renal allografts for the presence of recipient-derived cells. To circumvent dependency on gender mismatch, a polymerase chain reaction assay for highly polymorphic short tandem repeat marker (DNA fingerprinting) in combination with laser microdissection was applied. Pure tumor cell populations were harvested by laser microdissection after immunohistochemical (CD45/CD68) marking of contaminating leukocytes. In cases of gender mismatch (n = 2), results were confirmed by sex chromosome in situ hybridization. Two metanephric adenomas demonstrated microchimerism comprising both donor- and recipient-derived tumor cells. Two clear cell carcinomas, one transitional cell carcinoma, and one renal cortical adenoma were all of donor origin without chimerism. We conclude that except for metanephric adenomas, tumors arising in renal transplants originate completely from graft cells. The mixed derivation of metanephric adenomas indicates an incorporation of recipient-derived progenitor cells. This finding suggests that adult stem cells can assume neoplastic phenotypes.

The right diagnostic work-up: investigating renal and renovascular disorders.

Renovascular disease is present in about 10-40% of patients with end-stage renal disease, and constitutes the fastest-growing group of end-stage renal disease patients. The unselective correction of renal artery stenosis has led to disappointing results. Most studies that have compared conservative treatment with angioplasty have found only modest or no beneficial effects of angioplasty on renal function and blood pressure. It is therefore mandatory to evaluate the functional significance of a stenosis before intervention. Patients most likely to respond favourably to revascularization should be identified. Factors that affect outcome include the severity of renal artery stenosis, type of treatment of renal artery stenosis and, most importantly, underlying renal disease, which prevents a favourable response even after successful correction of renal artery stenosis. Doppler ultrasonography to evaluate the renal resistance index [1 - (end diastolic velocity/maximum systolic velocity) x 100] or captopril scintigraphy are the best methods by which to classify patients as responders or non-responders to intervention. In patients with a renal resistance index > or = 80%, improvement of renal function or blood pressure is highly unlikely, despite successful correction of renal artery stenosis. The value of the renal resistance index can also be extended to patients with non-stenotic renal diseases. Identifying patients at risk for irreversible loss of renal function and who may benefit from intervention is a high research priority.

The renal arterial resistance index and renal allograft survival.

BACKGROUND: Most renal transplants fail because of chronic allograft nephropathy or because the recipient dies, but no reliable factor predicting long-term outcome has been identified. We tested whether a renal arterial resistance index of less than 80 was predictive of long-term allograft survival. METHODS: The renal segmental arterial resistance index (the percentage reduction of the end-diastolic flow as compared with the systolic flow) was measured by Doppler ultrasonography in 601 patients at least three months after transplantation between August 1997 and November 1998. All patients were followed for three or more years. The combined end point was a decrease of 50 percent or more in the creatinine clearance rate, allograft failure (indicated by the need for dialysis), or death. RESULTS: A total of 122 patients (20 percent) had a resistance index of 80 or higher. Eighty-four of these patients (69 percent) had a decrease of 50 percent or more in creatinine clearance, as compared with 56 of the 479 patients with a resistance index of less than 80 (12 percent); 57 patients with a higher resistance index (47 percent) required dialysis, as compared with 43 patients with a lower resistance index (9 percent); and 36 patients with a higher resistance index (30 percent) died, as compared with 33 patients with a lower resistance index (7 percent) (P<0.001 for all comparisons). A total of 107 patients with a higher resistance index (88 percent) reached the combined end point, as compared with 83 of those with a lower resistance index (17 percent, P<0.001). The multivariate relative risk of graft loss among patients with a higher resistance index was 9.1 (95 percent confidence interval, 6.6 to 12.7). Proteinuria (protein excretion, 1 g per day or more), symptomatic cytomegalovirus infection, and a creatinine clearance rate of less than 30 ml per minute per 1.73 m2 of body-surface area after transplantation also increased the risk. CONCLUSIONS: A renal arterial resistance index of 80 or higher measured at least three months after transplantation is associated with poor subsequent allograft performance and death.

Incidence of polyomavirus-nephropathy in renal allografts: influence of modern immunosuppressive drugs.

BACKGROUND: In recent years an increasing number of cases with polyomavirus (PV)-nephropathy after renal transplantation were reported from several transplant centres. New, highly potent immunosuppressive drugs like tacrolimus or mycophenolate mofetil were accused as risk factors for this increase. However, data about the incidence of PV-nephropathy in correlation to different immunosuppressive therapy concepts are lacking. METHODS: All renal transplant biopsies performed at Hannover Medical School between 1999 and 2001 (n=1276) were immunohistochemically screened for the presence of PV-specific proteins. The results were correlated to the different immunosuppressive therapy protocols and patients with PV-nephropathy were compared with a matched control group. RESULTS: PV-nephropathy was found in <1% of all investigated allograft biopsies (11/1276) and in approximately 1% of all patients (7/638), respectively. All patients being immunohistochemically positive for PV-specific proteins also showed the typical morphological changes of PV-nephropathy. Four out of seven patients with PV-nephropathy were under triple immunosuppression comprising tacrolimus and mycophenolate mofetil. Under this immunosuppressive therapy protocol an eight times higher incidence and a 13 times higher risk (multivariate odds ratio 12.7) of PV-nephropathy was observed in our patients compared with the control group. CONCLUSIONS: PV-nephropathy is a rare but serious complication after renal transplantation. A small group of patients under intensive immunosuppression comprising tacrolimus in combination with mycophenolate mofetil has a significantly increased risk of acquiring this deleterious complication.

Renal resistance index and progression of renal disease.

The progression of renal disease depends on various clinical parameters such as hypertension and proteinuria. We recently showed that an increased renal resistance index measured by duplex ultrasound is associated with a poor prognosis in patients with renal artery stenosis. We now prospectively tested the hypothesis that a high renal resistance index (greater-than-or-equal 80) predicts progression of renal disease in patients without renal artery stenosis. In 162 patients newly diagnosed with renal disease, the resistance index (1-[end diastolic velocity/maximum systolic velocity]*100) was measured in segmental arteries of both kidneys. Creatinine clearance was measured at baseline, at 3, 6, and 12 months, and then at yearly intervals thereafter (mean follow-up 3 +/- 1.4 years). The combined endpoint was a decrease of creatinine clearance by greater-than-or-equal 50%, end-stage renal disease with replacement therapy, or death. Twenty-five patients (15%) had a renal resistance index value greater-than-or-equal 80 at baseline. Nineteen (76%) had a decline in renal function; 16 (64%) progressed to dialysis, and 6 (24%) died. In comparison, in patients with renal resistance index values <80, 13 (9%) had a decline in renal function, only 7 (5%) became dialysis-dependent, and 2 (1%) died (P<0.001). In a multivariate regression analysis, only proteinuria and resistance index were independent predictors of declining renal function. A renal resistance index value of greater-than-or-equal to 80 reliably identifies patients at risk for progressive renal disease.

Echo-doppler to predict the outcome for renal artery stenosis.

Not all patients with renal artery stenosis will benefit from angioplasty or surgery. For this reason it is not sufficient to diagnose the presence of renal artery stenosis, but one also has to evaluate its functional significance. Ultrasonographic detection of renal artery stenosis can be made with a sensitivity and specificity exceeding 90% by an experienced investigator. A combination of Doppler parameters making use of both direct and indirect signs of stenosis should be used. In our hands, a renal-renal ratio greater than 4 and--if this parameter was not measurable--an acceleration time longer than 70 msec was the best combination. The reversibility of hypertension or impaired renal function (i.e. the presence of renovascular hypertension or azotemia) after successful correction of renal artery stenosis can be assessed by measuring segmental artery resistance indices. A resistance index value greater than 0.80 makes a treatment effect highly unlikely, and these patients should not undergo angioplasty or surgery of their stenosis.